Australian Guidelines On Attention Deficit Hyperactivity Disorder

Australian Guidelines on Attention Deficit Hyperactivity Disorder (ADHD)
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Systematic Review
November 2008
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Introduction
This document presents research collated to inform the Guidelines for attention deficit hyperactivity disorder (ADHD) 2008. The research questions and tables are organised to reflect the order of the guidelines. Each table provides the lead author, a brief description of the sample and the design, a brief description of the intervention or diagnostic criteria, the outcome measures used and a brief conclusion. Readers are recommended to read the original articles for more details.
Funding
The Royal Australasian College of Physicians gratefully acknowledges the financial assistance for the development of these guidelines, which was provided by the Australian Government Department of Health and Ageing.
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Table of Contents
LIST OF RESEARCH QUESTIONS .........................................................................................................................4 LITERATURE REVIEW METHODS.......................................................................................................................7 ASSESSMENT AND DIAGNOSIS........................................................................................................................... 11 MEASURES OF IMPAIRMENT...................................................................................................................................... 11 RETROSPECTIVE RECALL OF CHILDHOOD ADHD SYMPTOMS ................................................................................... 17 PARENT AND TEACHER REPORTS .............................................................................................................................. 21 SELF AND THIRD-PARTY REPORTS............................................................................................................................. 29 PARENT REPORTS - BIAS .......................................................................................................................................... 35 NEUROPSYCHOLOGICAL ASSESSMENT MEASURES .................................................................................................... 39 NEUROPHYSIOLOGICAL MEASURES .......................................................................................................................... 51 NEUROIMAGING ....................................................................................................................................................... 59 PSYCHOSOCIAL MANAGEMENT ....................................................................................................................... 62
PSYCHOSOCIAL INTERVENTIONS............................................................................................................................... 62 PARENTING PROGRAMS ............................................................................................................................................ 71 MODERATORS AND MEDIATORS OF OUTCOMES FOR PSYCHOSOCIAL INTERVENTIONS............................................... 77 PSYCHOSOCIAL INTERVENTIONS WHEN COMORBIDITIES ARE PRESENT ..................................................................... 81 MEDICATION MANAGEMENT ............................................................................................................................ 85
STIMULANT MEDICATION ......................................................................................................................................... 85 LONG TERM USE OF STIMULANT MEDICATIONS ......................................................................................................... 94 STIMULANT MEDICATION - SIDE EFFECTS ................................................................................................................. 97 ATOMOXETINE ....................................................................................................................................................... 105 ATOMOXETINE - LONG TERM USE ........................................................................................................................... 108 ATOMOXETINE SIDE EFFECTS ................................................................................................................................. 111 OTHER MEDICATIONS ............................................................................................................................................. 115 COMPARING MEDICATIONS ..................................................................................................................................... 127 WHEN COMORBIDITIES ARE PRESENT ..................................................................................................................... 139 IMPACT OF MEDICATION ON TICS ........................................................................................................................... 152 WHEN DEVELOPMENTAL DISABILITIES ARE PRESENT ............................................................................................. 160 ADVERSE EVENTS GROWTH ................................................................................................................................. 166 ADVERSE EVENTS CARDIAC ................................................................................................................................. 175 ADVERSE EVENTS PSYCHIATRIC .......................................................................................................................... 181 ADHD MEDICATIONS AND SUBSTANCE ABUSE ....................................................................................................... 185 TREATMENT OF ADHD AND COMORBID SUBSTANCE ABUSE DISORDERS................................................................ 191 MEDICATION COMPARED TO AND COMBINED WITH OTHER STRATEGIES ................................... 195
COMPARING PSYCHOSOCIAL AND PHARMACOLOGICAL INTERVENTIONS ................................................................ 195 COMBINING PSYCHOSOCIAL AND PHARMACOLOGICAL INTERVENTIONS ................................................................. 201
MANAGEMENT IN AN EDUCATION SETTING.............................................................................................. 209 SCHOOL-BASED INTERVENTIONS ............................................................................................................................ 209 PEER SUPPORT AND MENTORING............................................................................................................................. 216 INTERVENTIONS IN ADULT EDUCATION SETTINGS ................................................................................................... 219 COMPLIMENTARY AND ALTERNATIVE MANAGEMENT STRATEGIES .............................................. 220 ELIMINATION AND RESTRICTION DIETS ................................................................................................................... 220 FATTY ACID SUPPLEMENTS ..................................................................................................................................... 223 CHIROPRACTIC ....................................................................................................................................................... 226 BEHAVIOURAL OPTOMETRY ................................................................................................................................... 227 BIOFEEDBACK ........................................................................................................................................................ 228 HOMEOPATHY ........................................................................................................................................................ 233 CEREBELLAR THERAPY........................................................................................................................................... 235 EXCERISE, MEDITATION AND RELAXATION ............................................................................................................. 237 SENSORY INTEGRATION INTERVENTIONS ................................................................................................................ 240 ADHD AND SOCIETY............................................................................................................................................ 242 REFERENCES ......................................................................................................................................................... 245
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List of research questions

Assessment and Diagnosis 1. In individuals suspected of having ADHD does the use of measures of impairment, in addition to DSM-IV/ICD10, further inform diagnosis and assessment? 2. In adolescents and adults with ADHD are retrospective self-reports of symptoms in childhood accurate? 3. In preschoolers, children or adolescents with ADHD is there consensus between parent and teacher reports of ADHD symptoms when assessed with parallel instruments?
4. In individuals with ADHD is there consensus between third party (parent, teacher or family member) and self-reports of ADHD symptoms when assessed with parallel instruments?
5. In preschoolers, children or adolescents with ADHD does the psychiatric status of the parent influence parent reports in the diagnosis and assessment for ADHD?
6. In individuals suspected of having ADHD does the inclusion of neuropsycholgical assessment measures, in addition to DSM-IV/ICD10, further inform diagnosis and assessment?
7. In individuals suspected of having ADHD does the inclusion of neurophysiological techniques, in addition to DSM-IV/ICD10, further inform diagnosis? 8. In individuals suspected of having ADHD does the inclusion of neuroimaging techniques, in addition to DSM-IV/ICD10, further inform diagnosis? Management: Psychosocial interventions 9. For individuals with ADHD, do psychosocial interventions, compared to no intervention or standard care, affect outcomes?
10. For preschoolers, children and adolescents with ADHD, does behaviour management in the form of parent training, compared to no intervention or standard care, affect outcomes? 11. For individuals with ADHD, what are the moderators and mediators of treatment response with psychosocial interventions? 12. When comorbidities are present in individuals with ADHD, do psychosocial interventions, compared to no intervention or standard care, affect outcomes?
Management: Medication 13a. For individuals with ADHD, do stimulant pharmacological interventions, compared with placebo, improve outcomes? 13b. For individuals with ADHD does the use of stimulant medications for 1 year or more, compared with placebo or standard care, affect outcomes? 13c. For individuals with ADHD who are taking stimulant medication, what are the main side effects?
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14a. For individuals with ADHD, does the use of atomoxetine, compared with placebo, improve outcomes? 14b. For individuals with ADHD does the use of atomoxetine for 1 year or more, compared with placebo or standard care, affect outcomes? 14c. For individuals with ADHD who are taking atomoxetine, what are the main side effects? 15. For individuals with ADHD, do other pharmacological interventions compared with placebo, affect outcomes? a. Clonidine b. Modafinil c. Selegiline d. Guanfacine e. Nicotine patch f. Bupropion g. Risperidone 16. For individuals with ADHD, do any pharmacological interventions confer an advantage over any other pharmacological interventions?
17a. When comorbidities are present in individuals with ADHD, do pharmacological interventions, compared to placebo improve outcomes? a. Anxiety b. Bipolor disorder c. Depression d. Disruptive behaviour disorder e. Epilepsy f. Tic disorders Tourette syndrome 17b. For individuals with ADHD who are taking medication, what is the risk of developing firstonset tics or worsening existing tics?
17c. When developmental disabilities are present in individuals with ADHD, do pharmacological interventions, compared to placebo improve outcomes? a. Learning disorders b. Developmental or intellectual disabilities c. Autism spectrum disorders 18. For preschoolers, children and adolescents with ADHD who are taking medication, what is the risk of impaired growth? 19. For individuals with ADHD who are taking medication, what is the risk of cardiovascular problems? 20. For individuals with ADHD who are taking medication, what is the risk of psychiatric adverse effects? 21. For individuals with ADHD, does the use of pharmacological interventions, compared to no intervention, alter the risk for substance abuse or medication misuse?
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22. For individuals with ADHD and substance use disorders do pharmacological or psychosocial interventions, affect outcomes? Management: Medication compared to and combined with other strategies 23. For individuals with ADHD, do psychosocial interventions compared to pharmacological interventions, affect outcomes? 24. For individuals with ADHD, do psychosocial interventions used alongside pharmacological interventions, compared with pharmacological interventions alone, affect outcomes? Management in an Education Setting 25. For children and adolescents with ADHD, do school-based interventions, compared to no intervention or standard care, affect outcomes?
26. For children and adolescents with ADHD, do peer support, tutoring or mentoring, compared to no intervention or standard care, affect outcomes? 27. For adults with ADHD, do University/TAFE-based interventions, that address ADHD, compared to no intervention or standard care, affect outcomes?
Management: complimentary and alternative strategies 28. For individuals with ADHD, do diet restrictions (artificial colours, artificial flavours and preservatives), compared with no intervention or standard care, affect outcomes? 29. For individuals with ADHD, does diet supplementation with fatty acids, compared with placebo or standard care, affect outcomes?
30. For individuals with ADHD, does chiropractics, compared with no intervention or standard care, affect outcomes?
31. For individuals with ADHD, does behavioural optometry, compared with no intervention or standard care, affect outcomes? 32. For individuals with ADHD, does biofeedback, compared with no intervention or standard care, affect outcomes?
33. For individuals with ADHD, does homeopathy, compared with no intervention or standard care, affect outcomes? 34. For individuals with ADHD, do cerebellar therapies (such as the Dore program), compared with no intervention or standard care, affect outcomes? 35. For individuals with ADHD, does participation in sport or exercise programmes, compared with no intervention or standard care, affect outcomes? 36. For individuals with ADHD, do sensory diets / sensory integrative treatments, compared with no intervention, affect outcomes?
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ADHD in society 37. For individuals with ADHD, does the use of interventions (pharmacological, psychosocial or other), compared with no intervention, improve driving performance?
Literature review methods

The aim of this systematic literature review is to assist in the development of guidelines for the assessment, treatment and care of individuals with ADHD. The methods used in the systematic review comply with NHMRC requirements (1-4).
Literature searches A comprehensive literature search for relevant research using multiple databases as well as internet searching, pearling and hand searches was carried out for each research question (Table 1). The literature review was designed to update the 1997 NHMRC Guidelines on ADHD. The literature searches were conducted to encompass the years1997 - 2007. Research publications meeting the NHMRC designated levels of evidence I-IV were sought (4). In the first instance a search was conducted to identify any systematic reviews or meta-analyses that were available to address each research question (Level I). If a systematic review or meta-analysis addressing the research question was not identified the search limits were extended to include Level II evidence. In the absence of Level I or II evidence, Level III and IV evidence was sought. Search strategies for systematic reviews / meta-analyses and randomised controlled trials are described in Table 2. The searches for each question were conducted by one reviewer. Twenty percent of the searches were independently conducted and checked for agreement by a second reviewer. Inclusion and exclusion criteria A set of individual inclusion and exclusion criteria were developed for each research question based on study population, intervention, comparator, relevant outcomes, study design, search period and language. For all questions the identified studies were excluded on the following rationale. Animal studies Inadequate outcome data presented Review articles with no original data Sample size of less than 10 participants The article could not be located Articles that fall outside the NHMRC designated levels of evidence I-IV.
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Table 1. Search methods and databases

Electronic Databases
The Cochrane Library Cochrane Database of Systematic Reviews (CDSR) Cochrane Database of Abstracts of Reviews of Effects (DARE) The Health Technology Assessment Database (HTA) Cochrane Central Register of Controlled Trials (CENTRAL) Cumulative Index to Nursing and Allied Health Literature (CINAHL) Excerpta Medica Database (EMBASE) Medline PsycInfo Clinical Evidence Current Controlled Trials metaRegister; http://controlled trials.com/ The Centre for Reviews and Dissemination (CRD); http://www.york.ac.uk/inst/crd/ Health Technology Assessment international http://www.htai.org/ Education databases ERIC ProQuest Education Journals Criminology databases Criminal justice abstracts Criminology : a SAGE full-text collection Pearling The reference lists of all included articles was searched for additional relevant studies Searches of Topic Specific Internet Sites Australian Psychological Society; http//www.psychology.org.au American Psychiatric Association; http://www.psych.org/search.cfm American Academy of Child and Adolescent Psychiatry; http://www.aacap.org/ European Society for Child and Adolescent Psychiatry; http://www.escap-net.org/ National Institute of Mental Health; http://www.nimh.nih.gov/nimhhome/index.cfm
Table 2. Standardised search strategies: based on the OVID interface for Medline
Search strategy for systematic reviews Search strategy for randomised controlled trials 1. (randomised controlled trial).pt 1. (systematic adj review*).tw. 2. (controlled clinical trial).pt 2. (data adj synthesis).tw. 3. (randomised controlled trial).tw 3. (published adj studies).ab. 4. rct.tw 4. (data adj extraction).ab. 5. meta-analysis/ 5. (double blind method).tw 6. (single blind method).tw 6. meta-analysis.ti. 7. (clinical adj trial).tw 7. guideline.pt. 8. or/1-7 8. practice guideline.pt. 9. comment.pt. 10. letter.pt. 11. editorial.pt. 12. animal/ 13. human/ 14. 12 not (12 and 13) 15. ADHD search terms 16. other search terms 17. combined search 18. 17 not (9 or 10 or 11 or 14) 19. or/1-8 20. 18 and 19
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Study Selection Process 1. All citations identified for each question or for a designated group of questions were collated into an Endnote database and duplicate references were removed. 2. The title and abstract of these citations were screened for relevance. Studies that would clearly not meet the inclusion criteria were excluded at the level of title and abstract. 3. The remaining studies were retrieved for assessment of the full-text. 4. The inclusion and exclusion criteria were applied to each retrieved article by two independent reviewers. Articles that did not meet the inclusion criteria following assessment of the full-text were excluded and are listed with the reasons for exclusion with each question. Articles that met the inclusion criteria were included for dataextraction and critical appraisal.
Data-Extraction and Critical appraisal Data were extracted into standardised data-extraction / critical appraisal tables. The internal and external validity of all included studies was critically appraised based on the NHMRC critical appraisal checklists (1) and the NHMRC interim levels and grades of evidence (4). In addition, the modified Overview Quality Assessment Questionnaire (OQAQ) (5-7) was used to assess the quality of systematic reviews and meta-analysis. The data-extraction / critical appraisal tables for each included study are available from the RACP on request.
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Table 3. Number of articles at each step for each question.

Q Number of articles identified for screening 116 507 Number of articles excluded at the title and abstract level 98 448 Number of fulltext articles retrieved for consideration 18 2. 11 3. 23 4. 15 5. 10 32 17 5 29 15 9 10 13a. 26 13b. 18 13c. 25 14a. 11 14b. 11 14c. 13 15. 43 16. 27 17a. 52 17b. 28 17c. 22 18. 21 19. 13 20. 5 23. 13 24. 7 8 13 25. 6 26. 38 3 4 8 1 0 13 1 4 8 2 0 4 6 10 Number of articles included
1 2-5
6 7 8 9 10 11 12 13-19
163 113 17 392 97 Q9-10 screened Q9-10 screened 533
131 97 12 363 82 289
21-22 23 24 25-26
27 28 29 30 31 32 33 34 35 36 37 38 39 17c**
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279 259 Q9-22 screened Q9-22 screened 189 145 21 25 63 15 10 59 35 16 42 83 69 66 196 159 18 21 55 14 10 46 34 12 34 81 69 62 190 149
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7 2. 7 3. 13 4. 10 5. 5 22 11 2 10 6 4 3 13a. 16 13b. 1 13c. 11 14a. 2 14b. 2 14c. 5 15. 16 16. 15 17a. 17 17b. 11 17c. 6 18. 14 19. 9 20. 3 23. 7 24. 4 5 10 25. 3 26. 12 0 3 3 1 0 6 1 1 3 1 0 4 3 1
** Expanded search on treatment of ADHD and comorbid learning disorders conducted separately in August 2008.
Assessment and diagnosis

Measures of impairment
Research question 1: In individuals with ADHD does the inclusion of measures of impairment, in addition to DSMIV/ICD10, further inform diagnosis and assessment? Sub question: Can measures of impairment distinguish between impaired and unimpaired individuals with ADHD? Selection Criteria Population Indicator Comparator Outcomes Inclusion Criteria Individuals with ADHD Measures of impairment
Individuals without ADHD
Diagnostic utility: predictive value and sensitivity & specificity
Ability to identify individuals with ADHD at high risk for functional impairment. Study Design
Search Period Language
Date of Search
Search terms
MeSH: Attention deficit disorder with hyperactivity/
Diagnosis/ or diagnosis, differential/ or assessment or predictive value of tests/ or sensitivity and specificity/
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English March 2008
NHMRC I-IV for diagnostic studies 1997 - present considered
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Text words: adhd or addh or adhs or hyperactive$ or hyperkin$ or (attention adj deficit) impairment or adaptive impairment or executive function$ questionnaires/ or rating scale$
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Preschoolers
Reference Lahey et al 2004 (8) Design Diagnostic case-control study Level III-3 Setting USA (clinical) Industry funding No Diagnostic instruments Diagnostic tool Diagnostic interview for children and parents; Impairment Rating Scale Population/Study information Population: 3.87.0-year-old children who met DSM-IV criteria for ADHD and children without ADHD Full ADHD: meets DSM-IV symptom criteria and has crosssituational impairment. Results The full ADHD group exhibited significantly greater global, academic, and social impairment during waves 2 4 than the situational ADHD group (p < 0.001) or the comparison children (p < 0.0001). The full ADHD diagnosis in wave 1 predicted the full diagnosis in wave 4, with a positive predictive value of 0.75 and a negative predictive value of 0.86. The situational ADHD group was significantly less likely to meet full diagnostic criteria for ADHD during waves 24 than the full ADHD group (p<0.0001).
Situational ADHD: meets DSM-IV symptom criteria and has impairment in one situation (home or school ). Study information: Design: case-control Duration: 3 years (yearly assessment waves 1-4).
Recruitment: Clinic attendees and community
Willcutt et al 1999 (9) Design Diagnostic case-control study Level III-3 Setting USA Industry funding None reported
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Diagnostic tool Hillside behaviour rating Scale (HBRS)
No. n (control subjects) = 130 n (children with situational ADHD) = 29 n (children with full ADHD) = 96
Outcome Measures: 1. Chi-square (Full ADHD vs no ADHD; situation ADHD vs no ADHD; full ADHD vs situational ADHD) Population: Pre-school children aged 3-7 years with DSM-IV diagnosis of ADHD (parent or teacher endorsed) and children without ADHD (age- and gendermatched). Study information: Design: case-control Duration: single rating
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34% of situational ADHD children met full diagnostic criteria for ADHD at least twice in waves 24 compared to 3.1% of comparison children. The situational ADHD group exhibited significantly greater global and academic impairment during waves 24 than the comparison group (p < 0.001). Multiple regression analysis of the independent contribution of the HBRS ratings for the prediction of function impairment demonstrated that the HBRS contributed a significant increment above parent and teacher ratings for 8-11 out of 16 variables of functional impairment.
Recruitment: Clinic referrals and community No. ADHD n=127, Non-ADHD controls n= 125 Outcome Measures: 1. Analysis of varience
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Children and adolescents

Reference Mota & Schachar 2000 (10) Design Diagnostic case-control study Level III-3 Setting Canada (clinical) Industry funding No Diagnostic instruments Diagnostic tool Parent Interview for child symptoms (PICS), Teacher telephone interview (TTI), Parent and teacher versions of the Ontario Child Health Survey (OCHS) Population/Study information Population: children aged 7-12 years, both with and without ADHD Study information: Design: case-control Duration: single rating Results Two algorithms generated from parent and teacher reports, termed subtype ROC and ADHD ROC. Parent (subtype ROC dQ = 0.41, and ADHD ROC dQ = 0.35) and teacher reports (subtype ROC dQ = 0.41, and ADHD ROC dQ = 0.41) algorithms were significantly more efficient than DSMIV (dQ = 0.72 and dQ = 0.53). In comparison with the DSM-IV, the ROC-based algorithms were 2 to 3 times more efficient in discriminating impaired from non-impaired children.
Recruitment: Patients referred from outpatient clinic
No. n=218 (controls n=35 ADHD n=183)
Outcome Measures: Combinations of ADHD symptoms were examined according to a receiver operating characteristic (ROC) based procedure to create diagnostic algorithms that predict impairment.
Gathje et al 2008 (11) Design Diagnostic case-control study Level III-3 Setting USA (clinical) Industry funding No
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Diagnostic tool Global Impairment Index (GII): combines 6 measures of impairment No. n=314 Diagnostic tool Impairment Rating Scale (IRS)
Population: consecutive patient referrals, children aged 5-17 years (81% of the 314 patients met the criteria for ADHD). Study information: Design: case-control Duration: single rating
Recruitment: Clinic referrals consecutive sample
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Significant (p<0.01) moderate correlations between GII and Maternal SNAP-IV and CBCL Attention Subscale. The correlation was stronger for the CBCL Attention subscale than for the maternal SNAP-IV symptoms. Correlations were low to moderate for individual impairment scales and the Maternal SNAP-IV and CBCL Attention Subscale. Variables that were significant predictors of impairment were gender, CBCL Attention subscale, PPVT (Peabody Picture Vocabulary Test) score and maternal SNAP-IV symptom count (p < 0.01) but not age or Gordons Diagnostic System vigilance task commissions. Inclusion of impairment (GII) and symptom scales reduced the number of positive diagnoses from 71% (2 symptom scales/1-SD cutoff) to 43% (2 symptom scales + impairment/1-SD cutoff) Sensitivity and specificity of IRS (parent and teacher rated) presented for each cut-point: sensitivity range 0.480.92, specificity range 0.65-0.99; PPV range 0.75-0.98, NPV range 0.59-0.87
Outcome Measures: 1. Correlation between GII and SNAP-IV and CBCL Attention Subscale 2. Predictors of impairment 3. Prevalence
Fabiano et al 2006 (12) Design Diagnostic case-control
Population: Children with DSMIV diagnosis of ADHD and control group non-ADHD Study information: Design: case-control
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study Level III-3 Setting USA Industry funding
Considers 4 studies, only study 1 relevant and reported here.
Duration: single rating Recruitment: Studies 1 & 2 = ADHD clinical referrals and community controls; studies 3 & 4 = elementary school population No. Study 1 (n=252) Outcome Measures: 1. Sensitivity 2. Specificity 3. Variance
Parent and teacher IRS contributed unique and substantial variance to the interviewer CGAS rating (a measure of future impaired functioning completed by an independent rater) beyond the prediction from ADHD symptoms alone.
Adults
Reference Biederman et al 2007 (13) Design Diagnostic case-control study Level III-3 Setting USA Industry funding Yes Diagnostic instruments Diagnostic tool Current Behavior Scale (CBS)
Population/Study information
Population: Males and females between the ages of 18 and 55 years, with or without diagnosis of ADHD Study information: Design: case-control Duration: single rating
Biederman et al 2008 (14)
Design Diagnostic crossclassification Level III-1 Quality Poor
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Diagnostic tool Current Behavior Scale (CBS) Empiricallyderived abridged 8-item scale and 99-item Current Behavior Scale (CBS), GAF, SAS No. n=200
Recruitment: Clinic referrals and community controls No. No ADHD control n = 138 ADHD n = 200
Outcome Measures: CBS ability to predict outcomes on the following measures; Global assessment of functioning (GAF) Total comorbid disorders Social adjustment scale current ADHD symptoms SES (education/occupation) full scale IQ WRAT (reading/arithmetic) Population: Adults aged 18-55 years with DSM-IV diagnosis of ADHD Study information: Design: cross-classification Duration: single rating Recruitment: Recruited via referrals and advertisements
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Results Using a cutoff at the 50th percentile; a ADHD + high CBS score identified poorer functional outcomes for global functioning, social adjustment comorbidities, WRAT-arithmetic and socioeconomic status (p<0.001) but not full scale IQ and WRAT reading when compared to both the no-ADHD control group and the ADHD + low CBS group (p < 0.001) Scores on the CBS above the 50th percentile identify adults with ADHD at significantly higher risk for functional morbidity beyond that conferred by the diagnosis of ADHD alone. The one factor solution provided eight items with factor loadings above 0.70. This abbreviated set of items was highly correlated with the 99-item CBS (0.91) and was similarly related to functional outcomes compared to the 99-item CBS (average correlation of 0.30 versus 0.32). Correlation between 8-item CBS and GAF = 0.37 Correlation between 8-item CBS and SAS = 0.53 Correlation between 99-item CBS and
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Setting USA Industry funding Yes
Outcome Measures: 1. Correlation between 8-item and 99-item CBS 2. Correlation between each version CBS and Global assessment of functioning (GAF) / Social adjustment scale
GAF = 0.44 Correlation between 99-item CBS and SAS = 0.55
Summary
Preschoolers: Two studies conducted in preschoolers met our inclusion criteria. Lahey et al (8) looked at the validity of the cross-situation impairment requirement in the diagnosis of ADHD in preschoolers. When full diagnostic criteria were met, DSM-IV ADHD plus impairment in two situations children exhibited significantly greater global, academic, and social impairment in the 3 annual follow-up assessments when compared to either controls or the group that met DSM-IV symptom criteria but had impairment in only one situation. However, the group with impairment in one situation exhibited significantly greater global and academic impairment at each follow-up than the no-ADHD control group and 34% later met full diagnostic criteria for ADHD compared to 3.1% of the controls. Willcutt et al (9) assessed the utility of the Hillside Behaviour Rating Scale (HBRS) and found that this scale made an independent contribution the prediction of functional impairment above parent and teacher ratings. Children and adolescents: Three studies conducted in children and adolescents met our inclusion criteria. Each assessed a different measure of impairment. Mota and Schachar (10) identified two algorithms generated from parent and teacher reports; subtype ROC and ADHD ROC that were more efficient than DSM-IV symptom counts in discriminating impaired from non-impaired children.
Gathje et al (11) assessed 6 individual measures of impairment and a combined measure and found low to moderate correlations with symptoms (Maternal SNAP-IV and CBCL Attention Subscale). The researchers also looked at which variables may be predictors of impairment and found gender, CBCL Attention subscale, PPVT (Peabody Picture Vocabulary Test) score and maternal SNAP-IV symptom count were significant predictors of impairment (11). Not surprisingly, the researchers also found that altering the number and type of scales used in diagnosis dramatically altered the number of positive diagnoses. Inclusion of impairment (GII) and symptom scales reduced the number of positive diagnoses.
Fabiano et al (12) assessed the utility of the impairment rating scale (IRS) and found that the parent and teacher IRS made an independent contribution to the prediction of impairment beyond the prediction from ADHD symptoms alone. Adults: Two studies conducted in adults with ADHD met our inclusion criteria. In the first study Biederman et al (13) assessed the ability of the Current Behavior Scale (CBS) to predict functional impairment in multiple areas. Using the cut off of the 50th percentile, the CBS was able to identify a sub group of adults with ADHD that were at significantly higher risk of functional impairment including global functioning, social adjustment, number of comorbidities and SES. In the second study, Biederman et al (14) assessed a short scale (8-item) derived from the CBS that was found to correlate well with the 99-item CBS and predicted poor functional outcomes in global functioning and social adjustment.
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Excluded studies Study Angold et al 1999 (15) Barkley et al 2006 (16) Bird et al 2000 (17) Canino et al 1999(18) Coghill et al 2006 (19) Hodges et al 1999 (20) Pressman et al 2006 (21) Steinhausen et al 2001 (22) Wolraich et al 2003 (23) Biederman et al 2006 (24) Abel et al 2007 (25)
Reason for exclusion Not specific to ADHD Does not address research question Not specific to ADHD Not specific to ADHD Does not address research question Not specific to ADHD Does not address research question Not specific to ADHD
Does not address research question Does not address research question Does not address research question
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Retrospective recall of childhood ADHD symptoms

Research question 2: In adolescents and adults with ADHD are retrospective self-reports of ADHD symptoms in childhood accurate? Selection Criteria Population Inclusion Criteria Adolescents or adults with ADHD undertaking self-report on childhood ADHD symptoms Indicator
Diagnosis and assessment of ADHD based on symptom measures (including; inattention, impulsivity, hyperactivity).
Comparator Outcomes
Informant ratings (professional or family)
Level of consensus between raters. Predictive value of selfreports.
Study Design Search Period Language Date of Search
NHMRC I-IV for diagnostic studies 1997 - present considered English
Search terms
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February 2008
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Text words: adhd or addh or adhs or hyperactive$ or hyperkin$ or (attention adj deficit) AND (teacher adj reports) or (parent adj reports) or (teacher adj question$) or (parent adj question$) or (teacher adj rating) or (parent adj rating) or (family adj report) or (partner adj report) or selfreport, informant, multisource
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Adults
Reference Loney et al 2007 (26) Design Diagnostic case-control study Level III-3 Setting USA outpatient psychiatric clinic Industry funding No Diagnostic instruments Diagnostic tool Multiple Symptom Subgrouping Method (MSSM ) Population/Study information Population: Individuals with hyperkinetic disorder diagnosed by DSM II with an average age of 9 years. Study information: Design: Case-control Duration: Follow up: adolescent stage (9-17 years), young adult stage (21-23 years), later adult stage (28-32 years) Recruitment: Clinic referrals Results Probands retrospective self-ratings made at age 21 and 30 for childhood (age 9) symptoms showed good agreement. Correlation coefficients; median r of .51; 15% to 40% overlap No significant differences between the means of the two sets of childhood symptoms rated 9 years apart.
No. probands n= 295 boys with ADHD [at initial referral] (+ n=60 same school controls; n=97 brothers of ADHD group)
Mannuzza et al 2002 (27) Design Diagnostic case-control study Level III-3 Setting USA Industry funding No
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Diagnostic tool Schedule for the Assessment of Conduct, Hyperactivity, Anxiety, Mood, and Psychoactive Substances (adults) Diagnostic tool Structured interview of
Outcome Measures: Retrospective self-reports of ADHD symptoms at each followup.
Population: Caucasian boys recruited at age 6to 12-years followed up at mean age 25 years who were referred to a no-cost psychiatric research clinic and comparison subjects with no record of behaviour problems prior to age 13 years Study information: Design: case-control Duration: 14-20 years
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Retrospective childhood diagnoses of ADHD were made for 78% of probands (N=137) and 11% of the comparison subjects (N=18) (sensitivity=0.78; specificity=0.89; odds ratio adjusted for socioeconomic status=26.47, Wald 2= 106.60, df=1, p<0.001). The kappa was 0.67, suggesting good agreement between retrospective diagnoses made at follow-up and diagnoses made in childhood. Pearson correlations between selfreports of childhood ADHD with the parent report that was collected at study
Recruitment: Clinically referred probands and comparisons recruited from nonpsychiatric departments of same hospital and community No. ADHD probands n=176 Non-ADHD comparison group n=168
Barkley et al 2002 (28)
Outcome Measures: Retrospective ADHD diagnosis made on self-report of childhood symptoms compared with childhood diagnosis. Population: Subjects between 1925 years who were diagnosed as hyperactive when they were aged
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Design Diagnostic case-control study Level III-3 Setting USA Industry funding No
disruptive behavior disorders (self rated), Parent interview of ADHD symptoms Reference test None Comparison Adult self-report of childhood symptoms vs parent rating during childhood
4-12 years. Community control group without behavioural problems. Study information: Design: case-control Duration: Single report Recruitment: Consecutive clinical referrals and community children recruited using snowball technique No. Final follow up (aged 19-25 years): n (hyperactive) = 147, n (community control) = 73 Outcome Measures: Agreement between self and informant ratings of childhood symptoms Population: Individuals with ADHD aged 20-50 years. Study information: Design: case-control
entry in childhood: r(219) = .44 for the CPRS ImpulsiveHyperactive factor; r(220) = .39 for the CPRS Hyperactivity Index; r(220) = .41 for the WWPARS. All were significant, p < .01. Agreement was moderate.
Murphy & Schachar 2000 (29) Design Diagnostic case-control study Level III-3 Setting Canada Industry funding No
Diagnostic tool Questionnaire based on DSM-IV criteria Reference test None
Summary
With this research question we have attempted to address the validity of childhood recollections of ADHD behaviour. Four studies were identified that met our inclusion criteria (26-29) and each took a different approach to addressing various aspects of this question. In a longitudinal study where self-reports of childhood symptoms were collected at age 21 and age 30, good agreement was seen between symptom reports despite being collected 9 years apart (26). Which suggests stability in the way symptoms are recalled over time (26). Mannuzza et al (27) also took advantage of a longitudinal study and compared retrospective diagnosis of childhood ADHD
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Comparison Self-reports vs parent report of childhood symptoms
Duration: Single rating of retrospective perceptions
Recruitment: Volunteers recruited from among the parents of children undergoing assessment at The Hospital for Sick Children, staff of the hospital, and friends and relatives of individuals working at the hospital. No. ADHD participants n = 50 (28 women and 22 men) Parents n = 43 mothers n = 7 fathers
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Agreement between participant and parent reports of childhood symptoms was good. The correlations obtained for inattentive symptoms, hyperactiveimpulsive symptoms, and total symptoms were r=0.76, df=48, p<0.001; r=0.69, df=48, p<0.001; and r=0.79, df=48, p<0.001, respectively. All correlations were statistically significant. The t tests comparing the means of the participant and parent scores were also statistically significant. The values obtained were inattentive symptoms, t=3.21, df=49, p=0.002; hyperactiveimpulsive symptoms, t=2.36, df=49, p=0.022; and total symptoms, t=3.40, df=49, p=0.001.
Outcome Measures: Agreement between self and informant ratings of childhood inattentive symptoms, hyperactiveimpulsive symptoms, and total symptoms.
based on adult self report to the actual childhood diagnosis and found good agreement between the two. In another longitudinal study Barkley et al (28) compared self-reports of childhood ADHD with the parent report that was collected at study entry in childhood and found moderate agreement between the two. Finally, Murphy et al (29) asked adults with ADHD and their parents to report on the ADHD symptoms that were seen in childhood. Good agreement was found between the two. Overall, these studies support the validity of using adult self report of childhood symptoms. Excluded studies Study Murphy et al 2003 (30) Schultz et al 2006 (31) Fossati et al (2001) (32) O'Donnell et al 2001 (33) Faraone et al 2006 (34) Dankaerts et al 1999 (35) Magnsson et al 2006 (36)
Reason for exclusion Not directly addressing question. Not directly addressing question. Not directly addressing question. Not directly addressing question. Not directly addressing question. Not self-reporting childhood symptoms Not self-reporting childhood symptoms
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Parent and teacher reports

Research question 3: In preschoolers, children or adolescents with ADHD is there consensus between parent and teacher reports of ADHD symptoms when assessed with parallel instruments? Selection Criteria Population Indicator Inclusion Criteria Individuals with ADHD or general population assessed by parent report Diagnosis and assessment of ADHD based on symptom measures (including; inattention, impulsivity, hyperactivity). Comparator Outcomes
Individuals with ADHD or general population assessed by teacher report Level of consensus between parents and teachers Predictive value of parent and teacher reports
NHMRC I-IV for diagnostic studies 1997 - present considered English February 2008
Search terms
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Text words: adhd or addh or adhs or hyperactive$ or hyperkin$ or (attention adj deficit) (teacher adj reports) or (parent adj reports) or (teacher adj question$) or (parent adj question$) or (teacher adj rating) or (parent adj rating) or (family adj report) or (partner adj report) or selfreport, informant, multisource
21
Preschoolers
Reference Murray et al 2007 (37) Design Diagnostic crossclassification Level III-2 Setting USA Industry funding None received Diagnostic instruments Diagnostic tool Conners Rating Scales parent and teacher Comparison Parent and teacher agreement Population/Study information Population: Children aged 3-5.5 years recruited for the PATS study Study information: Design: Cross-classification Duration: single rating Results Parent and teacher ratings internal reliability were both adequate or better (Cronbachs alpha 0.70) Parents reported significantly more Inattentive (p < 0.001) and Hyperactive-Impulsive (p < 0.001) symptoms than teachers
Recruitment: Via advertising for a treatment study for preschoolers with ADHD symptoms. No. n = 452
Outcome Measures: 1. internal consistency 2. parent teacher agreement 3. parent reports as predictors of teacher reports 4. teacher reports as predictors of parent reports
AmadorCampos et al 2006 (38) Design Diagnostic crossclassification Level III-2 Setting Spain Industry funding None
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Diagnostic tool Spanish-Catalan questionnaire containing 18items from the ADHD symptom list published in DSM-IV Comparison Parent and teacher agreement No. n:151
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Parent and teacher correlation was low for inattentive (r = 0.24, p < 0.01) and Hyperactive-Impulsive (r = 0.26, p < 0.01) symptoms Sensitivity: Probability that a teacher reported a symptom given that a parent had done so. (Mean, SD) Hyperactive-Impulsive (68.1, 7.00) Inattentive (52.5, 18.70) Specificity: probability that a teacher did not report a symptom given that a parent had not. (Mean, SD) Hyperactive-Impulsive (51.3, 7.93) Inattentive (61.2, 16.16) PPP: probability that symptoms were rated by parents as present given that teachers had endorsed them. (Mean, SD) Hyperactive-Impulsive (86.5, 10.3) Inattentive (68.6, 19.7) NPP: probability that a parent did not endorse a symptom that had not been reported by a teacher. (Mean, SD) Hyperactive-Impulsive (24.4, 13.63) Inattentive (43.9, 21.4) Overall parent and teacher agreement was low. Prevalence (%) in under 6 age group ADHD-I: 5.96% teachers, 1.32% parents. Discrepancy (p =0 .034) ADHD-HI: 5.96% teachers, 13.91% parents. Discrepancy (p<0.014) ADHD-C: 2.65% teachers, 0.66% parents. Discrepancy (not calculated)
Population: Children aged 4-12 years. Participants under 6 considered separately Study information: Design: Cross-classification Duration: Single rating Recruitment: Random sample derived from 48classrooms within 6-partially funded schools
Outcome Measures: Inter-informant agreement re: prevalence of ADHD-I, ADHD-HI and ADHD-C
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Reference DuPaul et al 1998 (39) Design Diagnostic crossclassification Level III-2 Setting USA Industry funding None received Diagnostic instruments Diagnostic tool AD/HD Rating Scale-IV (School and Home Version) Comparison Parent and teacher agreement Population/Study information Population: Children aged 7 to 17 years attending school. Study information: Design: Cross-classification study Duration: Test conducted twice 4 weeks apart Recruitment: Random community sample from two suburban school districts. No. n = 62 (28 boys 34 girls) Results Internal consistency, alpha coefficients: Parent: High (TS = 0.99, IA = 0.89, HI = 0.88) Teacher: High (TS = 0.94, IA = 0.96, HI = 0.88) Test-re-test reliability correlation coefficients: Parent: High (TS = 0.85, IA = 0.89, HI = 0.86) Teacher: High (TS = 0.9, IA = 0.89, HI = 0.89) Inter-rater agreement correlation coefficients: Parent versus teacher: moderate (TS = 0.41, IA = 0.45, H = 0.40)
Gomez et al 2007 (40)
Design Diagnostic crossclassification Level III-2 Setting Australia Industry funding No
Mitsis et al 2000 (41)
Design Diagnostic crossclassification Level III-2 Setting Not stated
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Diagnostic tool Disruptive behaviour rating scale (DBRS) Comparison Parent and teacher agreement Diagnostic tool Child Behavior Checklist (parentrated) and IOWA Conners Teachers Questionnaire Comparison Parent and teacher agreement
Outcome Measures: 1. internal consistency (ADHDRS) 2. test-re-test reliability (ADHDRS) 3. inter-rater reliability (ADHDRS) Total score (TS) Inattention (IA) Hyperactivity / Impulsivity (HI) Population: Children aged 6 11 years attending primary school Study information: Design: Cross-classification Duration: Single rating
Recruitment: Random community sample from eight primary schools
No. N = 213 (104 boys, 109 girls)
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Inter-rater agreement correlation coefficient: IA total score = 0.32 (p < 0.01) HI total score = 0.22 (p < 0.01) Mean scores: 7 of 9 IA symptoms and 7 of 9 HI symptoms and the total scores for both were significantly different when comparing teacher and parent ratings. With the parent rating always higher. Parent-teacher agreement for a diagnosis of ADHD (any subtype): Percent agreement = 74% Agreement regarding subtypes stated as quite poor (not defined). Parent-teacher agreement for number of ADHD Symptoms: Overall: adequate r = 0.42 (p = 0.001) Inattentive: r = 0.30 (p<0.01) Hyperactive-impulsive: r = 0.39 (p<0.001).
Outcome Measures: 1. inter-rater reliability (DBRS) 2. mean scores Inattention (IA) (9 symptoms) Hyperactivity / Impulsivity (IA) (9 symptoms) Population: Children aged 7-11 years
Study information: Design: Cross-classification Duration: Single rating
Recruitment: Sample of convenience (children with behavioural problems
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identified from an early study) Industry funding Funding source not stated No. n:74 (60 boys, 14 girls) Outcome Measures: 1. Parent-Teacher Concordance for ADHD Subtypes 2. Parent-Teacher Agreement for Number of ADHD Symptoms 3. Parent-Teacher Agreement for ADHD Symptoms in the School Setting Population: Children aged 5-14yrs Study information: Design: Cross-classification Duration: Single rating Parent-Teacher Agreement for ADHD Symptoms in the School Setting: Parents reported fewer hyperactive-impulsive symptoms in the school setting (p = 0.052). Percent agreement for individual symptoms ranged from 50-76% for hyperactive-impulsive symptoms and from 43-78% for inattentive symptoms. Correlation between teacher / parent ratings: Inattention scale: r= 0.41; Hyperactivity-Impulsivity: r=0.30
Power et al 1998 (42) Design Diagnostic crossclassification Level III-2 Setting USA Industry funding Funding source not stated
Diagnostic tool ADHD-RS-IV (Parent and teacher rated)
Comparison Parent and teacher agreement
Recruitment: Sample of convenience (children were those referred by their teachers for either or both academic and behavioral problems) No. n:147 (99 boys, 48 girls)
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Outcome Measures: Sensitivity, specificity, positive predictive power (PPP), adjusted PPP using kappa statistics (cPPP), negative predictive power (NPP), and adjusted NPP (variously for 80th, 85th, 90th, 93rd, and 98th percentile scores) using both the Inattention and Hyperactivity factors, as rated by a single and multiple informants
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Prediction based on a single informant using the Inattention factor. Not useful in predicting presence of ADHD/I and ADHD/COM For ADHD/I, Teacher ratings <80th percentile cNPP=0.76, whilst for ADHD/COM cNPP=0.65; cNPP values for parent ratings at the same threshold were 0.76 and 0.87, respectively. Prediction based on multiple informants using the Inattention factor. For prediction of both ADHD/I and ADHD/COM optimal combination was teacher rating 90th percentile and a parent rating 80th percentile (for the respective diagnoses, cPPP and sensitivity combinations were respectively 0.65 and 0.41, and 0.67 and 0.52. Prediction based on a single informant using the Hyperactivity-impulsivity factor. Teacher ratings not informative for ruling in or ruling out ADHD (either subtype), whilst parent ratings were able to rule in ADHD/COM 98th percentile (cPPP=0.67) and differentiate between sub-types 90th percentile (cPPP=0.70, sensitivity=0.65); also parent ratings below 80th percentile able to rule out ADHD/COM (cNPP=0.75, specificity=0.63) Prediction based on multiple informants using the Hyperactivityimpulsivity factor. For prediction of both ADHD/I and ADHD/COM optimal combination was teacher rating 80th percentile and a parent
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Antrop et al 2002 (43) Design Diagnostic crossclassification Level III-2 Setting Belgium Industry funding None received
Diagnostic tool Disruptive Behavior Disorder Rating Scale parent and teacher ratings
Population: Children aged 6-12 years Study information: Design: Cross-sectional Duration: Single rating
Comparison Parent and teacher agreement
Recruitment: Sample of convenience (derived from rural and non-rural special counseling/teacher and health care centres) No. n:55 (49-boys; 6-girls)
Outcome Measures: Pearson Correlation Coefficients (PCCs) and Intraclass Correlations (ICCs) for Ratings by Parents and Teachers on the DBDRS Diagnostic tool Spanish-Catalan questionnaire containing 18items from the ADHD symptom list published in DSM-IV Population: Children aged 4-12 years Study information: Design: Cross-classification Duration: Single rating
AmadorCampos et al 2006 (38) Design Diagnostic crossclassification Level III-2 Setting Spain Industry funding None received
Sherman et al 1997 (44)
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Comparison Parent and teacher agreement Diagnostic tool Diagnostic Interview for Children and Adolescents revised version (parent and teacher-rated) Comparison
Recruitment: Random sample derived from 48classrooms within 6-partially funded schools No. Total n:653 (278-boys; 375-girls) > 6 years n:502
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Paired t tests, identified significant differences (p<0.01) between parent and teacher for inattention, hyperactivity /impulsivity, and ODD symptoms. Parents reported more problem behaviors than teachers. Parents and teachers did not differ (p>0.05) in their ratings of CD symptoms. Overall parent and teacher agreement was low. Parent and teacher agreement between the informants in the prevalence of ADHD-I, ADHD-HI and ADHD-C was low Prevalence (%) Total sample: ADHD-I: 14.24% teachers, 3.98% parents. Discrepancy (p<0.001) ADHD-HI: 11.8% teachers, 10.41% parents. Discrepancy (p<0.688) ADHD-C: 5.82% teachers, 1.23% parents. Discrepancy (p<0.001) Sample 6-years: ADHD-I: 16.73% teachers, 4.78% parents. Discrepancy (p<0.001) ADHD-HI: 12.75% teachers, 9.56% parents. Discrepancy (p<0.05) ADHD-C: 6.77% teachers, 1.39% parents. Discrepancy (p<0.001) 15% of subjects were diagnosed with ADHD as per teachers ratings, compared with 6% by mothers reports (correlation not provided). 3% of subjects met criteria for ADHD in both school and home settings. Teachers ratings yielded moderate monozygotic (0.53) and dizygotic
rating 85th percentile (for the respective diagnoses, cPPP and sensitivity combinations were respectively 0.74 and 0.52, and 0.86 and 0.52. DBDRS scales: Inattention: PCC=0.13; ICC=0.01 Hyperactivity/ impulsivity: PCC=0.09; ICC=0.01 Oppositional defiant disorder (OOD): PCC=0.56*; ICC=0.45* Conduct disorder (CD)=0.36*; ICC=0.29* (nb: * p<0.05)
Outcome Measures: Inter-informant agreement re: prevalence of ADHD-I, ADHD-HI and ADHD-C
Population: Children aged 11-12 years Study information: Design: Cross-classification Duration: Single rating Recruitment: Sample of convenience derived from participants in a longitudinal,
Design Diagnostic crossclassification Level III-2
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Setting USA Industry funding Funding source not stated
Parent and teacher agreement
population-based Minnesota Twin Family Study. No. n:576 (boys only; either monozygotic or dizygotic twins) Outcome Measures: Percentage agreement (nb: interrater correlation analysis not presented) Population: Children aged 5-17 years Study information: Design: Cross-sectional Duration: Single rating
(0.37) concordance rates, compared with mothers reports, which indicated a high monozygotic (0.67) and a zero dizygotic concordance for ADHD.
Sprafkin et al 2001 (45) Design Crosssectional Level II Setting USA Industry funding Funding source not stated
Diagnostic tool ADHD Symptom Checklist -4 (parent and teacher rated) Reference test Physician diagnosis of ADHD Comparison Parent and teacher agreement
Recruitment: Consecutive referrals to a university hospital child psychiatry outpatient service No. n:103 (77-boys; 26-girls)
Wolraich et al 2004 (46) Design Crosssectional Level II Setting USA Industry funding No
Tripp et al 2006 (47)
Design Diagnostic case-control Level III-3
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Diagnostic tool Vanderbilt Rating Scale Reference test Physician diagnosis of ADHD Comparison Parent and teacher agreement Diagnostic tool CBCL CPRS TRF CTRS DBD Reference test Physician diagnosis of ADHD Comparison No. n:184
Outcome Measures: Sensitivity, specificity, positive and negative predictive values; and Pearson correlation between informant symptom severity scores Population: Children diagnosed with ADHD or screened to be at risk for ADHD. Study information: Design: Cross-sectional Duration: Single rating
Recruitment: Children from an urban primary school system
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Negative predictive values (specificity) Parent: 0.53 (0.59) Teacher: 0.62 (0.59) Combined: 0.78 (0.36) Correlations between parent and teacher symptom severity scores: ADHD-I: r=0.25 (p<0.05) ADHD-HI: r=0.46 (p<0.0001) ADHD-C: r=0.32 (p<0.01)
*
Positive predictive values (sensitivity) Parent: 0.67 (0.61) Teacher: 0.67 (0.70) Combined: 0.63 (0.91)
nb: PPV (sensitivity) and NPV (specificity) values only provided for symptom count)
Parent and teacher agreement for number of ADHD symptoms was low. Inattentive (r = .34, k = 0.27), Hyperactive/Impulsive (r = .27, k = 0.22) Performance Impairment (r = .31, k = 0.07). Parent and teacher agreement did not differ significantly by race
No. n:242 screen positive volunteers n:6171 initial screen Outcome Measures: Parent & teacher agreement ADHD diagnosis Population: Children aged 5 12 years Study information: Design: Case-control Duration: Single rating Recruitment: clinical sample of children referred for suspected ADHD
Two-setting requirement for diagnosis strictly enforced: Poor inter-rater agreement decreased diagnostic rates for: Inattentive (15%5%), Hyperactive/Impulsive (11%3%) Combined (23%7%).
Parent ratings (CBCL & Conners) for the ADHD and no-ADHD groups were only significantly different on 1/9 CBCL measures and 2/6 Conners measures. Teachers ratings (Conners & TRF) for the ADHD and No-ADHD groups were significantly different on 8/9 TRF and 7/7 Conners measures. With the ADHD group showing more behavioural symptoms.
Setting New Zealand Industry
26
funding No
Parent and teacher agreement
ADHD n: 108 No-ADHD n: 76 Outcome Measures: Parent & teacher agreement Sensitivity, specificity, positive and negative predictive values;
Teacher ratings where more accurate than parent ratings when considering sensitivity, specificity, and overall classification accuracy. Combining rating scales within informants did not improve classification accuracy. Combining across parent and teacher measures produced results consistent with teacher ratings. Parent and teacher agreement: Inattention: moderate (r = 0.38, p<0.01) Hyperactive/impulsive: none (r = -0.04, p<0.01) ODD: moderate (r = 0.32, p<0.01) CD: moderate (r = 0.33, p<0.01) Higher parenting stress, but not parent depressed mood was significantly related to parents reporting higher levels of the DBDRS inattention, hyperactivity/impulsivity and ODD behavior relative to teachers reports of this behavior (all p < 0.01).
van der Oord et al (2006) (48) Design Diagnostic yield Level IV Setting Netherlands Industry funding No details reported
Diagnostic tool Disruptive behavior disorder rating scale (DBDRS) Comparison Parent and teacher agreement
Population: Children aged 8-12 years with ADHD diagnosed using DSMIV
Study information: Design: Diagnostic yield Duration: single rating
Recruitment: Outpatient clinic No. 47 children diagnosed as ADHD combined type: n = 47 ADHD inattentive type: n = 16 ADHD hyperactive/impulsive type: n = 2 Outcome Measures: Parent & teacher agreement Parenting stress index CES-D to assess depressive symptoms
Summary
Preschoolers: Parent and teacher agreement on ADHD symptoms and identification of subtypes was found to be low in two studies conducted in preschoolers. The participants of the first study were preschoolers with ADHD recruited in the USA for a treatment study (37). The participants in the second study were a general population sample of Spanish schoolchildren (38). The quality of these studies was rated as poor. Children and Adolescents: Parent and teacher agreement on ADHD symptoms and identification of subtypes was found to be moderate to low in eleven out of eleven studies conducted in children. The quality of these studies was rated as poor. The identified studies utilised a variety of different ADHD rating scales, including, both narrow band and broad brand scales. Six studies recruited participants from clinical samples and five were recruited from the general population. Seven of the studies were undertaken in the USA. The remaining studies were undertaken in Spain (38), Belgium (43), the Netherlands (48) and Australia (40), providing some support that the low agreement between parent and teacher ratings holds true across different cultures. Only one study considered adolescents by including participants aged 5-17 (45). However data was not presented separately and it is not possible to draw specific conclusions on parent teacher agreement specific to adolescents.
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One major limitation of many the studies was failure to include a measure of internal consistency to enable confidence in the parent and teacher ratings themselves prior to comparing them.
Excluded studies Study Evans et al 2005 (49) Crystal et al 2001 (50) Gomez et al 2005(51) Gomez et al 2003 (52) Gomez et al 1999 (53) Power et al 1998 (54) Youngstrom et al 2000 (55) Weiler et al 1999 (56) Vaughn et al 1997 (57) Amador-Campos et al 2005 (58)
Reason for exclusion Comparison between Parent reports and observations Does not directly address question (No direct comparison of parent and teacher reports) Does not directly address question (No direct comparison of parent and teacher reports) Does not directly address question. (No direct comparison of parent and teacher reports) Does not directly address question. (No direct comparison of parent and teacher reports) Does not directly address question. (No direct comparison of parent and teacher reports) Not ADHD Does not directly address question. (No direct comparison of parent and teacher reports) Does not directly address question. (No direct comparison of parent and teacher reports) Does not directly address question.
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Self and third-party reports

Research question 4: In adolescents or adults with ADHD is there consensus between third-party reports (parent, partner, family member etc) and self-reports of ADHD symptoms when assessed with parallel instruments? Selection Criteria Inclusion Criteria
Population Indicator
Adolescents and adults with ADHD assessed by self-report
Comparator
Adolescents and adults with ADHD assessed by third-party report (parent, partner or family member)
Outcomes
Level of consensus between self-report and third-party report. Predictive value of self-report compared to third-party report.
Study Design Search Period Language
Date of Search
Search terms
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February 2008
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Adolescents
Reference Hope et al 1999 (59) Design Diagnostic crossclassification Level III-2 Setting USA Industry funding None reported Diagnostic instruments Diagnostic tool Diagnostic interview for children and adolescents revised version (DICA-R) adolescent selfand parent reports Comparison Adolescent selfreports versus parent report Population/Study information Population: Adolescents mean age: 13.17 years (sd: 1.89) and their mothers Study information: Design: Cross-classification Duration: Single rating Results ADHD symptom presentations identified in 31% of adolescent selfreports and 51% of parent reports. Parents reported significantly more (p<0.05) ADHD symptoms than adolescents.
Recruitment: Sample of convenience derived from local paediatric, psychology, and psychiatric outpatient clinics and newspaper advertisements. No. n:121 (54% males)
Rohde et al 1999 (60)
Design Diagnostic crossclassification Level III-2 Setting Brazil Industry funding None reported
Cantwell et al 1997 (61)
Design Diagnostic crossclassification Level III-2 Setting USA Industry funding
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Comparison Young adolescent self-report versus parent report Diagnostic tool Adolescent selfand parent-report of psychiatric diagnostic data Interviewer consensus diagnosis (not defined) Comparison Adolescent selfreports versus parent report
Diagnostic tool Children behavior checklist (parent and teacher report forms)
Outcome Measures: Level of agreement between parent and adolescent reports assessed by percentage agreement and kappa coefficients Population: Adolescents aged 1214 years Study information: Design: Cross-classification Duration: Single-rating
Recruitment: Random sample of young adolescents derived from 64-state schools No. n:191 participants (99-cases; 91 control subjects)
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Agreement between the parent and the adolescent report for ADHD symptoms was low: (39.4%; k =0.30). On the basis of adolescent-only reports 46.7% of participants were considered to have ADHD. On the basis of parent-only reports, 86.7% of participants were considered to have ADHD. On the basis of adolescents And parent reports, 33.3% of participants were considered to have ADHD. On the basis of adolescents Or parent reports, 100% of participants were considered to have ADHD. Overall, agreement between youngadolescents and parents was low. (k=0.45, p<0.001 (95% CI: 0.31-0.59)) Percentage agreement 90% Measures of agreement (k-coefficients) between: Adolescent and parent diagnosis, k= 0.51 (95% CI: 0.20-0.83); Moderate Parent and interviewer diagnosis, k= 1.00 (95% CI: not calculable); Full Adolescent and interviewer diagnosis, k= 0.51 (95% CI: 0.200.83); Moderate
Outcome Measures: Percent agreement and Inter-rater reliability (Kappa coefficient);
Population: Adolescents aged 1418 years Study information: Design: Cross-classification Duration: Single rating
Recruitment: Participants were a consecutive subset of a group of subjects randomly selected from 9-high schools for involvement in a broader cohort study The Oregon Adolescent Depression Project
30
None reported
And Self- and informant reports versus Interviewer consensus diagnosis
No. n:281 (52% female) Outcome Measures: Levels of concordance, and Percent agreement (kappa coefficient)
Adults
Reference Barkley et al 2002 (28) Design Diagnostic crossclassification Level III-2 Setting USA Industry funding None reported Diagnostic instruments Diagnostic tool Structured interview of disruptive behavior disorders (self-rated); Parent interview of ADHD symptoms Comparison Adult self-report versus Parent report Population/Study information
Population: Adults aged 19-25 years Study information: Design: Cross-classification* Duration: Single rating
Recruitment: Cases had previously been recruited as consecutive referrals to a childhood psychology service No. n:147 cases (~87% male) Outcome Measures: Percent agreement and Inter-rater reliability (Kappa coefficient); Correlation (Pearsons)
*
Downey et al 1997 (62) Design Diagnostic crossclassification Level III-2 Setting USA Industry funding None reported
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Diagnostic tool Symptom checklist for ADHD Adults (self- and informant reports) Comparison Adult self-reports versus independent informant No. n:78
Data presented in this study publication was derived from a cross-sectional followup of cases involved originally in a casecontrol study
Population: Adults with a mean age of 33.24 ( 11.39) years
Study information: Design: Cross-classification Duration: Tests repeated by participants and informants twice; once at screening and at formal interview at least 2-months later. Recruitment: Sample of convenience of cases attending a specialist clinic
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Results Correlation between self- and parent ADHD symptom reports: r(147) = 0.16, p > 0.05 Percentage agreement (overall) for a diagnosis of ADHD based on self- and parent-reports using DSMIIIR threshold (8 of 14 symptoms):: 53% (k = 0.073) Nb: Percentage agreement for not having ADHD as per self-and parentreports: 97% Nb: Percentage agreement for having ADHD as per self-and parent-reports: 53%. Re: inter-rater reliability and temporal stability of ADHD symptoms, Pearson correlations conducted on symptom checklist scores for patients versus informants, at Time-1 (screening packet completed at home and mailed to the clinic) versus Time-2 (baseline data provided at the clinic on the date of interview) were significant (p<0.001) with r-values ranging from 0.57-0.78. Re: percent agreement with the frequency occurrence of the respective ADHD symptoms listed on the symptom checklists (Time-1) as documented by self- and informantreports, it varied from 89.1% (k=0.39) for Difficulty sustaining attention to 57.8% (k=0.14) for Unpredictable behaviour
Outcome Measures: Inter-rater reliability assessed using Pearson correlations (at both time points), and the percent agreement (kappa coefficient) with the frequency with which each ADHD symptom listed on the symptom checklists (Time-1) was endorsed by ADHD patients versus
31
their observers. Zucker et al 2002 (63) Design Diagnostic crossclassification Level III-2 Setting USA Industry funding None reported Diagnostic tool ADHD behavior checklist (selfand informant reports) Comparison Young adult selfreports versus Informant report (parents, friend/roommate, spouse/partner or sibling) Population: Adults with a mean age: 23.59 6.60 years Study information: Design: Cross-classification Duration: Single rating of current symptoms and retrospective assessment of childhood symptoms Self-ratings of childhood and current symptoms were highly correlated (r=0.75 for ADHD-I; r=0.74 for ADHD-HI) Informant ratings of childhood and current symptoms were highly correlated, when the same informant completed both childhood and current ratings (r=0.59 for ADHD-I; r=0.65 for ADHD-HI) and when there were two different informants (r=056 for ADHDI; r =0.62 for ADHD-HI).
Recruitment: Sample of convenience derived from a database containing the results of psycho-educational evaluations of college students who presented with academic difficulties to an on-campus assessment clinic
No. n:281 (151 males;130 females) Outcome Measures: Inter-rater reliability assessed using Pearson correlations and the percent agreement (kappa coefficient)
Kooij et al 2008 (64)
Setting Netherlands
Industry funding Health Care Insurance Co. DSW
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Diagnostic tool The ADHD Rating Scale Conners Adult ADHD Rating Scales (CAARS) Brown AttentionDeficit Disorder Scale (BADDS) Diagnostic Interview Schedule-IV, section L (DIS-L). Comparison Adult self-reports versus Informant reports (parents and partners)
Population: Adults with a mean age: 36.6 years; sd: 10.3 Study information: Design: Cross-classification Duration: single measure
Recruitment: Sample of convenience derived from a specialist outpatient clinic No. n:120 (55% males)
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Moderate but significant (p<0.01) positive correlations between self- and informant ratings of current symptoms on both the ADHD-I and ADHD-HI subscales with similar correlations evident for childhood symptoms (r ranged from 0.55-0.65) Kappa coefficients were variable for current and childhood symptoms (0.190.49), suggesting low concordance for certain symptoms. ADHD Rating Scale: Agreement between different constructs was low for patientpartner (IA, r = 0.386; HI, r = 0.423) and patientinvestigator (IA, r = 0.348; HI, r = 0.440) comparisons. Partner and investigator ratings had comparable correlations with patient ratings. BADDS: Agreement was low (r = 0.4970.729), indicating a modest agreement between patient and partner in the measurement of the five clusters of the BADDS. CAARS-LV: Agreement was low (r =0.4390.609), particularly for Cluster E scored by the partner and the patient (r =0.439). The highest agreement was for Clusters D and C. DIS-L: Agreement between patients and parents with regard to Inattention and Hyperactivity/Impulsivity in childhood, was low (IA r =0.314;
Outcome Measures: Agreement* between different informants (multimethod) on the same factors (monotrait) using intra-class correlations (ICC)
* Nb: The authors of the study referred to this form of agreement as convergent validity
32
HI r =0.431). Murphy & Schachar 2000 (29) Diagnostic tool Questionnaire based on DSM-IV criteria (self and partner-rated) Population: Adults with ADHD aged 25-65 years and their partners Study information: Design: Cross-sectional Duration: Single rating of current and retrospective perceptions Recruitment: Subjects were volunteers recruited from among the parents of children undergoing assessment at The Hospital for Sick Children, staff of the hospital, and friends and relatives of individuals working at the hospital. No.
Comparison Adult (current) self-reports versus partner report
Setting Canada Industry funding None reported
n:100 (53 males, 47 females)
Outcome Measures: Agreement between self and informant ratings for inattentive symptoms, hyperactive-impulsive symptoms, and total symptoms. Young 2004 (65)
Setting Industry funding None reported
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Diagnostic tool Young ADHD QuestionnaireSelf-Report [YAQ-S] Young ADHD QuestionnaireInformant Report [YAQ-I] Comparison self-reports versus informant report Diagnostic tool Multiple Symptom Sub-
Population: Adults aged 25-32 years and their informants Study information: Design: Cross-classification Duration: Single rating
Recruitment: referrals to an adult ADHD assessment clinic and community controls
No. Participants / informants Clinical ADHD diagnosis n:83 / informants n:55 Clinical controls (referred, but noADHD) n:64 / informants n:33 Normal community control n:33/ informants n:30 Outcome Measures: Agreement between self and informant ratings. (Pearson correlation coefficients.) Four YAQ scales: ADHD Emotional Delinquency Social
T F A
Poor agreement between self-rated and informant-rated ADHD symptoms was found for all groups, and the Social scale for the ADHD group only ADHD ADHD: r = 0.22 Clinic controls: r = 0.27 Norm controls: r =0.20 Emotional ADHD: r = 0.55* Clinic controls: r = 0.62* Norm controls: r =0.42* Delinquency ADHD: r = 0.77* Clinic controls: r = 0.49* Norm controls: r =0.57* Social ADHD: r = 0.15 Clinic controls: r = 0.67* Norm controls: r =0.60* * p < 0.05 Poor agreement between probands and brothers on the severity of the probands symptoms
The correlations obtained for inattentive symptoms (r=0.70), hyperactive-impulsive symptoms (r=0.59), and total symptoms (r=0.69) between current adult case self-reports and partner ratings, were all statistically significant (p0.001). T-tests comparing the means of the current adult case self-reports and partner ratings were not statistically significant (inattentive symptoms, t=0.13, p=0.90; hyperactive-impulsive symptoms, t=1.56, p=0.12; and total symptoms, t=0.92, p=0.36).
Loney et al 2007 (26)
Population: Individuals with hyperkinetic disorder diagnosed by DSM II with an average age of 9
33
Design Diagnostic crossclassification Level III-2 Setting USA outpatient psychiatric clinic Industry funding No
grouping Method (MSSM )
years. Study information: Design: Cross-classification Duration: Follow up occurred as follows: Adolescent stage (9-17 years), young adult stage (21-23 years), later adult stage (28-32 years) Recruitment: Clinic referrals No. probands n= 295 boys with ADHD [at initial referral] (+ n=60 same school controls; n=97 brothers of ADHD group)
Correlation; Age 9: median of 8 symptoms rs = .26 Age 14: median of 8 symptoms rs = .21 Age 19: median of 8 symptoms rs = .20
Comparison Self-report versus brother report
Outcome Measures: Agreement between retrospective self-reports and brother reports of ADHD symptoms; inattention hyperactivity, impulsivity, fidgetiness, uncoordination, negativity, aggression and self-esteem deficits
Summary
Adolescents: Three studies in adolescents (59-61) all show low to moderate agreement between self reports and third-party reports (all studies used parents as the third party).
Adults :Six out of seven studies show low agreement between self reports and third party reports (parents, partners, friends, family members) using a variety of rating scales (28, 62-65) (26). One study found good agreement between self reports and third party reports (parents, partners, friends) (29). One possibility for the difference is that participants in the Murphy et al (29) study were recruited from the general community and were not clinic samples as was the case for all of the remaining studies. Discrepancies in self and informant agreement may also be influenced by factors such as conflict between the two over behaviour, communication problems or bias in partner choice (64). Excluded studies Study Achenbach et al 2005 Biederman et al 2007 (66) Young & Gudjonsson 2005 (67) Ferdinand et al 2004(68) Roberts et al 2005 (69)
R D
T F A
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Reason for exclusion Does not consider ADHD separately Compares maternal reports to maternal + adolescent reports Direct correlation of self- versus informant (parent)-report data was not presented with correlations restricted to analysis with neurophysiologic (reference) tests Not specific to ADHD Not specific to ADHD
Parent Reports - Bias

Research question 5: In preschoolers, children or adolescents with suspected ADHD does the psychiatric status of the parent influence parent reports in the diagnosis and assessment of ADHD. Selection Criteria Population Indicator Inclusion Criteria Individuals with ADHD assessed by parent report
Comparator Outcomes
Individuals with ADHD assessed by other methods
Impact of psychiatric status (depression, stress, ADHD etc) on parents reporting of ADHD symptoms
Study Design Search Period Language Date of Search Search terms
NHMRC I-IV for diagnostic studies 1997 - present considered English February 2008
Reference Diagnostic instruments
Baumann, et al 2004 (70) Design Diagnostic yield Level IV Setting
R D
Diagnostic tool Child behavior checklist (CBCL) Conners rating scale Disruptive behaviours rating scale
T F A
Results Ratings of internalizing and externalising symptoms by mothers of their own children correlated significantly with maternal depression (p < 0.01). NB: More specific behaviour measures were not correlated to maternal depression. There was no significant correlation between mothers depression and
Population/Study information Population: Mothers of 4-12 year old sons with ADHD diagnosed according to DSM-III-R. Study information: Design: Diagnostic yield Duration: Two experimental sessions held, each mother interacted with a child confederate with standardised behaviour (normal and deviant).
35
USA Industry funding National institute of mental health NB: Study designed to address the impact child behaviour on maternal distress and inclinations to drink alcohol Recruitment: Outpatient childrens clinic No. mothers n = 121 Never depressed n = 74 History of depression n = 44 confederate boys n = 10
ratings of the standardized child behaviour of the child confederate. There was no significant difference between ratings of their own children and confederate children for mothers never depressed and those with a history of depression.
Outcome Measures: Maternal ratings of own child Maternal ratings of confederate child van der Oord et al (2006) (48) Design Diagnostic yield Level IV Diagnostic tool Disruptive behavior disorder rating scale (DBDRS)
Population: Mothers of children with ADHD diagnosed using DSMIV
Study information: Design: Diagnostic yield Duration: Single rating
Setting Netherlands Industry funding No details reported
Chi et al 2002 (71) Design Diagnostic yield Level IV Setting USA
R D
Recruitment: Outpatient clinic Diagnostic tool CBCL Conners rating scale parent and teacher Teacher report form
No. 47 children diagnosed as ADHD combined type: n = 47 ADHD inattentive type: n = 16 ADHD hyperactive/impulsive type: n = 2 Outcome Measures: Maternal ratings of child Teacher ratings of child Parenting stress index CES-D to assess depressive symptoms
T F A
Parent and teacher agreement: Inattention: moderate (r = 0.38, p<0.01) Hyperactive/impulsive: none (r = -0.04, p<0.01) ODD: moderate (r = 0.32, p<0.01) CD: moderate (r = 0.33, p<0.01) Higher parenting stress, but not parent depressed mood was significantly related to parents reporting higher levels of the DBDRS inattention, hyperactivity/impulsivity and ODD behavior relative to teachers reports of this behavior (all p < 0.01). Maternal depression scores predicted mother teacher discrepancies in reports of ADHD symptoms (p<0.01), and general behaviour problems. NB: Mothers reported more externalising symptoms than teachers.
Population: Mothers of children aged 6-10 years with ADHD diagnosed based on DSM-IV 55.2 % Caucasian, 27% Afro American, 2.1% Latino, 15.5% other Study information: Design: Diagnostic yield Duration: Single measure Recruitment: Participants
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Industry funding No
recruited to a treatment trial from clinic and school referrals No. n = 96 Outcome Measures: Maternal ratings of child Teacher ratings of child Beck depression inventory Population: Mothers of children aged 6 years Study information: Design: Cross-classification Duration: single measure
Chilcoat et al 1997 (72) Design Diagnostic crossclassification Level III-2 Setting USA Industry funding No
Diagnostic tool CBCL Teachers report form
Recruitment: Birth cohort selected from 1983-1985 lists of newborn discharges from two hospitals. No. n = 801
Faraone, et al 2003 (73) Design Diagnostic yield Level IV Setting USA Industry funding None reported
Summary
Four studies were included that addressed the impact of maternal depression on maternal reports of child symptoms (48, 70-72). Two types of rating scales were used in these studies. The CBCL is a broadband rating scale that is designed to screen for a variety of symptoms, including ADHD symptoms, whereas the DBDRS is more specific to ADHD and considers symptoms of inattention, hyperactivity/impulsivity and CD/ODD behaviour. In the three studies that used the CBCL rating scale, mothers with a history of depression reported significantly more symptoms in the child when compared with mothers with no history of depression (70-72). In the two studies that used the DBDRS mothers having a history of depression was not significantly associated with maternal reports of symptoms (48, 70).
R D
Diagnostic tool DSMIIIR ADHD symptoms
Outcome Measures: Maternal ratings of child Teacher ratings of child Maternal history of psychiatric disorders (DSM-III) Population: Mothers of children aged 6-17 years with ADHD diagnosed according to DSM-II-r criteria Study information: Design: Diagnostic yield Duration: single measure Recruitment: community sample
No. No parental ADHD n = 231 Mother with ADHD n = 63 Father with ADHD n = 57
T F A
Rates of reporting of ADHD symptoms in the child across parent ADHD status only differed for 1 of 14 symptoms. Shifts activities was greater in the mother with ADHD group (p < 0.00) Results not influenced by child gender or ascertainment source (determined by comparison of ratings to no-ADHD siblings)
Mothers with a history of depression, anxiety or substance use disorders reported significantly more child internalizing and externalizing symptoms than mothers with no history of psychiatric disorders (all p < 0.0001).
Outcome Measures: Maternal reports of child ADHD
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One study considered the impact of maternal depression on maternal reports of child symptoms (48). High levels of parent stress was significantly related to parents reporting higher levels of the DBDRS inattention, hyperactivity/impulsivity and ODD behavior relative to teachers reports of this behavior. One study of children with ADHD found that parental ADHD did not impact upon on maternal reports of ADHD symptoms (73). Excluded studies Study Derks et al 2006 (74) Pfiffner et al 1999 (75) Stadelmann et al 2007 (76) Mick et al 2000 (77) Youngstrom et al 2000 (55)
Reason for exclusion Does not directly address question Does not directly address question Does not directly address question Does not directly address question (maternal depression outcomes) Not specific to ADHD
R D
T F A
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Neuropsychological assessment measures

Research question 6: In individuals suspected of having ADHD does the inclusion of neuropsychological assessment measures, in addition to DSM-IV/ICD10, further inform diagnosis? As studies of the diagnostic utility of neuropsychological assessment measures are available we can start from the position that these measures can discriminate between individuals with ADHD and individuals without ADHD. Selection Criteria Population Indicator Inclusion Criteria Individuals with ADHD
neuropsychological assessment measures [attention, memory, executive function, language and visual motor skills]
Comparator Outcomes
Individuals without ADHD
Diagnostic utility: predictive value and sensitivity & specificity Ability to differentiate between ADHD and other disorders Ability to differentiate between subtypes
Study Design
Date of Search
Search terms
MeSH: Attention deficit disorder with hyperactivity/ Neuropsycholical tests/ or Wechsler Scales/ or Intelligence tests/
R D
English February 2008
NHMRC I-IV for diagnostic studies 1997 - present considered
T F A
Text words: adhd or addh or adhs or hyperactive$ or hyperkin$ or (attention adj deficit) Continuous performance task or Continuous performance test or Wechsler IQ or Executive function or Measure$ of attention or neuropsychol$.ab.
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Individual neuropsychological measures

Reference Forbes 1998 (78) Design Diagnostic case-control Level III-3 Setting USA Industry funding No Revised Conners Teacher Rating Scale (RCTRS) ADD-H Comprehensive Teachers Rating Scale (ACTeRS) Diagnostic instruments Diagnostic tool Test of variables of attention (TOVA) Clinical assessment Population/Study information Population: Children aged between 6-12 years diagnosed as ADDHD (ADHD inattention and hyperactivity), ADD (ADHD inattention without hyperactivity) or other Study information: Design: case-control Results The ADDHD/ADD group differed significantly from the other group and displayed more omission errors (p < 0.001), slower response times (p < 0.01), greater variability (p < 0.001) and number of multiple responses (p < 0.01).
Recruitment: Clinical referrals for suspected ADHD.
No. n = 146 ADDHD/ADD group n=117 Other diagnoses group n = 29 ODD/CD n = 12 Learning disorders n = 10 Adjustment disorder or depression n = 7 Outcome Measures: Comparison of ADHD groups and other using the TOVA: Omission errors Commission errors Response time Variability Multiple response
Preston et al 2005 (79) Design Diagnostic case-control Level III-3 Setting USA Industry funding No
R D
Diagnostic tool Test of variables of attention (TOVA) ADHD diagnosis - structured clinical interview, the diagnostic interview schedule for children, fourth version (DISCIV) SNAP-IV parent, teacher
Population: Children aged between 6-14 years, either DSMIV diagnosis of ADHD or subclinical group Study information: Design: case-control
T F A
The TOVA classification criterion of any one variable, except commission errors, greater than 1.5 standard deviations from age and sex adjusted means correctly identified 80% of the ADDHD/ADD group and 72% of the OTHER group. The criterion of two or more variables, except commission errors, greater than 1 standard deviation from adjusted means correctly identified 67% of the ADDHD/ADD and 86% of the OTHER group. The RCTRS criteria correctly identified 83% of the ADDHD/ADD group and 78% of the OTHER group. The TOVA criterion correctly classified 11 of the 12 subjects incorrectly classified by the RCTRS. The ACTeRS criteria correctly identified 49% of the ADDHD/ADD group and 83% of the OTHER group. The TOVA criterion correctly classified 11 of the 15 subjects incorrectly classified by the ACTeRS. There were no significant differences between the ADHD group and the subclinical control group for any of the TOVA variables. The first criterion (1.5 SD in one variable) yielded a sensitivity of 37% and a specificity of 61%. The second criterion (1.0 SD in two variables) yielded a sensitivity of 30% and a specificity of 71%. Parent SNAP-IV cut-off scores demonstrated a higher sensitivity of 55% and comparable specificity of 66%. Teacher SNAP-IV cut-off scores demonstrated higher sensitivity than the second TOVA criteria (40% compared with 30%) and higher specificity than the first TOVA criteria (71% compared with 61%).
Recruitment: Clinical sample drawn from school population No. N= 167 ADHD = 116 Sub-clinical controls = 51 Outcome Measures: 1. TOVA 2. SNAP-IV
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Use of both the SNAP-IV and TOVA resulted in higher sensitivity but lower specificity than use of the SNAP-IV alone. Eg TOVA criteria 1 cut-off scores with parent SNAP-IV cut-off scores resulted in sensitivity of 82% and specificity of 30%. Schatz et al 2001 (80) Design Diagnostic case-control Level III-3 Setting USA Industry funding No Diagnostic tool TOVA Clinical DSM-IV diagnosis Conners Parent Rating Scale Population: Children and adolescents clinically diagnosed (using DSM-IV criteria) with ADHD mean age of 11.1 and controls (without ADHD) with mean age of 9.8 +/- 2.7 years Study information: Design: case-control There was a significant difference between the ADHD group and the control group on two of the three TOVA variables (Variability (p<0.01), Reaction Time (p<0.001) Omissions (not significant)).
Recruitment: Clinical referrals and community controls No. N = 48 ADHD n = 28, controls n = 20
Mayes & Calhoun 2002 (81)
Design Diagnostic case-control Level III-3 Setting USA Industry funding No
Mayes et al 2001 (82)
Design Diagnostic case-control Level III-3 Setting USA Industry funding
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Diagnostic tool Gordon Diagnostic system ADHD diagnosis DSM-IV criteria WISC-III Diagnostic tool Gordon diagnostic system (GDS) DSM-IV diagnosis (clinical interview)
Outcome Measures: 1. TOVA 2. Conners Parent Rating Scale Population: Children and adolescents aged 6 - 16 years with ADHD diagnosed by DSM-IV criteria and matched controls Study information: Design: case-control
Recruitment: Clinical referred population No. ADHD: n = 184 Non-ADHD: n = 46
T F A
The TOVA was found to have a sensitivity of 85.7% and specificity of 70%. False positive rate for TOVA was 30%. There was a significant difference between the ADHD group and the control group on the Conners Hyperactivity Index (p<0.001). The Conners was found to have a sensitivity of 78.6% and specificity of 100%. False positive rate 0%. IQ-GDS discrepancy score (13-point or greater discrepancy): Sensitivity: 75.5% Specificity: 47.8% Classification accuracy: 70% All GDS and IQ-GDS scores for children with and without ADHD differed significantly. IQ-GDS discrepancy score (13-point or greater discrepancy): Classification accuracy = 86% sensitivity = 90% specificity = 70%. PPV = 91% NPV 67% GDS composite score (standard score less than 90):
Outcome Measures: 1. Gordon Diagnostic system 2. WISC-III Population: Children with ADHD aged between 6-16 years. Diagnosed based on DSM-IV criteria as ADHD combined type or non-ADHD Study information: Design: case-control Recruitment: Consecutive clinical referrals for learning, attention, and / or behavior problems No. ADHD n= 165
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No
Non-ADHD n = 46 Outcome Measures: GDS standard scores IQ-GDS discrepancy scores
Classification accuracy = 79% PPV = 90% NPV = 52%
Rielly et al 1999 (83) Design Diagnostic case-control Level III-3 Setting Canada Industry funding No Quinn 2003 (84) Design Diagnostic case-control Level III-3 Setting USA Industry funding No
Diagnostic tool Gorgon diagnostic system (GDS) Disruptive Behavior Disorders (DBD) Rating Scale (parent and teacher)
Population: Boys aged 7- 9 years referred for a preschool history of language disorders Study information: Design: case-control
Recruitment: Consecutive clinical referrals No. n=99
Outcome Measures: 1. GDS 2. DBD Diagnostic tool Integrated visual and auditory continuous performance test (IVA CPT) ADHD behaviour checklist
Population: Adults with ADHD, healthy controls and a malingerer. The ADHD group were previously diagnosed based on DSM-IV criteria. Study information: Design: case-control
Oyler et al 1998 (85)
R D
ADHD n= 16 Malingerer n = 23 Control n = 19 Diagnostic tool Keiths auditory continuous performance test (ACPT) DSM-III/IV criteria
Recruitment: Clinical sample and normal controls
No. n = 60 Non-impaired n=44 (randomly assigned to control or malingerer groups)
T F A
GDS cutoff at 25th percentile: Sensitivity ranged from 3688% Specificity ranged from 18.968.9% PPV ranged from 25.5-36% NPV ranged from 71.9-87.9% There was a significant difference between ADHD and controls and malingerers on full scale attention quotient scores (p< 0.001). Significant differences were also found between the groups when auditory attention and visual attention were compared (p< 0.001). The CPTs impairment index results revealed: sensitivity 94%, specificity 91%, PPP 88%, NPP 95%. ADHD compared to no ADHD (CAPD included in both groups): Total Error Scores Specificity 83.3% Sensitivity 9.1% False positive 16.7% False negative 90.9% Vigilance Specificity 9.1% Sensitivity 91.7% False positive 8.3% False negative 90.9%
GDS cutoff at 5th percentile: Sensitivity ranged from 8-64% Specificity ranged from 31.189.2% PPV ranged from 20-36.8% NPV ranged from 71.9-77.6%
Outcome Measures: 1. IVA CPT sensitivity/specificity Population: Children aged 7-11 years. ADHD group had a paediatrician diagnosis of ADHD according to DSM-III/IV and or central auditory processing disorder (CAPD) Study information: Design: case-control Recruitment: Clinic referred ADHD sample and controls from researchers children and friends children
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No. n= 23 ADHD only n = 8 ADHD + CAPD n = 3 CAPD only n = 4 ADHD +/- CAPD n = 11 non ADHD n = 12 Outcome Measures: 1. ACPT sensitivity/specificity Population: Children aged between 6-11 years with DSM-IV diagnosis of ADHD +/- RD and control group without ADHD Study information: Design: Prospective cohort study Duration: 2 years Recruitment: Consecutive clinical referrals No. n=100
McGee et al 2000 (86) Design Diagnostic case-control Level III-3 Setting Canada, outpatient child mental health clinic Industry funding No
Diagnostic tool Conners, continuous performance test (CPT) Auditory continuous performance test (ACPT) Conners rating scale revised (parent and teacher versions)
Solanto et al 2004 (87) Design Diagnostic case-control Level III-3 Setting USA Industry funding No
Grodzinsky & Barkley 1999 (88) Design Diagnostic case-control Level III-3
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Diagnostic tool Conners Continuous Performance Test (CPT) Diagnosis Conners Adult Attention Deficit Disorder Rating Scale Brown AttentionDeficit Disorder Scale for Adults (Brown ADD Scale) Diagnostic tool Continuous Performance test (CPT) and other neuropsychologic al measures Diagnosis: DSMIIIR criteria, Child
Outcome Measures: 1. CPT 2. ACPT 3. phonological awareness 4. visual processing speed 5. visual motor performance Population: Adults diagnosed with ADHD or other psychiatric conditions based on DSM-IV criteria. Study information: Design: case-control
Recruitment: Adults presenting consecutively for evaluation to the outpatient Adult ADHD program No. ADHD n=70 other psychiatric group n=33
T F A
No significant correlation between Conners CPT index and the Conners parent or teacher rating scale. The overall index score of the Conners CPT correlated with total error score on ACPT, r(96)=0.34 (p<0.001). No significant difference between CPT scores for the ADHD group compared to control group. The RD group had higher CPT scores compared to control group (p = 0.007) Conners CPT did not distinguish between children with ADHD, Reading disorders, and controls. Phonological awareness scores were significantly lower for the RD group compared to the other groups (p < 0.05) Accuracy of classifying the ADHD group compared to the other psychiatric disorders group: CPT scores: Sensitivity: 47% Specificity: 86% Correct classification rate: 70% PPV: 70% NPV: 69% Brown scores: Sensitivity: 92% Specificity: 33% Correct classification rate: 74% PPV: 76% NPV: 67% Utility of individual tests (1.5 SDs above or below the mean): Sensitivity: 5-43% PPV ranged from: 50-100% NPV ranged from: 49-66% Classification rate: 49 to 70% NB: No combinations of measures tested.
Outcome Measures: 1. Brown ADD scale 2. CPT 3. CAARS Population: children aged 6-11 years with ADHD diagnosed based on DSM-IIIR criteria and matched control children without ADHD Study information: Design: case-control Recruitment: Clinical referrals and community
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Setting USA Industry funding No
Attention Profile (CAP)
recruited control group No. ADHD n = 66 community control group n = 64 Outcome Measures: 1. Continuous Performance Test 2. Controlled Oral Word Association Test (COWAT) 3. Hand Movements Scale 4. Porteus Mazes 5. Rey Osterrieth Complex Figure 6. Stroop Color-Word Association Test 7. Trail Making Test (A & B) 8. Wisconsin Card Sorting Test (WCST)
Inoue et al 1998 (89) Design Diagnostic case-control Level III-3 Setting Japan Industry funding No
Diagnostic tool CPT Actigraph MFFT Diagnosis DSM-IIIR criteria
Population: Boys aged 6-12 years previously diagnosed with ADHD according to DSM-III-R and non-ADHD controls. Study information: Design: case-control
Homack & Riccio 2004 (90) Design Systematic review of case-control studies Level III-3 Setting USA Industry funding None reported
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Diagnostic tool Stroop Color Word Test
Recruitment: Clinical referral because of maladaptation in the classroom due to restlessness. and community controls No. ADHD n = 20 boys control group n = 52 boys
Outcome Measures: 1. Actigraph 2. Continuous Performance test (CPT) 3. Matching familiar figures test.
Population: children and adolescents diagnosed with ADHD or other disorders and healthy controls
T F A
Sensitivity: Actigraph 65% CPT commission 85% CPT omission 85% MFFT 80% Specificity: Actigraph 76% CPT commission 86.5% CPT omission 84.6% MFFT 70.6% ADHD vs controls: (25 studies) The ADHD group had impaired performance on the Stroop tasks when compared to the control group. Mean weighted effect sizes Word = - 0.60 Colour = - 0.65 Word-colour = -0.52 Interference = -0.75 ADHD vs other clinical groups: (10 studies) The Stroop task did not discriminate ADHD groups from other clinical groups consistently across studies. The Stroop tasks may exhibit specificity in discriminating children with ADHD from other clinical groups
Study information: Design: Systematic review / metaanalysis of case-control studies No. ADHD n=11-65 controls n=12-43 other clinical groups n=10-43 Outcome Measures: 1. Stroop ColorWord Test
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(emotional disturbance, disruptive group, conduct disorder, psychiatric group). However, the Stroop did not exhibit specificity in discriminating children with ADHD from other clinical groups (learning disabled (LD), Autism, Tourette Syndrome). NB: Means of weighted effect sizes were not calculated due to the variability in clinical groups Romine et al 2004 (91) Design Systematic review of case-control studies Level III-3 Setting USA Industry funding None reported Diagnostic tool Wisconsin Card Sorting Test (WCST) Population: children and adolescents diagnosed with ADHD or other disorders and healthy controls Study information: Design: Systematic review of case-control studies No. not reported
Outcome Measures: 1. WCST
Dewey et al 2001(92)
Design Diagnostic case-control Level III-3 Setting Canada Industry funding No
R D
Diagnostic tool Test battery ADHD diagnosis DSM-IIIR
T F A
ADHD vs controls The ADHD group had impaired performance on the WISCT when compared to the control group (Percent Correct, Number of Categories, Total Errors, and Perseverative Errors.). Mean weighted effect sizes Percent Correct = 0.55 Total Errors = 0.58 Number of Categories = 0.51 Perseverative Errors = 0.52 Perseverative Responses = 0.46 Non-perseverative Errors = 0.24 Trials to category = 0.27 Failure to Maintain Set = 0.19 Total Correct = -0.18 ADHD vs other clinical groups The other clinical groups tended to perform more poorly than the ADHD groups eg learning disability. Impairment on the WCST is not specific to ADHD. NB: Means of effect sizes were not calculated due to the variability in clinical groups Academic (WISC-III), intellectual (WJR), and behavioral measures (CBCL) correctly classified 73.1% of participants. The WRAML correctly classified 58.5% of participants. Combining WRAML with the other measures correctly classified 77.5% of participants.
Population: Children who met DSM-IIIR criteria for ADHD, or had reading disorder +/- ADHD or normal controls Study information: Design: case-control Recruitment: Clinic population fixed ratio sampling No. ADHD n = 53 RD n= 63 ADHD + RD n= 63 Control group n= 112 Outcome Measures: 1. Wide Range Assessment of Memory and Learning
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2. 3. 4.
(WRAML) Wechsler Intelligence Scale for Children (WISC-III) Woodcock-Johnson PsychoEducational Battery (WJ-R) Achenback Child Behavior checklist (CBCL)
Neuropsychological measures used in testing batteries

Reference Youngwirth et al 2007 Design Diagnostic case-control Level III-3 Setting USA Industry funding No Diagnostic instruments Diagnostic tool NEPSY Conners Kiddie Continuous Performance Test Diagnostic criteria - Behavior Assessment Scale for ChildrenParent Rating Scale (BASCPRS), Disruptive Behavior Rating Scale-Parent Version (DBRS), NIMH-Diagnostic Interview Schedule for Children-IV (NIMH-DISC-IV) Population/Study information Results
Population: Preschoolers aged between 4 and 6 years. Children were assessed for ADHD and oppositional defiant (OD) symptoms according to DSM-IV criteria. Study information: Design: case-control NB: within a 4-year longitudinal study
Doyle et al 2000 (93)
R D
Diagnostic tool Test battery K-SADS-E
Recruitment: local pediatricians offices, child care centers, community centers, and birth record listings No. N=194 Hyperactive n=28 Hyperactive + OD n=29 OD n=14 Healthy controls n=123
Outcome Measures: 1. NEPSY: A Neuropsychological Assessment 2. Conners Kiddie Continuous Performance Test (K-CPT) Population: Children and adolescents aged 6-17 years who met DSM-IIIR criteria for ADHD and normal controls Study information: Design: case-control NB: within a 4 year longitudinal study
T F A
NEPSY: Significant difference between the Hyperactive + OD group and controls on 4/9 subscales. No significant differences between the hyperactive or OD group and the controls. K-CPT: Significant difference between the Hyperactive + OD group and controls on 5/13 subscales and between the hyperactive group and the control group on 2/13 subscales. No significant difference between OD group and controls. Individual scales Sensitivity: 0.20-0.93 Specificity: 0.36-0.94 PPV: 0.3-0.47 NPV: 0.8-0.94 NEPSY + KCPT Sensitivity: 0.68 Specificity: 0.75 PPV: 0.37 NPV: 0.92 Total predictive power: 0.74 Single neuropsychological tests had low sensitivity and limited discriminating ability. Combining multiple test results improved the ability to predict ADHD status but only modestly improved diagnostic efficiency as normal scores could not be used to rule out the diagnosis. Example: 4 abnormal tests, 1SD below the mean of controls Sensitivity: 42% Specificity: 88% PPP: 81%
Recruitment: Clinic referred subjects (including controls) No. ADHD n=113 Controls n=103
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Outcome Measures: 1. FSIQ from the Vocabulary and Block Design subtests of the Wechsler Intelligence Scale for Children--Revised Wechsler Adult Intelligence Scale--Revised 2. Rey-Osterrieth Complex 3. Wide Range Assessment of Memory and Learning 4. California Verbal Learning Test 5. The computerized Wisconsin Card Sorting Test 6. Stroop Color-Word 7. Scattered Letter Version of the Visual Cancellations Test 8. Auditory continuous performance test Berlin et al 2004 (94) Design Diagnostic case-control Level III-3 Setting Sweden Industry funding No Diagnostic tool Barkleys model of inhibition and executive functioning Clinical DSM-IV diagnosis (Conners Rating Scale parent and teacher)
NPP: 56% Total predictive value: 63%
Population: Boys aged 7-10 years. ADHD group had been diagnosed with ADHD according to the diagnostic criteria in DSM-IV. Matched control group without ADHD. Study information: Design: case-control
R D
No. n= 63 boys ADHD n= 21 Control n= 42 Diagnostic tool Test battery Diagnostic Interview for Children and Adolescents; DICAIV-P,
Recruitment: Clinical referrals and community recruited controls
Pineda et al 2007 (95) Design Diagnostic case-control Level III-3
Outcome Measures: 1. Difference between groups: * Errors of inhibition (go/no-go task, Stroop-like task) * Nonverbal working memory (time reproduction, hand movement task) * Internalization of speech * Regulation of affect/motivation arousal * Reconstitution of story (poor regulation of negative emotions and commission errors on CPT) * Intelligence (block design) 2. Sensitivity and specificity Population: Children aged 6 to 11 years old. Children in the ADHD group were previously diagnosed by a neurologist or psychiatrist based on DSM-IV Study information: Design: case-control
T F A
Significant difference between ADHD and controls for 7/9 variables (p<0.05). Block design and hand movement task were not significantly different. 3 models tested for diagnostic utility 1. The 7 significant variables Sensitivity: 81% Specificity: 88.1% Correct classification: 86% 2. 3 variables (time reproduction, inhibitory errors & regulation of negative emotions) Sensitivity: 76.1% Specificity: 90.5% Correct classification: 86% 3. 2 variables (time reproduction & inhibitory errors) Sensitivity: 81% Specificity: 78.6% Correct classification: 78.6% Statistically significant differences were found between ADHD and controls on cognitive effort, auditory skills, continuous performance test, working memory, visual-motor skills, verbal comprehension, and executive function measures (P < 0.05). Effect sizes: 0.24-0.54
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Spanish version Setting Columbia, USA Industry funding No Recruitment: Random selection from school population No. n = 621 ADHD n = 249 control n = 372 Outcome Measures: 1. The Mental Control domain of the Wechsler 2. Memory Scale 3. Target Detection Cancellation Test 4. Visual-Verbal Learning Curve 5. Complex Figure Test 6. Language Comprehension and Working Memory 7. Language Fluency 8. Wisconsin Card Sorting Test-Abbreviated Version (WCST-A) Population: Boys previously diagnosed with ADHD and healthy controls Study information: Design: case-control Sensitivity of individual scales: 49-69.5% Specificity of individual scales: 28-69% A combined 6 factor model accurately classified 61.9% of the sample. Sensitivity: 48% Specificity: 72% NPV: 65.6% PPV: 55.5%
Perugini et al 2000 (96) Design Diagnostic case-control Level III-3 Setting USA Industry funding No
Diagnostic tool Test battery Diagnosis based on: PPVT-R, DISC-IV, BASCPRS Hyperactivity Subscale
Katz et al 1998 (97)
Design Diagnostic case-control Level III-3 Setting USA Industry funding
R D
Diagnostic tool Test battery Diagnosis DSM-IIIR criteria and Utah criteria for ADHD No. ADHD: n = 58
Recruitment: Clinic and community No. ADHD n= 21 control group n=22
Outcome Measures: 1. Kaufman Hand Movements Scale 2. Stroop 3. The Controlled Oral Word Association Test (COWAT, or F-A-S) 4. Trail Making Test (A and B) 5. Arithmetic WISC-III 6. Digit Span -WISC-III 7. Conners Continuous Performance Test (CPT). Population: adult clinical patients who met criteria for ADHD, major depression, dysthymia, or a combination of ADHD and depression or dysthymia. Study information: Design: case-control Recruitment: Clinical sample self-referred
T F A
Significant difference between ADHD and controls for 2/7 measures: digit span (p<0.05) and CPT overall index (p < 0.01). Sensitivity for individual/combinations of tests ranged from: 0.05-0.76 Specificity for individual/combinations of tests ranged from: 0.45-1.0 PPV for individual/combinations of tests ranged from: 0.57-1.0 NPV for individual/combinations of tests ranged from: 0.52-0.72 12 individual test variables were selected to combine based on their ability to detect a significant difference between the ADHD group and the depression group. Discriminative accuracy of the combined variables was 82%. 96% of the ADHD group were correctly classified. Only 60% of the depression group were correctly classified.
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No
Depression: n = 20 Outcome Measures: 1. California verbal learning test 2. Paced auditory serial addition test 3. stroop test 4. speech perception 5. seashore rhythm 6. finger tip number writing 7. trail making 8. tactual performance tests from Halstead-Reitan battery 9. Wechsler Adult Intelligence Scale revised (WAIS-R), 10. Wechsler Memory Scale revised (WMS-R) 11. Conners CPT. Population: Adults aged 17 50 years. ADHD and other psychiatric condition diagnosed by DSM-IV criteria and healthy controls. Study information: Design: case-control
Walker et al 2000 (98) Design Diagnostic case-control Level III-3 Setting Australia Industry funding No
Diagnostic tool Test battery
R D
Recruitment: Referrals to an outpatient clinic for the assessment of ADHD in adults and community recruited controls No. n = 90 ADHD n=30 Other psychiatric condition n= 30 Controls n=30 Outcome Measures: 1. CPT 2. WAIS-R 3. COWAT 4. TMTA 5. Stroop
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ADHD vs healthy controls Significant difference between the ADHD group and the healthy control group on 11 /18 neuropsychological variables (p < 0.003). A model with four variables was tested for diagnostic utility. The variables were; number of commission errors, reaction time variability, colour-word score on the Stroop, and Digit Symbol score. Sensitivity: 93% Specificity: 90% ADHD vs other psychiatric conditions
Comparison of the ADHD group to the psychiatric condition group found no significant difference on any variable.
A model with three variables was tested for diagnostic utility. The variables were; response speed change with interstimulus interval, and psychomotor speed on Digit Symbol. Sensitivity: 63% Specificity: 80% Prediction of ADHD and psychiatric group membership, on the basis of rating scales of depression, anxiety and ADHD symptoms and neuropsychological variables. Sensitivity: 81%% Specificity: 85%
Summary
Individual neuropsychological measures: Fifteen studies were identified that addressed the use of individual neuropsychological measures for the diagnosis of ADHD compared to clinical diagnosis or rating scales (78-92). The resultant positive and negative predictive values and sensitivities and specificities were mixed (low, moderate and good).
49
Within this set of studies, two systematic reviews were identified that looked at the ability of neuropsychological measures to discriminate between individuals with ADHD and other clinical groups (90, 91). Romnie et al (91) addressed the use of the Wisconsin Card Sorting Test and found that compared to controls the ADHD groups consistently performed poorly on the WCST. However impairment on the WCST was not specific to ADHD as other clinical groups such as those with learning disability were also impaired. Homack et al (90) addressed the use of the Stroop colour word test and found that this measure could discriminate between individuals with ADHD and controls but did not consistently discriminate between individuals with ADHD and other clinical groups. Testing-Batteries: Seven studies were identified that looked at combining multiple neuropsychological measures in a testing battery for the diagnosis of ADHD in preschoolers (99), children, (93-96) adolescents (93) and adults (97, 98). All studies looked at different combinations of measures and the resultant sensitivities and specificities were low to moderate. Of particular note, in the two studies of adults (97, 98) the neuropsychological tests were examined in individuals with ADHD and in individuals with other psychiatric disorders. In both studies the ability of the tests to distinguish between the two groups was poor. The majority of studies took advantage of clinic referred samples, however, one study (95) took a random sample of participants from a general school population. In Pineda et als (95) large and methodologically robust study the neuropsychological tests could distinguish between ADHD and controls without ADHD at the group level, but at the individual level needed for diagnosis specificity and sensitivity were low - moderate (48% and 72% respectively).
Overall, the use of individual neuropsychological measures can discriminate between ADHD and no-ADHD at the group level but do not perform well for the classification of individuals. The combination of neuropsychological measures appears to moderately increase the diagnostic utility of these tests, but not to a reliable level. Importantly, both individual and combined measures appear to be very poor at distinguishing between individuals with ADHD and individuals with other psychiatric disorders. Excluded studies Study TOVA Wu et al 2007 (100) Chae et al 2002 (101) Gordons Carlozzi and Horner 2007 (102) Connors CPT Levy and Hobbes 1997 (103) Epstein et al 2003 (104) Egeland 2007 (105) Advokat et al 2007 (106) Auditory CPT Mahone et al 2005 (107) Test batteries Dige and Wik. 2005 (108) Biederman et al 2006 (109)
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Reason for exclusion
Not testing for use as a diagnosis tool Not testing for use as a diagnosis tool
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Not testing for use as a diagnosis tool
Not testing for use as a diagnosis tool
Not testing for use as a diagnosis tool Not testing for use as a diagnosis tool Not testing for use as a diagnosis tool Not testing for use as a diagnosis tool Not testing for use as a diagnosis tool Not testing for use as a diagnosis tool
Neurophysiological measures
Research question 7: In individuals suspected of having ADHD does the inclusion of neurophysiological techniques, in addition to DSM-IV/ICD10, further inform diagnosis? As studies of the diagnostic utility of EEG and ERP are available we can start from the position that neurophysiological techniques can discriminate between individuals with ADHD and individuals without ADHD.
Selection Criteria Population Indicator Comparator Outcomes
Inclusion Criteria Individuals with ADHD
neurophysiological testing (EEG/QEEG and ERP Individuals without ADHD
Diagnostic utility: predictive value and sensitivity & specificity Ability to differentiate between ADHD and other disorders
Study Design Search Period Language
Date of Search
Search terms
MeSH: Attention deficit disorder with hyperactivity/ Electroencephalography/ or evoked potentials/
Reference Smith et al 2006 (110)
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February 2008
Diagnostic instruments Diagnostic tool ERP Comparison DSM-IV criteria (Conners Parent and Teacher Rating Scales (CPRS-48 and CTRS-48), the
T F A
Text words: adhd or addh or adhs or hyperactive$ or hyperkin$ or (attention adj deficit) electrophysiologic techniques or quantitative electroencephalography or QEEG or EEG or ERP or event related potentials
Results Children aged 8-12 years: Diagnostic accuracy = 73.3% Sensitivity = 71.4% Specificity = 76.9% Children aged 13-18 years: Diagnostic accuracy = 58.7% Sensitivity = 56.9% Specificity = 62.5%
ERP Diagnostic Utility
Design Diagnostic case-control Level III-3 Setting
Population: Children and adolescents aged 8- 18 years with ADHD combined type, ADHD inattentive type and healthy controls. Diagnosis was made based on DSM-IV criteria. Study information: Design: Case-control
51
Australia Industry funding Not reported
Child Behaviour Check List (CBCL), and a developmental interview of parent(s))
Recruitment: Clinical subjects were referred to a private ADHD clinic. Control subjects were recruited from the local community. No. healthy control subjects n = 50 ADHD combined types n = 50 ADHD inattentive type n = 50 Outcome Measures: 1. Sensitivity/specificity ERP
ERP Impact of comorbid conditions

Reference Banaschews ki et al 2003 (111) Design Diagnostic case-control Level III-3 Diagnostic instruments Diagnostic tool ERP during a cued continuous performance test (CPT-A-X) Population/Study information
Setting Germany/Swi tzerland Industry funding No
Rothenberge r et al 2000 (112) Design Diagnostic case-control Level III-3 Setting
R D
Diagnostic tool ERP in an auditory selectiveattention task
Population: children aged 8 - 14 years with a verified ICD-10 diagnosis of hyperkinetic disorder, hyperkinetic conduct disorder, oppositional defiant/conduct disorder (ODD/CD), or no ICD-10 diagnosis except reading and/or spelling disorders. Participants were also diagnosed according to DSM-IV categories. Study information: Design: Case-control
Recruitment: Sequential clinical referrals
No. control group n = 18 Hyperkinetic disorder group n = 15 hyperkinetic conduct disorder group n= 16 oppositional defiant/ conduct disorder n = 15 Outcome Measures: 1. Performance measures (differences between groups) 2. Brain mapping measures Population: Boys (mean age 1112 years) who met the DSM-III-R criteria for ADHD-only, ADHD + CD, or ADHD + Tic and healthy controls Study information: Design: Case-control Duration: NR Recruitment: Poorly reported.
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Results Children with HD (but not comorbid children) showed slower and more variable reaction times compared to control children (p <0.024). The ADHD + CD group had a significantly smaller MMN (p = 0.01) compared to the control group.
Children with HD and ODD/CD-only but not comorbid children displayed reduced P3a amplitudes. The comorbid group of ADHD+ODD/ CD did not show additive and independent effects of ADHD and ODD/CD.
Significant group difference of MMN mean amplitude towards less negative values for all ADHD groups as compared to the control group (p < 0.05).
The ADHD-only and ADHD + Tic tended to show smaller MMN amplitudes but this
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Germany Industry funding No No. controls n = 11 ADHD only n = 11 ADHD+tic n = 11 ADHD+CD n = 9 Outcome Measures: 1. mean values (SD) ERP potentials for each group including Mismatch negativity (MMN), P3b and negative difference wave (Nd) Yordanova et al 2006 (113) Design Diagnostic case-control Level III-3 Diagnostic tool ERP Population: Boys who met the DSM III-R criteria for Tic disorders (TD)-only, ADHD-only, and combined TD+ADHD Study information: Design: Case-control Recruitment: Poorly reported. Clinical groups were primarily outpatients. No. Control: n= 14 TD n= 14 ADHD n= 14 ADHD+TD n = 11
was not significant (p = 0.13 and p = 0.57, respectively). Direct comparison of the ADHD + CD group with the ADHD only group or the ADHD+Tic group did not identify any significant differences. The groups did not differ in Nd amplitude or P3b.
Setting Germany/ Bulgaria Industry funding No
Reference
Monastra et al 1999 (114) Design Diagnostic case-control Level III-3 Setting USA Industry funding No
R D
Diagnostic instruments Diagnostic tool EEG- derived attentional index (theta-beta power ratios) Comparison Combined information from: clinical interview, behaviour rating scales and continusous performance tests. No. n=482 Females n = 207 Males n = 275
Outcome Measures: 1. ANOVA with two betweensubjects factors: TD and ADHD; and within-subjects task variables: Attended channel (attended vs nonattended) and Stimulus task relevance.
EEG Diagnostic utility
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Late the response was increased in the ADHD groups compared to the nonADHD groups (p < 0.05). No effects of TD were found. Combined TD+ADHD has a unique profile. Results Children aged 6-11 had higher QEEG when compared to other age groups (p < 0.001).
Spontaneous theta activity (4- 5Hz EEG) activity was larger in the ADHD groups compared to the no-ADHD groups: Significant interactions ADHD x region (p < 0.005) and ADHD x laterality (p < 0.01). No effects of TD were found. Early theta response was increased in the ADHD plus TD group only. TD X ADHD interaction (p < 0.01).
Population: Individuals aged 6-30 years, who were classified into clinical and non-clinical groups on the basis of Barkleys ADHD Clinical Parent Interview Study information: Design: case-control Recruitment: Recruited from schools, physicians and mental health professionals and advertising in newspaper
Significant difference in QEEG profile between both ADHD groups and controls (p<0.001). No significant difference between the ADHD groups.
Comparison of QEEG to clinical diagnosis Sensitivity 86% Specificity 98% PPV 99%
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Monastra et al 2001 (115) Design Study 1 : Diagnostic case-control Study 2: Cohort Study 3: Cohort Level III-3 Setting USA Industry funding No
Diagnostic tool EEG derived attentional index (theta/beta power ratios) Comparison Clinical interview and Attention Deficit Disorders Evaluation Scale (ADDES) TOVA Conners CPT
Outcome Measures: 1. Sensitivity, specificity, PPV of QEEG Population: children and adolescents aged 6-20 years with ADHD or healthy controls Study information: Design: case control/cohort study Recruitment: Clinical referrals and community controls No. Study 1 Cross-Validation ADHD-I n = 37 ADHD-H/C n = 59 Control n = 33
Study 1: Significant difference in QEEG profile between both ADHD groups and controls (p<0.001). No significant difference between the ADHD groups. Sensitivity 90% Specificity 94% PPV 98% NPV 76%
Study 2 Criterion-Related Validation Previous ADHD diagnosis n = 265 Study 3 Test Reliability Suspected ADHD n = 55 ADHD-I n = 20 ADHD-H/C n = 35
Coolidge et al 2007 (116) Design Crosssectional
Level III-2 Setting USA Industry funding No
R D
Diagnostic tool EEG derived attentional index (theta/beta power ratios) Reference test Coolidge Personality and Neuropsychology Inventory (CPNI) parent rated Includes an 18Recruitment: No. N=183
item DSM-IV-based ADHD scale
Outcome Measures: Study 1: Group differences Study 2: sensitivity, false negatives Study 3: Test-retest reliability
Population: children aged 6-18 years suspected by parents of having ADHD Study information: Design: cross-sectional
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Study 2: Agreement between QEEG results and other tests: ADDES: 83% agreement (p<0.001) TOVA: 70% agreement (p<0.01) Conners CPT: 48% (p<0.48) Agreement between tests and physician diagnosis: Sensitivity: QEEG: 80% ADDES: 78% TOVA: 72% Conners CPT: 49% False negative error rate: QEEG: 20% ADDES: 22% TOVA: 28% Conners CPT: 51% A Pearson product-moment correlation between the CPNI ADHD scale QEEG theta -beta power ratio indicated no relationship. r = 0.00, (P = 0.97) QEEG: Sensitivity = 50% Specificity = 36% Accuracy = 45% Psychiatric evaluation: ADHD diagnosis n = 16 no-ADHD diagnosis n = 10 Sensitivity: Rating scale: 81%, EEG: 94%
Study 3: Test-retest reliability coefficient: R=0.96 (p < 0.05) No significant difference between mean theta-beta power ratios for the ADHD group compared to the non-ADHD group (p = 0.25)
outpatient private clinic for behavioral and/or emotional problems
Quintana et al 2007 (117) Design Crosssectional
Diagnostic tool EEG theta-beta ratio Comparison Standard
Outcome Measures: 1. Between group differences 2. Correlation between tests 3. Sensitivity, specificity, accuracy of QEEG Population: Children and adolescents aged 6-21 years suspected of having ADHD. Study information: Design: cross sectional cohort
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Level III-1 Setting USA Industry funding No
Psychiatric Evaluation ADHD Rating ScaleIV
study Recruitment: Clinical referrals who presented with ADHD-like symptoms. No. n = 26 (23 males, 3 females) Outcome Measures: Sensitivity, specificity, classification accuracy, PPV for ratings scale and EEG Population: Children aged 7-12 years with ADHD diagnosed according to DSM-IV criteria and healthy controls. Study information: Design: Case-control Specificity: Rating scale: 22%, EEG: 100% Classification Accuracy: Rating scale: 60%, EEG: 96% Positive predictive power: Rating scale: 65%, EEG: not reported
Kovatchev et al 2001 (118) Design Diagnostic case-control Level III-3 Setting USA Industry funding No
Diagnostic tool EEG: Consistency Index (CI) Comparison Clinical diagnosis based on DSM-IV Rating scales ADHD Symptom Inventory Achenbachs Child Behavior Checklis Conners parent rating
Recruitment: Through newspaper and television advertisement No. Current study: ADHD group n= 17 (9 males and 8 females) Control group n= 18 (9 males and 9 females) Combined studies ADHD group n= 33 Control group n= 34
Magee et al 2005 (119) Design Crosssectional Level III-2 Setting
R D
Diagnostic tool EEG power in eyes closed conditions Comparison Clinical diagnosis based on DSM-IV
Previous data sets. 1. 6-10 year old males ADHD n =4, no-ADHD n = 4 2. 18-25 year old males ADHD n =6, no-ADHD n = 6 3. female college students (age not specified) ADHD n =6, no-ADHD n = 6 Outcome Measures: EEG: Power EEG: Consistency Index (CI)
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EEG power: ADHD versus controls Only one significant difference in all power bands and beta/theta power ratios; increased absolute theta (p = 0.04). Females: the CI in ADHD was 2 times lower than in controls, (p < .005) Males had a higher CI than females (p < 0.05). Participants under had non-significant higher CI (p = 0.06). A logistic regression model classified correctly 82% of all ADHD subjects and 77% of all control subjects. Classification accuracy = 80% (p <0.0001). Cluster analysis identified 3 ADHD groups with distinct EEG profiles; 1. 10 variables; 47.8% of ADHD sample 2. 6 variables; 36% of ADHD sample
CI: ADHD versus controls Males: the CI in ADHD was 4 times lower than in controls, (p < .005)
ADHD/control classification based on the CI matched the DSM-IV criteria for 88% of males and for 67% of females.
Meta-analysis of all data sets Average CI of the ADHD group was 29% versus 50% for the control group (p<0.0001).
Males had stronger CI differences between ADHD and controls (p < 0.05)
Sensitivity, specificity, overall classification accuracy Population: Boys aged 7-13 years with suspected ADHD. Study information: Design: cross-sectional Recruitment: Clinically referred children with suspected ADHD and community recruited controls
Analysis of young males only; Classification accuracy = 90% ADHD vs controls (using 12 variables): Correctly predicted group membership for 94.5% of ADHD group Correctly predicted group membership for 40.3% of controls Overall classification accuracy of 83.1%
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Australia Industry funding No
No. AD/HD combined type n=253 Control group n=67 Outcome Measures: 1. Sensitivity, specificity, overall classification accuracy
3. 4 variables; 16.2 % of ADHD sample Collective use of three regression equations based on the 3 distinct clusters gave an overall sensitivity of 89.0% and a specificity of 79.6%, with an overall classification accuracy of 87.0%.
EEG Impact of comorbid conditions

Reference Clarke et al 2002 (120) Design Diagnostic case-control Level III-3 Setting Australia Industry funding No Diagnostic instruments Diagnostic tool EEG Population/Study information
Population: Children aged 8 - 12 years with ADHD and comorbid RD (ADHD + RD), ADHD only, and healthy controls. Diagnosis by DSM-IV criteria. Study information: Design: Case-control
Recruitment: Clinical referrals and controls from schools and community
Clark, et al 2002 (121)
Design Diagnostic case-control Level III-3 Setting Australia Industry funding
R D
Diagnostic tool EEG
No. ADHD+ comorbid RD n = 20 ADHD n= 20 control group n = 20
NB: 18 males and 2 females in each group.
Outcome Measures: 1. EEG profile: Absolute and relative power estimates for the delta, theta, alpha and beta bands. Theta/alpha and theta/beta ratios
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Results ADHD versus ADHD plus RD: The EEG of the ADHD plus RD group had more relative theta (p < 0.01), less relative alpha (p < 0.05) and greater theta/alpha (p < 0.05) ADHD group. Significant regional differences included greater posterior relative delta (p < 0.05) and higher theta/alpha in the frontal regions (p < 0.05).
There was a significant difference in EEG profile between the ADHD groups and the control group.
ADHD versus control: There was a significant difference in EEG profile between the two ADHD groups and the control group. The EEG of the two ADHD groups had more absolute (p < 0.05) and relative theta (p < 0.001) than the control group, less relative alpha (p < 0.001) and beta (p <0.05), and greater theta/alpha (p < 0.001) and greater theta/beta (p <0.001) ratios than the control group. Significant regional differences were also apparent.
Population: Boys aged 8 -12 with ADHD (combined type) with or without comorbid ODD, diagnosed according to DSM-IV and matched healthy controls. Study information: Design: Case-control Recruitment: Clinical referrals and controls from schools and community No. ADHD combined type n = 20
EEG components of RD were distinct from the EEG profile of ADHD. ADHD versus control: There was a significant difference in EEG profile between the ADHD groups and the control group. The EEG of the two ADHD groups had more absolute (p < 0.05) and relative theta (p < 0.001) than the control group, less relative alpha (p < 0.001) and beta (p <0.05), and greater theta/alpha (p < 0.001) and theta/beta (p <0.001) ratios than the control group. Significant regional differences were also
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No
ADHD combined type+ comorbid ODD n = 20 controls n = 20 Outcome Measures: 1. EEG profile: Absolute and relative power estimates for the delta, theta, alpha and beta bands. Theta/alpha and theta/beta ratios
apparent. ADHD versus ADHD plus ODD: There was no significant main effect difference in the EEG profile of absolute delta, alpha or beta between the ADHD and ADHD plus ODD groups. Significant regional differences were found between the ADHD and ADHD plus ODD groups. The EEG of the ADHD group contained greater absolute theta than the EEG of the ADHD plus ODD group in the left hemisphere (p < 0.05), and less power in the right hemisphere (p < 0.05). EEG components of ODD are not distinct from the EEG profile of ADHD.
Summary
ERP: One study was identified that looked at the utility of ERP data in the diagnosis and assessment of children and adolescents for ADHD (110). Smith et al (110) used ERP data to classify children and adolescents relative to a clinical diagnosis of ADHD. Sensitivity of 71.4% and specificity of 76.9% was found for children aged 8-12 years but the values for adolescents aged 13-18 years were considerably lower (Sensitivity: 56.9%, Specificity: 62.5%). This study was conducted in Australia. Three studies were identified that show that the presence of comorbidities (Tics, ODD and CD) can impact on ERP data in children with ADHD (111-113).
EEG: Six studies were identified that had investigated the utility of EEG measures in the diagnosis and assessment of children, adolescents and adults for ADHD (114-119). The actual EEG measures utilised varied between the studies as did the components of the clinical diagnosis used as the reference test for comparison.
Four studies used theta-beta ratio as the EEG measure. Monastra et al (114) described a QEEGderived attentional index that was based on mean theta-beta power ratio across 4 tasks (eyes open resting, reading, listening and drawing). When tested against clinical interview and various behaviour scales and continuous performance tasks in participants aged 6-30 years of age a sensitivity of 86%, and a specificity of 98% was found. Monastra et al (115) repeated this study in participants aged 6-20 years and reported a sensitivity of 90% and a specificity of 94%. Coolidge et al (116) compared EEG theta-beta ratio against an 18-item DSM-IV-based ADHD scale that is part of the parent rated Coolidge Personality and Neuropsychology Inventory. Sensitivity of 50% and specificity of 36% was reported. Quintana et al 2007 (117) compared the theta-beta ratio to clinical diagnosis in 6-21 year olds referred to a clinic for their ADHD symptoms. Of 26 participants 16 were clinically diagnosed with ADHD and 10 with no ADHD. The sensitivity of the EEG measure was 94% and the sensitivity 100%. The accuracy of the ADHD Rating ScaleIV was included as a comparator in this study and a sensitivity of 81% and specificity of 22% was reported. Kovatchev et al 2001 (118) combined a specific set of EEG measures to derive what they termed a consistency Index (CI). When compared to clinical diagnosis they found the CI measure could correctly classify 82% of all ADHD subjects and 77% of all control subjects. Participants ranged
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T F A
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in age from 6-25 years and when looking only at participants aged less than 16 years overall accuracy increased from 80 to 90% (118). Magee et al (119) utilised total, absolute and relative power EEG measures in eyes closed conditions to assess boys aged 7-12 years against clinical diagnosis and established a sensitivity of 89.0% and a specificity of 79.6%. Two studies were identified that address the impact of comorbid conditions on EEG profile in children and adolescents with ADHD (120, 121). Clarke et al (120) found that the EEG components of reading disability were distinct from the EEG profile of ADHD. Clark, et al (121) found that EEG components of ODD were not distinct from the EEG profile of ADHD. Both studies were conducted in Australia. Excluded studies Study Baving et al 2006 (122) Yordanova et al 1997 (123) Aydn et al 2003 (124) Kemner et al 1998 (125) Du et al 2006 (126)
Reason for exclusion Exclude as children had ODD and NOT ADHD Not diagnosis
Not specific data for ADHD No control group ADHD and comorbid CD only
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T F A
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Neuroimaging
Research question 8: In individuals suspected of having ADHD does the inclusion of neuroimaging techniques, in addition to DSM-IV/ICD10, further inform diagnosis? Sub-question: Can brain imaging techniques discriminate between individuals with ADHD and individuals without ADHD? Selection Criteria Population Indicator Comparator Outcomes Inclusion Criteria Individuals with ADHD
Brain imaging techniques (MRI, fMRI, SPECT, PET etc) Individuals without ADHD
Ability to differentiate between individuals with ADHD and those without ADHD.
Search terms
MeSH: Attention deficit disorder with hyperactivity/ Diagnostic Imaging/ or magnetic resonance imaging/ or Positron-Emission Tomography/ or Tomography, EmissionComputed, Single-Photon/ or Magnetic Resonance Spectroscopy/
Reference
Valera et al 2007 (127)
Design Meta-analysis of case control studies Level III-3
R D
February 2008
Diagnostic instruments Diagnostic tool MRI
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Text words: adhd or addh or adhs or hyperactive$ or hyperkin$ or (attention adj deficit) Neuroimaging or fMRI or SPECT or structural imaging
Results Meta-analysis including all brain regions measured across all studies indicated global reductions for the ADHD subjects compared with control subjects, SMD = 0 .408, Z = 17.21, p < 0.001, 95% confidence interval (0.361 0.454). There was significant heterogeneity across regions and studies, 2 = 437.09, p < .001. Analysis of individual regions found 9
Population: Children and adolescents with ADHD. For ADHD diagnoses, 9 samples used DSM-IV criteria, 12 samples used DSM-III-R criteria, and 1 sample used both DSM-IV and DSM-III-R criteria. The mean age and age range were 11.0 (9.08 14.6) for ADHD and 11.3 (9.314.8) for control subjects.
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Study information: Design: Meta-analysis No. Total n (ADHD) = 565 Total n (controls) = 583 Outcome Measures: 1. Areas of brain activity showing significant difference between ADHD and controls
areas that showed significant differences between the ADHD group and the control group in at least 3 studies. The regions with the greatest significant reductions relative to control subjects were the cerebellum, the splenium of the corpus callosum, total and right cerebral volume, the right caudate, and various frontal regions. 25 regions were identified that showed no significant difference between the ADHD group and the control group in at least 3 studies.
Dickstein et al 2006 (128) Design Meta-analysis of casecontrol studies Level III-3 Setting USA Industry funding No
Diagnostic tool fMRI/PET Reference test None
Population: Children, adolescents and adults with and without ADHD Study information: Design: Meta-analysis of 16 fMRI and PET studies No. Total n (ADHD) = 184 Total n (controls) = 197
Summary
Two meta-analyses were identified that addressed neuroimaging. Valera et al (127) conducted a meta-analysis of 22 magnetic resonance imaging (MRI) studies conducted in children and young adolescents (mean age across studies was 11 years) with and without ADHD. The inclusion of all brain regions measured across all studies found a significant difference between the participants with ADHD and the healthy controls. The heterogeneity across the regions assessed and the measures used was significant. The researchers also looked at individual brain areas and identified several regions that were significantly different between the ADHD and control groups in at least 3 or in at least 2 studies. As the authors note that one of the key limitations of the work to date using MRI are that the studies have been conducted in a very distinct population group. The included studies were undertaken in children and young adolescents with no participants
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R D
Outcome Measures: 1. Areas of brain activation showing significant difference between ADHD and controls
T F A
Areas with significant differences seen in at least 2 studies were the pre-frontal and frontal lobes and deep frontal white matter. Separate meta-analyses were conducted on the foci reported by controls and the foci reported by individuals with ADHD. A comparison between the two was then made.
Controls > ADHD
There was a significantly greater probability of activation in a variety of regions for the control group relative to the ADHD group. This included; bilateral areas of frontal lobe, areas of parietal lobe, and parts of striatum.
ADHD>controls A small number of regions had a greater probability of activation in the ADHD group relative to the control group. These areas included the left frontal lobe, insular cortex, portions of middle frontal gyrus and in the left thalamus and the right paracentral lobule.
older than 15 years. To date only one small study has been conducted in adults (129). Similarly the study population has been primarily male, with only half the studies including females. Another important limitation of this work is the variability in the MRI measures, as brain regions have not been identically defined across studies. Dickstein (128) utilised a specific meta-analysis technique termed activation likelihood estimation (ALE) to compare brain activation between healthy controls and individuals with ADHD. The included studies were conducted primarily in children and adolescents and 5 studies were conducted in adults. The included studies utilised the neuroimaging techniques functional magnetic resonance imaging (fMRI) and positron emission tomography (PET). Separate metaanalyses were conducted on the foci reported by controls and the foci reported by individuals with ADHD. A comparison between the two was then made. A consistent pattern of decreased frontal activity was identified in the ADHD group compared to the control group. The limitations in the current research of fMRI and PET for comparing individuals with and without ADHD are similar to those described above in the MRI studies. The variation in reporting and the inconsistent use of standardised measures make it difficult to compare the results of individual studies. Few studies have considered large numbers of females and few studies (9 out of 16) make a direct comparison between the ADHD group and a control group. Excluded studies Study Seidman et al 2005 (130) Bush et al 2005 (131) Paloyelis et al 2007 (132)
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Reason for exclusion General review General review General review
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Psychosocial management
Psychosocial interventions
Research question 9. For individuals with ADHD, do psychosocial interventions, compared to no intervention or standard care, affect outcomes? Selection criteria Population Inclusion criteria Individuals with ADHD diagnosed according to standard criteria; DSM-III, DSMIII-R, DSM-1V or ICD10 Intervention
Psychosocial interventions (including psychotherapy, cognitive
behavioural therapy, behaviour therapy, education, coaching, counselling) Comparator Outcomes No intervention or standard care
Primary: Change in the incidence or severity of symptoms of ADHD (including; inattention, impulsivity, hyperactivity).
Secondary: School achievement, quality of life, social function. Study design Search period Language
NHMRC defined levels of evidence (I-IV) for intervention studies. 1997 - present English
Date of search
Search terms
MeSH: Attention deficit disorder with hyperactivity/ behavior therapy/ or psychotherapy/ or cognitive therapy/ or psychoanalysis/ or family therapy/ or counselling/ or mentors/
treatment outcome/
R D
March 2008
Intervention/ comparator Intervention Social skills training Comparator
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Text words: adhd or addh or adhs or hyperactive$ or hyperkin$ or (attention adj deficit) psychoeducation or (behav$ adj therapy) or (behav$ adj modification) or (behav$ adj management) or (cognitive adj remediation) or (multimodal adj treatment) or dialectical or CBT or coaching
Results 4/4 studies concluded that social skills training improved aspects of social functioning in children with ADHD.
Preschoolers, children and adolescents

Population/Study information Population: Children 5-12 years. 5/6 included studies the children had a diagnosis of ADHD according to DSM criteria. 1/6 the children were defined as having peer problems (Frankel
Reference de Boo & Prins 2007 (133) Design:
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Systematic review Level I Setting Netherlands Quality Adequate Industry funding Not reported
Varied
1997). Study information Design: systematic review of 6 studies addressing social skills training. 2 studies were not considered in determining efficacy. * Abikoff 2004 did not look at SST separately from medication and impact of SST is therefore uncertain. * Tutty 2003 did not measure social outcome measures. No. Antshel & Remer 2003; n = 120 Frankel 1997; n = 73 Miranda and Presentacion 2000; n =32 Pffiner and McBurnett 1997 n = 27 Medication: not reported Population: 6-13 year old children with DSM-IV criteria for ADHD.
Authors conclusions: No studies were replicated either by an independent research team or by the same investigators. Thus, none of these interventions can be classified as well established
Chronis et al 2004 (134) Design Case series Level IV Quality Poor Setting USA (Summer Treatment Program) Industry funding Yes
Intervention Camp setting with behaviour modification Comparator Camp setting with no behaviour modification
MTA Cooperative group 1999 (135) MTA Cooperative Group 2004 (136) Jensen et al 2007 (137)
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Intervention Behavioural treatment Comparator Community control
Study information: Design: Comparison of behaviour during treatment and during treatment withdrawal (5 weeks treatment, up to 2 days withdrawal and then treatment reinstated) Duration: 8 weeks No. n = 44 Medication: permitted. 19 children were receiving ADHD medication. Psychosocial intervention: Behaviour modification using a point system with feedback, reinforcers, and daily report cards (DRCs). All camp staff members participated in an intensive, 2-week training program. Outcome measures: 1. Point system 2. DRC 3. Productivity 4. Accuracy Population: Children aged 7-9.9 years meeting DSM criteria for ADHDcombined type Study information: Design: RCT (parallel design) 14 months: Behavioural treatment n = 144 24 months: Behavioural treatment n = 139 Community control n=135 36 months Behavioural treatment n = 127 Community control n=161
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The range of effect sizes (on treatment compared to treatment withdrawal) varied from -7.38 to -0.068. Note: No standardized rating scales for ADHD symptoms were used. 14 months: Behavioural management did not differ significantly from the community control group on any outcome. (both were significantly less effective than combined treatment or medication management) 24 months: Behavioural management did not differ significantly from the community control group on any outcomes 36 months: No significant difference between any of the treatment groups for all outcomes. Note: Between group comparisons not
Design Comparative study with
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concurrent controls Level III-2 Quality Adequate Setting USA (MTA study) Industry funding No
Psychosocial intervention: Behavioural treatment consisting of 35 parent training sessions, 10-16 face-toface teacher consultations, 8-week allday summer treatment program, 12 weeks of half-time paraprofessional behaviourally trained aide in the classroom, daily report card Community control: Community care participants received none of the study treatments, but were provided a report of their initial study assessments, along with a list of community mental health resources. Medication: Not permitted in the psychosocial intervention group
clear cut as all subjects were followed up according to their original treatment allocation, regardless of what they chose to continue with over the course of the 36 month follow-up.
Arnold et al 2004 (138)
Design Comparative study with concurrent controls Level III-2
Quality Poor (based on reporting in this publication) Setting USA (MTA study) Industry funding No
R D
Intervention Behavioural treatment Comparator Community control Study information: Design: 4-arm RCT Duration: 9 months
Outcome measures: 1. Swanson, Nolan, and Pelham Rating Scale (SNAP): parent and teacher 2. Wechsler Individual Achievement Test (WIAT) reading score 3. Social Skills Rating System (SSRS): parent- and teacher 4. Columbia Impairment Scale 5. DSM-IV psychopathology Population: Children aged 7-9.9 years rigorously diagnosed with combinedtype ADHD
No. Community control n=117-137 Behavioural treatment n=117-138
T F A
9 months: Behavioural management did not differ significantly from the community control group on any measure (p = 0.69) (both groups were significantly less effective than combined treatment or medication management). Nine and 14 month outcomes were similar.
Psych intervention: 35 parent training sessions, 10-16 face-to-face teacher consultations, 8-week all-day summer treatment program, 12 weeks of halftime paraprofessional behaviourally trained aide in the classroom, daily report card Medication: Not permitted in the psychosocial intervention group Outcome measures: 1. SNAP-IV: parent and teacher 2. Social Skills Rating System (SSRS): parent and teacher 3. Negative-ineffective discipline factor
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Adults
Stevenson et al 2003 (139) Design RCT Level II Quality Poor Setting Australia (Sydney) Industry funding No Intervention Self-help programme Comparator Waiting list control Population: Adults aged >21 years with DSM IV criteria for ADHD. Individuals in the intervention group had significantly improved ADHD symptoms over the waiting list control group. Effect size: 1.4 Note: p-values were not reported
Study information: Design: RCT (8 weeks treatment) Duration: 8 weeks (plus 2 months follow up for intervention group. The waiting list group received treatment after 8 weeks) No. Waiting list control n = 18 Intervention n = 17
Medication: Permitted. Intervention: 11/17 receiving ADHD medication. Waiting list control: 12/ 18 receiving ADHD medication.
Stevenson et al 2002 (140) Design RCT Level II Quality Poor Setting Australia (Sydney) Industry funding No
R D
Intervention Cognitive Remediation Programme (CRP). Comparator Waiting list control No. Waiting list n=21 Intervention n=22 Outcome measures:
Psychosocial intervention: self-help programme designed to teach strategies to manage the symptoms of ADHD with three components -self-help book, three therapist-led sessions and support people as coaches Outcome measures: 1. ADHD Symptom Rating Scale Population: Adults aged >21 years with DSM IV criteria for ADHD. Participants were accepted either unmedicated or on medication stabilised at the participants optimum dose.
Study information: Design: RCT (8 weeks treatment, two months and 1-year follow-up for treatment group, waiting list group received treatment after 8 weeks)
T F A
Individuals in the intervention group had significantly improved ADHD symptoms over the waiting list control group. Whether a participant was medicated or not had no significant effect on any outcome measure. Note: p-values were not reported
Duration: 8 weeks (plus 1 year follow up for the intervention group)
Medication: Permitted. Intervention: 11/22 receiving ADHD medication. Waiting list control: 12/21 receiving ADHD medication. Psych intervention: CRP 8 x 2-hour, weekly sessions with support people who acted as coaches, and participant workbooks with homework excercises.
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1. ADHD Symptom Rating Scale Hesslinger et al 2002 (129) Design Case series Level IV Quality Poor Setting Germany Industry funding No Intervention Cognitive behavioural therapy Comparator Waiting list (regular outpatient management: medication and behavioural management recommended) Population: Adults (19-44 years) clearly fulfilling DSM-IV criteria for ADHD Study information: Design: Case series with pre and posttest measures Duration: 3 months No. Regular management n=7 Intervention n=8 Participants improved on the outcome measures following intervention (Effect size: ADHD-CL; 2.22 (p = 0.01), SCL16; 1.35 (p = 0.02)). The outcomes for the control group were unchanged (Effect size: ADHD-CL 0.79; SCL-16 0.64 p-values not reported). There was no direct comparison between the intervention and the control group.
Psychosocial intervention: Cognitive behavioural therapy, based on the principles of dialectic behavioural therapy (DBT) for borderline personality disorder, modified to suit the specific needs and deficits of adults with ADHD. 13 x 2 hour weekly sessions
Medication: Permitted. 6/15 participants receiving medication for all or part of the study.
Philipson et al 2007 (141) Design Case series Level IV Quality Poor Setting Germany Industry funding No
R D
Intervention Cognitive behavioural therapy Comparator None
Outcome measures: 1. ADHD checklist (ADHD-CL) 2. Adaptive version of the symptom checklist (SCL-16) 3. Beck Depression Inventory (BDI)
Population: Adults (18-53 years) fulfilling DSM-IV and ICD-10 criteria for ADHD Study information: Design: Case series with pre and posttest measures Duration: 3 months No. n = 66 (27 females, 39 males) Medication: permitted (48/66 participants were receiving ADHD medications)
T F A
Note: it is unclear what treatment the comparison group actually received. Combined outcomes: Pre and posttreatment scores were significantly different (p < 0.001, effect size = 0.672). Multivariate analysis did not identify any significant effects of either treatment site or medication status. ADHD-CL: ADHD symptoms improved following treatment (p < 0.001, effect size = 0.411). SCL-90-R: ADHD symptoms improved following treatment ( p < 0.001, partial effect size = 0.217 ) BDI: Significant decrease (p < 0.001,effect size = 0.314) VAS: Health status rating showed a significant increase following treatment (p < 0.001, effect size = 0.475) Baseline BDI had a significant impact on the outcome of the SCL-90-R (p < 0.004, effect size = 0.139) and BDI (p < 0.001, effect size = 0.444) but not the
Psychosocial intervention: Cognitive behavioural therapy, based on the principles of dialectic behavioural therapy (DBT) for borderline personality disorder, modified to suit the specific needs and deficits of adults with ADHD. 13 x 2 hour weekly sessions at 4 different treatment sites. Outcome measures: 1. ADHD checklist (ADHD-CL) 2. Adaptive version of the symptom checklist (SCL-16) 3. Beck Depression Inventory (BDI) 4. Personal health status - visual
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analogue scale (VAS) Wiggins et al 1999 (142) Design Nonrandomised controlled trial Level III-2 Quality Poor Setting USA Industry funding No Intervention Psychoeducational group Comparator No treatment Population: Adults aged 31 to 52 years with ADHD Note: diagnostic criteria not specified Study information: Design: non-randomised controlled trial with pre-test and post-test outcomes Duration: not specified No. No treatment n=8 Intervention n=9 Medication: Not stated
ADHD-CL or the VAS. 3/7 ADHD symptom subscales were significantly improved comparing preand post-test scores in the intervention group; disorganisation, (p < 0.01) inattention (p < 0.01) and selfconfidence/self-esteem (p < 0.05). These measures were also reported to be significantly improved in the intervention group over the no treatment group (p values not specified). Reported effect sizes; disorganisation, (1.71) inattention (1.9) and self-confidence/self-esteem (1.37).
Psychosocial intervention: Psychoeducational group met for four sessions of 90 minutes, focused on problems members had with setting realistic goals; time management, attention and organisation; task completion and organizing and structuring their physical environment. Based on Group Pentagon approach.
Virta et al 2008 (143) Design Case-series Level IV Quality Poor Setting Finland Industry funding No
R D
Comparator Pre-treatment ratings of participants
Intervention Cognitive Behaviorally Oriented Psychological Group Rehabilitation
Outcome measures: 1. Wiggins Adult ADHD checklist Population: Adults aged 18 to 45 years with ADHD diagnosed according to DSM-IV criteria. Study information: Design: Case-series with pre-test and post-test outcome measures Duration: Control period (no treatment): 12 weeks Treatment period: 10-11 weeks No. n = 29 Medication: permitted (19/29 participants were receiving ADHD medications)
T F A
Self-report ratings: (29 participants) BADDS: Symptoms decreased over the treatment period in Activation ( p <.01, effect size = .27), Affect (p <.05, effect size = .15) and Total score (p <.05, effect size = .22) SCL-90 (SCL-16): ADHD symptoms decreased over the treatment period (p <.05, effect size =.18). No other significant differences were reported on any scale. Significant-other ratings: (24 participants) BADDS: Symptoms decreased over the control period in Activation (p < .05, effect size = .23), Attention (p < .05, effect size = .25), Effort (p < .05, effect size = .19) and Total (p < .05, effect size = .28). No significant differences were found over the treatment period (all p values > .05).
Psychosocial intervention: Administered by a psychologist in 1011 weekly sessions. Each rehabilitation group had 8-9 participants. There were three goals: (a) to enhance participants knowledge and understanding of ADHD and its impact on their lives (b) to improve participants skills in managing ADHD-related problems (c) to give participants a chance to discuss their problems with peers and to support each other. Outcome measures: Taken pre- & post-control period and pre- & post-treatment period Self-report or Significant-other report:
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1. DSM-IV total score (18 item check list). 2. Brown ADD Scale for Adults (BADDS). 3. Beck Depression Inventory (2nd Ed.) 4. SCL-90 and SCL-16 (checklist of ADHD characteristics) Solanto et al 2008 (144) Design Case-series Level IV Quality Poor Setting USA Industry funding No Intervention Cognitive behavioural therapy Comparator Pre-treatment ratings of participants Population: Adults aged 23 to 65 years with ADHD diagnosed according to DSM-IV criteria. Study information: Design: Case-series with pre-test and post-test outcome measures Duration: 8 or 12 week group cognative therapy program No. n = 38 at study start n = 30 completed the program Medication: permitted (26 participants were receiving ADHD medications) Psychosocial intervention: Meta-cognative therapy included components intended to provide training in specific skills, reinforce and shape positive behaviors, impart new cognitions to maintain adaptive self-management behaviors, and challenge maladaptive cognitive selfstatements. Weekly 2 hour group meetings with 5-8 participants. Outcome measures: Conners Adult ADHD Rating ScaleSelf Report: Long (CARRS-S:L) Brown ADD Scales (BADDS) On Time Management, Organisation and Planning Scale (ON-TOP) Self-report ratings: Symtpoms (CARRS-S:L): Significant decrease in DSM-IV Inattentive symptoms (p < 0.001, effect size = 0.588), but not DSM IV hyperactive symptoms (p > 0.01, effect size = 0.07) which were below the threshold for clinical significance pre-treatment. Executive Functioning (BADDs composite scores): Significant improvement (p < 0.001, effect size = 0.669)
Summary
Preschoolers: No studies were identified that addressed the use of psychosocial interventions in preschoolers. Children: One systematic review and 5 primary studies addressed the efficacy of psychosocial interventions for children with ADHD. The systematic review conducted by de Boo and Prins (133) was considered to be of adequate quality. The review examined the efficacy of social skills training programs. Four out of four studies reported that SST improved aspects of social functioning in children with ADHD. The content of the interventions and the durations varied in each of the studies. One study addressing the behavioural modification in a summer treatment program met the inclusion criteria. This study of a multi-component psychosocial management strategy by Chronis et al (134) reported improved behaviour when behaviour modification strategies were in use in the camp, compared to the two day withdrawal period when the behaviour strategies were not in use. This study had several major limitations that make the results difficult to interpret, such as no assessment with standardised ADHD outcome measures.
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Management / Orgnaisation / Planing (ON-TOP): Significant improvement in perceived competencies (p < 0.001, effect size = 0.615)
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The MTA study compared the use of multi-component psychosocial management with a community-care control group. In the reports that consider outcomes at 14 months (135) and 24 months (136), the behavioural management group did not differ significantly from the community control group on any outcome, and both were significantly less efficacious than the medication management and combined management groups. Arnold et al (138) also examined the outcome measures obtained at 9 months, when the behavioural management was still being intensively administered No significant difference was found between the multi-modal psychosocial management group and the community-care control group. No significant difference was found between any of the groups at 36 months (137). It is important to take into consideration that the community-care group it is not necessarily relevant to the Australian setting as multiple differences exist between the health care settings in Australia and the USA. Adolescents: No studies were identified that addressed the use of psychosocial interventions in adolescents.
Adults: Seven studies were identified that addressed different forms of cognitive behavioural therapy for adults with ADHD. Two of the studies were RCTs conducted in Australia. Stevenson et al 2002 (140) compared a therapist directed cognitive remediation programme with a untreated control group. The programme targeted attention problems, poor motivation, poor organizational skills, impulsivity, reduced anger control and low self-esteem. Significant improvements in ADHD symptoms were found following the treatment. Stevenson et al 2003 (139) compared a self directed self-help programme with a control group and again found significantly improvements in ADHD symptoms following the intervention. As these studies were conducted in Australia the results are readily generalisable to the target population of this review. Wiggins et al (142) reported benefits in the areas of disorganization, inattention and self concept/esteem for the group receiving a psycho-educational intervention compared to the no-treatment group. Two German studies (129) (141) using a cognitive behavioural therapy intervention based on dialectic behavioural therapy reported improvement in ADHD symptoms. Virta et al 2008 (143) reported on a Finish study of a group-based cognitive behavioural therapy intervention. There was improvement on self-reported symptoms of ADHD following treatment, however reports from significant others showed no improvement. Solanta et al 2008 (144) described another groupbased cognitive behavioural therapy intervention designed to target time management, organisation and planning skills. There was improvement on self-reported symptoms of inattention, executive function skills and time management, organisation and planning following treatment. Overall the studies in adults with ADHD using psychosocial interventions show benefits for the management of ADHD symptoms, however, each of the studies were rated as poor quality and the results should be interpreted cautiously. Several studies included participants who were concurrently taking medications for ADHD, but did not necessarily conduct a separate analysis to take this potential confounder into account. Two studies that did consider the impact of medication status on treatment outcome were Stevenson et al (140) and Philipson et al (141). Both studies reported that medication did not significantly impact on the outcomes of the psychosocial treatments under investigation.
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Excluded studies Study Binder et al 2000 (145) Fenstermacher et al 2006 (146) Gol & Jarus 2005 (147 693) Kern et al 2007(148) Klassen et al1999 (149) McGoey et al 2002 (150) Mrug et al 2007 (151) Pelham et al1998 (152) Rostain et al 2006 (153) Safren et al 2005 (154) Salomonsson 2006 (155) Shaffer et al 2001 (156) Smith et al (157) Weisz et al 2005 (158) Welch et al 2006 (159) Wells et al 2000 (160) White et al 2006 (161) Wilens et al1999 (162) Yovel et al 2007 (163)
Reason for exclusion Sample size less than 10 participants Sample size less than 10 participants Not a study of effectiveness Children are not diagnosed with ADHD at risk of ADHD Studies considered were primarily parent training (Consider for Question 23) Poor quality systematic review Not a study of effectiveness Narrative systematic review No comparison of psychosocial treatment alone versus a control group (Consider for Question 27) No comparison of psychosocial treatment alone versus a control group (Consider for Question 27) Case report. Not a psychosocial intervention. Motor regulation. Systematic review that includes two behaviour modification studies, both are case reports. No outcomes reported No ADHD data presented individually No outcomes reported Did not measure primary or secondary outcomes No comparison of psychosocial treatment alone versus a control group No comparison of psychosocial treatment alone versus a control group
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Parenting programs
Research question 10. For preschoolers, children and adolescents with ADHD, does behaviour management in the form of parenting programs, compared to no intervention or standard care, affect outcomes? Selection criteria Population Inclusion criteria Preschoolers, children and adolescents with ADHD diagnosed according to standard criteria; DSM-III, DSMIII-R, DSM-1V or ICD10 Intervention Comparator Outcomes
Parenting programs (individual couple training, group training) No intervention or standard care
Secondary: School achievement, quality of life, social function. Study design Search period Language Date of search
NHMRC defined levels of evidence (I and II) for intervention studies. 1997 - present English
Search terms MeSH: Attention deficit disorder with hyperactivity/
Reference
SonugaBarke et al 2004 (164) Design RCT Level II Quality Adequate
R D
May 2007
Intervention/ comparator Intervention Parenting program Comparator Waiting list control
Text words: adhd or addh or adhs or hyperactive$ or hyperkin$ or (attention adj deficit) parent training or PT or family based interventions or (behave$ adj parent adj training) or BPT or COPE (Community Parent Education) or PET (Parent effectiveness training) or Parent-Child Interaction Therapy or Triple P Positive Parenting Program
T F A
Results No significant differences between intervention and waiting list control group for ADHD outcomes.
Preschoolers
Population: 3 year old children displaying a preschool equivalent of ADHD and who met cut-off on WerryWeiss-Peters Activity Scale and the Parental Account of Childhood Symptoms Structured Clinical Interview Study information: Design & duration: RCT (8 weeks treatment + 15 weeks follow-up)
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Setting UK Industry funding No
No. Waiting list control n = 30 Intervention n = 59 Intervention: Parent training consisted of structured eight week program involving eight, one-hour weekly visits. All sessions were carried out on a one to one basis with mothers and their ADHD children in their homes. Outcome measures: 1. Parental account of childhood symptoms 2. Werry-Weiss-Peters hyperactivity scale 3. Behavior Checklist Population: 3 year old children displaying a preschool equivalent of AD/HD and who met cut-off on Werry-Weiss-Peters Activity Scale and the Parental Account of Childhood Symptoms Structured Clinical Interview Study information: Design & duration: RCT (8 weeks treatment + 15 weeks follow-up) No. Waiting list control n=20 Intervention n=58 (parent training n=30; parent counselling & support n=28)
SonugaBarke et al 2001(165) Design RCT Level II Quality Adequate Setting UK Industry funding No
Intervention Parenting program or parent counseling & support Comparator Waiting list control
R D
Intervention: both treatments consisted of a structured 8-week program involving eight one hour weekly visits by one of two specially trained health visitor therapist All sessions were carried out on a one to one basis with mothers and their AD/HD children in their homes. Parent training - educated about ADHD and introduced to a range of behavioural strategies for increasing attention and behavioural organisation and reducing defiant and difficult behaviour Parent counseling & support - Parents received no training in behavioural strategies. They were however, given the opportunity to explore issues of concern to them and to discuss their feelings about their child and the impact that the child had on the family in a nondirective, non threatening environment. Outcome measures: 1. Clinical interview using PACS 2. Observation
T F A
ADHD symptoms were reduced (p < 0.0001) and mothers sense of well being was increased (p < 0.005) in the parenting program group compared to the control group. Effect sizes for ADHD symptoms (PACS) were 0.87 for the parenting program and 0.48 for parent counselling & support.
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Children
Reference Corcoran & Dattalo 2006 (166) Design SR Level I Quality Adequate Setting USA Industry funding No Intervention/ comparator Intervention Individual, group, family, day treatment Comparator Control, comparison, pre and post Population/Study information Population: Parent involved psychosocial treatment for ADHD in a child (ranging in age from 0-18). Children had to meet diagnostic criteria or score in the clinical range on established measures of ADHD symptoms. Results Low to moderate effect size for child ADHD symptoms (0.3970). Larger effect sizes for other measures such as child academic performance (8.2041), child-family functioning (0.6730), and child internalizing (0.6349).
Study information: Design: meta-analysis of 16 studies (13 x random treatment and comparison groups and 3 x non-random treatment and comparison groups) No. 16 studies (sample sizes ranged from 16 to 443 with a mean of 91 and a median of 67) Outcome measures: 1. ADHD symptoms 2. Internalizing problems 3. Externalising problems 4. Social competence 5. Family functioning 6. Self control 7. Academic and/or learning disorders Population: Children aged between 60 and 119 months with a clinical diagnosis of ADHD. Study information: Design & duration: RCT (12 weeks treatment + 12 weeks follow-up)
Hoath & Sanders 2002 (167) Design RCT Level II Quality Adequate Setting Australia (NSW, QLD) Industry funding No
R D
Intervention Enhanced Group Triple P Comparator Waiting list control
No. Waiting list control n=11 families Intervention n=10 families
T F A
A significant interaction effect was observed, with parents in the EGTP condition reporting significantly lower levels of disruptive child behaviour on the ECBI intensity scale than the waiting list control condition. CAPS and SESBI scores failed to reach statistical significance between the groups. Note: p-vales not reported for the comparisons between groups.
Intervention: Enhanced Group Triple P (EGTP) targeting specific ADHD characteristics. The intervention involved distributing resources to the parents, five group sessions and four telephone consultation sessions.
Outcome measures: 1. Eyberg Child Behaviour Inventory (ECBI) 2. Child Attention Problems Rating Scale (CAPS) 3. Sutter-Eyberg Student Behaviour Inventory (SESBI)-Revised
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Pfiffner et al 2007 (168) Design: Randomised controlled trial Level II Setting USA Quality Adequate Industry funding No
Intervention Behavioral treatment (Child Life and Attention Skills Program) Comparator Wait-list control Treatment as usual
Population: 7-11 year old children with DSM-IV diagnosis for ADHD-I and IQ > 80 (Wechsler Abbreviated Scale of Intelligence). Study information: Design: Randomised controlled trial. Pre- and post-test outcome measures. Duration: Behavioral treatment 12 weeks, plus monthly clinic meetings for families post-treatment. Follow-up measures at 3-5 months post-treatment. No. n = 69 (5 cohorts of 12-16 participants) Medication: Stable use permitted. Psychosocial intervention: Behavioural treatment (reward-based) consisting of three arms; Teacher consultation: 4-5 half hour meetings of parent, teacher, child and therapist over 12 weeks. Daily report card. Individualized targeting of behaviors. Parent training: Individually tailored program. Parents attended 8 or 10 sessions and 5 family sessions. Trained in strategies for managing ADHD-I and associated impairments. Child skills training: Children taught skills for independence (academic, study, organizational, self-care and daily living skills) and skills for social competence. Outcome measures: 1. DSM-IV inattention symptoms (parent / teacher) 2. SCT scale: Inattention symptoms not on DSM-IV. (parent / teacher) 3. Social skills rating scale (SSRS) (parent / teacher) 4. Childrens Organisational Scale (COSS) (parent / teacher) 5. Test of Life Skill Knowledge (completed by the child) 6. Clinical Global Impressions (CGI) Improvement (parent / teacher) Population: Children aged 4-12 years with a DSM-IV diagnosis of ADHD.
DSM-IV inattention symptom count: Significant decrease relative to the control group; post-treatment (p = 0.0004; effect size = 0.184) and at follow-up (p = 0.029; effect size = 0.09) DSM-IV inattention symptom severity: Significant decrease posttreatment relative to the control group (p = 0.0001; effect size = 0.112) and at follow-up (p = 0.016; effect size = 0.11)
Van den Hoodfdakk er et al 2007 (169) Design: RCT
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Intervention Behavioral parenting program plus routine clinical care Comparator Routine clinical care
T F A
SCT symptoms: Significant decrease post-treatment relative to the control group (p = 0.0065; effect size = 0.224) Difference at follow-up not significant. SSRS: Significant decrease posttreatment relative to the control group (p = 0.0001 & effect size = 0.112) * COSS: Significant decrease posttreatment relative to the control group for organizational skills (p = 0.0093; effect size = 0.173) * Life skills knowledge: Significant decrease post-treatment relative to the control group (p = 0.0001; effect size = 0.644) * CGI-improvement: Significant decrease post-treatment relative to the control group. Parents; p = 0.0001 Teachers; p = 0.0012 * * Statistical details of between group difference at follow-up not reported. Within group differences between posttreatment and follow-up were not significant on any measure except the COSS which showed continued improvement ( treatment: p = 0.0034 control p = 0.002) BPT + RCC was superior to RCC alone in reducing behavioural (p = .017) and internalizing (p = .042) problems. No outcome differences were found in ADHD symptoms (p = .161) and parenting stress (p = .643). These results were equal for children with and without medication.
Study information: Design & duration: RCT (5 months of active intervention, follow-up 6 months post-intervention)
Level II Setting Netherlands Quality Adequate
No. Parent-training n=47 Control n=47 Intervention: Behavioral parent training: 12 120-minute sessions in group format led by two psychologists
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Industry funding No
Routine clinical care: care as usual family support and pharmacotherapy as required Outcome measures: Diagnostic Interview Schedule for Children-IV Child Behavior Checklist Conners Parent Rating Scale-Revised: Short Form Parenting Stress Index
Summary
Preschoolers: Two RCTs were identified that looked specifically at parenting programs for preschoolers with ADHD. Studies with lower levels of evidence were not sought. Sonuga-Barke et al (165) compared structured parenting programs with both parent counseling and support, and a wait-list control group. Parenting programs were found to have a greater impact on ADHD symptoms than the parent counseling and support intervention. This study was rated as adequate in quality. Sonuga-Barke et al (164) reported on a study where the same parent training program was conducted by non-specialist nurses, rather than specialist therapists as used in the previous study. In this study no differences were found between the group that had undergone 8 weeks of structured parent training and the control group. This study was rated as adequate in quality. Children: One meta-analysis and two RCTs were identified. Studies with lower levels of evidence were not sought.
The meta-analysis conducted by Corcoran and Dattalo (166) combined data from 16 studies that addressed parent involvement in the treatment of ADHD. The meta-analysis included 7 focused on parenting programs but was not limited specifically to parenting interventions. This well conducted meta-analysis found that family-based interventions impacted more on child-family functioning and academic performance than ADHD symptoms.
Hoath and Sanders (167) compared parenting programs to a wait-list control group in children aged 5-9 years. Parents in the parenting program group reported lower levels of child disruptive behaviour compared to the control group, and these benefits were maintained at 3 months after the end of the trial. Teacher rated measures were not different between the groups. The quality of this study was rated as adequate. This small study was conducted in Australia and as such the results are readily generalisable to the target population of this review. Pfiffner et al 2007 (168) utilised parenting programs as part of a three armed intervention that also included consultation with teachers and skills and knowledge training with the child. Children were aged 7-11 years and were diagnosed with ADHD-I. A positive impact of the intervention on DSM-IV symptom number and severity was seen at the end of the treatment period and at the 3-5month follow-up period. Other outcome measures showed improvement at the end of treatment, but this did not hold at the time of follow-up. van den Hoofdakker et al (169) compared behavioural parenting programs plus routine clinical care to routine clinical care alone over 5 months. Both groups showed improvement over time in behavioural, internalising and ADHD symptoms and parenting stress. Those receiving parenting strategies showed significant improvement in behavioural and internalising symptoms compared to those receiving routine clinical care only. ADHD symptoms and parenting stress did not differ between the groups.
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Excluded studies Study Bjornstad & Montgomery 2005 (170) Chronis et al 2004 (171) Danforth et al 2006 (172) Farmer et al 2002 (173) Huang et al 2003 (174) Lundahl et al 2006 (175) Maughan et al 2005 (176) Pelham et al1998 (152) Thomas & ZimmerGembeck 2007 (177)
Reason for exclusion Inclusion criteria for this systematic review were more stringent than the current analysis. Narrative review Not randomised controlled trial Systematic review where data on ADHD could not be extracted independently from other included studies. Not randomised controlled trial Systematic review with no data specific to ADHD Systematic review with no data specific to ADHD Narrative review No data specific to ADHD
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Moderators and mediators of outcomes for psychosocial interventions

Research question 11. For individuals with ADHD, what are the moderators and mediators of treatment response with psychosocial interventions? Selection criteria Population Inclusion criteria Children and adolescents with ADHD diagnosed according to standard criteria; DSM-III, DSMIII-R, DSM-1V or ICD10 Intervention
Psychosocial intervention (psychotherapy, parent-training, cognitive
behavioural therapy, behaviour therapy, social skills training, education, supportive counselling) Comparator Outcomes Study design Search period Language Date of search
No intervention or standard care Comparison of cases
Search terms A separate search was not performed: Pooled results of questions 9-10 were screened. Children
Reference
The MTA Cooperative Group 1999 (178) Design: Comparative study with concurrent controls Level III-2 Setting USA (MTA study) Quality Adequate Industry
R D
Intervention/ comparator Intervention Behavioural management Population/ study information Comparator Medication management Combined treatment Design: MTA study Community care Mediator Variables Attendance
Separate search not performed.
Population: Children aged 7-9.9 years meeting ADHD Diagnostic Interview Schedule for Children for ADHDcombined type
T F A
Results Comorbid anxiety: For children with anxiety disorders behavioural treatment was significantly better than community care and was no longer statistically different from medication management and combined treatment Public assistance: medication management yielded decreased closeness in parent-child interactions, and combined treatment yielded relatively greater benefits for teacherreported social skills Attendance: Impact on medication management
Moderator Variables Examined Gender Prior medication Comorbid ODD/CD Comorbid anxiety Public assistance
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funding No March et al (179) Design: Comparative study with concurrent controls Level III-2 Setting USA (MTA study) Quality Adequate Industry funding No Owens et al 2003 (180) Design Comparative study with concurrent controls Level III-2 Setting USA (MTA study) Quality Adequate Industry funding No Rieppi et al 2002 (181) Intervention Behavioural management Comparator Medication management Combined treatment Community care Population: Children aged 7-9.9 years meeting ADHD Diagnostic Interview Schedule for Children for ADHDcombined type Design: MTA study Moderator variables Examined Anxiety plus comorbid conduct problems (Anx/CD+) n = 122 Anxiety without comorbid conduct problems (Anx/CD-) n = 65 Comorbid anxiety plus or minus conduct disorders: For children with anxiety disorders behavioural treatment was significantly better than community care for parent rated measures irrespective of the presence or absence of comorbid conduct problems
Population: Children aged 7-9.9 years meeting ADHD Diagnostic Interview Schedule for Children for ADHDcombined type Design: MTA study
Design: Comparative study with concurrent controls Level III-2 Setting USA (MTA study) Quality Adequate
R D
Intervention Behavioural management Comparator Medication management Combined treatment Design: MTA study Community care
Moderator Variables Examined public assistance gender anxiety CD/ODD maternal education parental depressive symptoms, initial child ADHD severity child IQ
T F A
None of the 8 baseline child and family variables predicted treatment outcomes in any of the treatment groups. Parental depressive symptoms and severity of child ADHD were associated with decreased rates of excellence response in the medication management and combined treatment groups. Below average child IQ when combined with parental depressive symptom ms and severity of child ADHD was also associated with decreased rates of excellence response in the medication management and combine treatment groups Parent education: Children from more educated families showed superior reduction of ADHD symptoms with combined treatment. Whereas children from less educated homes showed no differential treatment response. Parent Occupation: For oppositionalaggressive symptoms children from blue-collar, lower SES households benefited most from Combined treatment. Whereas children from white-collar, higher SES homes generally showed no differential treatment response. Household income: No impact on
Population: Children aged 7-9.9 years meeting ADHD Diagnostic Interview Schedule for Children for ADHDcombined type
Outcome measures: 1. Developmental, Family, and Treatment Background Questionnaire 2. Hollingshead Four Factor Index of Social Status 3. 1989 Socioeconomic Index of Occupations
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Industry funding No
outcomes Marital status: No impact on outcomes
Summary
Preschoolers: No studies were identified that addressed moderators and mediators of outcomes for psychosocial interventions in preschoolers. Children: Four primary studies were identified that investigated the moderators and mediators of outcomes for psychosocial interventions. All were derived from the MTA study and were rated as being of adequate quality. The original MTA study compared four treatment groups; medication management, behavioural management, combined treatment and community care (135). In the reports that consider outcomes at 14 months the behavioural management group did not differ significantly from the community control group on any outcome. Both behavioural management and community care were significantly less efficacious than medication management and combined management (135). The MTA Cooperative Group (178) initially assessed five potential moderator variables (gender, prior medication, comorbid oppositional defiant disorder (ODD) or conduct disorder (CD), comorbid anxiety and public assistance (financial support for low-income families)) to determine whether these factors would impact on treatment response. The MTA Cooperative group (178) found that for children with anxiety disorders, behavioural treatment was significantly better than community care, and was no longer statistically different from medication management or combined treatment. In other words, children with both ADHD and anxiety responded equally well to behavioural management, medication management and combined treatment.
March et al (179) further analysed the results of the MTA study to determine whether the presence or absence of conduct disorders in addition to anxiety would alter the impact of anxiety as a moderator variable. For children with anxiety disorders, behavioural treatment was significantly better than community care for parent rated measures, irrespective of the presence or absence of comorbid conduct problems.
When Owens et al (180) specifically looked at treatment outcomes in the behavioural management group they reported that none of the potential variables examined (public assistance, gender, anxiety, CD/ODD maternal education, parental depressive symptoms, initial child ADHD severity and child IQ) impacted on the treatment response. These results contradict those of the MTA Cooperative Group (178) and March et al (179) which found comorbid anxiety moderated the treatment response and it is not clear whether these findings were not robust enough when considering optimal treatment response as undertaken by Owens et al (180) or it is a difference in how the analysis was conducted. Notably, Owens et al (180) also found that parental depressive symptoms, high severity of child ADHD and below average child IQ were, however, associated with a less efficacious response in the medication management and combined treatment groups.
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Rieppi et al (181) looked at several additional variables that had the potential to impact on treatment outcome in the MTA study. Rieppi et al (181) found that both parent education and parent occupation had an impact on treatment outcomes. Children from more educated families showed superior reduction of ADHD symptoms with combined treatment. Whereas children from less educated homes showed no differential treatment response. For oppositional-aggressive symptoms children from blue-collar households benefited most from the combined treatment.
Whereas children from white-collar homes generally showed no differential treatment response. Variables such as household income and marital status did not have an impact. Adolescents: No studies were identified that addressed moderators and mediators of outcomes for psychosocial interventions in adolescents. Adults: No studies were identified that addressed moderators and mediators of outcomes for psychosocial interventions in adults. Excluded studies Study de Boo and Prins(133) Hinshaw et al 2007 (182) Lundahl et al 2006 (175) Heriot et al 2008 (183) Arnold et al 2003 (184)
Reason for exclusion No empirical assessment of moderators and mediators No primary data presented ADHD data not presented separately Case studies. No combined statistical analysis. Exploratory data-analysis.
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Psychosocial interventions when comorbidities are present

Research question 12. When comorbidities are present in individuals with ADHD, do psychosocial interventions, compared to no intervention or standard care, affect outcomes? Selection Criteria Population Inclusion Criteria Individuals with ADHD diagnosed according to standard criteria; DSM-III, DSMIII-R, DSM-1V or ICD10 that also have a comorbidity or differential diagnosis Intervention Comparator Outcomes
No intervention or standard care
Primary: 1. Change in incidence or severity of symptoms of ADHD (including; inattention, impulsivity, hyperactivity). 2. Change in the incidence or severity of symptoms of comorbid conditions.
Secondary: School/work achievement, quality of life, social function. Study Design Search Period Language NHMRC defined levels of evidence (I-IV) for intervention studies 1997 - present English
Date of Search
Search terms A separate search was not performed: Pooled results of questions 9-10 were screened. Children and adolescents
Reference
Barkley et al 2001 (185)
Design Comparative study without concurrent controls Level III-3 Quality Adequate Setting USA
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Intervention/ comparator Intervention PSCT: Problem solving communicati on training Comparator PSCT: Problem solving communicati on training Plus BMT:
Separate search not performed.
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Results At post treatment follow up, 25% or less of participants in each group demonstrated clinical change as a result of treatment. There were no significant differences between therapies.
Population/Study information Population: Adolescents aged 12-18 years diagnosed with ADHD and ODD according to DSM-IV criteria
Study information: Design & Duration: Comparative study with 2 month follow up Group 1: 18 weeks PSCT Group 2: 9 weeks BMT followed by 9 weeks PSCT No. n = 97 Psychosocial intervention: PSCT: 18 weeks of training parents and teens in problem solving, communication and cognitive restructuring.
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Industry funding No
Behaviour management training
BMT: Taught parents to use contingency management methods for modifying inappropriate teen behaviour or for increasing pro-social or acceptable behaviour. Outcome measures: ADHD/ODD symptoms Relationship violence Behaviour during problem solving discussions Family conflict Communication style and level of conflict in parent-adolescent interaction
Jensen et al 2001 (186) Design Comparative study with concurrent controls Level III-2 Quality Adequate Setting USA Industry funding No
Intervention Behavioural treatment Comparator Community care
Population: Children aged 7 -9.9 years meeting DSM criteria for ADHD combined type.
Study information: MTA study Design & Duration: 4 arm RCT. 14 month follow up
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Intervention Behavioural management Comparator
No. Each child grouped into one of four categories: ADHD only (31% n=184), ADHD plus anxiety (14% n=81), ADHD plus ODD/CD (29% n=171), ADHD plus ODD/CD plus anxiety (24% n=143). Behavioural treatment n = 127 Community care n =116
Psychosocial intervention: 35 parent training sessions, 10-16 face-to-face teacher consultations, 8 week all-day summer treatment program, 12 weeks of half-time paraprofessional behaviourally trained aide in the classroom, daily report card.
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ADHD plus anxiety: Behaviour management improved outcomes (relative to the ADHD only group) for inattention, hyperactivity-impulsive, oppositional aggressive, total SNAP symptoms, internalizing symptoms, social skills, and maths and spelling outcomes. ADHD plus ODD/CD: No differential response to treatment compared to ADHD only. ADHD plus ODD/CD plus anxiety: Behaviour management improved outcomes (relative to the ADHD only group) for inattention, total SNAP symptoms, internalizing symptoms and overall composite score. ADHD plus anxiety plus or minus conduct disorders: For children with anxiety disorders behavioural treatment was significantly better than community care for parent rated measures
Community care: Participants received none of the study treatments, but were provided with a report of their initial study assessments, along with a list of community mental health resources. Outcome measures: SNAP-IV- parent and teacher Social skills rating systems (SSRS) parent and teacher
March et al 2000 (179) Design: Comparative
Population: Children aged 7-9.9 years meeting ADHD Diagnostic Interview Schedule for Children for ADHDcombined type Study information: MTA study
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study with concurrent controls Level III-2 Setting USA Quality Adequate Industry funding No
Medication management Combined treatment Community care
Design & Duration: 4 arm RCT. 14 month follow up No. Anxiety plus comorbid conduct problems (Anx/CD+) n = 122 Anxiety without comorbid conduct problems (Anx/CD-) n = 65 Psychosocial intervention: 35 parent training sessions, 10-16 face-to-face teacher consultations, 8 week all-day summer treatment program, 12 weeks of half-time paraprofessional behaviourally trained aide in the classroom, daily report card.
irrespective of the presence or absence of comorbid conduct problems.
Community care: Participants received none of the study treatments, but were provided with a report of their initial study assessments, along with a list of community mental health resources. Outcome measures: SNAP-IV- parent and teacher Social skills rating systems (SSRS) parent and teacher
Summary
Preschoolers: No studies met the inclusion criteria
Children and adolescents: Three studies were identified that investigated the efficacy of psychosocial interventions for ADHD when comorbid disorders are present. In a study rated as adequate in quality Barkley et al (185) compared two intervention strategies; problem solving communication training and behaviour management training plus problem solving communication training. The participants were adolescents aged 12-18 years diagnosed with ADHD and ODD. At the 2 month follow-up, only 25% of the participants in each group demonstrated improvement in either group. There were no significant differences between the two intervention strategies.
The remaining two studies were derived from the MTA study and were rated as being of adequate quality. The original MTA study compared four treatment groups; medication management, behavioural management, combined treatment and community care (135). In the reports that consider outcomes at 14 months the behavioural management group did not differ significantly from the community control group on any outcome. Both behavioural management and community care were significantly less efficacious than medication management and combined management (135). Jensen et al (186) reported on the impact of comorbidities on treatment efficacy. Behaviour management, compared to community care, was found to improve core ADHD symptoms and social skills outcomes for the ADHD plus anxiety group relative to participants with ADHD only. Behaviour management also improved core ADHD symptoms in the ADHD plus ODD/CD plus
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anxiety group. There was no differential response to treatment for the ADHD plus ODD/CD group compared to the ADHD only group. March et al (179) further analysed the 14 month outcomes of the MTA specifically addressing children with ADHD and comorbid anxiety disorders. For children with ADHD and anxiety, behavioural treatment was significantly better than community care for parent rated measures, irrespective of the presence or absence of comorbid conduct problems. Adults: No studies met the inclusion criteria
Excluded studies Study Aro et al 1999 (187) Jitendra et al 2004 (188) Avrium et al 2001 (189) Dpfner and Rothenberger2007 (190) Frankel et al 1997 (191) Patel and Curtis 2007 (192) Kolko et al 1999 (193) Jensen et al 2007 (137)
Reason for exclusion ADHD symptoms only Participants did not have ADHD and a comorbid disorder Overview, not treatment outcomes Overview, not treatment outcomes
Insufficient numbers of children with ADHD and ODD in the analysis, no data reported by group ADHD plus ODD Not controlled and no statistical analysis Combined psychosocial and medication
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Does not present separate detailed analysis of ADHD plus comorbid conditions
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Medication Management
Stimulant medication
Research question: 13a. For individuals with ADHD, do stimulant pharmacological interventions, compared with placebo, improve outcomes? Selection criteria Population Inclusion criteria
Individuals with ADHD diagnosed according to standard criteria; DSM-III, DSMIII-R, DSM-1V or ICD10
Intervention
Stimulant pharmacological interventions (eg. dexamphetamine and methylphenidate; long and short acting formulations)
Comparator Outcomes
Placebo
Secondary: School/work achievement, quality of life, social function. Study design
Search period Language
Date of search
Search terms MeSH: Attention deficit disorder with hyperactivity/ drug therapy/ or stimulants/ or methylphenidate/ or dexamphetamine/ or amphetamine salts/
Reference
Greenhill et al 2006 (194) Design RCT Level II Quality Adequate
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1997 onwards English March 2008
Intervention/ comparator Intervention MPH-IR Comparator Placebo
NHMRC defined levels of evidence (I-II) for intervention studies.
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Text words: adhd or addh or adhs or hyperactive$ or hyperkin$ or (attention adj deficit)
Results Statistically significant improvement with all but lowest dose of MPH-IR using CLAM/SNAP composite scores. Effect size (Dose) 0.22 (1.25mg) 0.48 (2.5mg) 0.52 (5mg) 0.87 (7.5mg)
Preschoolers
Population/Study information Population: Children aged 3 to 5.5 years with a DSM-IV consensus diagnosis of ADHD
Study information: Design & duration: PATS protocol: placebo-controlled titration phase, 4 week parallel design RCT and 10 month open label phase (~70 weeks total)
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No. Placebo n = 53 Active drug n = 61 Dose: Individual dose determined by titration (1.25mg, 2.5mg, 5mg or 7.5mg) Outcome measures: 1. Swanson, Nolan and Pelham (SNAP) rating scales 2. Conners, Loney and Milich (CLAM) scale Intervention MPH-IR Comparator Placebo Population: Children aged 4-6 years old who met the DSM-III-R criteria for the diagnosis of ADHD Study information: Design: cross-over RCT, 7-10 days on each dose. No. Placebo/ Active drug n = 41 Dose: Low dose MPH (0.3mg/kg) High dose MPH (0.5 mg/kg) Outcome measures: 1. Cognitive skills; Gordon Diagnostic System Delay and Vigilance Task 2. Behavioural; Conners Parent Rating Scale-Revised (CPRS-R) 3. Attention; Dot-to-Dot tasks, Cancellation task, Compliance task
Musten et al 1997 (195) Design RCT Level II Quality Poor Setting Canada Industry funding No
Reference King et al 2006 (196) Design Systematic Review Level I Quality Adequate Setting UK Industry funding No
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Intervention/ comparator Intervention MPH-IR or MPH-ER Comparator Placebo
Population: Children and adolescents under 18 years diagnosed with ADHD (ICD-10 or DSM-IV)
Study information: MPH-IR Low dose Design: 12 studies of 3 - 8 weeks duration. No. n = 491 Dose: <15mg/day
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Statistically significant improvement on cognitive tasks; Gordons Delay (p < 0.001) Gordons Vigilance (p < 0.01), CPRS-R learning, conduct and hyperactivity (all p < 0.001) but not tasks of child compliance and attention. . Results Low dose MPH-IR versus placebo 6/12 studies included Hyperactivity: 3/6 studies reported improvement in the MPH group. 3/6 found no significant difference. Quality of life: 1/1 study reported no significant difference between groups. Study quality: all rated as poor. Medium dose MPH-IR versus placebo 9/22 studies included Hyperactivity: 8/9 reported improvement in the MPH group. 1/9 found no significant difference between groups. Quality of life: 1/1 study reported benefit in the MPH group. No difference was found between groups using the Conners Global Index as assessed by the parents. Study quality: all rated as poor. High dose MPH-IR versus placebo 2/10 studies included Hyperactivity: 1/2 reported
MPH-IR Medium dose Design: 22 studies of 3 weeks - 3 months duration. No. n = 1219 Dose: 15 50mg/day MPH-IR High dose Design: 10 studies of 3 12 weeks information. No. n = 936* Dose: > 50 mg/day MPH-ER Low dose Design: 2 studies of 4 - 8 weeks
NB: Majority of included studies had industry funding
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duration. No. n =66 Dose: 20mg/day MPH-ER Medium dose Design: 5 studies of 3-4 weeks duration. No. n = 949* Dose: 20-40 mg/day MPH-ER High dose Design: 1 study of 4 weeks duration. No. n = 47 Dose: > 40 mg/day
improvement in the MPH group. 1/2 found no significant difference between groups. Quality of life: 1/1 study reported benefit in the MPH group. Study quality: all rated as poor. Low dose MPH-ER versus placebo 2/2 studies included Hyperactivity: 1/1 reported improvement in the MPH group. Quality of life: 1/1 study reported benefit in the MPH group. Study quality: 2/2 rated as poor.
Outcome measures: 1. Hyperactivity (using any scale that measured hyperactivity specifically) 2. Quality of life (using Clinical Global Impression (CGI) as a proxy)
King et al 2006 (196) Design Systematic Review Level I Quality Adequate Setting UK Industry Funding No
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Intervention DEX or DEX-TR Comparator Placebo
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Medium dose MPH-ER versus placebo 4/5 studies included Hyperactivity: 1/1 reported improvement in the MPH group. Quality of life: 2/4 study reported benefit in the MPH group. 2/4 did not report significance. Study quality: All rated as poor. High dose MPH-ER versus placebo 1/1 study included Hyperactivity: 0 studies Quality of life: 1/1 study reported benefit in the MPH group. Study quality: 1/1 rated as poor. Authors conclusions: The plethora of MPH studies suggest that MPH is effective at reducing hyperactivity and improving quality of life. It was noted that the majority of studies that evaluated the effectiveness of MPH did not adequately report their study methodology. Hence, the reliability of the study results is not known. Medium dose DEX (10 20mg/day) versus placebo 1/2 studies included Hyperactivity: 1/1 reported improvement in the MPH group for the symptom checklist, but not the parent questionnaire. Quality of life: 1/1 study reported benefit in the MPH group. Study quality: 1/1 rated as poor. High dose DEX (> 20 mg/day) versus placebo 1/2 studies included Hyperactivity: 1/1 reported improvement in the MPH group (no significance data). Quality of life: 1/1 study reported benefit in the MPH group. Study quality: 1/1 rated as good High dose DEX-TR (10-15mg/day) versus placebo
Study information: DEX Medium dose Design: 2 studies of 8 weeks - 15 months duration. No. n = 60 Dose: 10 20mg/day DEX High dose Design: 3 studies of 12 weeks 16 months duration. No. n = 65 Dose: > 20 mg/day
NB: majority of included studies had
DEX-TR High dose Design: 1 study of 3 months duration No. n = 18 Dose: 10-15mg/day
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industry funding
Outcome measures: 1. Hyperactivity (using any scale that measured hyperactivity specifically) 2. Quality of life (using Clinical Global Impression (CGI) as a proxy)
1/1 study included Hyperactivity: 1/1 reported improvement in the MPH group. Quality of life: 1/1 study reported benefit in the MPH group. Study quality: 1/1 rated as poor. Authors conclusions: DEX appears to be effective at reducing hyperactivity and improving quality of life, although this is based on a small number of studies. Only one study adequately reported the study methodology.
* Numbers not complete as confidential information not reported.
Adolescents
Reference Spencer et al 2006 (197) Design RCT Level II Quality Poor Setting USA Industry Funding Yes Intervention/ comparator Intervention MAS-ER Comparator Placebo Population/Study information
Population: Adolescents 13 - 17 years. DSM-IV-TR diagnosis of ADHD. Short term stimulant non-responders Study information: Design & duration: 8 weeks total 4 week parallel RCT No. Placebo n = 54 Active drug n = 226 Dose: Forced dose escalation. Group 1 (10mg/day) n = 56 Group 2 (20mg/day) n = 56 Group 3 (30mg/day) n = 58 Group 4 (40mg/day) n = 63
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Intervention MPH-ER Comparator Placebo Study information:
Outcome measures: 1. ADHD Rating Scale-IV (ADHD-RSIV) 2. Clinical Global Impressions (CGI)
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Results ADHD-RS-IV: Significant improvement in mean total scores for each treatment group compared to placebo (P < 0.005). Low baseline severity: improvements in the 20, 30, 40 mg/day groups compared to placebo (p < 0.01). High baseline severity: improvements in all active treatment groups compared with placebo (p < 0.02). CGI: A higher percentage of adolescents in all treatment groups were considered improved (10 mg/day 51.9% [p < 0.01]; 20 mg/day 66.0% [p < 0.001]; 30 mg/day 70.7% [p < 0.001]; 40 mg/day 63.9% [p < 0.001]) compared with adolescents receiving placebo (26.9%). Low baseline severity: Improvement in the 40mg/day group only was statistically significant compared with the placebo group (p = 0.023). High baseline severity: Improvement in the 20-mg/day group (p = 0.001), 30mg/d (p < 0.001), and 40-mg/d (p = 0.02) was statistically significant compared with the placebo group. Statistically significant improvement from baseline compared with placebo. ADHD-RS Investigator (p = 0.001), ADHD-RS Parent (p = 0.008), Conners-Wells (p = 0.001), CCI (p = 0.005)
Wilens et al 2006 (198) Design RCT
Population: Adolescents 13- 18 years. DSM-IV diagnosis of ADHD. Exclusions; history of non-response to MPH.
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Level II Quality Adequate Setting USA Industry Funding Yes
Design & duration: 15 week study; 2 week parallel RCT No. Placebo n = 90 Active drug n = 87 Dose: Determined by titration; 1870mg/day. Outcome measures: 1. ADHD Rating Scale (ADHDRS) (parent and investigator) 2. Conners-Wells Adolescent Selfreport of Symptoms Scale 3. Child Conflict Index (CCI) 4. Clinical Global Impressions (CGI) Improvement Subscale (investigator) 5. Global assessment of effectiveness (investigator)
The percentage responding to treatment was greater in the treatment group than the placebo group; ADHD-RS Investigator (p = 0.03), Investigator global assessment of effectiveness (p = 0.04), CGI (p = 0.01), Conners-Wells (p = 0.007). Note: This study had major design limitations: Possible bias in favour of the active medication by only including participants who could tolerate the medication, and who responded in the dose titration phase.
Adults
Reference Faraone et al 2004 (199) Design Meta-analysis Level I Quality Poor Setting USA Industry Funding Yes Intervention/ comparator Intervention MPH-IR Comparator Placebo
Population: Adults diagnosed with ADHD using DSM-III, DSM-III-R or DSM-IV diagnostic criteria. Study information: Design: Meta-analysis of 6 RCTs No. Placebo n = 113 Active drug n = 140 Dose: Mean daily dose; Low - 44mg/High 70mg
Biederman et al 2006 (200) Design: RCT Level II Quality Adequate Setting USA Industry funding Yes
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Intervention MPH-ER Comparator Placebo
Outcome measures: 1. ADHD Symptoms; ADHD Rating Scale: hyperactivity; impulsivity; inattention; total 2. Quality of life: Global Improvement Global rating, Global assessment scale Population: Adults aged 19-60 years diagnosed with ADHD using DSM-IV diagnostic criteria.
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Results Improvement in ADHD symptoms and quality of life for the treatment group compared to placebo. Pooled mean effect size for all included studies; 0.9 (p = 0.001) % of participants responding to treatment was greater in the treatment group than the placebo group; CGI (much improved/very much improved) p = 0.01, AAISRS (> 30% reduction) p = 0.001, AAISRS (> 50% reduction) p = 0.001, CGI & AAISRS combined p = 0.002. Significant improvement in inattention (p < 0.001) and hyperactive/impulsive (p = 0.03) DSM-IV symptoms from baseline to endpoint in the treatment group compared to the placebo group.
Study information: Design & duration: 6 week parallel RCT No. Placebo n = 77 Active drug n = 72 Dose: Individual dose titration: mean daily dose = 1mg/kg Outcome measures: 1. Adult ADHD Investigator System Report Scale (AAISRS) 2. Clinical Global Impression (CGI) Improvement scale 3. DSM-IV symptoms (inattention, hyperactive/impulsive
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Jain et al 2007 (201) Design RCT Level II Quality Adequate Setting Canada Industry funding Yes
Intervention MPH-MLR Comparator Placebo
Note: Clinical Response defined as; much or very much improved on the CGIImprovement scale plus a >30% reduction in AAISRS score. Population: Adults aged 18-60 years diagnosed with ADHD using DSM-IV diagnostic criteria. Study information: Design & duration: 5-11 week crossover RCT (3 week active drug treatment) plus optional 6 months open label extension No. Placebo/active drug n = 50 Dose: Individual dose titration; Max dose 80mg/day Outcome measures: 1. Clinical Global Impression (CGI) Global Improvement scale 2. Conners Adult ADHD Rating Scale-Short Version (CAARS: self & observer) 3. The LIFE questionnaire.
The Percentage of participants responding to treatment was greater in the treatment group than the placebo group. CGI (much/very much improved); p = 0.0158, CAARS- self (T-score <65); p = 0.0001 and CAARSobserver (T-score <65); p = 0.0707 Effect sizes [95% CI]: CGI; 0.90 [0.43-1.36] CAARS-Self; 0.53 [0.08-0.99]
Kooij et al 2004 (202) Design RCT Level II Quality Good
Setting The Netherlands Industry funding No
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Intervention MPH-IR Comparator Placebo Intervention MPH-IR Comparator Placebo
Note: Clinical Response defined as; much or very much improved on the CGIImprovement scale and a CAARS T score less than 65. Population: Adults that met DSM-IV diagnostic criteria for ADHD (Dutch version)
Study information: Design: 7 week cross-over RCT (3 weeks on active treatment) No. Placebo/Active drug n = 45 Dose: Mean dose = 0.9mg/kg per day Outcome measures: 1. Dutch self-report-version of the DSM-IV ADHD rating scale 2. Clinical Global Impression Scale 3. Dutch version of the Sheehan Disability Scale 4. Global Assessment of Functioning scale (GAF)
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No significant difference between active drug and placebo on quality of life measures (LIFE questionnaire). The percentage of participants responding to treatment was greater in the treatment group than the placebo group. DSM-IV ADHD rating scale; p = 0.011. CGI; p =0.011. DSM-IV ADHD rating scale plus CGI; p = 0.003 No significant difference between active drug and placebo for the GAF measure. The percentage of participants responding to treatment was greater in the treatment group than the placebo group; CGI & AAISRS combined; p < 0.0001. (analysis for the group completing the study)
Note: Clinical Response defined as; much or very much improved on the CGI severity scale plus a >30% symptom reduction in the self-reported DSM-IV ADHD rating scale. Population: Adults aged between 19 and 60 years that met DSM-IV diagnostic criteria for ADHD Study information: Design: 6 week parallel RCT No. Placebo n = 42 Active drug; n = 104
Spencer et al 2005 (203) Design RCT Level II
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Quality Adequate Setting USA Industry funding Yes
Dose: Individual dose titratation; Max dose = 1.3 mg/kg Outcome measures: 1. Adult ADHD Investigator System Report Scale (AISRS) 2. Clinical Global Impression (CGI) Scale Note: Clinical Response defined as; much or very much improved on the CGIImprovement scale plus a >30% reduction in AAISRS score. Population: Adults aged 19-60 years diagnosed with ADHD using DSM-IV diagnostic criteria. Study information: Design: 7 week cross-over RCT (3 weeks on active treatment) No. Placebo/Active drug n = 27 Dose: Forced dose escalation; 10mg/day to 60mg/day mean daily dose 54mg
Spencer et al 2001 (204) Design RCT Level II Quality Adequate Industry funding Yes
Intervention MAS Comparator Placebo
Weisler et al 2006 (205) Design RCT Level II Quality Adequate Setting USA Industry funding Yes
Paterson et al 1999 (206) Design RCT Level II Quality
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Intervention MAS-ER Comparator Placebo Intervention DEX Comparator Placebo Study information:
Outcome measures: 1. ADHD Rating Scale 2. Clinical Global Impression (CGI) Scale Population: Adults aged over 18 years that met DSM-IV diagnostic criteria for ADHD
Study information: Design: 4 week parallel RCT No. Placebo; n = 64 Active drug; n = 191 Dose: Forced dose escalation Group 1 (20mg/day) n = 66 Group 2 (40 mg/day) n = 64 Group 3 (60 mg/day) n = 61
T F A
The percentage of participants responding to treatment was greater in the treatment group than the placebo group; CGI (much improved/very much improved) p < 0.001, AAISRS (> 30% reduction) p < 0.001 Statistically significant improvement in measures of ADHD RS total (20 mg; p = 0.01, 40 mg; p < 0.001, 60mg; p < 0.001), ADHD RS - inattentive (20 mg; p = 0.005, 40 mg; p = 0.001, 60mg; p < 0.001) and ADHD RS hyperactive/impulsive (20 mg; p = 0.01, 40 mg; p = 0.002, 60mg; p < 0.001) Statistically significant improvement in the 4 hour post dose CAARS-S-S (p =.002) and the 12-hour post dose CAARS-S-S ADHD index (p < 0.001) The percentage of participants with a CGI rating of much improved/very much improved was greater for the active medication group than the placebo group (p < 0.001) Combined endpoint effect size for ADHD-RS was 0.8 (95% CI not reported). Statistically significant improvement of hyperactive (p = 0.004), inattentive (p < 0.001) and total (p < 0.001) symptoms (investigator rated) in the group receiving DEX compared to the placebo group. The % of participants with a CGI rating of much improved/very much improved
Outcome measures: 1. ADHD Rating Scale 2. Conners Adult ADHD Rating ScaleShort Version-Self-Report (CAARS-SS) 3. Clinical Global Impressions (CGI) severity improvement - efficacy
Population: Adults aged over 18 years with at least four inattentive and/or five hyperactive symptoms during the previous 6 months on the DSM-IV ADHD symptom checklist. Individuals with major psychiatric comorbidities were excluded.
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Adequate Setting Australia Industry funding No
Design: 6 week parallel RCT No. Placebo; n = 21 Active drug; n = 24 Dose: Not reported Outcome measures: 1. ADHD symptom scores (investigator rated) 2. Clinical Global Impressions (CGI) Global Severity Index Population: Adults aged over 21 years who met DSM-IV criteria for a diagnosis of ADHD Study information: Design: 6 week cross-over RCT, 2 weeks on active drug No. Placebo/ Active drug n = 22 Dose: Determined by titration. Max dose 40 mg/day Outcome measures: 1. ADHD Behavior Checklist for Adults: self-rated (symptom total, hyperactive, inattentive)
was greater for the active medication group than the placebo group (p < 0.001)
Taylor & Russo 2000 (207) Design RCT Level II Quality Adequate Setting USA Industry funding Not reported Taylor & Russo 2001 (208) Design RCT Level II Quality Adequate Setting USA
Intervention DEX Comparator Placebo Modafinal (data not extracted)
Industry funding Not reported
Summary Preschoolers: Two short-term studies were identified that addressed the use of stimulant medication for ADHD in preschoolers. Both studies looked at the use of MPH. No other types of stimulants have been tested in this population. Musten et al (195) described improvement in core ADHD symptoms. However, there was no significant improvement in measures of child compliance and attention tasks. The quality of this study was rated as poor. More recently Greenhill et al (194) found that 2.5, 5, and 7.5mg doses of MPH produced significant reductions in ADHD symptoms compared to placebo. The authors described an increase in the number and type of side effects compared to older children and found that the effect sizes were smaller than those for older children on the same medication. Although the overall quality of this study was considered adequate there were several limitations in reporting (for example no baseline
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Comparator Placebo Guanafacine (data not extracted)
Intervention DEX
Population: Adults diagnosed with ADHD using the DSM-IV ADHD Behavior Checklist for Adults
Study information: Design: 6 week cross-over RCT, 2 weeks on active drug No. Placebo/ Active drug n = 17 Dose: Determined by titration. Max dose 20 mg/day
Outcome measures: 1. DSM-IV ADHD Behaviour Checklist for adults (symptom total, hyperactive, inattentive) 2. Copeland Symptom Checklist for Adult Attention Deficit Disorder
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Statistically significant reduction in total symptoms (p < 0.05) and hyperactivity (p < 0.05) but not inattention or Copeland measures when receiving active medication compared to placebo.
Statistically significant reduction in total symptoms (p < 0.001), inattention (p < 0.01) and hyperactivity (0.05) when receiving active medication compared to placebo.
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comparison of the placebo and MPH groups) and as a result there is a need for caution in interpreting the results. Children and adolescents: King et al (196) reviewed the efficacy of MPH and DEX in children and adolescents with ADHD. The quality of the included studies was mixed, with many studies considered to be poor quality. Taking the methodological quality into consideration and some variations in results the overall conclusion was that stimulant medication may improve symptoms and quality of life in this population. This conclusion is based on 25 controlled trials of MPH and 5 of DEX. Although there have been numerous controlled trials of stimulant medications in children and adolescents the vast majority are studies of short to medium duration and the longterm impact of stimulants is not clear. Only a very few studies address stimulant use for periods two years or more.
Two additional studies were included that address the use of stimulants in adolescents. Spencer et al (197) found a significant improvement in core ADHD symptoms in adolescents assigned to the MAS-ER group over those assigned to placebo. The quality of this study was rated as poor and the results should be interpreted with caution. Wilens et al (198) investigated the use of MPH-ER in adolescents and reported an improvement in ADHD symptoms. However, the design of this study was such that only participants that tolerated the drug in the titration phase were included in the parallel comparison of active drug and placebo. This creates the potential for bias in favour of the active drug. Adults: Five studies that investigated the use of MPH in adults with ADHD were included. Faraone et al (199) described a meta-analysis of 6 randomised controlled trials, which supported the conclusion that MPH was effective in reducing symptoms of ADHD in adults. The methodological limitations of this meta-analysis resulted in this study being rated as poor quality. Four primary studies of good or adequate quality (200-203) reported consistent improvement in core ADHD symptoms for adults treated with MPH but the results for quality of life measures were less clear. Two studies of adequate quality addressed the use of mixed-amphetamine salts (204, 205) and reported benefit for both the immediate-release and extended-release formulations. Three studies of adequate quality (206-208) compared the use of DEX to placebo and reported improvement in core ADHD symptoms. Measures that look at the impact of medication on quality of life were not included in these studies. It should be noted that the majority of the identified studies have been sponsored, at least in part, by the manufactures of the medications. Excluded studies Study Biederman et al 2005 (209) Biederman et al 2006 (210) Fallu et al 2006 (211) Firestone et al1998 (212) Goodman et al 2005(213) Levin et al 2006(214) McGoey et al 2002 (150) McGough et al 2006 (215) Wilens et al 2002 (216) Wilens et al 2006(217)
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Reason for exclusion Not randomised controlled trial Not randomised controlled trial
Not randomised controlled trial Only safety data reported Not randomised controlled trial Clinic population Poor quality systematic review Not randomised controlled trial Poor quality systematic review Not randomised controlled trial
Long term use of stimulant medications

Research question 13b. For individuals with ADHD does the use of stimulant medications of 1 year or more, compared with placebo or standard care, affect outcomes? Selection Criteria Population Inclusion Criteria Individuals with ADHD diagnosed according to standard criteria; DSM-III, DSMIII-R, DSM-1V or ICD10 Intervention Comparator Outcomes
Pharmacological interventions given for 1 year or more
Placebo / no intervention / non-pharmacological interventions
Secondary: School/work achievement, quality of life, social function. Study Design Level I-III-2 for interventions [Studies must have a concurrent control group] Search Period Language 1997 - present English
Date of Search
Reference
MTA Cooperative Group 1999 (135) MTA Cooperative Group 2004 (136) Jensen, et al
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March 2008
Intervention/ comparator Intervention Medication management Comparator Community control
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Results 14 months: Statistically significant improvements in the medication management group over community control for inattention (parent and teacher-rated p=0.001), hyperactivity/impulsivity (parent and teacher-rated p=0.001), ODD aggression (teacher-rated only p=0.004), SSRS (parent-rated only [pvalue not reported]).
Population/Study information Population: children aged 7-9.9 years with DSM-IV diagnosis of ADHD. Study information: Design & duration: pseudo-RCT (parallel design) No. 14 months: community control n=146, medication management n=144 24 months:
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2007 (137) Design Comparative study with concurrent controls Level III-2 Quality Adequate Setting USA MTA study Industry funding No (Govt funded)
community control n=135, medication management n=128 36 months: community control n=116, medication management n=115 Dose: Varied Outcome measures: 1. SNAP: parent- and teacher-rated ADHD symptoms; parent- and teacher-rated ODD symptoms 2. Wechsler Individual Achievement Test (WIAT) reading score 3. Social Skills Rating System: parent- and teacher-rated
Groups were equivocal on classroom observation, ODD aggression (parentrated), SSRS (teacher-rated), parent child relations (assertion). 24 months: Medication management was more effective compared to the community control group for core ADHD symptoms (MTA medication vs not: p < 0.001) Effect size for ADHD symptoms: 0.3 No significant difference between groups for social skills (SSRS) (MTA medication vs not: p < 0.09) 36 months: No significant difference between medication management and community control groups on any measure (p-values not presented).
Summary
Preschoolers: No studies met our inclusion criteria that addressed the long-term safety and efficacy of ADHD medications in preschoolers. Children and adolescents: The Multimodal Treatment Study of ADHD (MTA) study addresses the long term use of stimulant medication for children with ADHD. No other studies met the inclusion criteria. The MTA Cooperative Group have now analysed study data at 14 months (135), 24 months (136) and 36 months (137). The MTA study compared four treatment groups; medication management, behavioral management, combined treatment and community care. Comparing the medication management group to the community control group to assess the effects of long-term stimulant use at the 14 month and 24 month time points the medication management was found to be superior to community control in improving core ADHD symptoms (135, 136). At both 14 and 24 months there were no significant differences between groups on measures of academic achievement or social skills (135, 136). At 36 months there was no significant difference between the medication group and the community control group on any measure. The MTA study has two critical methodological limitations that make it difficult to interpret the results and draw clear conclusions. The study was not placebo-controlled, placing restrictions on determining the efficacy of the interventions. In addition, following the conclusion of 14 month study participants were allowed to change treatment allocation, but continued to be followed up according to their initial treatment allocation regardless of what treatment they chose to use. Adults: No studies met our inclusion criteria.
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Effect sizes of medication algorithm effect at 14 months and 36 months: 14mth 36mth ADHD symptoms 0.86 - 0.10 ODD symptoms 0.49 - 0.06 Impairment 0.37 - 0.02 Social skills 0.42 - 0.04 Reading achievement 0.04 - 0.05
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Excluded studies Children and Adolescents Study Reason for exclusion Preschoolers Vitiello et al 2007 (218) 10 month study and open label Greenhill et al 2006 (194) 10 month open label extension period addresses adverse events only Children and adolescents King et al 2006 (196) Of 43 included studies the longest was 9 months 2 studies of 6 months & remaining studies were 3 months or less. Schachar et al 2002 (219) Go back to primary research as only 3/14 RCTs were 52 weeks Abikoff et al 2004a(220) Comparison groups are: MPH vs MPH+psychosocial vs Hechtman et al 2004 (221) MPH+attention control therefore does not contribute to pharm Abikoff et al 2004b (222) vs placebo/other non-pharm intervention Paternite et al 1999 (223) No control group Barbaresi et al 2006 (224) retrospective study and no control group Charach et al 2004 (225) no control group Wilens et al 2005 (226) Open label Gadow et al 1999 (227) Include in comorbidities Hechtman et al 2004 (228) Does not address primary or secondary outcome measures Konrad et al 2007 (229) Does not address primary or secondary outcome measures Barkley et al 2003(230) Does not address research question Fischer et al 2002 (231) Does not address primary or secondary outcome measures McGough et al 2005 (232) Open label
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Stimulant medication - side effects

Research question 13c. For individuals with ADHD who are taking medication, what are the main side effects? Selection criteria Population Inclusion criteria Individuals with ADHD diagnosed according to standard criteria; DSM-III, DSMIII-R, DSM-1V or ICD10 Intervention Comparator Outcomes Study design Pharmacological intervention
Placebo or other ADHD medications
Primary: side effects, adverse events
NHMRC defined levels of evidence (I-IV) for intervention and prognosis studies.
Search period Language Date of search
1997 - present English March 2008
Reference
Firestone et al 1998 (212) Musten et al 1997 (195) Design RCT Level II Quality Poor Setting Canada
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Preschoolers
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Results Side effects were significantly increased in mean number (p < .001) and severity (p < .001) in the High dose MPH group compared to placebo and in the High dose MPH group compared to the low dose MPH group. High dose MPH was associated with a significant increase in the following ratings compared to placebo; sad/unhappy (p < .001) decreased appetite (p < .001) nightmares (p < .01) drowsiness (p < .01) talks less with others (p < .01) uninterested in others (p < .001)
Population/Study information Population: Boys aged 4-6 years with a diagnosis of ADHD based on DSMIII-R criteria. Study information: Design & duration: Cross-over design RCT with 7-10 days on each arm No. n = 32 (27 boys 5 girls) Dose: Low dose 0.3 mg/kg High dose 0.5 mg/kg Outcome measures: 1. Side Effects Rating Scale (SERS) (Rate severity on a scale of 0 to 9 for 17 symptoms associated with MPH)
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Industry funding No
High dose MPH was also associated with a significant decrease in irritability (P < .001) and anxiousness (P < .001) compared to placebo. No significant effects from low dose MPH compared to Placebo. 21/183 (11%) of children withdrew due to adverse events Side effects that were significantly increased in the MPH group compared to placebo; RCT Phase: appetite decrease (p < 0.03) trouble sleeping (p < 0.03) weight loss (p < 0.03) Titration phase: Moderate to severe adverse events Decreased appetite (p < 0.03) Emotional outbursts (p < 0.03) Weight loss (p < 0.05)
Wigal et al 2006 (233) Design RCT Level II Quality Poor Setting USA (PATS) Industry funding No
Intervention MPH-IR Comparator placebo
Population: Children aged 3 to 5.5 years with a DSM-IV consensus diagnosis of ADHD Study Information: Design & duration: PATS protocol 70 week study with a placebo controlled titration phase, 4-week parallel design RCT and 10 month open label phase No. n = 183 RCT: Placebo n = 53 Active drug n = 61 Dose: Individual dose determined by titration (0 mg, 1.25mg, 2.5mg, 5mg or 7.5mg)
Reference King et al 2006 (196) Design Systematic review Level III-2 (not only RCTs considered) Quality Adequate Setting
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Intervention/ comparator Intervention MPH, DEX or ATX Comparator placebo Outcome measures: 1. Adverse events
Outcome measures: 1. Clinician rated adverse events Open ended questionsVital Signs Pulse & blood pressure (BP) Temperature Height, and weight Tachycardia & Hypertension Severity of abnormal movements (Yale Tic Severity Scale) 2. Parent/Teacher rated adverse events: Pittsburgh side effects rating scale - 4-
point (none, mild, moderate, or severe) drug-specific scale
3. Withdrawal due to adverse events
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Parent rated (lowest dose at which significant) trouble sleeping (5 mg p < 0.005) appetite loss (5 mg p < 0.003) stomachache (5 mg p < 0.02) dull/tired/listless (5 mg p < 0.02) Social withdrawal (5 mg p < 0.03) buccal-lingual movements (1.25 mg p
< 0.01)
Teacher rated (lowest dose at which significant) Appetite loss (1.25 mg p < 0.02) Dull/listless (5 mg p < 0.01)
Population/Study information Population: Children and adolescents under 18 years diagnosed with ADHD (ICD-10 or DSM-IV) Study information: Design: systematic review of data from 64 studies, 38 of which reported on adverse events. RCTs and open-label studies were considered
Results MPH: Higher dosages of MPH-IR appear to be associated with the occurrence of headache, loss of appetite, stomach ache and insomnia compared with placebo. MPH-ER appears to be associated with decreased appetite and increased insomnia. DEX: High doses of DEX appear to be associated with decreased appetite and increased sleeping problems. ATX: ATX of any dose may impair appetite. MPH-IR versus MPH-ER: Higher
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UK Industry funding No
occurrence of headache in the MPH-ER group. (1 study) MPH versus DEX: No statistically significant differences in adverse events were detected in the 2 studies comparing MPH and DEX. MPH-ER versus ATX: Higher occurrence of decreased appetite and increased insomnia in the MPH-ER group compared to ATX. (1 study)
Adults
Reference Biederman et al 2006 (200) Design: RCT Level II Quality Adequate Setting USA Industry funding Yes Jain et al 2007 (201) Design RCT Level II Quality Adequate Setting Canada Industry funding Yes Intervention/ comparator Intervention MPH-ER Comparator Placebo
Population: Adults aged 19-60 years diagnosed with ADHD using DSM-IV diagnostic criteria. Study Information: Design: 6 week parallel RCT No. Placebo n = 77 Active drug n = 72 Dose: Individual dose titration: mean dose = 1mg/kg/day Outcome measures: 1. Open ended questions 2. weight and height 3. vital signs
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Intervention MPH-MLR Comparator Placebo
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Author conclusions: Overall reporting of adverse was poor and adequate and informative data regarding the potential adverse effects of MPH, DEX and ATX are lacking. Results Adverse events that were significantly increased in the MPH group compared to placebo; decreased appetite (p < 0.001), tension/jitteriness (p < 0.001), gastrointestinal (p = 0.03) sleep problems (p = 0.02), depression (p = 0.02), dizziness (p = 0.02), cardiovascular complaints (p = 0.04) and anxiety (p = 0.03) Significant decrease in weight in the MPH group compared to placebo (p < 0.001). No participants withdrew due to adverse events. Adverse events that were significantly increased in the MPH group compared to placebo; anorexia (p = 0.0325), nervousness (p = 0.0047), and anxiety (p = 0.0082) There was a higher adverse event severity in the MPH group compared to placebo (p = 0.0066 and ITT analysis p = 0.0014). The MPH group had a significantly greater mean weight loss than the placebo group (p = 0.0001). There were no significant differences
Population: Adults aged 18-60 years diagnosed with ADHD using DSM-IV diagnostic criteria. Study Information: Design: 5-11 week cross-over RCT (3 week active drug treatment) plus optional 6 months open label extension No. Placebo/active drug n = 50 Dose: Individual dose titration; Mean dose: 57.8 mg/day & Max dose: 80mg/day Outcome measures: 1. Spontaneous reporting of side effects 2. adverse event subscale on the Patient satisfaction survey (unpublished and no further details provided)
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between MPH and placebo in terms of diastolic/systolic BP or heart rate. No serious adverse events occurred, although 84% and 58% of participants experienced at least one adverse event on MPH and placebo respectively. No participants withdrew due to adverse events. The only adverse effect that occurred significantly more often using MPH than using placebo, was loss of appetite (22% v. 4%; p = 0.039).
Kooij et al 2004 (202) Design RCT Level II Quality Good Setting Netherlands Industry funding No Spencer et al 2005 (203) Design RCT Level II Quality Adequate Setting USA Industry funding Yes
Intervention MPH-IR Comparator Placebo
Population: Adults that met DSM-IV diagnostic criteria for ADHD (Dutch version) Study Information: Design: 7 week cross-over RCT (3 weeks on active treatment) No. Placebo/Active drug n = 45 Dose: Mean dose: 0.9mg/kg/day
Outcome measures: 1. Modified Side Effects Rating Scale
Population: Adults aged between 19 and 60 years that met DSM-IV diagnostic criteria for ADHD
Spencer et al 2001 (204) Design RCT Level II Quality Adequate Industry funding Yes Weisler et al 2006 (205)
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Intervention MAS Comparator Placebo Intervention MAS-ER
Study Information: Design: 6 week parallel RCT No. Placebo n = 42 Active drug; n = 104 Dose: Individual dose titration; Mean dose: 1.1mg/kg/day Outcome measures: 1. Adverse events (method not reported) 2. Discontinuation rates
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14/104 (13%) individuals taking MPH withdrew due to adverse events compared to 2/42 (5%) in the placebo group. The only adverse event causing discontinuation that was significantly different from placebo was high blood pressure (p < 0.0001). Adverse events occurring more frequently in the MPH group than the placebo group were; decreased appetite (p < 0.01), dry mouth (p < 0.001) and moody (p < 0.001). Statistically significant increases in pulse (p < 0.001), ECG ventricular rate (p < 0.001) and QTc interval (p < 0.01) but not diastolic or systolic blood pressure were associated with MPH treatment. Adverse events that were significantly increased in the MAS group compared to placebo were appetite suppression (p = 0.03), weight loss (p < 0.001) and agitation (p = 0.05). 23/191 individuals receiving active drug withdrew from the study due to adverse events. Most commonly,
Population: Adults aged 19-60 years diagnosed with ADHD using DSM-IV diagnostic criteria. Study Information: Design: 7 week cross-over RCT (3 weeks on active treatment) No. Placebo/Active drug n = 27 Dose: Forced dose escalation; 10mg/day to 60mg/day mean daily dose 54mg Outcome measures: 1. Adverse events: open ended questions Population: Adults aged over 18 years that met DSM-IV diagnostic criteria for ADHD
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Design RCT Level II Quality Adequate Setting USA Industry funding Yes
Comparator Placebo
Study Information: Design: 4 week parallel RCT No. Placebo; n = 64 Active drug; n = 191 Dose: Forced dose escalation Group 1 (20mg/day) n = 66 Group 2 (40 mg/day) n = 64 Group 3 (60 mg/day) n = 61 Outcome measures: 1. Spontaneously reported adverse events 2. Discontinuation rates
insomnia (3.9%), agitation (1.6%), anxiety (1.6%), and nervousness (1.6%). The most commonly reported adverse events were dry mouth (27.4%), anorexia/decreased appetite (25.5%), insomnia (23.9%), and headache (23.6%). Statistically significant treatment effect of MAS XR on pulse (p = 0.025), heart rate (p < 0.001), QT (p = 0.002) and QTcB (p = 0.003) intervals and systolic BP (p = 0.015) but not on diastolic BP (p = 0.135). Significant impact on effect on weight (p < 0.001). Insomnia (38%), irritability (14%), muscle tension (24%) and appetite suppression (19%) were the most common adverse events for individuals taking DEX. No significant differences in the prevalence of side effects between DEX and placebo.
Taylor & Russo 2000 (207) Design RCT Level II Quality Adequate Setting USA
Intervention DEX Comparator Placebo Modafinal (data not extracted)
Population: Adults aged over 21 years who met DSM-IV criteria for a diagnosis of ADHD Study Information: Design: 6 week cross-over RCT, 2 weeks on active drug No. Placebo/ Active drug n = 22 Dose: Determined by titration. Mean dose: 21.8 8.9 mg/day Outcome measures: 1. Spontaneous reporting of side effects.
Industry funding Not reported Taylor & Russo 2001 (208) Design RCT Level II Quality Adequate Setting USA
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Intervention DEX Comparator Placebo Guanafacine (data not extracted)
Population: Adults diagnosed with ADHD using the DSM-IV ADHD Behavior Checklist for Adults Study Information: Design: 6 week cross-over RCT, 2 weeks on active drug No. Placebo/ Active drug n = 17 Dose: Determined by titration. Mean dose: 10.2 7.4 mg/day
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No participants withdrew from the study. Muscle tension (5/17) was the most commonly reported adverse event for individuals taking DEX. There were no significant differences in the number of side effects between DEX and placebo.
Outcome measures: 1. 18 item rating scale for typical side effects
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Summary
Preschoolers: Two clinical trials were identified that reported on adverse events in preschoolers receiving MPH. The first study was a cross-over trial of short duration (7-10 days each on placebo, low dose MPH (0.3 mg/kg) and high dose MPH (0.5 mg/kg)) (195, 212). The higher dose of MPH resulted in a significant increase in number and severity of adverse events including decreased appetite, nightmares, feeling sad/unhappy, and social ratings such as talks less with others compared with both placebo and the lower dose of MPH. There were no significant differences between low dose MPH and placebo. This study was rated as poor in quality. In the second study Wigal et al (233) described the adverse events identified in the PATS protocol. This study was a trial of intermediate length (~17 months) that was rated poor in quality. The side effects that were significantly increased in the MPH group include decreased appetite, trouble sleeping, weight loss, emotional outbursts and social withdrawal. In both studies the authors have found that the profile of unwanted side effects differed to those seen in school-age children where decreased appetite, delay of sleep onset, headaches, and stomachache are generally the most frequently reported side effects. Wigal et al (233) reported that 11% of the participants withdrew from the study because of unwanted side effects in the PATS protocol. This is high compared with the Multimodal Treatment Study of ADHD (MTA) which looked at school-aged children. In the MTA study less than 1% of the participating children withdrew because of unwanted side effects. Children and adolescents: King et al (196) reviewed the occurrence of adverse events in children and adolescents receiving MPH, DEX and ATX. The main conclusions drawn are as follows: Higher dosages of MPH-IR appear to be associated with the occurrence of headache, loss of appetite, stomach ache and insomnia compared with placebo.
MPH-ER appears to be associated with decreased appetite and increased insomnia. DEX: High doses of DEX appear to be associated with decreased appetite and increased sleeping problems.
Adverse events data from head-to-head comparisons of medications were limited. One study comparing MPH-IR and MPH-ER found a higher occurrence of headache in the MPH-ER group. In two studies comparing DEX and MPH no statistically significant differences in adverse events were detected and in one study comparing ATX and MPH-ER, decreased appetite and increased insomnia were more frequent in the ER-MPH group. King et al (196) discussed the poor reporting of adverse events in the literature, concluding that informative data regarding the potential adverse effects of MPH, DEX and ATX are lacking. Of the 64 studies included in the clinical effectiveness section of the review, 38 contributed some data to the analysis of adverse events. However, this contribution was minimal in the majority of cases. Adults: Two studies were identified addressing the use of MPH-IR in adults. In the cross-over trial reported by Kooij et al (202) participants received active medication for a total of three weeks. There were no withdrawals due to adverse effects and the only adverse event that occurred significantly more often using MPH than placebo was loss of appetite. The quality of this study was rated as good. The six week parallel trial reported by Spencer et al (203) had a higher withdrawal rate due to adverse events in the MPH-IR group (13%) compared to the placebo group (5%). The number of participants withdrawing due to high blood pressure was significantly increased in the MPH-IR group compared to placebo. Adverse events occurring more frequently in the MPH group than the placebo group were; decreased appetite, dry mouth
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and moodiness. The quality of this study was rated as adequate. The apparent increase in reported adverse events in Spencer et als study (203) compared to Kooij et al (202) may reflect the longer study duration and the higher dose (1.1/mg/kg/day compared to 0.9mg/kg/day). Biederman et al (200) found an increase in decreased appetite, tension/jitteriness, gastrointestinal problems, sleep problems, dizziness, cardiovascular complaints, anxiety and weight loss in participants receiving MPH-ER compared to placebo. This 6 week study was rated as adequate in quality. Jain et al (201) examined multi-layer release methylphenidate (MPH-MLR) an extendedrelease formulation. During the 3 week randomised controlled trial, anxiety, nervousness, weight loss and anorexia were increased in the group receiving MPH compared to the placebo group. In addition, the severity of the adverse events was increased in the MPH group. No withdrawals due to adverse events occurred over the duration of the study (~ 7 months). The quality of this study was rated as adequate. Spencer et al (204) addressed the use of MAS in adults in a cross-over trial with 3 weeks on active medication. Appetite suppression, weight loss and agitation were increased in the MAS group compared to placebo. This study was rated as adequate in quality. Weisler et al (205) conducted a 4 week RCT with MAS-ER. 125 of participants withdrew from the study as a result of adverse events. Dry mouth, anorexia/decreased appetite, insomnia, and headache were the most frequently reported adverse events. Weight was significantly decreased in the MAS-ER group compared to placebo. This study was adequate in quality.
Two studies addressed the use of DEX in adults (207, 208). Both studies found no significant difference in the number of side effects in the DEX group compared to the placebo group. Insomnia, irritability and muscle tension were the most common adverse events for participants taking DEX in one study (207) and muscle tension was most frequent adverse event in the second study (208). Overall: As highlighted by King et al (196) there are several limitations in adverse events reporting in the literature. Many studies provide only limited information about adverse events and standardised reporting between studies is lacking. Measures of adverse events vary widely between reports. The most frequently used measures were open ended questions and rating scales that are limited to the most common side effects associated with the medication in question. When only one of these methods is used there is considerable room for bias in reporting. Developmental age may also impact on reporting, as younger children may not have the communication skills to clearly convey side effects. Finally, the long term safety effects of ADHD medications are not clearly established as long term studies of adverse events are rare. Excluded studies Study Biederman et al 2005 (209) Fallu et al 2006 (211) Faraone et al 2004 (199) Flavia Dorrego et al 2002(234) Greenhill et al 2006 (194) Jensen et al 2007 (137) Horrigan and Barnhill 2000 (235)
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Reason for exclusion No comparator employed.
No comparator employed. Adverse events or side effects not reported insufficient details of adverse events/side effects
Did not report reported data which were informative to the analysis of adverse events. Adverse events or side effects not reported No comparator employed.
Levin et al 2006 (214) McGough et al 2006 (215) Paterson et al 1999 (206) Reimherr et al 2007 (236) Short et al 2004 (237) Wilens et al 2006 (217) Wilens et al 2002 (216) Wilens et al 2006 (198)
Restricted clinic population (methadone-maintained patients) No comparator employed. Adverse events or side effects not reported Outcomes not directly relevant to question Adverse event data combined for MPH and MAS Participants with hypertension, consider for Question 16 Adverse events and side effects not adequately reported. Adverse events and side effects not adequately reported.
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Atomoxetine
Research question 14a. For individuals with ADHD, does the use of atomoxetine, compared with placebo, improve outcomes? Selection criteria Population Inclusion criteria Individuals with ADHD diagnosed according to standard criteria; DSM-III, DSMIII-R, DSM-1V or ICD10 Intervention Comparator Outcomes
Non-stimulant pharmacological interventions (eg. atomoxetine) Placebo
Secondary: School/work achievement, quality of life, social function. Study design Search period Language Date of search Search terms NHMRC defined levels of evidence (I-II) for intervention studies. 1997-2008 English
MeSH: Attention deficit disorder with hyperactivity/ drug therapy/ or atomoxetine/
Reference King et al 2006 (196) Design Systematic Review Level I Quality Adequate Setting UK
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March 2008
Intervention/ comparator Intervention ATX Comparator Placebo
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Text words: adhd or addh or adhs or hyperactive$ or hyperkin$ or (attention adj deficit) tomoxetine
Results Low/medium dose ATX (<1.5mg/kg/day) versus placebo 3/3 studies included Hyperactivity: 3/3 studies reported improvement in the ATX group. The lowest dose of ATX examined in 1/1 study (0.5 mg/kg/day) was not significantly different from placebo. Quality of life: 3/3 studies reported improvement for the ATX group. The lowest dose of ATX examined in 1/1 study (0.5 mg/kg/day) was not significantly different from placebo. Study quality: 1/3 studies rated as good and 2/3 rated as poor.
Population/Study information Population: children and adolescents under age of 18 diagnosed with ADHD (ICD-10 or DSM-IV)
Study information: ATX low/medium dose Design: 3 studies of 6 8 weeks duration. (all parallel design) No. Placebo n = 311 ATX n = 338 Dose: <1.5mg/kg/day
ATX high dose: Design: 6 studies of 7 weeks 9 months duration (all parallel design)
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Industry funding No NB: The majority of included studies did have industry funding
No. Placebo n = 327 ATX n = 499 Dose: 1.5mg/kg/day Outcome measures: 1. Hyperactivity (using any scale that measured hyperactivity specifically) 2. Quality of Life (using Clinical Global Impression (CGI) as a proxy)
High dose ATX (1.5mg/kg/day) versus placebo 6/6 studies included Hyperactivity: 5/6 studies reported improvement in the ATX group. 1/6 found no significant difference between groups. Quality of life: 4/4 studies reported improvement for the ATX group. Study quality: 2/6 studies rated as good and 4/6 rated as poor. Authors Conclusions: There was consistent evidence that ATX was superior to placebo for hyperactivity and CGI. Studies on ATX more often reported the study methodology well, and the results are likely to be reliable.
Adults
Reference Michelson et al 2003 (238) Design RCT ( x2) Level II Quality Adequate Setting USA Industry funding Yes Intervention/ comparator Intervention ATX Comparator Placebo
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Population: Adults who met DSM-IV criteria for ADHD
Study information: Design: 10 week parallel RCT No. Study 1 Placebo n = 139 Active drug n =141 Study 2 Placebo n = 127 Active drug n = 129 Dose: Determined by titration. (Start dose 60mg/day & max dose 120 mg/day)
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Results Study 1: Statistically significant improvement in the ATX group (103/141) over placebo (107/139) in all ADHD symptom measures and 2 of 4 Sheehan disability measures. Study 2: Statistically significant improvement in the ATX group (94/129) over placebo (104/127) in all ADHD symptom measures but no significant difference in any of 4 Sheehan disability measures.
Outcome measures: 1. Conners Adult ADHD Rating ScaleShort Version (CAARS); total score, hyperactive/impulsive, inattentive (Investigator/Self rated) 2. Clinician Global Impression (CGI) Severity Scale 3. WenderReimherr Adult Attention Deficit Disorder Scale 4. Social and occupational functioning (Sheehan disability scale)
Summary
The safety and efficacy of ATX has not been established in children less than six years of age (239) and no studies were found that addressed the use of ATX in preschoolers. King et al (196) reviewed the efficacy of ATX in children and adolescents with ADHD and found consistent results in support of the conclusion that ATX may reduce symptoms and improve
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quality of life. This conclusion is based on 9 placebo-controlled double-blind RCTs of short duration using either a low/medium dose (<1.5mg/kg/day) or a high dose (>1.5mg/kg/day). The quality of the included studies was mixed and the majority of these trials have been sponsored, at least in part, by the manufacturers of ATX. In adults two randomised controlled trials (reported in one article) met our inclusion criteria. These studies reported by Michelson et al (238) found that ATX was effective in reducing symptoms associated with ADHD. However, the effect of ATX on the Sheehan disability measures such as work life, social life and family life was less clear. The long term safety and efficacy of ATX has not been established. The longest trials reported on to date are open label studies of up to two years in children (6-7 years) (240), adolescents (241) and adults (242). Excluded studies Study Adler et al 2006 (243) Adler et al 2005 (242) Adler et al 2006 (244) Faraone et al 2005 (245) Faraone et al 2005 (246) Kratchovil et al 2006 (240) Reimherr et al 2005 (247) Wilens et al 2006 (248) Wilens et al 2006 (241)
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Reason for exclusion Study was not placebo controlled Study was not a randomised controlled trial Study was not a randomised controlled trial Study was not a randomised controlled trial Study did not address primary or secondary outcomes outlined in inclusion criteria Combines data from randomised controlled trials and nonrandomised controlled trials. Study did not address primary or secondary outcomes outlined in inclusion criteria Does not directly address the research question Combines data from randomised controlled trials and nonrandomised controlled trials.
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Atomoxetine - long term use

Research question 14b. For individuals with ADHD does use of atomoxetine for 1 year or more, compared with placebo or standard care, affect outcomes? Selection Criteria Population Inclusion Criteria Individuals with ADHD diagnosed according to standard criteria; DSM-III, DSMIII-R, DSM-1V or ICD10 Intervention Comparator Outcomes
Pharmacological interventions given for 1 year or more
Placebo / no intervention / non-pharmacological interventions
Secondary: School/work achievement, quality of life, social function. Study Design Level I-III-2 for interventions [Studies must have a concurrent control group] Search Period Language Date of Search Search terms 1997 - present English
Reference
Michelson et al 2004 (249) Design RCT Level II Quality Adequate Setting International
R D
March 2008
Intervention/ comparator Intervention Atomoxetine Comparator Placebo Outcome measures:
T F A
Results Statistically significant difference between ATX and placebo for ADHDRS (total score, inattention and hyperactivity/impulsivity subscales all p<0.001), CGI-S (0.003), CPRS (ADHD index and hyperactivity scale both p<0.001), but not for CTRS (all measures P>0.05), and CHQ. Significant difference between groups on both dichotomous outcomes: Symptom return to 90% or greater baseline ADHD RS total score and increase in CGI-S of at least 2 points
Population/Study information Population: children aged 6 to 15 years who met DSM-IV criteria for ADHD.
Study information: Design & duration: Randomized double-blind controlled trial, 12 weeks open label, 9-month, double-blind, relapse prevention phase No. placebo n=124, ATX n=292 Dose: divided twice daily dose to maximum 1.8 mg/kg/day
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academic collaboration Industry funding Yes
1. 2. 3.
4. Buitelaar et al 2007 (250) Design RCT Level II Quality Adequate Setting International academic collaboration Industry funding Yes Intervention Atomoxetine Comparator Placebo
Investigator-administered version of the ADHD RS Clinical Global ImpressionSeverity (CGI-S) Revised Conners Parent and Teacher Rating Scales: Short Form (CPRS-R:S and CTRS-R:S) Child Health Questionnaire (CHQ)
(p=0.002); 50% increase in ADHD RS total score and increase of 2 or more in CGI-S score from scores at the time of randomization (p<0.001).
Population: children aged 6 to 15 years who met DSM-IV criteria for ADHD.
Study information: Design & duration: Randomized double-blind controlled trial, 18 months (12 weeks open label, 9-month, double-blind, relapse prevention phase, second randomization for further 6 months) No. placebo n=82, ATX n=81 Dose: divided twice daily dose to maximum 1.8 mg/kg/day Outcome measures: 1. Investigator-administered version of the ADHD RS 2. Clinical Global ImpressionSeverity (CGI-S) 3. Revised Conners Parent and Teacher Rating Scales: Short Form (CPRS-R:S and CTRS-R:S) 4. Child Health Questionnaire (CHQ)
Summary
Preschoolers: No studies met our inclusion criteria that addressed the long-term safety and efficacy of atomoxetine in preschoolers.
Children and adolescents: Michelson et al (249)and Buitelaar et al(250) report two separate comparative arms of a study that addressed the long-term use of ATX compared to placebo. In the first part of this study, participants who had responded to ATX in a 10 week open-label trial were then randomised to receive ATX or placebo for 9 months. In the second part of the study, participants that had completed 1 year of double-blind atomoxetine treatment were then randomly assigned to continued ATX or placebo for 6 months.
Michelson et al (249) described the outcomes of the first randomisation of ATX treatment compared to placebo. A statistically significant difference between ATX and placebo for improvement of core ADHD symptoms was found on some (ADHD RS and CPRS-R:S) but not all measures (CTRS-R:S). Buitelaar et al (250) reported on the comparison of outcomes for the final 6 months of the study, finding that ATX was effective compared to placebo for two outcomes measures of ADHD symptoms (ADHD RS and CTRS-R:S). The quality of both studies was rated as adequate. While there is some evidence from this research supporting the long-term effectiveness of ATX for children and adolescents with ADHD, the design of this study allows for bias towards a favourable outcome for the ATX group compared to placebo. Participants were initially screened
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R D
T F A
Significant difference in 50% worsening in ADHD- RS severity score above the last pre-randomization visit between groups: ATX 7.4% Placebo 19.5%
Statistically significant difference between ATX and placebo for ADHDRS total score (p<0.001), inattention subscore (p=0.002), hyperactivity / impulsivity subscore (p<0.001), CTRSR:S (p<0.001), but not for CPRS-R:S (p=0.54), and CHQ (0.35).
in an open-label trial and only those that responded to ATX treatment went on to participate in the long-term trial. Adults: No studies met our inclusion criteria. Excluded studies Children and Adolescents Study Reason for exclusion Children and adolescents King et al 2006 (196) Of 43 included studies the longest was 9 months 2 studies of 6 months & remaining studies were 3 months or less. Schachar et al 2002 (219) Go back to primary research as only 3/14 RCTs were 52 weeks Buitelaar et al 2004 (251) Open label Perwien et al 2006 (252) Open label Kratchovil et al 2006 Open label studies (240) Wilens et al 2005 (241) Open label studies Bakken et al 2008 (253) Treatment length under 1 year. Adults Adler et al 2005 (242) Open label
R D
T F A
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Atomoxetine side effects

Research question 14c. For individuals with ADHD who are taking atomoxetine, what are the main side effects? Selection criteria Population Inclusion criteria Individuals with ADHD diagnosed according to standard criteria; DSM-III, DSMIII-R, DSM-1V or ICD10 Intervention Comparator Outcomes Study design Atomoxetine
Placebo or other ADHD medications
Primary: side effects, adverse events
NHMRC defined levels of evidence (I-IV) for intervention and prognosis studies.
Search period Language Date of search Search terms
Reference King et al 2006 (196) Design Systematic review Level III-2 (not only RCTs considered) Quality Adequate Setting UK
R D
Intervention/ comparator Intervention MPH, DEX or ATX Comparator placebo Outcome measures: 1. Adverse events
T F A
Results MPH: Higher dosages of MPH-IR appear to be associated with the occurrence of headache, loss of appetite, stomach ache and insomnia compared with placebo. MPH-ER appears to be associated with decreased appetite and increased insomnia. DEX: High doses of DEX appear to be associated with decreased appetite and increased sleeping problems. ATX: ATX of any dose may impair appetite. MPH-IR versus MPH-ER: Higher occurrence of headache in the MPH-ER group. (1 study)
Population/Study information Population: Children and adolescents under 18 years diagnosed with ADHD (ICD-10 or DSM-IV) Study information: Design: systematic review of data from 64 studies, 38 of which reported on adverse events. RCTs and open-label studies were considered
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Industry funding No
MPH versus DEX: No statistically significant differences in adverse events were detected in the 2 studies comparing MPH and DEX. MPH-ER versus ATX: Higher occurrence of decreased appetite and increased insomnia in the MPH-ER group compared to ATX. (1 study)
Wang et al 2007 (254) Design Randomised double blind comparative study Level III-3 Quality Poor Setting China, Mexico, Korea
Intervention ATX Comparator MPH
Population: children and adolescents aged 6-16 with a DSM-IV diagnosis of ADHD Study Information: Design: head to head comparison Duration: 8 weeks No. ATX n = 164 MPH n = 166 Dose: MPH 0.2-0.6 mg/kg/day ATX 0.8-1.8 mg/kg per day
Industry funding Yes Wilens et al 2006 (241) Design Systematic review Level III-3 Quality Poor Setting USA Industry funding Yes
R D
Intervention ATX Comparator Placebo None
Outcome measures: 1.Treatment-emergent adverse events (TEAEs) 2. Weight 3. Vital signs
Population: Adolescents 12 to 18 with ADHD diagnosed by DSM-IV Study Information: Design: Systematic review of 13 clinical trials (6 RCT & 8 open-label) Duration: 2 weeks 2 years No. ATX treated n = 601 Treatment duration; 3 months or more n = 537 2 years n = 219 Dose: ATX 0.8-1.8 mg/kg per day
T F A
Most frequent TEAEs (% of treatment group) ATX: anorexia (37.2%), decreased appetite (28%), somnolence (26.2%) & nausea (20.1%) MPH: anorexia (25.3%), decreased appetite (19.3%), nausea (20.1%) & headache (9.2%) Somnolence (p <0.001), vomiting (p = 0.007), nausea (p = 0.014), anorexia (p = 0.024) & dizziness (p = 0.024) were reported significantly more often in the ATX group compared with the MPH group 31/601 (5.2%) of adolescents withdrew due to adverse events. The most frequently reported events causing discontinuation were nausea (0.7%), upper abdominal pain (0.3%), and headache (0.3%). The most frequent adverse events were; headache (42.6%), nasopharyngitis, (24.6%), nausea (21.3%) and upper abdominal pain (20.5%)
Author conclusions: Overall reporting of adverse was poor and adequate and informative data regarding the potential adverse effects of MPH, DEX and ATX are lacking. Withdrawal due to TEAEs ATX 18/164 MPH 6/166 The difference in number of withdrawals was significant (p =/0.011)
Outcome measures: 1. Adverse events 2. Vital signs, electrocardiography, and laboratory studies
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Adults
Reference Michelson et al 2003 (238) Design RCT ( x2) Level II Quality Adequate Setting USA Industry funding Yes Intervention/ comparator Intervention ATX Comparator Placebo Population/Study information Population: Adults who met DSM-IV criteria for ADHD Study Information: Design & duration: 10 week parallel RCT No. Study 1 Placebo n = 139 Active drug n =141 Study 2 Placebo n = 127 Active drug n = 129 Dose: Determined by titration. (Start dose 60mg/day & max dose 120 mg/day) Results Withdrawal from the studies due to adverse events was significantly greater in the ATX group compared with placebo in study II but not study I. Adverse events that were significantly increased in the ATX group compared to placebo; Dry mouth, insomnia, nausea, decreased appetite, difficulty attaining or maintaining an erection (all p < 0.001)
Outcome measures: 1. open ended questioning for adverse events 2. monitoring of vital signs and laboratory data.
Adler et al 2006 (243)
Design Randomised double blind, comparative study Level III-3 Quality Poor Setting USA Industry funding Yes
Summary
Preschoolers: No studies met the inclusion criteria Children and adolescents: King et al (196) reviewed the occurrence of adverse events in children and adolescents receiving ATX. The main conclusions drawn are as follows: ATX of any dose may impair appetite. In one study comparing ATX and MPH-ER, decreased appetite and increased insomnia were more frequent in the ER-MPH group.
R D
Comparator ATX Low dose
Intervention ATX High dose
Population: Adults who met DSM-IV criteria for ADHD Study Information: Design: head to head comparison No. and Dose: 1. ATX 80 mg once a day n = 108 2. ATX 40 mg twice a day n = 110 Duration: 6 week RCT (7 month study)
Outcome measures: 1. treatment-emergent adverse events (TEAEs) 2. Arizona Sexual Experiences Scale (ASEX; male and female versions)
T F A
18/110 (16%) participants withdrew due to adverse events. The most frequent adverse events were; headache (40 mg 22.7%; 80 mg 32.4%), insomnia (40 mg 25.5%; 80 mg 16.7%), nausea (40 mg 16.4%; 80 mg 32.4%), dry mouth (40 mg 17.3%; 80 mg 17.6%) and appetite decrease (40 mg 13.6%; 80 mg 19.4%). Only Nausea significantly increased at the one daily dose (p = 0.007) Males from both ATX groups showed a significant change in sexual dysfunction scores from baseline to endpoint (40 mg p < 0.01; 80 mg p = 0.002). No significant change for women.
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Two primary studies published after the King et al (196) review were also included in our analysis. Wilens et al (241) addressed the use of ATX in adolescents, reviewing 13 clinical trials (6 randomised controlled trials and 8 open-label extension studies) of up to 2 years in length. Reporting of adverse events in this review was limited. 31/601 adolescents discontinued due to adverse events, the most frequent of which were headache, inflammation of the nose and pharynx (nasopharangitis), nausea and upper abdominal pain. This study was rated as poor in quality. Wang et al (254) compared the use of ATX and MPH in children and adolescents. Withdrawals from the study due to adverse events were significantly greater in the ATX group. Somnolence (drowsiness), nausea, anorexia and dizziness occurred more frequently in the ATX group than the MPH group. This study was rated as poor quality. Adults: Two studies were identified that addressed the use of ATX in adults. Michelson et al (238) reported on two identical randomised controlled trials conducted over 10 weeks. Discontinuation from the studies due to adverse events was less than 10%. The withdrawals were significantly greater in the ATX group compared with placebo group in study II but not study I. Dry mouth, insomnia, nausea, decreased appetite and difficulty attaining or maintaining an erection were significantly increased in the groups receiving ATX compared to the placebo group. The quality of this study was rated as adequate. Adler et al (243) compared the use of 80mg of ATX when given either once or twice a day. The most frequent adverse events were: headache, insomnia, nausea, dry mouth and appetite decrease. Nausea was significantly increased in the group receiving ATX once a day compared to twice a day. Men, but not women, from both groups showed a significant change in sexual dysfunction scores at the end of the study. The quality of this study was rated as poor. Atomoxetine and liver injury: It should also be noted that there have been 3 case reports of severe liver injury in children and adults using ATX (255, 256). These individuals recovered when the drug was discontinued. As a result of these rare cases the precautionary information accompanying the medication now warns against the use of ATX with jaundice or laboratory evidence of liver injury (257). As these are case reports, they do not meet the inclusion criteria for the literature review and were not included for data-extraction and critical appraisal. Excluded studies Study Adler et al 2005 (242) Adler et al 2006 (244) Faraone et al 2005 (245) Faraone et al 2005 (246) Lee et al 2004 (258) Ledbetter et al 2005 (259) Reimherr et al 2005 (247) Wilens et al 2002 (216)
R D
Reason for exclusion Interim analysis of an included study Outcomes not directly relevant to question Outcomes not directly relevant to question Outcomes not directly relevant to question Case report Case report Outcomes not directly relevant to question Adverse events and side effects not adequately reported.
T F A
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Other medications
Research question 15. For individuals with ADHD, do other pharmacological interventions compared with placebo, affect outcomes? a. Clonidine b. Modafinil c. Selegiline d. Guanfacine e. Nicotine patch f. Bupropion d. Risperidone Selection Criteria Population Inclusion Criteria
Intervention Comparator Outcomes
Non-stimulant pharmacological interventions Placebo
Study Design
Date of Search
Search terms MeSH: Attention deficit disorder with hyperactivity/ drug therapy/ or antidepressive agents, second-generation/ or antidepressant agents/ serotonin uptake inhibitors/
R D
Secondary: School/work achievement, quality of life, social function. Systematic reviews or meta-analysis of randomised controlled trials, randomised controlled trials (NHMRC levels of evidence I & II)
T F A
Text words: adhd or addh or adhs or hyperactive$ or hyperkin$ or (attention adj deficit) modafinil or provigil or modavigil or sparalon or tricyclic antidepressant or imipramine or clomipramine or desipramine or amitriptyline or nortriptyline or monoamine oxidase inhibitors or phenelzine or tranylcypromine or selegiline or ssri or bupropion or venlafaxine or nefazodone or mirtazapine or alpha-2 agonist or clonidine or guanafacine or betablocker or propranolol or nicotine or Risperidone
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Clonidine Children and adolescents

Reference Palumbo et al 2008 (260) Adverse events in Daviss et al 2008 (261) Design RCT Level II Quality Adequate Setting USA (multisite) Industry funding Yes Intervention/ comparator Intervention Clonidine (or clonidine + MPH or MPH alone) Comparator Placebo Population/Study information Population: Children aged 7 to 12 years who met DSM-IV criteria for ADHD Results ADHD symptoms: Significant improvement in Conners ASQ-parent and CGAS only in the clonidine group over placebo (p=0.01 and p < 0.0001 respectively) whereas Conners ASQteacher demonstrated no difference (p=0.52).
Study information: Design & duration: parallel design RCT 8 weeks dose titration and 8 weeks maintenance No. placebo n=30 clon n=31 MPH n=29 clon+MPH n= 32 Dose: clon: max 0.6mg/day (as 3-4 times daily doses), MPH: max 60mg/day
Reference
Biederman et al 2006 (262) Design RCT Level II Quality Adequate
R D
Intervention/ comparator Intervention Modafinil Comparator Placebo
Outcome measures: 2. Conners Abbreviated Symptom Questionnaire for Teachers (ASQTeacher), 3. Conners Abbreviated Symptom Questionnaire for Parents (ASQParent) 4. Childrens Global Assessment Scale (CGAS)
Modafinil Children and adolescents
T F A
Adverse events: Dull / tired / listless (p < .0001) and drowsiness/sedation (p < .0001) were reported more frequently (parent and teacher) in participants receiving clonidine. Bradycardia was more frequent in the clonidine groups (p = .02), but no other significant group differences for electrocardiogram and other cardiovascular outcomes. Moderate or severe adverse events were more common in the clonidine group (p = .0006) but were not associated with higher rates of early study withdrawal Results Efficacy 300mg single daily dose produced statistically significant improvement in ADHD symptoms measured on the ADHD Rating scale school and home versions and the Conners ADHD Rating scale (p < 0.05). Divided doses of modafinil did not result in consistent improvement in ADHD symptoms on all scales. No statistically significant difference in CGI between placebo and the 3 different doses of modafinil (p-values not reported). Adverse events Common adverse events that were more frequent in the modafinil group
Population: Children aged 6-13 with DSM-IV diagnosis of ADHD
Study information: Design: RCT, 4 weeks No. Placebo n=51; Mod n=197 Dose: 300mg/day using different dose regimes: 300mg am/0mg pm; 100mg/200mg; 200mg/100mg (<30kg body weight); 400mg/day (200mg/200mg) (30kg body weight)
Setting USA (multicentre) Industry funding Yes
Outcome measures: 1. ADHD Rating School IV (School version) 2. ADHD Rating Scale IV (Home version) 3. Conners ADHD/ DSM-IV Rating Scale 4. Clinical Global Impressions of
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Improvement
compared with placebo; insomnia*, pain, cough, decreased appetite, fever and rhinitis. * significantly more frequent (p = 0.03). Discontinuation due to adverse events: Modafinil: 4% Placebo: 0% No significant difference between modafinil and placebo groups in weight or heart rate or blood pressure measures during treatment.
Greenhill et al 2006 (263) Design RCT Level II Quality Adequate Setting USA (multicentre) Industry funding No
Intervention Modafinil Comparator Placebo
Population: children aged 6 to 17 years with a diagnosis of ADHD using the full DSM-IV diagnostic criteria Study information: Design: RCT, 9 weeks No. Placebo n=67; Mod n=131 Dose: individually optimised dose starting at 85mg daily, gradually increased to maximum of 425mg daily Outcome measures: 1. ADHD-RS-IV Home Version 2. ADHD-RS-IV School Version 3. CGI-I 4. Test of Variables of Attention 5. Conners Parent Rating Scale V revised short form 6. Social Skills Rating Scale 7. Child Health Questionnaire
Rugino & Samsock 2003 (264) Design RCT Level II Quality Adequate
R D
T F A
Efficacy Statistically significantly more responders (based on CGI) in the modafinil group than placebo (p=0.0001). Statistically significant improvement in modafinil group over placebo for ADHD home (p<0.0001), ADHD school (p<0.0001), TOVA (p=0.001) and Conners (p=0.001). Effect sizes: ADHD-RS-IV School Version total score 0.63 (95% CI 0.510.76); ADHD-S-IV Home Version total score was 0.78 (95% CI 0.66-0.91) Adverse events Common adverse events that were more frequent in the modafinil group compared with placebo; insomnia, headache, decreased appetite and weight loss all significantly greater in the modafinil versus placebo (p < 0.05) Discontinuation due to adverse events: Modafinil: 5% Placebo: 6% No significant difference between modafinil and placebo groups in heart rate or blood pressure measures during treatment. Efficacy Statistically significant improvement in subjective parent questionnaire in modafinil group over placebo (p<0.004). Statistically significant improvement in post-treatment TOVA (p0.02), CTRS and CPRS (p<0.05), but not ADHD-RS scores. Adverse events (Limited reporting) Modafinil group: Delayed sleep onset: 4/11 Transient stomach ache: 2/11 Transient headache: 1/11
Population: Children aged 5 to 15 years with an average Conners Teacher Rating Scale ADHD index t score of 70 or higher and an average percentile score for the ADHD Rating Scale IV of 70 or higher
Study information: Design: RCT, 6 weeks No. Placebo n=11, Mod n=11 Dose: started at 100mg/day titrated to effect gradually up to max 400mg/day Outcome measures: 1. TOVA 2. CTRS and CPRS DSM-IV ADHD
Setting USA (single site)
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Industry funding Not stated
total score 3. ADHD Rating Scale IV (ADHDRS Home and School Versions) 4. Subjective parental questionnaires
Transient mood disorder: 1/11 Placebo group: Sleepiness: 1/11 Irritability: 1/11 Decreased appetite: 1/11 Tonsillitis: 1/11 Pharyngitis: 1/11 Efficacy Significantly more much improved or very much improved (CGI) in the modafinil group than placebo (p<0.001).
Swanson et al 2006 (265) Design RCT Level II Quality Adequate Setting USA (multicentre) Industry funding Yes
Population: children aged 6 to 17 years who met DSM-IV-TR criteria for ADHD Study information: Design: RCT, 7-week fixed dose, 2weeks observation after abrupt discontinuation No. Placebo n=64, Mod n=125 Dose: initial dose 85mg/day, gradually titrated to max 340mg/day (body weight <30kg) or 425mg/day (body weight 30kg) Outcome measures: 1. ADHD-RS-IV school version 2. ADHD-RS-IV home version 3. CGI 4. TOVA 5. CPRS:R-S 6. SSRS 7. Child Health Questionnaire (CHQ)
Wigal et al 2006 (266) Design RCT Level II Quality Adequate
Setting USA (multicentre) Industry funding Yes
R D
Population: children aged 6 to 17 years, with a diagnosis of ADHD based on criteria from DSM-IV-TR
T F A
Statistically significant improvement in ADHD-RS School (p<.0001), ADHDRS Home (p=.001), CPRS:R-S (p<.001). Note: on SSRS and CHQ significant effects of modafinil were present in some, but not all measures. Only examples provided: the problem behaviours total score (p=0.031) and CHQ psychosocial summary score (p=0.039). Adverse events Common adverse events that were more frequent in the modafinil group compared with placebo; insomnia*, decreased appetite* weight loss* and headache. * significantly more frequent (p = 0.03). No significant difference between modafinil and placebo groups in heart rate or blood pressure measures during treatment. Efficacy Statistically significant improvement for all three modafinil groups (all patients, prior stimulant group and stimulant nave group) over placebo in ADHD-RS School (p<.0001, <.001and <.0001 respectively), ADHD-RS Home (p<.0001, <.0001 and <.0001 respectively). Greater improvements from baseline to final visit in mean CPRS scores were shown for modafinil compared with placebo for oppositional behaviour, cognitive problems/inattention, hyperactivity, and ADHD index scores (all p<0.001). Note: individual p-values not presented although the proportion of responders (CGI-I) was significantly greater for
Study information: Design: 3 RCTs, 9 weeks each No. Placebo n=215, Mod n=423 Dose: initially 85mg/day titrated gradually to max 425mg/day (2 studies); initial dose 85mg/day, gradually titrated to max 340mg/day (body weight <30kg) or 425mg/day (body weight 30kg) (1 study)
Outcome measures: 1. ADHD-RS-IV school version 2. ADHD-RS-IV home version 3. CGI S 4. CGI-I 5. CPRS:R-S
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those receiving modafinil than for those receiving placebo at all study visits (p<0.0001). Adverse events Common adverse events that were more frequent in modafinil group compared with placebo; insomnia (mod 27%, placebo 4%), decreased appetite (mod 16%, placebo 3%) and headache (mod 20%, placebo 13%). P values not reported. Discontinuation due to adverse events: Modafinil: 5% Placebo: 6%
Biederman et al 2005 (267) Design RCT Level II Quality Adequate
Population: children aged 6 to 17 years, with a diagnosis of ADHD based on criteria from DSM-IV-TR Study information: Design: RCT, 9 weeks No. Placebo n=82, Mod n=164 Dose: 170-425mg modafinil once daily Outcome measures: 1. ADHD-RS-IV school version 2. ADHD-RS-IV home version 3. CGI-I
Setting USA (multicentre) Industry funding Not reported
Reference
Rubinstein et al 2006 (268) Design RCT Level II Quality Adequate
R D
Intervention/ comparator Intervention Selegiline Comparator Placebo Outcome measures:
T F A
No significant difference between modafinil and placebo groups in weight loss, heart rate or blood pressure measures during treatment. Efficacy More modafinil treated patients much improved or very much improved (CGI-I) than placebo (48% vs 17%), significance not reported. Statistically significant improvement in modafinil group vs placebo on ADHDRS-IV school version (p<0.0001, effect size 0.69, 95% CI 0.57-0.82). Similar differences in symptom improvement were observed on the ADHD-RS-IV home version between the modafinil-treated and placebotreated groups, however figures were not presented. Adverse events Common adverse events that were more frequent in the modafinil group compared with placebo: insomnia (modafinil 29%, placebo 4%; p < 0.05) and loss of appetite (modafinil 16%, placebo 4%; p < 0.05). Results ADHD symptoms: Significant difference (p<0.05) between selegiline and placebo on Sustained attention tasks, Parent/ teacher-rated inattention, Parent/ teacher-rated hyperactivity, Parent/ teacher-rated peer interactions, but not on Impulsivity tasks and Parent/ teacher-rated impulsivity Note: actual SNAP data was not
Selegiline Children and adolescents
Population: children aged 613 years with a DSM-IV diagnosis of ADHD
Study information: Design & duration: crossover design RCT with 4-weeks on each medication No. placebo/selegiline n=11 Dose: twice daily, total of 10mg/day
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Setting Canada (hospital) Industry funding No
1. 2. 3.
4. 5. 6.
SNAP parent SNAP teacher Composite from Word Matching, Letter Cancellation, and Passage Comprehension Students tasks Composite from Word Matching, Oral Reading, and Computational Math subtests.
presented Adverse events: Reporting limited. No significant difference in the number of side effects for selegiline compared to placebo.
Guanfacine Children and adolescents

Reference Biederman et al 2008 (269) Design RCT Level II Quality Good Setting USA (multicentre) Industry funding Yes Intervention/ comparator Intervention Guanfacine extended release (GXR) Comparator Placebo Population/Study information
Population: children and adolescents aged 6 to 17 years inclusive who met DSM-IV criteria for ADHD Study information: Design & duration: Parallel design RCT 5 weeks dose escalation + 3 weeks downward tapering No. placebo n=86 GXR 2mg/day n=87 GXR 3mg/day n=86 GXR 4mg/day n=86 Dose: GXR 2-4mg/day depending on group allocation
Reference
Shytle et al 2002 (270) Design RCT Level II Quality Adequate
R D
Intervention/ comparator Intervention Nicotine Comparator Placebo
Outcome measures: 1. ADHD Rating Scale IV (ADHDRS-IV) total score 2. Clinical Global Impression of Severity (CGI-S) 3. Clinical Global Impression of Improvement (CGI-I) 4. Parents Global Assessment (PGA) 5. Conners Parent Rating Scale Revised: Short Form (CPRSR) 6. Conners Teacher Rating Scale Revised: Short Form (CTRS-R)
T F A
Results ADHD symptoms: Statistically significant improvement (p<0.05) in CGI-I scores for all GXR dosages over placebo. Significant improvement in ADHDRS-IV scores in the GXR groups over placebo (p<0.0002 for all three GXR groups vs placebo). Posthoc analysis of the ADHD-RS-IV revealed treatment effect sizes: 0.64 (GXR 2mg/day), 0.66 (GXR 3mg/day) and 0.86 (GXR 4mg/day). All GXR groups showed significant improvement (p<0.05) in CPRS-R and CTRS R mean day total scores compared with placebo. Adverse events: Reporting limited. No tests of significance. Most frequent side effects in the guanfacine group were somnolence, fatigue, upper abdominal pain and sedation. There was a dose related increase in mean blood pressure and pulse rate. No data reported on changes in weight. Results ADHD symptoms: Only learning problems and hyperactivity subscale of CPRS was significantly improved in nicotine group over placebo, no other significant differences between groups. Note: no significant difference between groups on CGI although no actual data was reported.
Nicotine patch Children and adolescents
Population/Study information Population: outpatient children and adolescents 8- 18 years of age who satisfied DSM-IV criteria for ADHD Study information: Design & Duration: 7-day RCT pilot No. placebo n=5, nicotine n=5 Dose: Transdermal nicotine patch 5mg/16 hours
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Outcome measures: 1. CPRS (Conners Parent Rating Scale) 2. CGI
Adverse events: Reporting limited. The most common adverse events were nausea, stomach ache, itching under the patch and dizziness.
Modafinil Adults
Reference Taylor & Russo 2000 (207) Design RCT Level II Quality Adequate Setting USA (Washington) Industry funding Not reported Intervention/ comparator Intervention Modafinil Comparator Placebo Population/Study information
Population: Adults aged over 21 years with DSM-IV diagnosis of ADHD
Study information: Design & duration: 3-phase crossover RCT, 2 weeks on each of modafinil, amphetamine and placebo, 4-day washout in between No. Placebo/Active drug n=22 Dose: 100mg/day (2x50mg capsules) gradually increased as tolerated to maximum 400mg per day Outcome measures: 1. ADHD Behavior Checklist for Adults: self-rated
Reference
Taylor & Russo 2001 (208) Design RCT Level II Quality Adequate Setting USA (clinic(s)) Industry funding None reported
R D
Intervention/ comparator Intervention Guanfacine (or DAMP) Comparator Placebo
Guanfacine Adults
Population: Adults aged 21-57 years diagnosed with ADHD using DSM-IV criteria
T F A
Results Efficacy Statistically significant improvement on ADHD behavior checklist: total score (p<0.001); hyperactivity subscale (p<0.01); inattention subscale (p<0.001). Adverse events Common adverse events: insomnia (modafinil 19%, placebo 19%), muscle tension (modafinil 19%, placebo 5%) and irritability (modafinil 14%, placebo 10%). No significant differences between the groups. Results ADHD symptoms: Statistically significant improvement on ADHD Behaviour checklist total score (p<0.05) and inattentive subscore (p<0.05) for guanfacine treatment over placebo. Hyperactivity subscore was only marginally non-significantly different between the groups (p=0.052). Note: p-values for change in Copeland scores were not presented. Adverse events: No significant difference between the number of side effects between gguganfacine and placebo.
Study information: Design & duration: randomised double-blind placebo controlled crossover study, 3x2-week treatment periods No. placebo/guanfacine/DAMP n=17 Dose: guanfacine: single daily dose maximum 2mg/day; DAMP: single daily dose maximum 20mg/day Outcome measures: DSM-IV ADHD Behaviour Checklist for adults Copeland Symptom Checklist for Adult Attention Deficit Disorder
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Bupropion Adults
Reference Kuperman et al 2001 (271) Design RCT Level II Quality Adequate Setting USA (community) Industry funding Yes Wilens et al 2001 (272) Design RCT Level II Quality Adequate Intervention Bupropion sustained release Comparator Placebo Intervention/ comparator Intervention Bupropion sustained release or MPH Comparator Placebo Population/Study information Population: Adults aged 18-60 years with a DSM-IV diagnosis of ADHD Study information: Design & duration: Randomised, double-blind, parallel study 7 weeks duration No. Placebo n=11, Bup n=11, MPH n=8 Dose: Bup: twice daily dose titrated to max 300mg/day; MPH: titrated to max 0.9mg/kg divided into 3 doses/day Outcome measures: 1. CGI Scale 2. ADHDRS-self Results ADHD symptoms: No statistically significant benefit of bupropion or MPH over placebo on CGI (p = 0.14) and ADHDRS (p = 0.69). Adverse events: Reporting limited. Number of participants experiencing an adverse event; Bupropion 69%, placebo 67%. The most common adverse events for bupropion were dry mouth (4/13), headache (2/13) and insomnia (2/13).
Setting USA (clinic) Industry funding Yes
Wilens et al 2005 (273) Design RCT Level II Quality Adequate
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Intervention Bupropion sustained release Comparator Placebo
Population: adults aged between 20 and 59 years with DSM-IV diagnosis of ADHD Study information: Design & duration: parallel-design RCT. 6 weeks No. placebo n=19, Bup n=21 Dose: up to 200mg twice daily (sustained release)
Outcome measures: 1. Clinical Global Impression (CGI) scale 2. ADHD Symptom Checklist
T F A
ADHD symptoms: Significant improvement in bupropion group over placebo on CGI scale (p=0.007), and ADHD symptom checklist (p=0.02). ADHD symptom checklist mean change scores were significantly higher in the bupropion group over placebo (p=0.05). Adverse events: No statistically significant differences between bupropion and placebo in the rates of any single adverse event, in the rate of at least one adverse event or in heart rate, blood pressure. The most frequently reported adverse events (more than 2 reports) were headache (bup: 19%; placebo: 16%), gastrointestinal problems (bup: 19% placebo 16%), insomnia (bup: 38% placebo 16%), aches or pains (bup: 10% placebo 5%), dry mouth (bup: 10% placebo 0%), and chest pain (bup: 10% placebo 0%). ADHD symptoms: Statistically significant improvement in CGI-I rating in bupropion group over placebo (p=0.003) and reduction in symptoms on ADHD symptom checklist (p=0.004). Mean change scores for CGI-I (p=0.01) and CGI-S (p=0.009) were also significantly higher in the bupropion
Population: adults aged 18 to 60 years who met DSM-IV criteria for ADHD
Study information: Design & duration: randomized, double-blind, placebo-controlled, parallel-group, flexible-dose trial, 8 weeks No. placebo n=81, bup n=81 Dose: 300mg-450mg in single daily
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dose Setting USA (multisite) Industry funding Outcome measures: 1. Investigator-rated ADHD-RS 2. Conners Adult ADHD Rating Scale-Self Report (CAARS-S:S) 3. Conners Adult ADHD 4. Rating Scale-Observer (CAARSO:S) 5. ADHD Clinical Global Impression of Improvement and Severity scales
group over placebo. Conners (observer) rating scale was significantly improved in the bupropion group over placebo (p=0.044). Conners (self-report) was significantly improved in the bupropion group over placebo when measured at 10am (p=0.033), 4pm (p=0.004) and 10pm (p=0.024). Adverse events: The most frequently reported adverse events (more than 2 reports) were headache (bup: 17%; placebo: 14%), dry mouth (bup: 12% placebo 5%), insomnia (bup: 10% placebo 7%), nausea (bup: 9% placebo 4%), and naopharengitis (bup:9% placebo 2%).
Reimherr et al 2005 (274) Design RCT Level II Quality Adequate Setting USA Industry funding Yes
Summary
Preschoolers: No studies that met our inclusion criteria were identified. Children and adolescents: Clonidine: Palumbo et al (260) described a 16 week RCT in children with ADHD that compared MPH, clonidine, MPH and clonidine combined and placebo. Comparison of clonidine to placebo found a significant improvement in parent rated ADHD symptoms and the global assessment scale for the clonidine over placebo. However, there was no difference on teacher rated ADHD symptoms. The quality of this study was rated as adequate. Daviss et al (261) reported on the adverse events in this study. Participants receiving clonidine had a greater incidence of dull / tired / listless and drowsiness / sedation side effects. Bradycardia was also more frequent in the clonidine groups, but no other significant group differences were seen for electrocardiogram and other cardiovascular outcomes. Moderate or
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Comparator Placebo Outcome measures: 1. WRRAADS 2. CGI 3. WSAS 4. GAF
Intervention Bupropion sustained release
Population: adult outpatients aged >18 years who met DSM-IV criteria and Utah Criteria for ADHD Study information: Design & Duration: 6-week paralleldesign RCT No. placebo n=24, Bupropion n=35 Dose: maximum dose of 400mg/day (200mg twice daily)
T F A
For bupropion compared to placebo there was a significant increase in pulse over time (p = 0.012) and a significant decrease in weight (p = 0.002). ADHD symptoms: No significant differences between bupropion and placebo for any outcome. The exception was a post-hoc analysis of the percentage of participants 50% improved on WRRAADS (p<0.05). Adverse events: Reporting poor. No significant difference in side effects. No detail provided.
severe adverse events were more common in the clonidine group, but were not associated with higher rates of early study withdrawal. Modafinil: Six placebo controlled double-blind RCTs of short duration (4-9 weeks) were identified that examined the efficacy of modafinil compared to placebo in children and adolescents with ADHD. The studies were consistent in finding that Modafinil was effective in reducing the number and severity of symptoms of ADHD compared to placebo (262-267). Across the six studies, the most common adverse events that were observed more frequently in the modafinil group compared to placebo were insomnia, headache, loss of appetite and weight loss. The quality of the six studies was rated as adequate. All trials were conducted in the USA. Selegiline: One study compared selegiline to placebo in children with ADHD. Rubinstein et al (268) conducted a 4 week cross-over RCT with 11 participants. Selegeline was found to significantly improve symptoms of inattention and hyperactivity (parent and teacher rated) but did not improve impulsivity. Reporting of adverse events was limited. There was no significant difference in the number of side effects for selegiline compared to placebo. The quality of this study was rated as adequate.
Guanfacine: Biederman et al (269) described a 8 week parallel design RCT in children and adolescents with ADHD comparing 3 doses of guanfacine- extended release (2, 3 and 4mg/day) to placebo. There was a significant improvement in ADHD symptoms on all measures in all guanfacine doses over placebo. Adverse event reporting was limited, with no tests of significance conducted. The most frequently reported side effects in the guanfacine group were somnolence, fatigue, upper abdominal pain and sedation. There was a dose related increase in mean blood pressure and pulse rate. The quality of this study was rated as good.
Nicotine patch: Shytle et al (270) described the comparison of nicotine patch to placebo in children and adolescents with ADHD. In this 7-day pilot parallel-design RCT 5 participants received placebo and 5 the nicotine patch. Only the learning problems and hyperactivity subscale of CPRS was significantly improved in the nicotine group over placebo, no other significant differences between groups (eg CPRS impulsivity, conduct and anxiety and CGI). Reporting of adverse events was limited. The most common adverse events were nausea, stomach ache, itching under the patch and dizziness. The quality of this study was rated as adequate. Adults: Modafinil: In adults one RCT met our inclusion criteria. This study reported by Taylor and Russo (207) found that modafinil was effective in reducing the symptoms associated with ADHD as measured by self-report. This small study involved 22 participants who received modafinil treatment for 2 weeks. The most common adverse events reported in this study were insomnia, muscle tension and irritability. The quality of the study was rated as adequate.
The long term safety and efficacy of modafinil has not been established for the treatment of individuals with ADHD in any population group as no clinical trials of longer than 3 months have been reported. The outcome measures utilised in current trials have focused exclusively on ADHD symptoms and no attempt has been made to evaluate the impact on quality of life or social or school/work functioning Guanfacine: Taylor & Russo (208) described a 6 week cross-over RCT in adults with ADHD where participants received guanfacine, DEX and placebo for 2 weeks each. guanfacine was effective compared to placebo in reducing ADHD symptoms. There was no significant
R D
T F A
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difference between the number of side effects for guanfacine compared with placebo. The quality of this study was rated as adequate. Bupropion: Four trials compared the use of bupropion sustained release to placebo in adults with ADHD. Kuperman et al (271) compared the use of Bupropion-sustained release to MPH and placebo in adults with ADHD. In this parallel design RCT conducted for 8 weeks no significant difference was found for bupropion over placebo for either of the ADHD symptom measures used in this study (CGI responder and ADHD-RS). The reporting of adverse events in this study was limited. The most common adverse events reported in the bupropion group were dry mouth, headache and insomnia. The quality of this study was rated as adequate. Wilens et al (272) described a 6 week parallel-design RCT in adults with ADHD. A significant improvement was reported in ADHD symptoms in the bupropion group compared to placebo. There were no statistically significant differences between bupropion and placebo in the rates of any single adverse event, in the rate of at least one adverse event or in heart rate or blood pressure. The most frequently reported adverse events were headache, gastrointestinal problems, insomnia, aches or pains, dry mouth and chest pain. The quality of this study was rated as adequate.
Wilens et al (273) described an 8 week parallel design RCT in adults with ADHD. ADHD symptoms were reported to be improved in the bupropion group compared to placebo on multiple measures. The most frequently reported adverse events for participants taking bupropion were headache, dry mouth, insomnia, nausea, and nasopharyngitis. There was also a significant increase in pulse over the course of treatment and a significant decrease in weight. The quality of this study was rated as adequate.
Reimherr et al (274) reported on a 6-week parallel-design RCT in adults with ADHD. There were no significant differences between bupropion and placebo for measures of ADHD symptoms. Adverse events were poorly reported. It was stated that there was no significant difference in side effects between bupropion and placebo, however no details were provided. The quality of this study was rated as adequate. The results of the studies comparing bupropion to placebo have been variable with 2/4 studies reporting no difference and 2/4 studies reporting that bupropion improved symptoms of ADHD compared to placebo. All studies have been short-term assessments with relatively small numbers of participants. Additional studies are required to determine the efficacy of bupropion for ADHD symptoms.
Excluded studies Study Tricyclic Antidepressants No trials post 1997 identified Bupropion Monuteaux et al 2007 (275) Wilens et al 2003 (276) Riggs et al 1998 (277) Clonidine
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T F A
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Reason for exclusion
Does not address primary or secondary outcome measures Not randomised controlled trail (open-label) Not randomised controlled trail (open-label)
Connor et al 1999 (278)
Connor et al 2000 (279) Hazell et al 2003 (280) Tianeptine Niederhofer et al 2004 (281) Guanfacine Lee et al 1997 (282) Reboxetine Mozes et al 2005 (283) Ratner et al 2005 (284) Risperidone (285) Venlafaxine Findling et al 2007 (286) Mukaddes et al 2004 (287) Carbamazepine Davids et al 2006 (288) Buspirone Malhotra et al 1998 (289) Niederhofer 2003 (290) Selegiline Mohammadi et al 2004 (291) Akhondzadeh et al 2003 (292) Ernst et al 1997 (293) Nortriptyline Prince et al 2000 (294) Nicotine Poltavski et al 2006 (295) Levin et al 2001(296) Modafinal Ballon and Feifel 2006 (297) Amiri et al 2007 (298) Turner et al 2004 (299) Swanson et al 2004 (300) Rugino and Copley (301) Boellner et al 2006 (302)
Some studies with co-morbid diagnoses and primary studies all older than 1995 other than Connor et al 2000 which is not placebo controlled Include in comorbidities question Include in comorbidities question Not randomised controlled trial (within subjects design and no placebo)
Less than 10 participants & no control
Not randomised controlled trail (open-label) Not randomised controlled trail (open-label)
Not randomised controlled trail (open-label) Not randomised controlled trail (open-label) Not randomised controlled trail (open-label) Less than 10 participants
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Not randomised controlled trail (open-label) Not randomised controlled trail (open-label) and less than 10 participants Not placebo controlled Not placebo controlled
Physiological study and no placebo results presented.
Not randomised controlled trail
T F A
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Does not address primary and secondary outcome measures Primary and secondary outcome measures not adequately addressed. Broad systematic review including non-ADHD studies
Not randomised controlled trial (no placebo control) Does not address primary or secondary outcome measures Not randomised controlled trial (open label) Not randomised controlled trial (open label) Not randomised controlled trial (open label)
Comparing medications
Research question: 16. For individuals with ADHD, do any pharmacological interventions confer an advantage over any other pharmacological interventions? Selection criteria Population Inclusion criteria Individuals with ADHD diagnosed according to standard criteria; DSM-III, DSMIII-R, DSM-1V or ICD10 Intervention Comparator Outcomes Pharmacological intervention
Other pharmacological intervention
Secondary: School/work achievement, quality of life, social function. Study design Search period Language Date of search NHMRC defined levels of evidence (I-II) for intervention studies. 1997 - present English
Reference King et al 2006 (196) Design Systematic Review Level I Quality Adequate Setting UK Industry Funding No
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Intervention/ comparator Intervention MPH-IR Comparator MPH-ER Outcome measures:
Separate search not performed
Comparisons of stimulant medications Children and adolescents

T F A
Results Low dose MPH-IR versus low dose MPH-ER Hyperactivity: 1/1 study reported no significant differences between groups. Quality of life: No studies Adverse events: 1/1 study reported no significant differences between groups. Study quality: 1/1 study rated as poor. High dose MPH-IR versus medium dose MPH-ER Hyperactivity: 1/1 study reported no significant differences between groups. Quality of life: 1/1 study reported no significant differences between groups. Adverse events: 1/1 study found a significant increase in headaches in the MPH-ER group. Study quality: 1/1 rated as poor. Authors conclusions: There appears to be little evidence supporting a difference in the effectiveness of
Study Information: Low dose MPH-IR versus low dose MPH-ER Design: 1 Cross-over design RCT of 8 weeks duration No. n = 19 Dose: MPH-IR <15mg/day MPH-ER <20mg/day High dose MPH-IR versus medium dose MPH-ER Design: 3 studies, 2 confidential. The third study was a parallel design RCT of 4 weeks duration No. n = 312 Dose: MPH-IR >30mg/day MPH-ER 20-40mg/day
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King et al 2006 (196) Design Systematic Review Level I Quality Adequate Setting UK Industry Funding No NB: Majority of included studies were industry funded
Intervention MPH Comparator DEX
1. Hyperactivity (using any scale that measured hyperactivity specifically) 2. Quality of Life (using Clinical Global Impression (CGI) as a proxy) Population: Children and adolescents under 18 years diagnosed with ADHD (ICD-10 or DSM-IV) Study information: Medium dose MPH-IR versus Low dose DEX Design: 1 cross-over design RCT of 4 weeks duration. No. n = 125 Dose: MPH = 15-30mg/day DEX = 10mg/day Medium dose MPH-IR versus Medium dose DEX Design: 1 cross-over design RCT of 3 weeks duration. No. n = 29 Dose: MPH = 15-30mg/day DEX = 10-20mg/day Outcome measures: 1. Hyperactivity (using any scale that measured hyperactivity specifically) 2. Quality of Life (using Clinical Global Impression (CGI) as a proxy)
immediate-release and extended-release MPH.
Reference King et al 2006 (196) Design Systematic Review Level I Quality Adequate Setting UK Industry Funding No
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Intervention/ comparator Intervention MPH Comparator ATX
Comparing stimulant medications to non-stimulant medications Children and adolescents

Population/Study information Results
T F A
Medium dose MPH-IR versus medium dose DEX Hyperactivity: 1/1 study reported no significant difference between groups. Quality of life: Not reported Adverse events: Not adequately reported. Study quality: 1/1 rated as good. Authors conclusions: Although the studies reported variable results, the one study that reported no statistically significant differences between the two drugs was deemed to be of good quality, whereas the quality of the others was poor. High dose MPH-IR versus high dose ATX Hyperactivity: 1/1 study reported no significant difference between groups. Quality of life: 1/1 study reported no significant difference between groups. Adverse events: 1/1 study reported no significant difference between groups. Study quality: Rated as poor. Medium dose MPH-ER versus low/medium dose ATX Hyperactivity: 1/1 study reported a significant difference in favour of the MPH group. Quality of life: 1/1 study reported a significant difference in favour of the MPH group. Adverse events: 1/1 study reported a significant increase in reduced appetite and insomnia in the MPH group. (No difference in headache and stomach
Medium dose MPH-IR versus low dose DEX Hyperactivity: 1/1 study reported in favour of MPH in the teacher rated scales, but no significant difference between groups in the parent rated scales. Quality of life: Not reported Adverse events: 1/1 study reported no significant difference between groups. Study quality: 1/1 rated as poor.
High dose MPH-IR versus High dose ATX Design: 1 parallel design RCT of 10 weeks duration. No. MPH n = 44 ATX n = 184 Dose: MPH = >30mg/day DEX = >1.5mg/day Medium dose MPH-ER versus Low/Medium dose ATX Design: 1paralell design RCT of 3 weeks duration. No. MPH-ER n = 850 ATX n = 473 Dose: MPH-ER = 20-40mg/day ATX = <1.5mg/day Outcome measures: 1. Hyperactivity (using any scale that
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measured hyperactivity specifically) 2. Quality of Life (using Clinical Global Impression (CGI) as a proxy)
ache) Study quality: Rated as poor. Authors conclusions: The study that compared MPH-IR and ATX reported no differences between the drugs for hyperactivity or CGI. The study that compared ATX with MPH-ER found significant improvement in favour of MPH for both hyperactivity and CGI. However, this study also reported a higher incidence of reduced appetite and insomnia in the MPH group.
Sangal et al 2006 (303) Design RCT Level II Quality Adequate Setting USA Industry funding Yes
Intervention MPH-IR Comparator ATX
Population: Children aged 6-14 years with ADHD diagnosed by DSM-IV criteria
Wang et al 2007 (254) Design RCT Level II Quality Adequate
Setting China, Korea, Mexico Industry funding Yes
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Intervention MPH Comparator ATX
Study Information: Design: Cross-over RCT with 7 weeks double blind treatment No. n = 85 Group 1. n = 41 MPH/ATX Group 2. n = 44 ATX/MPH Dose: Dose escalation MPH; 0.45 mg/kg/day - 1.8 mg/kg/day ATX; 0.5 mg/kg/day - 1.8 mg/kg/day
Outcome measures: 1. ADHD RS 2. Clinical Global Impression (CGI) Severity scale 3. Conners Parent Rating ScaleRevised: Short Form (CPRS-R:S) 4. Daily Parent Ratings of Evening and Morning Behavior (DPREMB) Population: Children and adolescents aged 6-16 years with ADHD diagnosed by DSM-IV criteria Design: Parallel RCT of 8 weeks duration No. MPH n = 166 ATX n = 164 Dose: Individual dose titration ATX; 0.8 - 1.8 mg/kg/day MPH; 0.2 - 0.6 mg/kg/day Outcome measures: 1. ADHDRS-IV-Parent: Inv 2. Conners Parent Rating ScaleRevised Short Form (CPRS-R:S): ADHD Index 3. CGI-ADHD-S scale
T F A
These studies did not adequately report study methodology, and the results should be interpreted with caution. ADHD symptoms: ATX was found to be superior to MPH in improving parent rated behaviour. DPREMB Total Score; p = 0.003. No significant difference was found between ATX and MPH using measures of ADHD RS, CGI or CPRSR:S. Adverse events; Statistically significant differences were reported for decreased appetite and insomnia, which were more frequent with MPH than with ATX. In addition, ATX produced a significantly greater increase in diastolic blood pressure and heart rate than MPH ADHD symptoms: No significant difference between groups on any measure. Adverse events: Significant increase in anorexia, nausea, somnolence, dizziness and vomiting in the ATX group compared to the MPH group.
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Newcorn et al 2008 (304) Design RCT Level II Quality Adequate Setting USA (multisite) Industry funding Yes
Intervention ATX Comparator MPH-XR Placebo
Participants: Children and adolescents aged 6-16 who met the DSM IV diagnostic criteria for ADHD Study information: Design: Parallel design RCT Duration: 6 weeks No. ATX: n = 222 MPH n = 220 Placebo n = 74 Other analyses Previous stimulant treatment n = 301 Stimulant naive at study entry n=191 Dose: ATX: 0.8-1.8 mg/kg/day MPH: 18-54 mg/day
ADHD symptoms: Response rate All participants Placebo (24%) MPH (56%) superior to placebo (p < 0.001, NNT =3, effect size = 0.8) ATX (45%) superior to placebo (p = 0.003, NNT = 5, effect size = 0.6) MPH superior to ATX (p = 0.02 NNT = 9) Previous stimulant treatment: Placebo (23%) MPH superior to placebo (51%, p=0.002, NNT=4), ATX not superior to placebo (37%, p=0.09; NNT=7) MPH superior to ATX (p=0.03; NNT=8)
Outcome measures Responder: 40% decrease on ADHDRS CGI ADHD severity index Conners Parent Rating Scale Daily Parent Ratings of Evening and Morning BehaviorRevised Child Health Questionnaire
Wigal et al 2005 (305) Design RCT Level II Quality Adequate
R D
Intervention MAS-ER Comparator ATX
T F A
Stimulant nave Placebo (25%) MPH superior to placebo (64% p<0.001; NNT=3) ATX superior to placebo (57%, p=0.004; NNT=4) MPH and ATX not significantly different (p=0.43, NNT=14). Other measures ATX and MPH differed significantly from placebo on all other measures except; Child Health Questionnaire psychosocial summary score for patients with prior stimulant exposure (ATX versus placebo: p=0.65) and the Daily Parent Ratings of Evening and Morning Behavior morning subscore (MPH versus placebo: p=0.053). Adverse events: MPH significantly different to placebo for decreased appetite, insomnia, heart rate, diastolic blood pressure and decreased weight (all p < 0.05). ATX significantly different to placebo for any adverse event, decreased appetite, heart rate, diastolic blood pressure and decreased weight (all p < 0.05). ADHD symptoms: Symptom improvement was statistically significantly greater in the MAS-ER group for several measures (SKAMP deportment & attention, CGI and Maths test scores). Reported effect sizes SKAMP deportment MAS-ER 1.12; ATX 0.2
Population: Children aged 6-12 years with ADHD diagnosed by DSM-IV criteria
Study Information: Design: Parallel RCT of 18 days duration No. MAS-ER n = 107 ATX n = 108 Dose: Dose escalation MAS-ER 10mg-30mg
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ATX 0.5 mg/kg/day to 1.2 mg/kg/day Setting USA Industry funding Yes Outcome measures: 1. SKAMP teacher rating scale (deportment & attention) 2. Clinical Global Impressions (CGI) scale (Severity & Improvement) 3. Conners Global Index ScaleParent version (CGIS-P). 4. The Pediatric Quality of Life Inventory 5. Academic performance Math test scores
SKAMP attention MAS-ER 1.09; ATX 0.02 Maths problems attempted MAS-ER 1.83; ATX 0.88 Maths problems answered correctly MAS-ER 1.85; ATX 0.83 Quality of life: No significant difference was found between groups for the Pediatric Quality of Life Inventory or CGIS-P. Adverse events: No difference in the number of adverse events. Most common adverse events for; MAS ER insomnia, appetite decrease, upper abdominal pain, anorexia, and headache. ATX - somnolence, appetite decrease, upper abdominal pain, vomiting, and headache. ADHD symptoms: Both the MPH and the modafinil group showed a significant improvement in ADHD symptoms over time. No difference between the two medication groups p<0.96 in either the parent or teacher ADHD rating scaleIV.
Amiri et al 2000 (298) Design RCT Level II Quality Good
Intervention Modafinil Comparator MPH
Population: Aged of 615 years, DSM-IV-TR diagnostic criteria for ADHD). Additional inclusion criteria included total and/or subscale scores on ADHDRS-IV, at least 1.5 standard deviations above norms for patient's age and gender. Study information: Design: parallel design RCT Duration: 6-weeks No. modafinil n = 30 (23 boys & 7 girls) MPH n = 30 (24 boys & 6 girls) Dose: Modafinil: 200300 mg/day (once daily) depending on weight MPH: 2030 mg/ day depending on weight.
Setting outpatient clinic, Tehran Industry funding No
Palumbo et al 2008 (260) Adverse events reported in; Daviss et al 2008 (261) Design RCT Level II Quality Adequate
R D
Intervention Clonidine Comparator MPH-IR Placebo MPH-IR + Clonidine
Outcome measures: Parent and Teacher ADHD Rating Scale-IV ADHD-RS-IV Population: Children aged 7 to 12 years enrolled in school, each subject met DSM-IV criteria for ADHD of any subtype.
T F A
Adverse events: Decreased appetite (p = 0.03) and difficulty falling asleep (p = 0.05) occurred more frequently in the MPH group than the modafinil group. There were no other significant differences in number of side effects between groups. ADHD symptoms: Direct comparison of the MPH group versus the clonidine group found no significant differences on any scale. Conners ASQ Teachers Participants receiving MPH (combined or MPH) showed greater improvement than those not receiving MPH (clondine/placebo) (p = 0.008). Clonidine (Clonidine or combined) compared to no clonidine (MPH or placebo) did not improve ADHD symptoms. Conners ASQ Parents Participants receiving clonidine
Study information: Design: parallel design RCT Duration: 16 weeks (8 weeks dose titration and 8 weeks maintenance) No: clonidine n = 31 MPH n = 29 Combined n =32 Placebo n = 30 Dose: Clonidine: maximum dose 0.6 mg/day.
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MPH: maximum dose 60 mg/day Setting schools USA Industry funding Yes Outcome measures Conners Abbreviated Symptom Questionnaire for Teachers , Iowa Conners Teacher Rating Scale, Conners Abbreviated Symptom Questionnaire for Parents, Childrens Global Assessment Scale, Conners Continuous Performance Task, Wechsler Individual Achievement Test
(Clonidine or combined) showed greater improvement than those not receiving clonidine (MPH/placebo) (p = 0.003). CGAS Participants receiving clonidine (Clonidine or combined) showed greater improvement than those not receiving clonidine (MPH/placebo) (p = 0.0002). Adverse events: Dull / tired / listless (p < .0001) and drowsiness/sedation (p < .0001) were reported more frequently (parent and teacher) in participants receiving clonidine. Bradycardia was more frequent in the clonidine groups (p = .02), but no other significant group differences for electrocardiogram and other cardiovascular outcomes.
Mohammadi et al 2004 (291) Design RCT Level II Quality Adequate
Setting Outpatient clinic Tehran, Iran. Industry funding No
R D
Intervention Selegiline Comparator MPH Intervention Selegiline Comparator MPH
Population: Children and adolescents aged 615 years, diagnosed as having ADHD according to DSM-IV criteria Study information: Design: parallel design RCT Duration: 60 days No: Selegine n = 20 MPH n = 20
T F A
Moderate or severe adverse events were more common in the clonidine group (p = .0006) but were not associated with higher rates of early study withdrawal ADHD symptoms: No significant difference in treatment efficacy found between medication groups. Selegiline group showed improved ADHD symptoms as rated by teachers (p < 0.001) and parents (p < 0.001). MPH group showed improved ADHD symptoms as rated by teachers (p = 0.003) and parents (p < 0.001). Adverse events: The five most frequent adverse events were; Headache (Selegiline n = 1 / MPH n = 6), anorexia (Selegiline n = 2 / MPH n = 4), sleep disturbance (Selegiline n = 1 / MPH n = 3), irritability (Selegiline n = 1 / MPH n = 2) and weight loss (Selegiline n = 1 / MPH n = 2). No tests of significance were performed. ADHD symptoms: No differences observed between the medication groups on either parent or teacher ratings. Both groups showed improvement in ADHD symptoms
Dose: Selegiline: Average daily dose; 7.6mg. Highest dose; 10 mg/day MPH: Average daily dose; 25.5 mg. Highest dose; 1 mg/kg/day MPH, or a maximum of 40 mg/day Outcome measures ADHD-RS (Parent and Teacher)
Akhondzade h et al 2003 (292) Design
Participants: Children (20 boys and 8 girls) between the ages of 49 who met the DSM IV diagnostic criteria for ADHD
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RCT Level II Quality Adequate Setting outpatient child and adolescents clinic, Iran. Industry funding Not reported
Study information: Design: Parallel design RCT Duration: 4 weeks No. Selegiline: n = 14 MPH n = 14 Dose: Selegiline 5 mg/day (under 5 years) and 10 mg/day (over 5 years) MPH: 1 mg/kg/day Outcome measures Parent ADHD Rating scale Teacher ADHD rating scale
(both p < .001 at week 4 on parent and teach ratings). Adverse events: Decreased appetite (p = 0.05), difficulty falling asleep (p = 0.02) and headaches (p = 0.01) were observed more frequently in the MPH group.
Comparing stimulant medications to non-stimulant medications Adults

Reference Taylor & Russo 2000 (207) Design RCT Level II Quality Adequate Intervention/ comparator Intervention Modafinil Comparator DEX Placebo Population/Study information Results
Population: Adults aged over 21 years with DSM-IV diagnosis of ADHD
Setting USA (Washington) Industry funding Not reported
Taylor & Russo 2001 (208) Design RCT Level II Quality Adequate Setting
R D
Intervention Guanfacine Comparator DEX
Study information 3-phase crossover RCT, 2 weeks on each of modafinil, DEX and placebo, 4day washout in between No. Modafinil vs dextroamphetamine n=22 Dose: Modafinil: maximum 400mg per day. DEX: maximum 40mg per day. Outcome measures: ADHD Behavior Checklist for Adults: self-rated
T F A
ADHD symptoms: No significant difference between the modafinil and DEX groups for total score, hyperactivity or inattention. Significant reduction in total symptoms (p < 0.001) inattention (p < 0.01) and hyperactivity (p < 0.05) for DEX compared to placebo. Statistically significant improvement on total score (p<0.001), hyperactivity subscale (p<0.01), inattention subscale (p<0.001) for modafinil compared to placebo. Adverse events: Common adverse events: insomnia (modafinil 19%, DEX 38%, placebo 19%), muscle tension (modafinil 19%, DEX 24%, placebo 5%) and irritability (modafinil 14%, DEX 14%, placebo 10%). No significant differences between medication and placebo. ADHD symptoms: No significant differences between guanfacine and DEX groups. Significant reduction in ADHD symptoms: total score (p<0.05) and inattentive subscore (p<0.05) for guanfacine treatment over placebo. Significant reduction in ADHD symptoms: total score (p<0.05) and inattentive subscore (p<0.05) for DEX treatment over placebo.
Population: Adults diagnosed with ADHD with DSM-IV diagnosis of ADHD
Study information Design: crossover RCT Duration: 3 x 2 week treatment periods with 4 day-washout period between each. No: n = 34 Dose: determined by titration. Guanfacine: Maximum dose 2mg/day
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USA (Washington) Industry funding Not reported
DEX: Maximum dose 20mg/day. Outcome measures DSM-IV ADHD Behaviour Checklist for adults Copeland Symptom Checklist for Adult Attention Deficit Disorder Adverse events: Number of side effects similar in when receiving Guanfacine or DEX (no tests of significance performed). No significant difference between number of side effects between either medication and placebo.
Weiss et al 2006 (306) Design RCT Level II Quality Adequate Setting outpatient psychiatric clinic in USA and Canada Industry funding Yes
Intervention Paroxetine Comparator DEX Placebo DEX + Paroxetine
Population: Adults aged 18-66 years, meeting DSM-IV diagnostic criteria for ADHD. Study information: Design: crossover RCT Duration: 20 weeks No: n = 64 Dose Paroxetine: maximum 40mg/day p.o DEX: maximum 20mg per day p.o.
Outcome measures ADHD rating scale CGI-I clinician rating scale Global Assessment of Function (GAF)
Kuperman et al 2001 (271) Design RCT Level II Quality Adequate
Setting Community via newspaper advertisement Industry funding Yes
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Intervention BupropionSR Comparator MPH Placebo
Population: Adults (18-60 years of age) with a diagnosis of DSM-IV ADHD Study information: Design Parallel design RCT Duration: 8 weeks. No: Bupropion: n= 11 MPH n = 8 Placebo n = 11
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In the group completing the study ADHD symptoms significantly lower for DEX (DEX and DEX/PAR) compared to no DEX (PAR and placebo) (p = 0.012). Improvement was also seen for GAF (p = 0.037) and CGI (p < 0.001). ITT analysis did not reach significance. Paroxetine (DEX/PAR and PAR) compared to no paroxetine (DEX and placebo) had no effect on ADHD symptoms in either the group completing the study or in the ITT analysis. Adverse events: No significant difference in the mean number of adverse events between medication groups. ADHD symptoms: No direct statistical comparison of Bupropion and MPH. No significant difference between bupropion or MPH over placebo on CGI responder (p=0.14) or ADHD-RS (p = 0.69) Adverse events: Reporting limited. Number of participants experiencing an adverse event; Bupropion 69%, MPH 75% and placebo 67%. Most common adverse events: Bupropion dry mouth (4/13), headache (2/13) and insomnia (2/13). MPH appetite suppression (3/12) and insomnia, tremor, sweats, jitteriness (2/12). Placebo tiredness 2/12.
ADHD symptoms: No direct statistical comparison of DEX alone and paroxetine alone.
Dose: Bupropion: maximum dose 300mg/day (200mg at 8.00am and 100mg at 4pm) MPH: maximum dose of 0.9mg/kg/day ( 3 doses 8.00am, noon and 4pm) Outcomes: CGI Scale, ADHD symptoms checklist severity scale
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Summary
Preschoolers: No studies meeting the inclusion criteria were identified. Children and adolescents: Comparing stimulant medications Immediate-release stimulants versus extended-release stimulants: King et al (196) compared the efficacy of the immediate-release and extended-release stimulant medications in children and adolescents with ADHD. The results of two studies were discussed. Both studies compared immediate-release MPH to extended-release MPH and found no differences in hyperactivity or quality of life measures. One study found that the incidence of headaches was increased in the group taking MPH-ER. Both studies were rated as being poor quality and were short-term studies (4-8 weeks only).
MPH versus DEX: King et al (196) compared the efficacy of MPH and DEX in children and adolescents with ADHD. Two studies were identified that made this comparison. In the first study, when looking at the impact of DEX and MPH on ADHD symptoms, MPH was found to be superior in the teacher rated scales, but no significant difference was found between groups in the parent rated scales. No differences in adverse events were found between the groups. The second study found no differences between the two medications on hyperactivity measures, but did not adequately report on adverse events. Neither study reported on quality of life measures. The quality ratings given to these studies were mixed, with the first being rated as poor and the second as good. Comparing stimulant to non-stimulant medications MPH versus ATX: King et al (196) identified two studies that compared the efficacy of MPH with ATX. One study found no significant differences between the MPH-IR and ATX on measures of hyperactivity, quality of life and adverse events. The second study found that MPHER was superior to ATX on the hyperactivity and quality of life measures. The occurrence of reduced appetite and insomnia was increased in the MPH-ER group. Both studies were of short duration (3-10 weeks) and were rated as poor quality.
Three additional studies were identified that compare MPH to ATX in children and adolescents. Sangal et al (303) found that ATX was superior to MPH in improving parent rated behaviour. However, no other significant difference was found between ATX and MPH on other measures of ADHD symptoms. Decreased appetite and insomnia were reported more frequently in the MPH group than the ATX group, while ATX was reported to produce a significantly greater increase in diastolic blood pressure and heart rate than MPH. The quality of this study was rated as adequate. Wang et al (254) found no significant difference between the ATX group and MPH group on any measure of ADHD symptoms. Several adverse events (anorexia, nausea, somnolence, dizziness and vomiting) were, however, reported more frequently in the ATX group. The quality of this study was rated as adequate. Newcorn et al (304) compared MPH-XR, ATX and placebo in children and adolescents with ADHD in a 6 week parallel-design RCT. This study involved more than 500 participants. The primary outcome measure employed by this group was a 40% decrease in ADHD symptoms on the ADHD-RS. Both MPH and ATX were superior to placebo. MPH was found to be superior to ATX. Subgroup analysis comparing those with and without previous stimulant therapy found that MPH was superior to ATX in the group that had previously received stimulants, but there was no significant difference in treatment outcomes for ATX and MPH in the group that were stimulant nave. A direct statistical comparison on adverse events for the two medications was not made.
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However comparison to placebo demonstrated that MPH was significantly different to placebo for decreased appetite, insomnia, heart rate, diastolic blood pressure and decreased weight. ATX was significantly different to placebo for any adverse event, decreased appetite, heart rate, diastolic blood pressure and decreased weight. The quality of this study was rated as adequate. The results of the studies comparing ATX to MPH have been variable with 2/5 studies reporting no difference, 1/5 reporting ATXs superiority and 2/5 reporting MPHs superiority. All studies have been short-term assessments of the two medications. Additional longer term studies are required. MAS versus ATX: One study was identified that compared ATX to an extended-release formulation of mixed amphetamine salts (MAS-ER) in children (6-12 years). Wigal et al (305) reported that MAS-ER was superior to ATX on teacher rated measures and academic achievement measures (maths tests). No differences were found in parent rated measures, quality of life measure or adverse events. The quality of this short-term study was rated as adequate. MPH versus modafinil: One study was identified that conducted a head to head comparison of MPH and modafinil in children and adolescents with ADHD. Amiri et al (298) described a 6week parallel design RCT that was rated adequate in quality. Both the MPH and the modafinil group showed a significant improvement in ADHD symptoms over time. There were no differences between the two medication groups in parent or teacher rated ADHD symptoms. The incidence of decreased appetite and difficulty falling asleep was increased in the group taking MPH.
MPH versus clonidine: Palumbo et al (260) described a 16 week RCT in children with ADHD that compared MPH, clonidine, MPH and clonidine combined and placebo. Direct comparison of the MPH group versus the clonidine group found no significant differences on any scale. Comparisons of participants receiving MPH (combined or MPH) those not receiving MPH (clondine or placebo) showed greater improvement in ADHD symptoms for those receiving MPH on the Conners ASQ Teachers. Whereas, participants receiving clonidine (clonidine or combined) showed greater improvement than those not receiving clonidine (MPH or placebo) on the Conners ASQ Parents and CGAS scales. The quality of this study was rated as adequate. Daviss et al (261) reported on the adverse events in this study. Participants receiving clonidine had a greater incidence of dull / tired / listless and drowsiness/sedation side effects. Bradycardia was also more frequent in the clonidine groups, but no other significant group differences were seen for electrocardiogram and other cardiovascular outcomes. Moderate or severe adverse events were more common in the clonidine group, but were not associated with higher rates of early study withdrawal.
MPH versus seligiline: Two studies compared seligiline with MPH. Mohammadi et al (291) described a 60 day, parallel-design RCT in children and adolescents with ADHD. Both seligiline and MPH were found to improve ADHD symptoms (parent and teacher rated). There was no significant difference in treatment efficacy found between the medication groups. Reporting of adverse events was limited and no tests of significance were performed to enable appropriate comparisons between the medication groups. The quality of this study was rated as adequate. Akhondzadeh et al (292) compared seligiline with MPH in a 4 week RCT in children with ADHD. Both groups showed improvement in parent and teacher rated ADHD symptoms. No significant differences were observed between the medication groups on either parent or teacher ratings. Decreased appetite, difficulty falling asleep and headaches were observed more frequently in the MPH group than the seligiline group. The quality of this study was rated as
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adequate. There was no placebo control group used in either study, as a result it is not possible to draw direct conclusions regarding medication efficacy. Adults: Four head to head medication comparisons that met our inclusion criteria have been conducted in adults. All compare stimulants to non-stimulant medication. DEX versus modafinil: Taylor & Russo (207) conducted a 6 week cross-over RCT in adults with ADHD where participants received modafinil, DEX and placebo for 2 weeks each. Both medications where effective compared to placebo in reducing ADHD symptoms and there was no significant difference between the treatment outcomes for modafinil and DEX. There was no significant difference in the frequency of adverse events between either of the medications and placebo. The quality of this study was rated as adequate. DEX versus guanafacine: Taylor & Russo (208) described a 6 week cross-over RCT in adults with ADHD where participants received guanafacine, DEX and placebo for 2 weeks each. Both medications were effective compared to placebo in reducing ADHD symptoms. There were no significant differences between treatment outcomes between guanfacine and DEX. The reported number of side effects was similar for guanfacine and DEX and there was no significant difference between the numbers of side effects for either medication compared with placebo. The quality of this study was rated as adequate.
DEX versus paroxetine: Weiss et al (306) reported on a 20 week cross-over RCT that compared paroxetine alone, DEX alone, paroxetine plus DEX and placebo in adults with ADHD. There were no direct comparisons of DEX alone and paroxetine alone. Comparisons were made between groups receiving DEX (DEX and DEX/PAR) compared to not (PAR and placebo) and groups receiving paroxetine (DEX/PAR and PAR) compared to not (DEX and placebo). In the analysis of participants that completed the study, ADHD symptoms were significantly lower for DEX (DEX and DEX/PAR) compared to no DEX (PAR and placebo). However, the ITT analysis did not reach significance. Paroxetine (DEX/PAR and PAR) compared to no paroxetine (DEX and placebo) had no effect on ADHD symptoms in either the group completing the study or in the ITT analysis. There was no significant difference in the mean number of adverse events between medication groups. The quality of this study was rated as adequate. MPH versus bupropion: Bupropion-sustained release was compared to MPH and placebo in adults with ADHD in a study by Kuperman et al (271). In this parallel design RCT conducted for 8 weeks no significant difference was found between bupropion or MPH over placebo for either of the ADHD symptom measures used in this study (CGI responder and ADHD-RS). There was no direct statistical comparison of Bupropion and MPH. The reporting of adverse events in this study was very limited. The most common adverse events were dry mouth, headache and insomnia for bupropion, appetite suppression and insomnia, tremor, sweats, jitteriness for MPH and tiredness for placebo. Excluded studies Study Banaschewski et al 2006 (307) Biederman et al 2006(308) Faraone et al 2006 (309) Kemner et al 2005 (310)
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Reason for exclusion Does not consider head to head trials Post-hoc analysis on included study Does not consider head to head trials Published version of study reported in King et al 2006 with no
Michelson et al 2004 (311) Connor et al 1999 (278) Connor et al 2000 (279) Hornig-Rohan et al 2002(312) Dorrego et al 2002 (313) Levin et al 2006 (214) Faraone et al 2007(314) Gibson et al 2006 (315)
additional data Unable to access full study information Not all included studies placebo controlled Include in comorbidities Include in comorbidities Not a comparison Does not address research question Head to head outcomes in included study Wigal et al 2005 (305) Review combining open-label and RCTs.
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When comorbidities are present

Research question 17a. When comorbidities are present in individuals with ADHD, do pharmacological interventions, compared to placebo improve outcomes? a. b. c. d. e. f. Anxiety Bipolor disorder Depression Disruptive behaviour disorder Epilepsy Tic disorders Tourette syndrome
NB: Treatment of ADHD and comorbid substance use disorders are considered in research question 18 Selection Criteria Population
Study Design
Search Period Language Date of Search
Search terms
Depressive Disorder, Major/ or tic disorders/ Tourette Syndrome/ or Attention Deficit and Disruptive Behavior Disorders/ Conduct Disorder/ or Depression/ or Anxiety/ or Anxiety Disorders/ or Comorbidity/
R D
Inclusion Criteria Individuals with ADHD diagnosed according to standard criteria; DSM-III, DSMIII-R, DSM-1V or ICD10 that have a co-morbid disorder diagnosed according to standard criteria. Pharmacological intervention Placebo Primary: 1. Change in incidence or severity of symptoms of ADHD (including; inattention, impulsivity, hyperactivity). 2. Change in the incidence or severity of symptoms of comorbid conditions. Secondary: School/work achievement, quality of life, social function. NHMRC levels of evidence I-II Study with a clear focus on the impact of medication on the ADHD and the co-morbid disorder. 1997 - present English March 2008
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Text words: adhd or addh or adhs or hyperactive$ or hyperkin$ or (attention adj deficit) comorbid$
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ADHD with comorbid anxiety Children and adolescents

Reference Diamond et al 1999 (316) Design RCT Level II Quality Adequate Setting USA Industry funding None reported Intervention/ comparator Intervention MPH Comparator Placebo Population/Study information Population: Children aged 6 to12 years who met the DSM-III-R criteria for ADHD. Participating children were subsequently assessed for anxiety based on child-self report (RCMAS) or parent-report (PICS; DSM-II-R criteria) and classified as either ADHD + ANX or ADHD - ANX Study information: Design & Duration: RCT 3-4 week titration. Follow-up at 4 months. No. n = 91 Placebo: ADHD + ANX n=19 Placebo: ADHD ANX n = 26 MPH: ADHD + ANX n=19 MPH: ADHD ANX n = 27 Dose: Titrated to 0.7 mg/kg Results Comparison between the ADHD + ANX and ADHD ANX groups on behavioural measures found no significant differences in treatment response between the groups at the end of titration or at 4 months. Adverse events: No Significant difference between the ADHD + ANX and ADHD ANX groups in the number of adverse events.
Geller et al 2007 (317) Design RCT Level II Quality Adequate Setting USA (multisite) Industry funding Yes
R D
Comparator Placebo
Intervention Atomoxetine
Outcome measures: IOWA Conners rating scale (IOWA-C) Telephone Interview Probe (TIP) Population: Children and adolescents ages 8 to 17 years who met the DSMIV criteria for ADHD and for at least one of the following anxiety disorders: separation anxiety disorder, generalized anxiety disorder, or social phobia. Study information: Design & Duration: 12 week RCT No. placebo n=89, ATX n=87 Dose: 1.2 mg/kg/day (daily dose not >120mg regardless of weight)
Outcome measures: ADHDRS-IV-PI Clinical Global Impressions-Severity of Illness (CGI-S) Clinical Global ImpressionsImprovement of Illness (CGI-I) PARS Multidimensional Anxiety Scale for Children(MASC) Life Participation Scale for ADHD-Revised (LPS-ADHD-R) Child Health Questionnaire-ParentCompleted Full Length (CHQ-PF50)
T F A
Statistically significant reduction in all ADHD and anxiety measures in ATX compared to placebo (all p<0.05). Adverse events: ATX treatment was associated with significantly more decreased appetite (p = 0.025) and weight loss (p < 0.001).
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ADHD with comorbid bipolar disorder Children and adolescents

Reference Findling et al 2007 (318) Design RCT Level II Quality Adequate Setting USA Industry funding Yes Intervention/ comparator Intervention MPH Comparator Placebo Population/Study information Population: Children and adolescents ages 5 to 17 years meeting DSM-IV criteria for a diagnosis of a bipolar spectrum disorder and a comorbid diagnosis of ADHD Results Significantly greater improvement (p<0.05) in ADHD and bipolar symptoms with MPH compared to placebo for all outcomes except the following: CPRS-48 Learning Problem subscale T score (p=0.08) CPRS-48 Anxiety subscale T score (p=0.45) CPRS-48 Psychosomatic subscale T score (p=0.98)
Study information: Design & Duration: 4-week crossover RCT No. n=16 (crossover) Dose: B1: 5mg twice daily B2: 10mg twice daily B3: 15mg twice daily Outcome measures: ADHD Rating Scale-IV Conners Parent Rating Scale (CPRS48) CDRS-R YMRS CGI-S Population: Children and adolescents 617 years of age who met the DSMIV criteria for both bipolar I or bipolar II disorder (in either the mixed, manic, or hypomanic phase) and ADHD. Study information: Design & Duration: 8 week open label treatment with divalproex sodium to stabilise mania symptoms followed by a 4-week crossover RCT No. n=30 (crossover) Dose: 5 mg by mouth b.i.d. Outcome measures: Young Mania Rating Scale Clinical Global Impression (CGI) improvement subscale
Scheffer et al 2005 (319) Design RCT Level II Quality Poor Setting USA Industry funding Yes
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Comparator Placebo (+divalproex sodium)
Intervention MAS (+divalproex sodium)
T F A
Adverse events: Reporting limited. Side effects occurring more frequently when receiving MPH than placebo were; insomnia, decreased appetite and stomach aches. Not tests of significance were performed. Significant improvement in the MAS group over the placebo group in the CGI Improvement Score for ADHD Symptoms (p=0.0001). No difference in the Young Mania rating scale. Adverse events: Reporting was limited. Reported side effects included abdominal pain, diarrhea, nausea, appetite increase, headache, drowsiness, difficulty falling asleep, irritability, and rash. Not specified if side effects were more frequently associated with MAS treatment. No tests of significance.
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ADHD with comorbid depression Children and adolescents

Reference Bangs et al 2007 (320) Design RCT Level II Quality Adequate Setting USA Industry funding Yes Intervention/ comparator Intervention Atomoxetine Comparator Placebo Population/Study information Population: adolescents aged 1218 years who met the criteria for both ADHD and MDD (major depressive disorder) per the DSMIV Study information: Design & Duration: 9-week RCT No. placebo n=70, ATX n=72 Dose: 1.2-1.8 mg/kg/day once daily Results Statistically significant improvement in the ATX group over placebo for the following outcomes: CGI-I scale responder (score 1 or 2) (p<0.001 ADHDRS-IV Parent:Inv (p<0.001, ES 0.84)
Outcome measures: ADHDRS-IV-Parent: Inv scale CDRS-R Clinical Global Impressions Improvement (CGI-I) and Severity of Illness (CGI-S) scales Montgomerysberg Depression Rating Scale (MADRS)
Reference
Design Meta-analysis Level I Quality Adequate
Setting USA/Canada Industry funding Yes
Hazell et al 2006 (322) Design RCT Level II Quality Adequate
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Intervention/ comparator Intervention Atomoxetine Comparator Placebo Intervention Atomoxetine Comparator Placebo
ADHD with comorbid disruptive behaviour disorders Children and adolescents

Population: children and adolescents, aged 6 16, who met DSM-IV criteria for ADHD, some subjects (30%) met the requirements for ODD according to DSM-IV
Study information: Design & Duration: meta-analysis of 3x RCTs (6-8 weeks) No. placebo n=200, ATX n=312 Dose: Once-daily dose up to 1.8 mg/kg/day
T F A
There was no significant improvement in depression symptoms (CDS-R). Adverse events: ATX treatment was associated with significantly more nausea (p< 0.002) and decreased appetite (p < 0.003). Statistically significant improvements in the ATX group over placebo for: ADHDRS-IV-Parent:Inv (p<0.001), CGI (p=0.003), CPRS-ADHD Index (p=0.014), CHQ (psychosocial summary only) (p=0.016) for children with ADHD and comorbid ODD. No significant difference in the CPRSR:S oppositional subscale change scores. No differential response between those with and without ODD. Adverse events: Not reported. No statistically significant difference in number of participants relapsing (based on ADHD RS and CGI scores) or mean time to relapse between the atomoxetine-treated groups with or without comorbid ODD [mean (SE) days to relapse, ADHD/+ODD: 215 (7.38); ADHD/ODD: 211 (7.61); log rank p=0.08] or for the placebo groups, regardless of the presence or absence of
Outcome measures: ADHDRS-IV Conners Parent RS, revised: short form (CPRS-R:S) CGI Child health questionnaire (CHQ) Population: children and adolescents aged 615 years who met DSM-IV criteria for ADHD. ODD was a common comorbidity, affecting 179 patients (43% of the sample). Study participants were responders to ATX in a 10 week ope-label trial. Study information: Design & Duration: 42-week RCT
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Setting International (33 sites) Industry funding Yes Newcorn et al 2005 (323) Design RCT Level II Quality Adequate Setting USA (multisite) Industry funding Yes
No. placebo n=124, ATX n=292 Dose: minimum dose of 0.5mg/kg/day to a maximum of 1.8 mg/kg/day Outcome measures: ADHD RS Clinical Global Impressions of Severity (CGI-S) Population: Children and adolescents 8 to 18 years of age who met DSM-IV criteria for ADHD, 39% also met DSM-IV criteria for ODD.
ODD [mean (SE) days to relapse, ADHD/+ODD: 136 (11.35); ADHD/ ODD: 151 (9.13); log rank p=0.22]. Adverse events: Not reported
Intervention Atomoxetine Comparator Placebo
Study information: Design & Duration: 8-week RCT (preceded by initial 12-18 day washout) No. placebo n=31, B1: n= 21; B2: n= 27; B3: n= 36 Dose: B1: 0.5mg/kg/day B2: 1.2mg/kg/day and B3: 1.8mg/kg/day as a divided dose b.i.d. Outcome measures: ADHDRS-IV-Parent:Inv Conners Parent Rating Scale-Revised Short form Clinical Global Impressions of Severity (keyed to ADHD severity) Child Health Questionnaire Conners Parent Rating Scale-Revised Short form oppositional subscale Population: Boys aged 7-13 years of age who met DSM-III-R Axis I criteria for ADHD of whom 7 and 9 had comorbid CD and ODD respectively
Kolko et al 1999 (193) Design RCT Level II Quality Adequate Setting USA Industry funding None reported
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Intervention MPH (+/behavioural modification) Comparator Placebo Intervention Clonidine + stimulant therapy Comparator Study information:
Study information: Design & Duration: 9-week crossover RCT No. n=16 (crossover) Dose: twice daily dose low dose MPH (0.3mg/kg per dose) or high-dose MPH (0.6 mg/kg/dose)
T F A
There were significant differences for ODD status and treatment on the CPRS-R:S ADHD Index (ODD: p=0.022, treatment p<0.001) and CGIADHD-S (ODD: p=0.033, treatment p=0.004), but only treatment on the ADHD:RS-IV-Parent:IV total score (p=0.003). Adverse events: not reported Effect sizes for MPH Measure Group B Mean (SD) Classroom I/O 1.63 (1.24) O/D 0.59 (1.20) OAS 0.59 (1.09) Peer Conflicts 0.59 (1.50) Pos. Mood/Beh -0.18 (1.13) Enrichment I/O 1.66 (1.11) O/D 1.00 (1.14) OAS 0.27 (1.03) Peer Conflicts 0.58 (1.01) Pos. Mood/Beh -0.36 (1.14) I/O = inattentive/overactive; O/D oppositional/defiant; OAS= Overt aggression scale; Pos. Mood/Beh = Positive mood/behavior. Adverse events: Not adequately reported. 2 (9%) participants withdrew due to side effects. Statistically significant reduction in parent reported mean ratings of conduct (p<0.05) and hyperactive (p<0.05) symptoms but not for teacher reported conduct (p = 0.81) and hyperactive (p = 0.74) symptoms for children taking
Statistically significant (p<0.05) improvements in CGI and CPRS and some subscales of CHQ in children and adolescents with ADHD+ODD treated with ATX compared to placebo.
Hazell et al 2003 (280) Design RCT
Outcome measures: Abbreviated IOWA/Conners rating scale (I/O & O/D) Subset of 3 items (verbal aggression, physical aggression against objects and physical aggression against people) from the Overt Aggression Scale (OAS) 3-item Positive Mood/Behavior Scale 4-item Peer Conflicts Scale Population: children and young adolescents aged 6 to 14 years of age with ADHD and comorbid ODD or CD diagnosed by DSM-IV criteria
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Level II Quality Good Setting Australia Industry funding No
Placebo + stimulant therapy
Design & Duration: 6-week RCT No. placebo n=29, Clon n=38 Dose: 0.05-0.1mg twice daily Outcome measures: Conners revised parent and teacher report checklists; Conduct and hyperactive subscale
clonidine compared to placebo. Treatment effect became significant in week 5 and 6 of the trial. Adverse events: Statistically significant decrease in pulse rate (p = 0.08) and systolic blood pressure (p = 0.09) and increases in parent reported drowsiness (p < 0.05) and dizziness (p < 0.05) in the clonidine group compared to placebo.
Aman 2004 (324) Design RCT Level II Quality Adequate Setting Canada, USA, South Africa Industry funding None reported
Intervention Risperidone +/- stimulants Comparator Placebo +/- stimulants
Population: children aged 5-12 years with DSM-IV diagnosis of ADHD and conduct disorder or other disruptive behaviour disorders
Study information: Design & Duration: Two 6-week RCTs results combined for post-study analysis. No. placebo only n = 39 placebo + stimulant n = 38 risperidone only n=43 risperidone + stimulant n=35 Dose: maximum allowable dose of 0.06 mg/kg/day Outcome measures: N-CBRF - Conduct Problem subscale (16 items) and the Hyperactive subscale (9 items) ABC - Hyperactivity/Noncompliance and Irritability subscales
Reference
Tourettes Syndrome Study Group 2002 (325) Design RCT Level II Quality Good Setting USA Industry funding Yes
R D
Intervention/ comparator Intervention Clonidine, MPH or Clonidine +MPH Comparator Placebo
ADHD with comorbid Tics or Tourettes Children and adolescents

T F A
Risperidone (either alone or with concurrent stimulant therapy) was significantly more effective on the NCBRF conduct and hyperactivity measures (both p<0.0001) and the ABC irritability (p = 0.004) and hyperactivity measures (p = 0.004). Addition of risperidone to stimulant treatment resulted in significantly better control of hyperactivity (p < 0.001) than stimulant treatment alone. Adverse events: The most common adverse events in risperidone-treated patients were somnolence, headache, dyspepsia, rhinitis, and vomiting. No tests of significance reported. Increase in weight and BMI in the risperidone groups compared to placebo (p < 0.001). Results Statistically significant improvement in ADHD symptoms, TIC severity and global function in all medication groups compared to placebo. ADHD symptoms ASQ-Teacher: MPH+Clon p<0.0001 Clon p=0.02 MPH p=0.02 ASQ-Parent: MPH+Clon p<0.002 Clon p=0.009 MPH p=0.002 Global function: C-GAS MPH+Clon p<0.0001 Clon p=0.003 MPH p=0.001
Population: children aged 7-14 years with DSM-IV criteria for ADHD and Tourette disorder, chronic motor tic disorder or chronic vocal tic disorder.
Study information: Design & Duration: 16-week RCT No. placebo n=32, MPH n=37, Clon n=34, MPH+Clon n= 33 Dose: max daily dose MPH: 60mg, max daily dose Clon 0.6mg Outcome measures: Conners Abbreviated Symptom Questionnaire (ASQ)-Teacher score Continuous performance task (CPT) Child Global Assessment Scale (CGAS) Tic Symptom Self-Report (TSSR)
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Yale Global Tic Severity Scale (YGTSS)
Tic severity; YGTSS total score MPH+Clon p = 0.003 Clon p=0.003 MPH p=0.01 Adverse events: Individual reporting of worsening of tics MPH (20%) Clon alone (26%) and placebo (22%). Clonidine was associated with increased sedation. MPH produced significant improvements in ADHD symptoms over placebo for all doses (all scales p<0.05).
Gadow et al 2007 (326) Design RCT Level II Quality Adequate Setting USA Industry funding Yes
Population: Children aged 6-12 years with DSM-III-R or DSM-IV diagnosis of ADHD and either chronic motor tic disorder or Tourettes syndrome
Study information: Design & Duration: 8-week crossover RCT No. n=71 (crossover) Dose: MPH-IR 0.1mg/kg; B2: MPH-IR 0.3mg/kg; B3: MPH-IR 0.5mg/kg Outcome measures: YGTSS Shapiro Tourette Syndrome Severity Scale TS-CGI Global Tic Rating Scale 2-Minute Tic and Habit Count Global Tic Rating Scale Simulated Classroom task AP/TRS IOWA Conners Teachers Rating Scale MOMS parent only Peer Conflict Scale Simulated Classroom task CPT
Allen et al 2005 (327) Design RCT Level II Quality Good Setting USA Industry funding Yes
R D
Population: children or adolescents 717 years+6 months and weighing between 20 and 80 kg who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for ADHD and had concurrent Tourette syndrome or chronic motor tic disorder Study information: Design & Duration: 20-week RCT No. placebo n=72, ATX n=76 Dose: 0.5 to 1.5 mg/kg/day (maximum total daily dose of 110 mg, regardless of the subjects weight) Outcome measures: YGTSS total score Tic Symptom Self- Report (TSSR) CGI-Tic/Neuro-S ADHDRS-IV-Parent:Inv CGI-Overall-S CGI-ADHD/Psych-S
T F A
No significant differences in physician rated tic severity between the groups on the YGTSS and GTRS. Significant increase in simple (p < 0.0091) but not complex (p < 0.1792) motor movements (0.3 and 0.5 mg/kg 9 placebo) as measured on the 2-Minute Tic/Habit Count. Significant improvement in tic severity on GTRS-teacher (total tic severity p < .0015) but not GTRS-parent. Adverse events: Significant differences for the MPH groups compared to placebo included somatic index items [sleep, appetite, headache, upset-stomach, dizziness] (p = 0.0001), increased heart rate (p = 0.0386), increased diastolic blood pressure (p = 0.0326) and decreased body weight (p = 0.004). Statistically significant improvement (all p<0.05) on all ADHD outcome variables in the ATX group over placebo. Primary measure of Tic severity (YGTSS) did not show any significant difference between groups. Only one scale significantly improved in ATX group over placebo for tics: CGI-Tic/Neuro-S (p=0.002) Adverse events: Discontinuation rates did not differ between groups. Significant differences for the ATX group compared to placebo included decreased appetite (p = 0.01), nausea (p = 0.002), increased heart rate (p < 0.001) and decreased body weight (p < 0.001).
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Spencer et al 2008 (328) Design RCT Level II Quality Adequate Setting USA (multisite) Industry funding Yes
Population: children or adolescents at least 7 years of age but less than 17 years and 6 months and weighing between 20 and 80 kg, who met DSMIV criteria for ADHD and concurrent Tourette Syndrome Study information: Design & Duration: 20-week RCT (10- to 18-day screening and washout period, 3-week dose-titration phase and a 15-week acute treatment phase) No. placebo n=56, ATX n=61 Dose: 0.5-1.5 mg/kg/day, as a divided dose, maximum total daily dose of 110 mg, regardless of the subjects weight Outcome measures: YGTSS total score Tic Symptom Self-Report (TSSR) CGI-Tic/Neuro-S ADHDRS-IV-Parent:Inv CGI-ADHD/Psych-S CGI-Overall-S
Analysis of Allen et al 2005 (327) for ADHD + Tourette syndrome group only. Statistically significant improvement in ADHD symptoms in ATX group compared to placebo for all scales (p<0.05) except for CGI-ADHD/PsychS (p=0.072).
Spencer et al 2002 (329) Design RCT Level II Quality Adequate Setting USA Industry funding Yes
R D
Intervention Desipramine Comparator Placebo Intervention Guanfacine Comparator Placebo
Population: Outpatient children and adolescents aged between 5 and 17 years with the DSM-IV diagnosis of combined-type ADHD and chronic motor tic disorder, chronic vocal tic disorder or Tourette disorder.
Study information: Design & Duration: 6-week duration No. placebo n=20, Des n=21 Dose: up to 3.5mg/kg in 25mg capsules in twice daily doses Outcome measures: Wide range achievement test (reading and arithmetic) Wechsler Intelligence Scales-Revised subtest: vocabulary, block design, arithmetic, digit span and digit symbol Clinical Global Impressions Scale ADHD Rating Scale Y Clinical Global Impressions Scale Yale Global Tioc Severity Scale (YGTSS) Global Assessment of Functioning (GAF) Population: children aged between 7 and 15 years, a DSM-IV diagnosis of ADHD (any type), a DSM-IV tic disorder (any type) Study information: Design & Duration: 8-week RCT
T F A
Statistically significant improvement in Tic symptoms in ATX group compared to placebo for the following scales: YGTSS total, YGTSS Motor, CGITic/Neuro-S (all p<0.05) but not for YGTSS phonic (p=0.126), TSSR (p=0.135). Adverse events: Significant increases in mean pulse rate (p < 0.001) and treatment-emergent nausea (p = 0.005), decreased appetite (p = 0.005), and decreased body weight (p < 0.001) in the ATX group compared to placebo. There was no difference in tic worsening between the groups. Statistically significant improvement in the Desipramine group over placebo for ADHD (ADHD-RS p < 0.001) and tics measures (YGTSS p < 0.001) and Global functioning (GAF p = 0.001). Adverse events: Statistically significant increase in heart rate (p < 0.005), blood pressure (p < 0.03) and reports of decreased appetite (p < 0.02) in the desipramine group compared to placebo. Statistically significant improvement in guanfacine group over placebo for ADHD measures: CGI global improvement scale (p<0.001), ADHD Rating Scale (Teacher) (p<0.01) and CPT (p<0.04) and for tics measures:. Yale Global Tic Severity Scale total
Scahill et al 2001 (330) Design RCT Level II
146
No. placebo n=17, Guanfacine n=17 Dose: maximum allowable dose was 4 mg/day in three divided doses Outcome measures: ADHD Rating Scale Clinical Global Impression global improvement score Parent Conners Questionnaire Yale Global Tic Severity Scale Continuous Performance Test
score (p=0.05). No significant difference between groups for Parent Conners Questionnaire hyperactivity index score Adverse events: No significant differences between groups reported.
Summary
Preschoolers: No studies met our inclusion criteria that addressed the efficacy of medications in preschoolers with ADHD and co-morbid disorders.
Children and adolescents: Anxiety: Two studies were identified that looked at the treatment of ADHD and comorbid anxiety disorder. Diamond et al (316) looked at the use of MPH in a four-month parallel design RCT and found no difference in the treatment response when anxiety was comorbid with ADHD or when anxiety was absent. No Significant difference was found between the groups in the number of adverse events.The quality of this study was rated as adequate. Geller et al 2007 (317) examined the treatment of ADHD and comorbid anxiety with ATX in a 12-week parallel design RCT and reported a reduction in symptoms of both ADHD and anxiety. ATX treatment was associated with significantly more reports of decreased appetite and weight loss compared to placebo.The quality of this study was rated as adequate.
Bipolar disorder: Two studies were identified that addressed the treatment of ADHD and comorbid bipolar disorder in children and adolescents. Findling et al (318) described a small study of MPH in 16 participants in a 4-week crossover RCT. This study reported improvement in the symptoms of both ADHD and bipolar disorder for MPH compared to placebo. Side effects occurring more frequently when receiving MPH than placebo were; insomnia, decreased appetite and stomach ache. The quality of this study was rated as adequate. Scheffer et al (319) conducted an initial 8-week open-label treatment with divalproex sodium to stabilise mania symptoms followed by a 4-week crossover RCT comparing MAS to placebo in children and adolescents with ADHD and comorbid bipolar disorder. An improvement in ADHD symptoms was found for MAS compared to placebo. Reporting of adverse events was poor. The quality of this study was rated as poor. Depression: One study was identified that addressed the treatment of ADHD and comorbid depression. In this study by Bangs et al (320) ATX was compared to placebo in a 9-week parallel-design RCT in participants with ADHD and comorbid major depressive disorder. There was a significant improvement in ADHD symptoms, but not in depression symptoms. When compared to placebo, ATX treatment was associated with significantly more nausea and decreased appetite.The quality of this study was rated as adequate. Tics and Tourettes syndrome: Six studies were identified that addressed the use of various medications for the treatment of children and adolescents with ADHD and comorbid Tics or Tourettes syndrome.
R D
T F A
147
The Tourettes Syndrome study group (325) reported on a 16 week parallel design RCT that looked at the use of clonidine, or MPH or clonidine + MPH compared to placebo in children and adolescents with ADHD and comorbid Tourettes syndrome or chronic motor tics disorder or chronic vocal tics disorder. Significant improvement was observed for ADHD symptoms, tic severity and global functioning in all medication groups compared to placebo. The greatest benefit was seen in the clonidine + MPH group. There was no worsening of tics in the medication groups compared to placebo. Reporting on adverse events was limited, clonidine was found to increase sedation and there was no cardiac toxicity identified for any medication. The quality of the study was rated as good. One study, Gadow et al (326) reported on a 8 week crossover design RCT comparing 3 doses of MPH-IR to placebo in children with ADHD and comorbid Tourettes syndrome or chronic motor tics disorder. All doses of MPH produced significant improvements in ADHD symptoms over placebo. There were no differences in tics severity between the groups. Adverse events occurring more frequently when receiving MPH-IR included somatic index items such as sleep, appetite, headache, upset-stomach, dizziness, increased heart rate, increased diastolic blood pressure and decreased body weight. The quality of the study was rated as adequate.
One study (reported in two articles) looked at ATX compared to placebo. Allen et al (327) described a 20-week parallel-design RCT comparing ATX to placebo in children and adolescents with ADHD and comorbid Tourettes syndrome or chronic motor tics disorder. ATX was demonstrated to improve ADHD symptoms compared to placebo, however there was no improvement in tic severity on the primary measure (YGTSS). The adverse events more common in the ATX group included decreased appetite, nausea and decreased body weight. The quality of this study was rated as good. Spencer et al (328) described a sub-group analysis of the study reported in Allen et al (327) focused on the group with ADHD and comorbid Tourette syndrome only. An improvement was seen in ADHD symptoms in the ATX group compared to placebo as well as a reduction in tic severity on most measures, the exception being self report. Adverse events occurring significantly more often in the ATX group were mean pulse rate, nausea, decreased appetite and decreased body weight. There was no difference in tic worsening between the groups. The quality of this study was rated as adequate.
Spencer at al (329) described a 6-week parallel-design RCT that compared desipramine to placebo in children and adolescents with ADHD and comorbid Tourettes syndrome or chronic motor tics disorder or chronic vocal tics disorder. The desipramine group showed improvement in ADHD symptoms, tic severity and global functioning compared to the placebo group. The adverse events significantly more frequent in the desipramine group were increased heart rate and blood pressure and decreased appetite. The quality of this study was rated as adequate.
Scahill et al 2001 (330) reported on an 8-week parallel-design RCT comparing the use of guanafacine to placebo in children and adolescents with ADHD and comorbid tics. ADHD symptoms and improved in the guanfacine group compared to placebo in most measures, with the exception of Parent Conners Questionnaire hyperactivity index score. Tic severity improved in the guanfacine group compared to placebo. There were no significant differences in adverse events between groups; however, a relative decrease in heart rate and blood pressure was reported in the guanafacine group. The quality of this study was rated as adequate Disruptive behaviour disorders: Six studies were identified that addressed the use of various medications for the treatment of children and adolescents with ADHD and comorbid disruptive behaviour disorders; oppositional defiant disorder (ODD) or conduct disorder (CD).
R D
T F A
148
Three studies addressed the use of ATX compared to placebo in the treatment of children and adolescents with ADHD and ODD. Biederman et al (321) described a meta-analysis of three RCTs that compared the use of ATX and placebo in children and adolescents with ADHD - with and without comorbid ODD. ATX significantly reduced ADHD symptoms, regardless of whether ODD was comorbid or not. No significant difference was seen in the CPRS-R:S oppositional subscale change scores. Adverse events were not described. The quality of this study was rated as adequate. Newcorn et al (323) compared the use of ATX to placebo in children and adolescents with ADHD with and without comorbid ODD. There was a significant improvement in ADHD symptoms with ATX at 1.2 mg/kg/day for individuals without comorbid ODD and ATX at 1.3mg/kg/day for individuals with comorbid ODD. When ODD was present treatment with all ATX doses reduced ODD symptoms (CPRS-R:S oppositional subscale) compared to placebo. Regardless of ODD status improvements on quality of life measures were reported. Adverse events were not described. The quality of this study was rated as adequate.
Hazell et al (322) described an analysis aimed at determining the risk of relapse in the treatment of ATX in children and adolescents with ADHD with and without comorbid ODD. Participants in this 42-week RCT were individuals whose ADHD symptoms had previously improved in an 8 week open-label trial with ATX. ATX compared to placebo was effective in maintaining decreased ADHD symptoms, regardless of the presence or absence of comorbid ADHD. In addition, the presence of comorbid ODD did not impact upon the rate of relapse in ADHD symptoms during treatment. The main limitation of this study in evaluating the efficacy of ATX is that at the start of the trial participants were known responders to ATX treatment. Adverse events were not described. The quality of this study was rated as adequate. One study (193) reported on the use of MPH to treat children (boys only) with ADHD and comorbid ODD or CD. In a 9-week crossover RCT with a high and low dose of MPH, symptoms of ADHD and conduct improved with both doses of MPH compared to placebo. The reporting of adverse events in this study was poor. Two participants withdrew due to side effects. The quality of this study was rated as adequate.
One study (280) was identified that compared the addition of clonidine or placebo to ongoing stimulant treatment in children and young adolescents with ADHD and comorbid CD or ODD in a 6-week parallel-design RCT. Hazell et al (280) found a significant reduction in parent reported conduct and hyperactive symptoms but not teacher reported conduct or hyperactive symptoms for children taking clonidine compared to placebo. Improvement in symptoms became significant in the clonidine group compared to placebo in week 5 and 6 of the trial. Decreases in pulse rate and systolic blood pressure and increases in parent reported drowsiness and dizziness were observed in the clonidine group compared to placebo. This study was conducted in Australia and as such can be considered readily generalisable to the target population of this review. The quality of this study was rated as adequate.
Epilepsy: No studies met our inclusion criteria. Current research in this area is reviewed in (331). Adults: No studies met our inclusion criteria that addressed the efficacy of medications in adults with ADHD and co-morbid disorders.
R D
T F A
149
Excluded studies Study General Ghuman et al (332) MTA Studies (135-137, 178, 179, 186, 333) Anxiety Abikoff et al 2005 (334) Kratochvil et al 2005 (335) Bipolar Disorder DelBello et al 2001 (336) Biederman et al 1999 (337) Carlson et al 2000 (338) Kowatch et al 2003 (339) Soutullo et al 2002 (340) Hah and Chang 2005 (341) Tramontina et al 2007 (342) Depression Spencer et al 2006 (343) Kratochvil et al 2005 (335) Daviss et al 2001 (344) Hornig-Rohan and Amsterdam 2002 (312) Disruptive Behaviour Disorders (includes Oppositional defiant disorder & conduct disorder) Connor et al (345) Sinzig et al (346)
Reason for exclusion Does not present results separately for each comorbid condition. Not a randomised controlled trial not placebo controlled
Not a randomised controlled trial as no placebo-only controlled arm Not a randomised controlled trial as no placebo-only controlled arm
Treatment outcomes for ADHD and comorbid bipolar disorder are not described Not a randomised controlled trial Not a randomised controlled trial Not a randomised controlled trial (open label) Not a randomised controlled trial Less than 10 participants Not a randomised controlled trial (open label)
Klein et al 1997 (347)
R D
Does not directly answer research question. Study focused on prediction of therapeutic response. Not a randomised controlled trial as no placebo-only controlled arm Not a randomised controlled trial (open label) Not a randomised controlled trial
T F A
150
Spencer et al 2006 (348) Polzer et al 2007 (349) Connor et al 2000 (279) Snyder et al 2002 (350)
Aggression symptoms not comorbid disruptive behaviour disorders Aggression symptoms not comorbid disruptive behaviour disorders Not all participants had ADHD and data not presented separately Not all participants had ADHD and data not presented separately Does not directly answer research question. Study focused on adverse events. Not a randomised controlled trial (open label) Not all participants had ADHD and data not presented
separately TICs & Tourette syndrome Castellanos et al 1997 (351) Gadow et al 1999 (227) Gadow et al 2002 (352) Gilbert et al 2007 (353) Boon-yasidhi et al 2005 (354) Epilepsy Gross-Tsur (355)
Participants did not have a specific ADHD diagnosis, only symptoms of ADHD. Not a randomised controlled trial Did not compare medication to placebo in data-analysis Not a randomised controlled trial (open label) Not a randomised controlled trial (open label)
Does not address primary or secondary outcomes
R D
T F A
151
Impact of medication on Tics

Research question 17b. For individuals with ADHD who are taking medication, what is the risk of developing firstonset tics or worsening existing tics? Selection Criteria Population Inclusion Criteria Individuals with ADHD diagnosed according to standard criteria; DSM-III, DSMIII-R, DSM-1V or ICD10 Intervention
Pharmacological intervention (methylphenidate, dexamphetamine or atomoxetine)
Comparator Outcomes Study Design Search Period Language Date of Search Search terms
Placebo
Occurrence of first-onset tics or change in level of existing tics NHMRC defined levels of evidence I-IV for aetiology studies. 1997 - present English March 2008
MeSH: Attention deficit disorder with hyperactivity/ tic disorders/ or Tourette Syndrome/
Reference
Firestone et al 1998 (212) Musten et al 1997 (195) Design RCT Level II Quality Poor Setting Canada Industry
R D
Preschoolers
T F A
Results Number of participants displaying tics or nervous movements Placebo = 3.13% MPH 0.3 mg/kg = 9.38% MPH 0.5 mg/kg = 12.50% No significant difference between MPH (low or high dose) and placebo No significant difference between MPH (low or high dose) and placebo for the number of participants who improved or deteriorated on the measure of tics or nervous movements
Population: Children aged 4-6 years with a diagnosis of ADHD based on DSM-III-R criteria. Study information: Design & duration: Cross-over design RCT with 7-10 days on each arm No. n = 32 (27 boys 5 girls) Dose: Low dose 0.3 mg/kg High dose 0.5 mg/kg Outcome measures: 1. Side Effects Rating Scale (SERS) (Rate severity on a scale of 0 to 9 for 17 symptoms associated with MPH)
152
funding No
Tics and stimulant medication Children and adolescents with no pre-existing tics
Reference Wolraich et al 2001 (356) Design RCT Level II Quality Adequate Setting USA (multi centre) Industry funding Yes Comparator placebo Intervention/ comparator Intervention OROS MPH IR MPH (over capsulated Ritalin) Population/Study information Population: Children aged 6-12 years, diagnosed with any sub type of ADHD. Children on MPH or had been on MPH with a daily dose not greater than 60mg were eligible for the study. 15/282 participants with comorbid tics at study start. Results NB: Reporting on tics limited and no tests of significance.
Study information: Design & Duration: parallel design RCT 28 days No. OROS MPH n=94 MPH tid n=94 Placebo n=89
Evans et al 2001 (357) Design RCT Level II Quality Adequate Setting USA (university clinic) Industry funding No
R D
Intervention MPH Comparator Placebo
Dose: All subjects received 3 OROS systems (active or placebo) and 1 IR capsule (active or placebo) at 7.30am and an additional IR capsule (active or placebo) at 11.30, 15.30, subjects dosed for 28 days.
Outcome measures: Safety Sleep quality- Adverse events (AE) reported on day 7,14, and 28 Population: Adolescents with a mean age 13.8 (SD=1.2) years with primary DSM-IIIR diagnosis of ADHD.
T F A
Thirteen subjects reported to have tics during the trial. 9 had tics before the onset of the study. Five participants reported tics as an adverse event (new onset or significant increase in tics). OROS MPH n=0 MPH tid n=1 Placebo n=4 NB: Reporting on tics limited and no tests of significance. Participant numbers that had tics rated as moderate or severe on at least 1 day. Placebo: n = 17 MPH 10mg: n = 15 MPH 20mg: n = 9 MPH 30 mg: n = 7
Study information: Design & Duration: crossover RCT; 6 weeks. No. n = 45 Dose: MPH = 10 mg, 20mg or 30 mg Outcome measures: Teacher ratings: Side effects
153
Diamond et al 1999 (316) Design RCT Level II Quality Adequate Setting Canada, (Community setting) Industry funding No
Population: Children aged 6 to12 years who met the DSM-III-R criteria for ADHD. Participating children were subsequently assessed for anxiety based on child-self report (RCMAS) or parent-report (PICS; DSM-II-R criteria) and classified as either ADHD + ANX or ADHD ANX Study information: Design & Duration: cross-over RCT 3-4 week titration. Follow-up at 4 months. No. MPH n=46 ADHD + ANX n=19 ADHD ANX n = 27 placebo n=45 Placebo: ADHD + ANX n=19 Placebo: ADHD ANX n = 26
There was no difference in the number of reports of tics between children in the MPH or control group. Post hoc, sub-group analysis however indicated that children in the ADHDANX group taking MPH showed a greater increase in tic symptoms than any other group.
Law and Schachar 1999 (358)
Design Pseudorandomised RCT Level III-1 Quality Adequate Setting Canada (urban paediatric hospital) Industry funding
R D
Intervention MPH Comparator Placebo No prior tics n = 63 MPH n = 41 Placebo n = 12
Dose: Target dose for titration was 0.7 mg/kg bid (twice daily) and involved increasing the dosage weekly in 5mg increments. Dose could be adjusted throughout the trial if there was concern about side effects or a lack of behavioural response. No details provided on placebo
Outcome measures: Telephone Interview Probe (TIP): Questionnaire administered over the phone relating to side effects in the following categories: affective, over focusing, physiological, and tics. Population: Children with a mean age of 8 years that met DSM-IIIR criteria for ADHD.
T F A
Participants with no prior tics: Number developing new tics MPH: 10 (19.6%) Placebo: 2 (16.7%) No significant difference between MPH and placebo ( p=0.59) Participants with pre existing tics: Number with worsening tics MPH: 7 (33%) Placebo: 2 (33.3%) No significant difference between MPH and placebo p=0.70 Tourette-like symptoms developed in 2 participants receiving MPH.
Study information: Design & Duration: 1 year parallel RCT No. Initial randomization MPH: n = 46 Placebo n = 45 Participants allowed to change to the other treatment group: Final No. MPH n = 72 Placebo n = 18
Pre-existing tics n = 27 MPH n = 21 Placebo n = 6
154
No Dose: MPH: 0.5mg/kg mean
Palumbo et al 2004 (359) Study 1: (360) Study 2: (361) Study 3: (356) Design RCT Level II Quality Adequate Setting USA Industry funding Yes
Intervention MPH-IR or OROS MPH Comparator Placebo
Outcome measures: Tic severity: Barkley 10-point scale Population: Study 1 and 2: Children aged 612. Study 3: Children aged 613 years. All patients had a confirmed diagnosis of ADHD based upon DSM-IV criteria and did not have Tourettes syndrome. Study information: Design & Duration: Study 1: n = 64 (crossover) 1 week Study 2: n = 70 (crossover) 1 week Study 3: n = 282 (parallel) 4 weeks MPH-IR: n = 97 OROSMPH: n = 95 Placebo n = 90
Pooled data from the three trials Percentage of patients experiencing tics; OROS MPH: 4.0% MPH-IR: 2.3% Placebo: 3.7% No significant differences in the incidence of tics across the three treatment groups (p = 0.5249).
Dose: In all three studies participants received one of three dose levels. OROS MPH: 18, 36, or 54 mg q.d. MPH-IR: 5, 10, or 15 mg t.i.d.
Tics and stimulant medication Children and adolescents with ADHD and comorbid tics or Tourettes syndrome.
Reference Intervention/ comparator Intervention MPH IR Comparator Placebo Population/Study information Results
Gadow et al 2007 (362)
Design RCT Level II Quality Adequate
Setting State University of New York (Community sample) Industry funding No
R D
Outcome measures: Tic severity - Parent report
Population: children aged 6-12 years with ADHD diagnosed according to DSM-III-R or DSM-IV and either chronic motor tic disorder or Tourettes syndrome. Study information: Design & Duration: 8-week crossover RCT No. n=71 (crossover) Dose: MPH-IR 0.1mg/kg; B2: MPHIR 0.3mg/kg; B3: MPH-IR 0.5mg/kg Outcome measures: Yale Global Tic Severity Scale (YGTSS) Global Tic Rating Scale (GTRS) 2 minute tic and habit count GTRS- parent GTRS - teacher
T F A
Proportion of patients reporting tics with prior history of tics; MPH-IR: 3/5 OROS MPH: 9/9 Placebo: 6/8 P-value Not reported No significant differences in physician rated tic severity between the groups on the YGTSS and GTRS. Significant increase in simple (p < 0.0091) but not complex (p < 0.1792) motor movements (0.3 and 0.5 mg/kg 9 placebo) as measured on the 2-Minute Tic/Habit Count. Significant improvement in tic severity on GTRS-teacher (total tic severity p < .0015) but not GTRS-parent.
155
The Tourettes Syndrome Study Group 2002 (325) Design RCT Level II Quality Good Setting USA Industry funding No
Intervention MPH or Clonidine, or Clonidine +MPH Comparator Placebo
Population: children aged 7-14 years with DSM-IV criteria for ADHD and Tourette disorder, chronic motor tic disorder or chronic vocal tic disorder. Study information: Design & Duration: 16 week parallel design No. placebo n=32 MPH n=37 Clon n=34 MPH+Clon n= 33 Dose: max daily dose MPH: 60mg Outcome measures: Yale Global Tic Severity Scale (YGTSS) Global Tic Rating Scale (GTRS): parent or teacher Tic Symptom Self-Report (TSSR): parent or teacher
Proportion of individual subjects reporting a worsening of tics as an adverse effect was no higher in those treated with MPH (20%) than those being administered CLON alone (26%) or placebo (22%).
Between-group diff: (98.3%CI); p-value MPH v placebo: YGTSS-total: (0.7, 18.1); p=0.01 GTRS-parent: (-0.2, 6.5); p=0.03 GTRS-teacher: (-1.4, 4.4); p=0.20 TSSR-parent (motor): (-0.5, 8.1); p=0.04 TSSR-parent (vocal): (0.5, 7.0); p=0.006 TSSR-teacher (motor): (-0.4, 7.9); p=0.03 TSSR-teacher (vocal): (-1.4, 4.2); p=0.24 CLON plusMPH v placebo: YGTSS-total: (2.1, 19.8); p=0.003 GTRS-parent: (0.1, 6.9); p=0.01 GTRS-teacher: (0.3, 6.2); p=0.009 TSSR-parent (motor): (0.4, 9.1); p=0.01 TSSR-parent (vocal): (-0.1, 6.5); p=0.02 TSSR-teacher (motor): (0.0, 8.5); p=0.02 TSSR-teacher (vocal): (-2.0, 3.6); p=0.48
Reference Allen et al 2005 (327) Design RCT
Level II (Intervention) Quality Good Setting USA Industry funding Yes
R D
Intervention/ comparator Intervention Atomoxetine Comparator Placebo
Tics and non-stimulant medication - ATX Children and adolescents

Population: Children and adolescents (7 - 17 years) with DSM-IV diagnosis of ADHD and comorbid chronic tic disorder or Tourette syndrome.
T F A
Overall: Compared with placebo, measured tic severity lessened in all active treatment groups in the following order: CLON + MPH, CLON alone, MPH alone. Results Between-group differences (95% CI and p-values): YGTSS total score 95%CI: -0.13-4.88; p=0.063 Tic Symptom Self- Report (TSSR): 95%CI: -0.32-3.94; p=0.095 CGI-Tic/Neuro-S: 95%CI: 0.23-0.98; p=0.002 Summary: No increase in tic severity in the ATX group compared to placebo. A significant decrease on one of three measures of tic severity (CGITic/Neuro-S) in favour of ATX over placebo.
Study information: Design & Duration: Parallel design RCT; 18-weeks (inclusive of a 3-week titration phase) No. n = 148 ATX n = 72 placebo n = 76) Dose: 0.5 - 1.5 mg/kg/day Outcome measures: 1. Yale Global Tic Severity Scale (YGTSS): total score/ motor/phonic 2. Tic Symptom Self-Report (TSSR) 3. Clinical Global Impressions tic/neurologic severity scale score CGITic/Neuro-S
156
Spencer et al 2007 (328) Design RCT Level II Quality Adequate Setting USA Industry funding Eli Lilly & Co.
Population: Children or adolescents (aged 7-17 years) with ADHD (as per DSM-IV criteria) and concurrent Tourette syndrome Study information: Design & Duration: RCT; 20-weeks (inclusive of a 3-week titration phase and pre-screening plus wash-out phases) No. Group-A (atomoxetine): n=56; Group-B (placebo): n=61 Dose: Variable divided dose within total range of 0.5-1.5mg/kg/day
Between-group differences (95% CI and p-values): YGTSS total score 95%CI: 0.38-6.03; p=0.027 Tic Symptom Self- Report (TSSR): 95%CI: -0.63-4.65; p=0.135 CGI-Tic/Neuro-S: 95%CI: 0.23-1.09; p=0.003 Summary: No increase in tic severity in the ATX group compared to placebo.
Outcome measures: Re: Tic Severity: YGTSS total score Tic Symptom Self- Report (TSSR) CGI-Tic/Neuro-S
The Tourettes Syndrome Study Group 2002 (325) Design RCT Level II Quality Good Setting USA Industry funding No
Intervention MPH or Clonidine, or Clonidine +MPH Comparator Placebo
Population: children aged 7-14 years with DSM-IV criteria for ADHD and Tourette disorder, chronic motor tic disorder or chronic vocal tic disorder. Study information: Design & Duration: 16 week parallel design No. placebo n=32 MPH n=37 Clon n=34 MPH+Clon n= 33 Dose: max daily dose MPH: 60mg Outcome measures: Yale Global Tic Severity Scale (YGTSS) Global Tic Rating Scale (GTRS): parent or teacher Tic Symptom Self-Report (TSSR): parent or teacher
R D
T F A
A significant decrease on two of three measures of tic severity (YGTSS-total score and CGI-Tic/Neuro-S) in favour of ATX over placebo. Proportion of individual subjects reporting a worsening of tics as an adverse effect was similar across the groups MPH (20%) CLON (26%) or placebo (22%).
Between-group differences CLON v placebo: YGTSS-total: p=0.003 GTRS-parent: p=0.02 GTRS-teacher: p=0.10 TSSR-parent (motor): p=0.03 TSSR-parent (vocal): p=0.01 TSSR-teacher (motor): p=0.13 TSSR-teacher (vocal): p=0.24 CLON plusMPH v placebo: YGTSS-total: p=0.003 GTRS-parent: p=0.01 GTRS-teacher: p=0.009 TSSR-parent (motor): p=0.01 TSSR-parent (vocal): p=0.02 TSSR-teacher (motor): p=0.02 TSSR-teacher (vocal): p=0.48
Overall: Compared with placebo, measured tic severity lessened in all active treatment groups in the following order: CLON + MPH, CLON alone, MPH alone.
157
Summary
Stimulant medication Preschoolers: One clinical trial was identified that reported on tics in preschoolers receiving MPH (195, 212).This cross-over trial of short duration (7-10 days each on placebo, low dose MPH (0.3 mg/kg) and high dose MPH (0.5 mg/kg)) reported no significant differences between either low or high dose MPH and placebo for the number of participants displaying tics or nervous movements. This study was rated as poor in quality. Children and adolescents: Five studies were identified that addressed the incidence of tics in children with ADHD receiving MPH compared to placebo. Wolraich et al (356) described a parallel design RCT conducted for 28 days that compared OROS MPH, MPH-IR and placebo. Four participants from the placebo group and 1 participant from the MPH-IR group (out of 277 total) reported either the first onset of tics or an increase in pre-existing tics. The quality of this study was rated as adequate. Reporting on tics in this study was limited and no tests of significance were undertaken.
Evans et al (357) undertook a 6 week cross-over RCT that compared three doses of MPH to placebo (10, 20 and 30mg). The number of participant that had tics rated as moderate or severe on at least 1 day was greatest in the placebo group and decreased with increasing doses of MPH. The quality of this study was rated as adequate. Reporting on tics was limited in this study and no tests of significance were conducted. A 4 month cross-over trial by Diamond et al (316) comparing MPH to placebo found that there was no significant difference in the reporting of tics for the MPH group compared to placebo for both teacher and parent ratings of side effects. The quality of this study was rated as adequate.
Law and Schachar (1999) (358) conducted a comparison of MPH with placebo in a clinical trial of 12 months duration. For participants with no prior tics, there was no significant difference between the MPH and placebo groups in the number of participants reporting the first-onset of tics. For participants with pre-existing tics there was no significant difference between MPH and placebo in the number of participants reporting worsening tics. The main methodological limitation of this study was that although initially randomised into even numbered groups, participants were allowed to change medication over the course of the trial. The quality of this study was rated as adequate. Palumbo et al (2004) (359) pooled the data from the three short trials (1-4 weeks) comparing MPH-IR, OROS MPH and placebo. The percentage of patients experiencing tics was not significantly different between either of the MPH formulations and placebo. The quality of this study was rated as adequate.
Two studies specifically looked at the use of MPH in children and adolescents with ADHD and comorbid tics or Tourettes syndrome. The Tourettes Syndrome study group (325) compared clonidine, or MPH or clonidine + MPH to placebo in a 16 week RCT. Tic symptoms significantly improved in the MPH group compared to placebo. There was no worsening of tics in the MPH groups compared to placebo. The quality of the study was rated as good. Gadow et al (326) reported on a 8 week crossover design RCT comparing 3 doses of MPH-IR to placebo. There were no differences in tics severity between the any of the MPH-IR doses and placebo for the physician or parent rated measures (YGTSS, GTRS and GTRS-parent). Tic severity did improve on teacher ratings (GTRS-teacher) for the MPH group compared to placebo. The only scale showing a significant increase in tics in the MPH group compared to placebo was the simple
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motor movements on the 2-Minute Tic/Habit Count. The quality of the study was rated as adequate. NB: No studies considered adolescents older than 14. Non-stimulant medication Preschoolers: No studies identified that met our inclusion criteria. Children and adolescents: Two primary studies were identified that addressed the impact of ATX in children and adolescents with ADHD and comorbid tic disorders or Tourette syndrome (328) (327). In an 18 week parallel design RCT Allen et al (327) found that there was no increase in tic severity in participants receiving ATX compared to placebo. There was a decrease in tic severity on one of the three scales used to measure tic severity in the group receiving ATX compared to placebo. The quality of the study was rated as good. Spencer et al (328) conducted a 20 week parallel design RCT and found similar results. There was no increase in tic severity in participants receiving ATX compared to placebo. There was a decrease in tic severity on two of the three outcome measures that favoured ATX over placebo. The quality of the study was rated as adequate. One primary study was identified that addressed the impact of clonidine in children and adolescents with ADHD and comorbid tic disorders or Tourette syndrome. The Tourettes Syndrome study group (325) reported on a 16 week parallel design RCT that looked at the use of clonidine, or MPH or clonidine + MPH compared to placebo. Tic severity improved in the clonidine group compared to placebo. There was no worsening of tics in the clonidine group compared to placebo. The quality of the study was rated as good. Adults: No studies identified that met our inclusion criteria. Excluded studies Study Castellanos et al 1997 (351) Ghuman et al 2001 (363) Gadow (1999) (227) Gadow et al 2002 (352) Efron et al 1997 (364) Nolan and Gadow 1997 (365) Nolan et al 1999 (366)
Pelham et al 2005 (360) Quinn et al 2004(367) Smithee et al 1998 (368) Spencer et al 1999 (369) Swanson et al 2003 (361) Varley et al 2001(370) Ledbetter, M. 2005 (259) Lee et al 2004 (258) Schachar et al (1997) (371) Wolraich et al 2003 (356)
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Reason for exclusion Tics with comorbid symptoms of hyperactivity not an actual diagnosis of ADHD Study not controlled Follow-up study not controlled Did not compare medication to placebo in data-analysis Study not controlled Does not directly address research question
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159
Does not directly address research question (medication withdrawal) Described in Palumbo 2004 Does not directly address research question Does not present results for tics separately Does not directly address research question Described in Palumbo 2004 Study not controlled Case study Case study Reporting on tics limited Described in Palumbo 2004
When developmental disabilities are present

Research question 17c. When developmental disabilities are present in individuals with ADHD, do pharmacological interventions, compared to placebo improve outcomes? a. Learning disorders b. Developmental or intellectual disabilities c. Autism spectrum disorders Selection Criteria Population Inclusion Criteria
Individuals with developmental disabilities and either ADHD diagnosed
according to standard criteria; DSM-III, DSM-III-R, DSM-IV, ICD10 or symptoms of ADHD. Intervention Comparator Outcomes
Pharmacological intervention Placebo
Primary: 1. Change in incidence or severity of symptoms of ADHD (including; inattention, impulsivity, hyperactivity). 2. Change in the incidence or severity of symptoms of the developmental disability.
Secondary: School/work achievement, quality of life, social function. Study Design
Date of Search
Search terms
MeSH: Attention deficit disorder with hyperactivity/ Drug therapy/ child development disorders, pervasive/ or developmental disorders or developmental disabilities/ or autistic disorder/
Learning disorders/ or language disorders/ or dyslexia/ or agraphia/ or anomia/ or speech disorders/
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1997 - present English
NHMRC levels of evidence I-II
March 2008 August 2008 an expanded search of learning disorders only
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Text words: adhd or addh or adhs or hyperactive$ or hyperkin$ or (attention adj deficit) learning disorders or developmental or autism or aspergers or bipolar disorder or comorbid or comorbidity Reading impairment or learning disability or language impairment or handwriting or articulation disorder or phological disorder
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ADHD with learning disorders Children and adolescents

Reference Grizenko et al 2006 (372) Design RCT Level II Quality Adequate Setting USA Industry funding Intervention/ comparator Intervention MPH Comparator Placebo Population/Study information Population: children with ADHD (DSM-IV) with or without a learning disorder aged 6 to 12 years Study information: Design & Duration: 2-week crossover RCT No. n=95 (crossover) Dose: MPH 0.5 mg/kg Outcome measures: Consensus clinical response Results Children with ADHD: 75% were classified as responders to MPH. Children with ADHD and LD: 55% were classified as responders to MPH (significantly different to to ADHD alone p = 0.034) Children with ADHD and LD (mathmatics): 37% were classified as responders to MPH Children with ADHD and LD (reading): 67% were classified as responders to MPH Adverse events: Not reported.
ADHD with developmental or intellectual disabilities Children and adolescents

Reference
Pearson et al 2003 (373) Design RCT Level II Quality Adequate Setting USA Industry funding Yes
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Intervention/ comparator
Population: children with ADHD (DSM-III-R criteria) and intellectual disability with a mean age of 10.9 years
Study information: Design & Duration: 4-week crossover RCT No. n=24 (crossover) Dose: B1: MPH 0.15 mg/kg b.i.d. (breakfast and lunch time) B2: MPH 0.30 mg/kg b.i.d. (breakfast and lunch time) B3: MPH 0.60 mg/kg b.i.d. (breakfast and lunch time) Outcome measures: The ADD-H Comprehensive Teacher Rating Scale (ACTeRs) Conners Teacher Rating Scale (CTRS) Conners Parent Rating Scale (CPRS; 48-item revision) Revised Behavior Problem Checklist (RBPC) The Aberrant Behavior Checklist (ABC; Community version) Personality Inventory for ChildrenRevised (PIC-R)
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Results For teacher ratings 9/11 measured subscales were demonstrated a significant difference for the high dose of MPH compared to the low dose MPH and placebo. For example CTRS ratings; inattention (p = .024), hyperactivity (p < .001), aggression (p < .001), and asocial behavior (p = .009). For parent ratings 1/20 measured subscales demonstrated significant improvement in the high dose MPH over placebo/low dose MPH. CPRS hyperactive/impulsive subscale was significantly improved in the high dose over placebo/low dose MPH (p = 0.018). No significant improvements, relative to placebo, occurred at the low does of MPH. Adverse events: At the high and medium MPH dose there was significant increases in loss of appetite (p = .02) and sleeping problems (p = .005) compared to placebo. At the high MPH dose insomnia was significantly increased compared to placebo (p < .05).
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Aman 2003 (374) Design RCT Level II Quality Adequate Setting USA/NZ Industry funding Yes
Population: children and adolescents 4-17 years (study 1), 5-13 years (study 2), 5-14 years (study 3) with ADHD (DSM-III) and intellectual disability Study information: Design & Duration: 2-4 week (for each drug) crossover RCTs (3 studies) No. n=90 (crossover) Dose: 0.40 mg/kg once daily in am Outcome measures: CTRS (Conners) teacher rating CASQ parent rating Revised Behavior Problem Checklist (RBPC) parent rating Aberrant Behavior Checklist parent and teacher rating Matching to Sample (MTS) task Seat Movement Matching Familiar Figures (MFF) task Continuous Performance Task (CPT)
Reference
Handen et al 2000 (375) Design RCT Level II Quality Adequate Setting USA Industry funding No
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Intervention/ comparator Intervention MPH Comparator Placebo Outcome measures: Side Effects Checklist
ADHD with pervasive developmental disorders Children and adolescents

Population: Children aged 5.6 - 11.2 years with autism and symptoms of ADHD (Conners Hyperactivity Index Teacher score of 15 points plus) Study information: Design & Duration: 3 week crossover RCT with 7 days on each arm. No. n=13 (crossover) Dose: MPH1: 0.3 mg/kg MPH2: 0.6 mg/kg
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Variable Effect size Teachers CTRS Inattention 0.46 CTRS Hyperactivity 0.69 CASQ 0.56 ABC Hyperactivity 0.58 Parents RBPC Motor Excess 0.26 ABC Hyperactivity 0.35 Global Rating 0.56 Adverse events: not reported ADHD symptoms: Significant decreases were found between placebo and one or both of the MPH doses for the Hyperactivity Index of the Conners (p < 0.000), IOWA Conners (p < 0.004), and 2 of 5 ABC factors (Hyperactivity (p < 0.003) and Inappropriate Speech (p < 0.001)). Responders: 8 of 13 children Autism symptoms: No significant difference measured by the child autism rating scale between MPH and placebo. Adverse events: 5 children experienced significant adverse side effects especially at the 0.6 mg/kg dose. Social withdrawal, dullness, sadness, and irritability. 3 children were unable to complete one of the MPH doses due to side effects
Statistically significant improvement (p<0.05) in the MPH group over placebo for the following variables: Teacher rated CTRS conduct problem CTRS Inattention CTRS Hyperactivity CTRS Global CASQ ABC Irritability ABC hyperactivity/ noncompliance Parent rated RBPC Conduct Problems RBPC Motor excess ABC - hyperactivity / noncompliance Global rating
Conners Hyperactivity Index (Responder = minimum 50% decrease)
IOWA Connners Teacher Rating Scale Aberrant Behavior Checklist (ABC)

Child Autism Rating Scale
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RUPP Autism Network (376) Posey et al 2007 (377) Design RCT Level II Quality Adequate Setting USA Industry funding Yes
Population: Children aged 5 -14 years with autistic disorder, aspergers disorder or PDD not otherwise specified and symptoms of ADHD Study information: Design & Duration: 1 week test dose followed by 4 week crossover RCT with one week on each arm No. n=72 initial n= 66 in the RCT autism n = 47 Aspergers disorder n = 5 PDD-NOS n = 14 Dose: MPH1: 0.3 mg/kg per day MPH2: 0.6 mg/kg per day MPH3: 1.25 mg/kg per day Outcome measures: (376) Aberrant Behavior Checklist (ABC) Hyperactivity subscale
ADHD symptoms: Significant improvement on the ABC hyperactivity score rated by teacher; p =.009 and parent; p < .001). Significant improvement for MPH compared to placebo on the SNAP-IV parent (p < 0.001) and teacher ratings (p < 0.006) Significant medication effects: Inattention subscale [parent: p < 0.009; teacher: p < 0.004] Hyperactivity/Impulsivity subscale [parent: p <0.001; teacher: p < 0.02]
(377) SNAP-IV Childrens Yale-Brown Obsessive Compulsive Scales- PDD (CYBOCSPDD)
Arnold et al 2006 (378) Design RCT Level II Quality Adequate Setting USA Industry funding Yes
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Intervention ATX Comparator Placebo
autism n = 7 Aspergers disorder n = 1 PDD-NOS n = 8
Population: Children and adolescents aged 5-15 years with autistic disorder, aspergers disorder or PDD not otherwise specified and symptoms of ADHD
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Optimal dose effect size: SNAP-IV ADHD parent; 0.73 (p < 0.001) and teacher; 0.46 (p < 0.001). No significant effects of dose on SNAP-IV ratings of ODD
Autism symptoms: No significant difference on the CYBOCS-PDD measure between MPH and placebo.
Adverse events: 6 children did not enter the RCT phase as they did not tolerate the MPH. 7 children did not complete the RCT phase due to adverse side effects Appetite decrease, difficulty falling asleep, irritability and emotional outburst were all more significantly frequent with one or more of the MPH doses than placebo (p < 0.05). ADHD symptoms: DSM-IV ADHD
hyperactive/impulsive symptoms (p =0.005 effect size 1.27) but not inattentive symptoms (p= 0.053, effect size 0.89) were significantly improved for ATX compared to placebo 2 of 5 ABC factors (Hyperactivity (p <
Study information: Design & Duration: 14 week crossover RCT with 6 weeks each arm + 1 week washout No. n= 16 (cross-over)
0.043 effect size 0.90) and lethargy/social withdrawel (p < 0.01 effect size 1.18)) were significantly improved with ATX. Adverse events: All 16 participants experienced mild upset stomach and/or nausea / vomiting when taking ATX compared to 5 on placebo (p < 0.006). Fatigue (0.004) and racing heart rate (p < 0.048) were also significantly more frequent for ATX compared to control. ADHD symptoms: Parent ratings on the Conners Parent-Teacher Questionnaire (p <0.02) and teachers ratings on the ABC (irritability; p < 0.03, hyperactivity p < 0.01, stereotypy
Dose: ATX max dose:1.4 mg/kg/day Outcome measures: DSM-IV ADHD symptoms Aberrant Behavior Checklist (ABC) Population: Boys (mean age 7.3 yrs for lofexidine and 9.2 yrs for placebo) with autistic disorder (ICD-10) and symptoms of hyperactivity and impulsivity
Niederhofer et al 2002 (379) Design
Intervention Lofexidine Comparator Placebo
163
RCT Level II Quality Adequate Setting Austria Industry funding Yes Study information: Design & Duration: 14 week crossover RCT with 6 weeks each arm + 1 week tapering No. n = 12 (cross-over) Dose: lofexedine max dose: 0.8-1.2 mg/day Outcome measures: Conners Parent-Teacher Questionnaire parent rated Aberrant Behavior Checklist (ABC) teacher rated
p < 0.04 and inappropriate speech p < 0.03) and the symptom checklist scores revealed a significant improvement with lofexidine compared to placebo No clinician ratings showed significant differences between lofexidine and placebo. Adverse events: Drowsiness and decreased activity more frequent for lofexidine compared to placebo (p < 0.02)
Summary
Preschoolers: No studies met the inclusion criteria
Children and adolescents Learning disorders: No studies met the inclusion criteria.
Developmental or intellectual disabilities: Two studies were identified that addressed the use of MPH in children and adolescents with ADHD with comorbid mental retardation. Pearson et al (373) employed a 4-week crossover design RCT to test the efficacy of high, medium and low dose MPH compared to placebo in 24 children with ADHD and comorbid mental reatrdation. An improvement in ADHD symptoms as rated by teachers, but not by parents, was found for the highest does of MPH over placebo. No significant improvements in ADHD symptoms were seen at the lowest dose of MPH. At the high and medium MPH dose there was significant increases in loss of appetite and sleeping problems compared to placebo. At the high MPH dose insomnia was significantly increased compared to placebo. The quality of this study was rated as adequate. Aman et al (374) described 3 crossover-design RCTs of 2-4 weeks that tested the efficacy of low dose MPH compared to placebo in children and adolescents with ADHD and mental retardation. A significant improvement in ADHD symptoms was seen for MPH compared to placebo. The authors note, however, that the effect sizes are moderate and not as high (~half) as those seen in studies of children with a normal IQ. Adverse events were not reported. The quality of this study was rated as adequate.
Pervasive developmental disorders: Four cross-over RCTs of short duration (3-14 weeks) were identified that considered the impact of medication (MPH, ATX or lofexidine) on ADHD symptoms in children and adolescents with pervasive developmental disorders (375-379). Two studies of adequate quality reported improvements in symptoms of hyperactivity, inattention and impulsivity when treated with MPH compared to placebo (375-377). Both studies reported significant side effects when receiving MPH compared to placebo; social withdrawal, dullness, sadness, and irritability (375) and appetite decrease, difficulty falling asleep, irritability and emotional outburst (376, 377). One study reported benefits in hyperactive/impulsive but not inattentive symptoms when treated with ATX compared to placebo (378). Side effects of mild upset stomach and/or nausea / vomiting occurred in all participants when taking ATX compared to 5 on placebo. Fatigue and racing heart rate also occurred significantly more often when children were treated with ATX compared to control. One study investigated the use of lofoxedine in boys with autistic disorder and ADHD symptoms. While parent and teacher ratings hyperactivity, irritability, stereotypy and inappropriate speech showed significant improvement compared to placebo, no clinician ratings were significant.
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Drowsiness and decreased activity more frequent side effects that were seen for lofexidine compared to placebo. Adults: No studies met the inclusion criteria Excluded studies Study Learning Disorders Aro et al 1999 (187) Buckley et al 2006 (380) Keulers et al 2007 (381) Tucha and Lange 2004 (382) Fosi et al 2006 (383) Grizenko et al 2006 (372) Francis et al 2001 (384) Bental and Tirosh (385) McInnes et al 2007 (386) Developmental disabilities Handen et al 1999 (387)
Reason for exclusion Not medication Not a randomised controlled trial Not a randomised controlled trial Does not directly address research question
Case reports. Not a randomised controlled trial. Does not directly answer research question. Results presented as a comparison of responder versus non-responder. Does not directly answer research question. Treatment outcomes are not primary or secondary outcome measures. Does not directly answer research question. Treatment outcomes are not primary or secondary outcome measures. Does not directly answer research question. Treatment outcomes are not primary or secondary outcome measures.
Pearson et al 2004 (388)
Pearson et al 2004 (389) Jou et al 2004 (390) Aman et al 2002 (391)
Eapen et al 2005 (392) Agarwal et al 2001 (393) Keulers et al 2007 (394) Pervasive Developmental Disorders Posey et al 2006 (395) Posey et al 2004 (396) Santosh et al 2006 (397) Arnold et al 2006 (378) Troost et al 2006 (398) Jou et al 2005 (399) Chavez et al 2006 (400) Jesner et al 2007 (401)
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Not all participants had ADHD and data not presented separately Treatment outcomes are not primary or secondary outcome measures. Reanalysis of Pearson et al 2003 (373) and Pearson et al 2004 (388) with no tests of significance. Not a randomised controlled trial Not all participants had ADHD and data not presented separately Not a randomised controlled trial (open label) Non-standard ADHD outcome measures and poor reporting. Not a randomised controlled trial
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165
Not a randomised controlled trial (open label) Not a randomised controlled trial (retrospective study) Not a randomised controlled trial Participants did not have a specific ADHD diagnosis, only symptoms of ADHD. Not a randomised controlled trial (open label) Not a randomised controlled trial (retrospective study) Meta-analysis that does not include any studies with comorbid ADHD. Systematic review that does not include any studies with comorbid ADHD.
Adverse events growth

Research question 18. For preschoolers, children and adolescents with ADHD who are taking medication, what is the risk of impaired growth? Selection criteria Population Inclusion criteria Individuals with ADHD diagnosed according to standard criteria; DSM-III, DSMIII-R, DSM-1V or ICD10 Intervention Comparator Pharmacological intervention
Children with ADHD not taking medication
Matched controls without ADHD not taking medication Outcomes Study design
Primary: growth, weight, height, body mass index (BMI)
NHMRC defined levels of evidence (I-IV) for intervention or aetiology studies.
Search period Language Date of search
Search terms MeSH: Attention deficit disorder with hyperactivity/ drug therapy/ or stimulants/ or methylphenidate/ or dexamphetamine/ or amphetamine salts/ or atomoxetine/
Reference
Swanson et al 2006 (402) Design RCT and extension
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Intervention/ comparator Intervention Stimulant medication MPH-IR Comparator Normative data
Stimulant treatment and growth: Preschoolers

Population/Study information Population: Children aged 3 - 5.5 years with a DSM-IV consensus diagnosis of ADHD. All stimulant nave. Study Information: Design: PATS protocol - RCT (4 weeks) extension (10 months) No. n = 140 (n = 95 had 1 year of continuous treatment) Dose: mean dose14.2 mg Duration: ~1 year Outcome measures: 1. Height, weight, malnutrition index Results
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Text words: adhd or addh or adhs or hyperactive$ or hyperkin$ or (attention adj deficit) growth or height or weight
Prior to treatment the children were larger (an average of 2.04 cm taller and 1.78 kg heavier) than expected compared with normative controls (height p < 0.001, weight p < 0.001). Children with 1 year of stimulant treatment had annual gains that were 20.3% less than expected for height (1.38 cm/yr) and 55.2% less than expected for weight (1.32kg/yr).
Level II (Intervention) Quality Adequate Setting USA (PATS
166
Study) Industry funding No
and BMI values converted to agecorrected standard scores (z-scores) and percentiles using the normative growth charts and transformations provided by the Centers for Disease Control (2000)
Stimulant treatment and growth: Children

Reference Lisska and Rivkes, 2003 (403) Design Retrospective cohort study Level III-2 (Aetiology) Quality Adequate Setting USA Industry funding No Intervention/ comparator Intervention Stimulant medication (MPH) Comparator Untreated siblings Population/Study information Population: 1. Children with a mean age of 8.7 2.5 years for males & 8.7 2.7 years for females with ADHD (basis of diagnosis not stated). 2. Untreated siblings within 3 years of age to the treated child. Same house, same doctor. Study Information: Design: Retrospective review of medical records No. MPH treated n = 84 Untreated n = 87 Dose: males; 22.5 mg (range; 5-85 mg/day) Females; mean dose 18 mg (range; 1045 mg/day) Duration: 3 years Results Significant reduction of height for males after 3 and 4 years of treatment (p = 0.05, p = 0.01 respectively).
MTA Cooperative Group (404) Design Comparative study with concurrent controls
Level III-2 (Intervention) Quality Adequate
Setting USA (MTA Study) Industry funding No
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Intervention Stimulant medication (MPH) Comparator Children with ADHD & stimulant nave Classmates; local normative comparison group (24 & 36 month follow-up only)
Outcome measures: 1. Height Population: Children between 7.0 and 9.9 years of age at study start. Diagnosis of ADHD Combined type based on DSM-III-R criteria Study Information: Design: Sub-group analysis of the MTA study No. 1. Newly medicated: stimulant nave at entry receiving MPH at each assessment point. n = 88 2. Consistently medicated: medication prior to trial & receiving MPH at each assessment point. n = 70 3. Inconsistently medicated: MPH at some assessment points. n = 147 4. Stimulant naive at entry and remained nave. n = 65 2. Local normative comparison group n = 213/279 Dose: average dose 32.8 mg/day Duration: 3 years
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Significant reduction of height for females after 3 years of treatment (p = 0.05). At 3 years there was a significant reduction in relative height (p < 0.0001) and weight (p < 0.0004) for children receiving MPH. Dose was significantly related to a reduction in relative height (p < 0.0010) but not relative weight (p = 0.2486). No evidence of growth rebound with growth rates of treated children equivalent to those of untreated children (24-36mths).
Outcome measures: 1. Height and weight converted to agecorrected standard scores (z-scores) and percentiles using the normative growth charts and transformations provided by
167
the Centers for Disease Control (2000) Charach et al 2006 (405) Design Retrospective cohort study Level III-3 (Aetiology) Quality Adequate Setting Canada Industry funding No Intervention Stimulant medication (MPH or DEX) Comparator Normative data Population: Children 5-12 years at study start. Diagnosis of ADHD Combined type based on DSM-III-R criteria Study Information: Design: Retrospective analysis of height and weight measures No. n = 79 Dose: Converted to MPH-IR equivalent (1.09 0.31 0.70 0.32)mg/kg/day Duration: 5 years Outcome measures: 1. Annual height and weight values converted to age-corrected standard scores (z-scores) and percentiles using the normative growth charts and transformations provided by the Centers for Disease Control (2000) 2. Growth changes from baseline to yearly endpoints using regression models. Population: children, 612 years of age. DSM-IV diagnosis of ADHD. Study Information: Design: Retrospective analysis of height and weight measures No. n = 568 Dose: 10-30mg/day MAS-ER Duration: 6-30 months Estimated risk from linear modelling of results; Significant decrease in height when dose is > 2.5mg/kg/day after four years of treatment (p < .05). Significant decrease in weight when dose is > 1.5mg/kg/day after one year of treatment (p < .05).
Faraone et al 2005 (406) Design Retrospective cohort study Level III-3 (Aetiology) Quality Poor Setting USA Industry funding Yes
Gadow et al, 1999 (227) Design Prospective cohort study Level II (Aetiology)
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Comparator Normative data Intervention Stimulant medication (MPH) Comparator Normative data
Intervention Stimulant medication (MAS-ER)
Outcome measures: 1. Height, weight, and BMI values converted to age-corrected standard scores (z-scores) and percentiles using the normative growth charts and transformations provided by the Centers for Disease Control (2000) 2. Growth changes from baseline to endpoint using regression models.
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Significant decrease in weight, height and BMI following 14 months treatment with MAS-ER. Loss in expected height weight and BMI was not significant in the second year of treatment. Weight and body BMI were greatest for the heaviest children, and the losses in expected height were greatest for the tallest children. Loss in expected growth was dosedependent for height (p = 0.03) but not for weight (p = 0.1). Larger deficits were associated with younger age at baseline for weight (p = 0.03) and height (p = 0.003) Prior stimulant therapy was significantly associated with lower baseline z scores for weight (p = 0.0003), height (p = 0.004) and BMI (p = 0.005) than other subjects. Non-significant decrease in weight (0.72 kg, p = 0.59) and height (0.67 cm, p = 0.59) gain following two years of stimulant treatment.
Population: Children aged of 6.1-11.9 years with a diagnosis of ADHD based on DSM-III-R criteria and either chronic motor tic disorder or Tourette disorder. Pervious participation in an 8week RCT with MPH. Study Information: Design: Prospective analysis of height and weight measures
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Quality Adequate Setting USA Industry funding No Pliszka et al 2006 (407) Design Retrospective cohort study Level III-3 (Aetiology) Quality Poor Setting USA Industry funding Yes
No. n = 34 Dose: MPH 30 mg/day Duration: 2 years Outcome measures: 1. Weight and height converted to percentiles based on growth tables; National Center for Health Statistics percentiles (1979) Population: Children with mean age of 8.5 2.1 (MPH) and 9 2.3 (MAS) years diagnosed with ADHD (basis not reported). Study Information: Design: Retrospective analysis of height and weight measures No. MPH1 year n = 113 & 3 years n = 42 MAS 1 year n = 66 & 3 years n = 21 Dose: Max: MPH 34.8 13 mg/day MAS 22.7 9.3 mg/day Duration: 1-3 years
Intervention Stimulant medication (MPH or MAS) Comparator Normative data
Poulton & Cowell 2003 (408)
Design Retrospective cohort study Level III-3 (Aetiology) Quality Adequate Setting Australia Industry funding No
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Intervention Stimulant medication (MPH or DEX) Comparator Normative data Intervention Stimulant medication (MPH-ER)
Outcome measures: 1. Height, weight, and BMI values converted to age-corrected standard scores (z-scores) and percentiles using the normative growth charts and transformations normative growth charts and transformations provided by the National Center for Health Statistics (year not stated)
2. Growth changes from baseline to endpoint using regression models. Population: Children 3.111.4 years diagnosed with ADHD based on DSMIV criteria. Taking MPH or DEX for 6 months or more. 19.6% were also taking clonidine. Study Information: Design: Retrospective review of medical records No. n = 51 (MPH n =19 DEX n = 32) Dose: MPH 1.0 0.24 mg/kg/day DEX 0.5 0.13 mg/kg /day Duration: 42 months
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Following 3 years of treatment the MAS group showed greater decreases than the MPH group for weight (p = 0.029) and BMI (p < 0.004) but not height. Cumulative dose of stimulants had a negative relationship with change in height (p = 0.011). The baseline measurements of the cohort were greater than the normative data (height p < 0.2, weight p < 0.001). Progressive decline in both height and weight SDS after starting stimulant medication, which was significant after 6 and 18 months (p < 0.001) and 30 months (p < 0.01). Height deficit was 0.64 cm in 0.5 years, 1.52 cm in 1.5 years, 2.33 cm in 2.5 years, 2.44 cm in 3.5 years Height velocity was slowest during the first 6 months of treatment and remained significant for the first 30 months (p < 0.01) At 21 months; Height deficit was 0.23cm less than expected from an absolute height of 145.6 cm. Weight deficit was 1.23kg less than expected from an absolute weight of 39.2 kg.
Weight and BMI significantly decreased with time (p < 0 .001), no significant change in height.
Outcome measures: 1. Height, weight and height velocity corrected for age and sex by conversion to standard deviation scores (SDS) (1979 American data).
Spencer et al 2006 (409) Design Retrospective
Population: Children 6- 13 years diagnosed with ADHD based on DSMIV criteria. (86% had previously received stimulants)
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cohort study Level III-3 (Aetiology) Quality Poor Setting USA Industry funding No
Comparator Normative data
Study Information: Design: Retrospective analysis of height and weight measures No. n = 178 Dose: mean: 1.1mg/kg/day at study start: 1.2 mg/kg/day at study end Duration: 21 months Outcome measures: 1. Height, weight, malnutrition index and BMI values converted to agecorrected standard scores (z-scores) and percentiles using the normative growth charts and transformations provided by the Centers for Disease Control and prevention (2000) 2. Growth changes from baseline to endpoint using regression models.
BMI deficit was 0.45kg/m2 less than expected from an absolute BMI of 18.1kg/m2 Greater decreases in height and weight for younger children (p = 0.001, p < 0.001 respectively) Not significant for BMI or malnutrition. Greater decrease in growth for stimulant naive children compared to those who had previously received stimulants (height p = 0.123; weight p = 0.003; BMI p = .063; Malnutrition index p =.027) Drug holidays did not impact upon changes in growth.
Zachor et al 2006 (410)
Design Retrospective cohort study Level III-3 (Aetiology) Quality Adequate Setting USA
Industry funding No Faraone& Giefer 2007 (411) Design Prospective cohort study Level II (Aetiology) Quality Adequate
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Intervention Stimulant medication (MAS or MPH or DEX) Comparator Normative data Intervention MPH transdermal (worn for 13 hours/day) Comparator Normative data
Population: Children 3.111.4 years diagnosed with ADHD based on DSMIV criteria. Study Information: Design: Retrospective review of medical records. No. n = 89 (DEX n = 29; MAS n = 27; MPH n= 33) Dose: (not reported) Duration: 3 years
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Height, weight and BMI decreases were greater in the second year (p = 0.055, p < 0.001, p < 0.001 respectively) Impact of dose on height only, with a significant difference between the min and max doses (p = 0.006) No significant impact of baseline quartiles on growth deficits. Significant decrease in weight for the first 24 months of treatment (3 months p = 0.001; 6 months p = 0.002; 12 months p = 0.028; 24 months p = 0.009) but was not significantly decreased at 36 months (p = 0.140). Significant decrease in height at 6 months (p = 0.004) and BMI at 3 months (p = 0.025) but no other time points. The mean deficits in growth rate per year were 0.68 cm for height, 1.3 kgfor weight, and 0.49 units for BMI. Weight and BMI z scores (but not height) were significantly influenced by dose (p = .003 and p < .001, respectively) with larger deficits seen in response to higher doses. Remaining in the trial longer predicted in larger deficits in weight (p = .009) and BMI (p = .013) but not height (p =
Outcome measures: 1. Height, weight and BMI values converted to age-corrected standard scores (z-scores) and percentiles using the normative growth charts (1974).
Population: Children 612 years diagnosed with ADHD based on DSMIV criteria.
Study Information: Design: Prospective analysis of height and weight measures No. n = 127 n = 31 participants participated for 2+ years Dose: Individualized - 6.25 cm2 (0.5
mg/hour) to 50 cm2 (3.6 mg/hour).
Duration: 6-36 months
170
.894) Setting USA Industry funding Yes Outcome measures: 1. Height, weight and BMI values converted to age-corrected standard scores (z-scores) and percentiles using normative growth charts from Centers for Disease Control and Prevention (2000). Being nave to stimulant treatment was predictive of larger deficits in z scores for weight (p = .001) and BMI (p = .001) but not height (p = .274).
Non-stimulant treatment and growth: Children and adolescents

Reference Kratchovil et al 2006 (240) Design Retrospective cohort study Level III-3 (Aetiology) Quality Adequate Setting USA Industry funding Yes Intervention/ comparator Intervention NonStimulant (ATX) Comparator Normative data Population/Study information Results
Population: Children 6 and 7 years of age diagnosed with ADHD based on DSM-IV criteria. Enrolled in clinical trials for at least 2 years.
Study information: Design: Meta analysis of 13 clinical trials; 7 RCT, 6 open label No. height n = 90 weight n = 95 Dose: Max dose 1.5 - 2.0 mg/kg/day Duration: 2 years
Spencer et al 2005 (412)
Design Retrospective cohort study Level III-3 (Aetiology) Quality Adequate Setting USA Industry funding Yes
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Intervention NonStimulant (ATX) Comparator Normative data Intervention NonStimulant (ATX)
Outcome measures: 1. Height, weight and BMI values converted to age-corrected standard scores (z-scores) and percentiles using the normative growth charts and transformations provided by the Centers for Disease Control (2000) Population: Children and adolescents 6 -16 years of age diagnosed with ADHD based on DSM-IV criteria. Enrolled in clinical trials for at least 2 years.
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Following 2 years of treatment with ATX mean actual weight was 2.5 kg lower than expected and mean actual height was 2.7 cm less than expected. Based on predictions from baseline height and weight. Growth rate differences primarily occurred in the first 18 months. Note: no measures of statistical significance were reported Following 2 years treatment with ATX there was a reduction in expected weight equivalent to 0.87 kg (z score 0.11, p < .001), BMI (-0.09, p < .006) and height equivalent to 0.44 cm (0.06, p = 0.055). The impact of ATX treatment on weight and height was greater in children starting treatment with ATX before 9 years (weight p = 0.005; height p = 0.048). The impact of age at treatment start was not significant for BMI (p = 0.492) Initial significant decrease in weight reaching a maximum decrement at 15 months (p < 0.001). No significant difference to norms for 3-5 year
Study information: Design: Pooled data from 13 clinical trials; 7 RCT, 6 open label No. n = 412 Dose: max dose 1.8 mg/kg/day Duration: 2 years Outcome measures: 1. Height, weight and BMI values converted to age-corrected standard scores (z-scores) and percentiles using the normative growth charts and transformations provided by the Centers for Disease Control (2000) Population: Children and adolescents 6 -17 years of age diagnosed with ADHD based on DSM-IV criteria and weighing more than 20kg at study
Spencer et al 2007 (413) Design
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Prospective cohort study Level II (Aetiology) Quality Adequate
entry. Comparator Normative data Study information: Design: Prospective analysis of height and weight measures No. n = 61 (subset of a larger study) Dose: mean dose 1.46 mg/kg/ day (SD = 0.53). Duration: 5 years Outcome measures: 1. Height, weight and BMI values converted to age-corrected standard scores (z-scores) and percentiles using normative growth charts from Centers for Disease Control and Prevention (2000).
measures. Initial significant decrease in height reaching a maximum decrement at 18 months (p < 0.001). No significant difference to norms for 2-5 year measures. BMI maximum decrement not reported. No significant difference from norms at 5 years.
Summary
Stimulants and growth - preschoolers: One study was identified that investigated the impact of stimulants on growth in preschoolers. As part of the PATS protocol Swanson et al (402) found that following 1 year of MPH treatment, both height and weight were lower than expected (1.38cm and 1.32kg) based on predictions from baseline height and weight. The quality of this study was considered to be adequate.
Stimulants and growth children: Ten studies were identified that addressed the impact of stimulant treatment on growth in children. The majority of studies were carried out using population based normative data as a control to predict expected changes in height and weight from baseline to endpoint, enabling a comparison to actual outcomes (227, 405-411). Two studies utilised the more robust methodology of concurrent control groups (403, 404). Lisska and Rivkes (403) conducted a retrospective review of medical records in children using matched siblings as the control group. Following three years of treatment with MPH, there was a significant reduction in relative height and weight in children receiving MPH. The quality of this study was considered to be adequate. The MTA study compared four treatment groups; medication management, behavioural management, combined treatment and community care. The MTA Cooperative Group (404) have now analysed height and weight data for children treated with stimulants at 14, 24 and 36 months. Following 3 years of treatment with MPH, there was a significant reduction in height compared to the control groups (children with ADHD who had never taken stimulant medication and matched classmates). Medication dose was significantly related to the reduction in height but not in weight. The quality of this study was considered to be adequate.
Three studies were medical chart reviews of children receiving various stimulant treatments, where the type of stimulant used was not considered independently (405, 408, 410). Poulton and Cowell (408) conducted a retrospective review of medical records over 3.5 years of children receiving either MPH or DEX. This Australian study reported a significant decrease in height and weight after 6 months of stimulant treatment that remained significant at 30 months. Increase in height was slowest in the first 6 months. The quality of this study was considered to be adequate. Zachor et al (410) conducted a retrospective review of medical records in children receiving MAS, MPH or DEX for a period of 3 years. Significant decreases in weight were reported for the first 24 months of treatment, no longer significant at 36 months. Significant decreases in height and BMI were seen at 6 months and 3 months respectively. The quality of this study was
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considered to be adequate. Charach et al (405) conducted a retrospective analysis of annual height and weight measures over a five year period of treatment with either MPH or DEX. Modeling of the results predicts a significant decrease in height at doses greater than 2.5/mg/kg/day after four years of treatment, and in weight in doses greater than 1.5/mg/kg/day after one year of treatment. The quality of this study was considered to be adequate. Gadow et al (227) assessed children with ADHD and comorbid tic or Tourette disorder receiving MPH treatment for a period of two years. A non-significant decrease in height and weight was reported (227). The quality of this study was considered to be adequate. Spencer et al (409) conducted a retrospective analysis of growth measures in children receiving MPH-ER for a period of 3.5 years. Height, weight and BMI were decreased compared to expected measures, but were not reported to be significant. 86% of the participants had previously received stimulant medication. When results were compared between these children and children who were stimulant nave at the start of the study, there was a greater decrease in height and weight that was significant for weight. A significantly greater decrease in height and weight was seen in younger children. Medication dose was significantly related to the reduction in height but not in weight. The quality of this study was considered to be poor.
Pliszka et al (407) assessed growth in children treated with MPH or MAS for a period of 1- 3 years. For the group as a whole, weight and BMI were significantly decreased, while reduction in height was not significant. In children treated for 3 years, the MAS group showed a greater decrease in weight and BMI, but not height, than the group receiving MPH. The quality of this study was considered to be poor. Faraone et al (406) assessed children receiving MAS-ER for 6-30 months. Decreases in height and weight were significant at 14 months, but were not significant in the second year of treatment. Medication dose was significantly related to the reduction in height but not in weight. Larger weight and height deficits were seen in the younger children when results were stratified for age. The quality of this study was considered to be poor.
Faraone et al (411) assessed children receiving MPH-transdermal for 6-36 months. Significant decreases in height, weight and BMI were observed. Medication dose was significantly related to the reduction in weight and BMI but not height. Larger weight and BMI deficits were seen in children when they were stimulant nave. The quality of this study was considered to be adequate.
Although the studies are disparate in methodology, and as a result difficult to compare, there do appear to be several trends emerging. Eight of the ten studies reported significant decreases in height and/or weight following stimulant treatment (403-408, 410, 411). The remaining two studies reported a non-significant decrease in height and weight (227, 409). Those studies that considered the impact of dose found that increased dose was linked to a decrease in height but not weight (404, 406, 407, 409). One study found that dose was related to a decrease in weight but not height (411).When results were analysed by age, the impact of treatment on growth was found to be greatest on younger children (406, 409). This is also supported by the decreases in growth seen in the preschoolers assessed in the PATS protocol (402). Three studies reported that the impact of stimulant treatment on growth is greatest at the start of the treatment period (406, 408, 410). Non-stimulants and growth: Three studies were identified that addressed the impact of the nonstimulant medication ATX on growth. Kratchovil et al (240) conducted a meta-analysis of weight and height data collected from 13 clinical trials, involving children aged 6 and 7 who had
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received treatment with ATX for two years or more. Both height and weight were lower than expected (2.7cm and 2.5kg, respectively) based on predictions from baseline height and weight. Kratchovil et al (240) reported that the growth rate differences primarily occurred in the first 18 months. The weight and height percentiles reached their lowest point at 18 months and appeared to increase in the following 6 months. The quality of this study was considered to be adequate. Spencer et al (412) assessed weight and height data collected from 13 clinical trials involving children and adolescents aged 6 -16 who had received treatment with ATX for two years or more. Overall, there was a reduction in expected weight and height (0.87kg and 0.44cm respectively) based on predictions from baseline height and weight. When the results were stratified based on age at the time of starting treatment, the impact of ATX treatment on weight and height was greater in children starting treatment before 9 years. The quality of this study was considered to be adequate. Spencer et al (413) described a subset of a long-term open-label trial consisting of 61 study participants who had received ATX continuously for 5 years. Significant decreases in height and weight were seen in the first 2 years of the study. At the 5 year time point there was no significant differences in z scores or percentiles between the study participants and the control normative data set. The quality of this study was considered to be adequate. Overall: There are a large number of studies considering the impact of ADHD medications on growth. Very few studies employ concurrent controls of either children with ADHD not taking medication or children without ADHD. The majority of studies use normative data as their controls. This methodology is limited as the normative controls chosen are not necessarily well matched with the study population. For example, several studies found that the study population at baseline was significantly larger than the normative controls (402, 411, 413, 414) } and one study used control data from more than 30 years ago (410). Many of the studies were conducted retrospectively, either as analyses of medical records, or as analyses of clinical trial data. The main limitation with retrospective analysis is that it may not be possible to consider potential confounding variables such as adherence with medication. Excluded studies Study Biederman et al 2003 (415) Kramer et al 2000 (416)
Spencer et al 1998 (417)
MTA Cooperative Group 2004 (136) Sund and Zeiner 2002 (418) Wilens et al 2003 (226) MTA Cooperative Group 1999 (419)
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Reason for exclusion Cross sectional study design that did not meet criteria for NHMRC levels of evidence Cross sectional study design that did not meet criteria for NHMRC levels of evidence Cross sectional study design that did not meet criteria for NHMRC levels of evidence Data included in Swanson et al 2007 No comparison to control data No comparison to control data Data included in Swanson et al 2007
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Adverse events cardiac

Research question 19. For individuals with ADHD who are taking medication, what is the risk of cardiovascular adverse events? Selection criteria Population Inclusion criteria Individuals with ADHD diagnosed according to standard criteria; DSM-III, DSMIII-R, DSM-1V or ICD10 Intervention Comparator Outcomes Study design Search period Language Date of search Pharmacological intervention
Placebo or Rates of adverse events in the general population Primary: cardiac adverse events or cardiovascular safety
NHMRC defined levels of evidence (I-IV) for intervention studies. 1997 - present English March 2008
Reference
Villalba et al 2006 (420)
Design Retrospective cohort study Level III-3 (prognosis) Quality Adequate Setting USA
R D
Intervention/ comparator Intervention ATX MPH Amphetamine DEX Comparator Estimated rates of sudden cardiac death in the general population
FDA assessment of ADHD medications

Population/Study information Population: 1. Individuals prescribed Amphetamine/ DEX or MPH before Jan 1999 and after Dec 2003. 2. Individuals prescribed ATX from Nov 2002 until Feb 2005. Study Information: Post-marketing safety review of sudden deaths during treatment with drugs used to treat ADHD. Outcome measures: 1. Number of deaths in the Adverse Event Reporting System 2. Estimated rate of death per 100000 Patient years (estimated by dividing
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Text words: adhd or addh or adhs or hyperactive$ or hyperkin$ or (attention adj deficit) Cardio$ or (sudden adj cardiac adj death)
Results Methylphenidate Total Number of deaths: 18 14 paediatric and 4 adult Estimated rate per 100000 Patient years: MPH = 0.1 Authors conclusions: No deaths appear solely or directly related to MPH. 6/14 paediatric sudden deaths occurred in children with structural cardiovascular abnormalities that likely preceded the use of MPH Amphetamine/dextroamphetamine Total Number of deaths: 20 14 paediatric and 6 adult
175
Industry funding No
prescriptions dispensed by 12)
Estimated rate per 100000 Patient years: MAS = 0.4 DEX = 0.1 Authors conclusions: 6/14 paediatric cases of sudden death had structural cardiovascular abnormalities or predisposing factors for sudden death Atomoxetine Total Number of deaths: 7 3 paediatric and 4 adult Estimated rate per 100000 Patient years: ATX = 0.9 Authors conclusions: None of the patients had structural cardiovascular abnormalities. However, the extent of the role of ATX in these deaths is difficult to establish. Methylphenidate Total Number of deaths: 8 7 paediatric & 1adult non-excluded deaths per million MPH prescriptions: ~0.22 paediatrics & ~0.34 adults sudden deaths per million MPH prescriptions: ~0.16 paediatrics & ~0.07 adults
Gelperin et al 2004 (421) Design Retrospective cohort study Level III-3 (prognosis) Quality Adequate Setting USA Industry funding No
Intervention methylphenid ate Amphetamine Dexampheta mine Comparator Estimated rates of sudden cardiac death in the General Population
Population: Individuals prescribed Amphetamine/dextroamphetamine or methylphenidate 1999-2003
Study Information: Post-marketing safety review of sudden deaths during treatment with drugs used to treat ADHD. Outcome measures: 1. Number of deaths in the Adverse Event Reporting System 2. Nonfatal cardiovascular adverse events and Nonfatal cerebrovascular adverse events
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Number of nonfatal cardiovascular/ cerebrovascular events: 19 8 paediatric & 11 adult Nonfatal cardiovascular events per million MPH prescriptions: ~0.18 paediatrics & ~0.74 adults Amphetamine/dextroamphetamine Total Number of deaths:18 12 paediatric and 5 adult non-excluded deaths per million MAS/DEX prescriptions: ~056 paediatrics & ~0.95 adults sudden deaths per million MAS/DEX prescriptions: ~0.36 paediatrics & ~0.53 adults Number of nonfatal cardiovascular/ cerebrovascular events: 35 18 paediatric and 17 adult Nonfatal cardiovascular events per million MAS/DEX prescriptions: ~0.53 paediatrics & ~1.79 adults
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Stimulants
Reference Samuels et al 2006 (422) Design RCT Level II Quality Adequate Setting USA Industry Funding Not reported Wilens et al 2005 (423) Design RCT Level II Quality Adequate Setting USA Industry Funding Yes Intervention MPH MAS Comparator Placebo Comparator Placebo Intervention/ comparator Intervention Current stimulant at usual dose (MPH, MAS, or DEX) Population/Study Information Population: Children 515 years with a DSM-IV diagnosis of ADHD. Inclusions: Taking stimulant medication at a stable dose. Exclusions: also taking medication that might increase blood pressure or documented hypertension requiring therapy. Study information: Design: crossover design. 4 days on placebo and 4 days on active drug No. n = 17 (11 with full data) Dose: Childs usual dose Outcome measures: 1. Heart rate and blood pressure (every 20 min for 24 h) Results Significant increase in measures of diastolic blood pressure (p = 0.021), total heart rate (p = 0.004) and rate pressure product (p = 0.008) when taking stimulant medication. Note: No data presented for individual drugs or previous duration of stimulant treatment.
Donner et al 2007 (424)
Design Pre-test/post test outcomes Level IV Quality Adequate Setting USA Industry
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Intervention MAS-ER Comparator Placebo
Population: Adults aged 18-60 (average age of 39 9 years). 45% male. DSM-IIIR or DSM-IV diagnosis of ADHD. Enrolled in placebo controlled trials of medication versus placebo.
Design: Retrospective analysis of clinical trials. MPH and MAS trials; cross-over design of 7 weeks duration. No. MPH n = 18 placebo n = 17 MAS n = 26 placebo n = 17
Dose: MPH = 65mg/day (endpoint) MAS = 54mg/day (endpoint) Outcome measures: 1. Heart rate and blood pressure Population: Children 612 years of age. ADHD diagnosis by DSM-IV criteria. Inclusions: 1. known psychostimulant responders tolerant to stimulants 2. Good medical health, with normal BP and pulse, and have clinically normal ECG results. Study Information: Design: open label study up to 15 weeks No. n = 2968 (76% male) Dose: 10-40mg/day Outcome measures: 1. Pulse, blood pressure, ECG,
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Significant increase in systolic blood pressure for MAS group (p < 0.05) and heart rate MPH group (p < 0.05). No difference between groups. Statistically significant increase (baseline to endpoint) in pulse rate ( p < 0.0001), systolic blood pressure (p < 0.001), diastolic blood pressure (p < 0.001) and all ECG measures (p = 0.0075 to p < 0.0001). Cardiovascular adverse events: 2% of children receiving 10-30 mg/day ~3% of children receiving 40 mg/day Discontinuation due to cardiovascular adverse events: 7/2968
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Funding Yes Findling et al 2005 (425) Design 1. RCT 2. pre& post test outcomes Level 1. II 2. IV Quality 1. Adequate 2. Poor Setting USA Industry Funding Yes Wilens et al 2005 (426) Design 1. RCT 2. pre& post test outcomes Level 1. II 2. IV Intervention MAS-ER Comparator Placebo
cardiovascular adverse events
Population: Children aged 6 to 12 years with a DSM-IV diagnosis of ADHD. Inclusions: Blood pressure and pulse in the normal range. Study Information: Design: 1. parallel RCT of 4-weeks duration (3 weeks active treatment) 2. Pre-test/post-test outcomes of 24 months duration No. 1. n = 580 Placebo n =210 MAS-ER n = 374 2. n = 568 Dose: 10-30mg/day Outcome measures: 1. Pulse, blood pressure, ECG 2. Cardiovascular adverse events
1. Short-term study: No significant changes in blood pressure, pulse, and ECG in children on active drug compared to placebo. 2. 2 year study: Significant change from baseline in; systolic blood pressure and diastolic blood pressure (p < 0.05), pulse (p < 0.001) and QT interval (p < 0.001). Discontinuation due to cardiovascular adverse events: 4/568
Intervention MAS-ER Comparator Placebo
Quality 1. Adequate 2. Poor Setting USA Industry Funding Yes
Winterstein et al 2007 (427) Design Retrospective cohort study Level III-2 (Aetiology) Quality Poor Setting
R D
Intervention
MPH amphetamines [pemoline]
Population: Adolescents aged 1317 years with a DSM-IV diagnosis of ADHD. Inclusions: Blood pressure and pulse in the normal range. Exclusions: a history of nonresponse to stimulant medication; a documented allergy or intolerance to mixed amphetamine salts, MAS XR, or amphetamines Study Information: Design: 1. parallel RCT of 4-weeks duration 2. Pre-test/post-test outcomes of 6 months duration No. Placebo n =69 MAS-ER n = 233 (<75kg) n = 25 (>75kg) 2. n = 138 Dose: < 75 kg 10-40 mg/day > 75kg 40-60mg/day
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1. No significant difference in blood pressure. No significant difference in ECG in the 10-40 mg MAS XR group. Heart rate was statistically significantly increased in the 50-60 mg treatment groups compared with the placebo group (p = 0.007). Discontinuation due to cardiovascular adverse events: 2/327 2. Significant change from baseline to 6 month endpoint in; systolic blood pressure (p = 0.0252), pulse (p < .0001 and QT interval (p < 0.0001). No discontinuations due to cardiovascular adverse events.
Cardiac death Seventy-three deaths were recorded. All cause mortality rate: 58.4 per 100 000 patient-years. Circulatory causes mortality rate: 4.0 per 100 000 person-years No cardiac death occurred during 42 612 person-years of stimulant use. Risk for emergency dept. visits for
Outcome measures: 1. Pulse, blood pressure, ECG 2. Cardiovascular adverse events Population: Individuals aged 320 years with ADHD. Patients at risk (congenital anomalies of the heart and other hereditary diseases linked to cardiac conditions) prior to their ADHD diagnosis were identified. Study Information: Design: Retrospective cohort of Medicaid claims over a 10 year period (1994-2004)
Comparator Placebo
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USA Industry Funding Yes
No. Dose: Outcome measures:

1.cardiac death 2. first hospital admission for cardiac causes 3. first emergency department visit for cardiac causes.
cardiac causes. Current use of stimulants use vs non-use: 20% increase - adjusted HR: 1.20 (95% CI : 1.04 1.38) Former use of stimulants vs non-use: No difference adjusted HR: 1.02; 95% CI: 0.861.20). Risk for hospital admissions for cardiac causes. Current use of stimulants use vs non-use: 21% increase - adjusted HR: 1.21 (95% CI : 1.06 1.39) Former use of stimulants vs non-use: No difference adjusted HR: 0.96; 95% CI: 0.831.12). Note: no separation of data for the different stimulant medications.
Non-stimulants atomoxetine
Reference Wernicke et al 2003 (428) Design RCT Level II Quality Adequate Setting USA Industry Funding Yes Intervention/ comparator Intervention ATX Comparator Placebo Population/Study Information
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Population: Children/adolescents and adults with a DSM-IV diagnosis of ADHD. Exclusions: Clinically significant electrocardiogram abnormalities or current or past history of clinically significant elevation of blood pressure.
Study Information: Design: Combined data from 5 RCTs of up to 10 weeks. children/adolescents (3 trials) and adults (2 trials) No. children/adolescents ATX n = 335 placebo = 204 Adults ATX n = 270 placebo = 266 Dose: children/adolescents Study 1 & 2 0.5 mg/kg/day Study 3 Group 1. 0.5 mg/kg/day Group 2. 1.2 mg/kg/day Group 3. 1.8 mg/kg/day adults Study 1 & 2 Start - 60 mg/day max 120 mg/day. Outcome measures: 1. Pulse, blood pressure, ECG 2. Cardiovascular adverse events
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Results All groups had a statistically significant increase in mean pulse rate (Children/adolescents p < 0.001; adults p < 0.001) and QTcB (Children/ adolescents p < 0.004; adults p < 0.001) Significant increase in mean systolic blood pressure in adults (p = 0.002) and diastolic blood pressure in children/ adolescents (p = 0.002). Cardiovascular adverse events: Palpitations significantly increased in adults and occurred more frequently in the ATX group than the placebo group (p = 0.037). Discontinuation due to cardiovascular adverse events: children/adolescents 0/335 and adults 4/258
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Summary
The USA Food and Drug Administration (FDA) has conducted two post-marketing safety reviews of sudden deaths during treatment with ADHD medications (420, 421). The reviews include episodes of sudden death, non-fatal cardiovascular events and cerebrovascular events, which have been submitted to the FDA. Cases of sudden death are rare and in many cases structural cardiovascular abnormalities or predisposing factors for sudden death were present prior to commencing medication. The authors make the point that the review is limited by a number of factors (420). First, the adverse event reporting system involves unsolicited reporting which can be variable due to incomplete reporting, under-reporting and greater reporting with recently approved drugs (420). Second, medication exposure is estimated based on prescription rates and not true exposure (420).
Five primary studies were identified that directly addressed the impact of stimulant medication (MPH, MAS and DEX) on cardiovascular function (422-426). The quality of all studies was rated as adequate. Three studies were conducted with children, one with adolescents and one with adults. All studies reported increases in heart rate and blood pressure when taking stimulant medications compared to placebo. Three trials looked specifically at MAS-ER. In these trials, discontinuation rates due to cardiac adverse events occurred in 1% or less of participants. The trials are of short to intermediate duration (up to 2 years) and there is no information on the long term effects of stimulants on cardiovascular function.
Winterstein et al 2007 (427) conducted a retrospective cohort analysis of Medicaid data over a 10 year period for children and adolescents with ADHD. Current stimulant use was associated with a 20% increase in risk of emergency department admissions for cardiac related incidents and 21% increase in risk for hospital admissions for cardiac causes. The stimulants considered in this study were MPH, amphetamines and pemoline which is now not used due to concerns about liver toxicity. There is no stratification of data by stimulant type. Wernicke et al (428) combined the data from 5 randomised controlled trials conducted in children, adolescents (3 trials) and adults (2 trials) with ATX. Statistically significant increases in mean pulse rate for all groups and mean systolic blood pressure in adults, and diastolic blood pressure in children and adolescents were reported. There were no discontinuations due to cardiac adverse events in children and adolescents (n = 335) and 4 out of 258 adults discontinued due to cardiac adverse events. The longest trial included in this study was 10 weeks. There is no information on the long term effects of ATX on cardiovascular function. Excluded studies Study Stowe et al 2002 (429) Kratochvil et al 2006 (240) Wilens et al 2006 (241) Wilens et al 2006 (217)
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180
Reason for exclusion Uncontrolled trial In sufficient detail and data to extract anything meaningful about heart rate/blood pressure. In sufficient detail and data to extract anything meaningful about heart rate/blood pressure. Clinic population
Adverse events psychiatric

Research question 20. For individuals with ADHD who are taking medication, what is the risk of psychiatric adverse events? Selection criteria Population Inclusion criteria Individuals with ADHD diagnosed according to standard criteria; DSM-III, DSMIII-R, DSM-1V or ICD10 Intervention Comparator Outcomes Pharmacological intervention Placebo
Primary: psychiatric adverse events suicide, suicidal ideation, aggression, psychosis or mania.
Study design Search period Language Date of search
NHMRC defined levels of evidence (I-IV) for intervention studies. 1997 - present English March 2008
Reference
Mosholder 2006 (FDA) (430) Design Systematic Review
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Intervention/ Comparator Population/Study information Intervention ATX MPH Comparator Placebo or No comparator
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Text words: adhd or addh or adhs or hyperactive$ or hyperkin$ or (attention adj deficit) Suicide or (psychiatric adj adverse adj event) or psychosis or mania or agression
Results (Drugs available in Australia presented here. Full list in data-extraction sheet) Psychosis/mania (A) Suicidal events (B) Aggression events (C) DB = double blind OL = open label Trials N A B C Concerta 4 DB 7 OL Placebo 317 Drug DB 321 Drug OL 284 0 0 8 0 0 6 0 0 52
FDA analysis of ADHD medications
Population: All individuals in clinical trials for ADHD medications Study information: All RCTs and open label studies.
181
Level I (Aetiology) Quality Adequate Setting USA Industry Funding No
Outcome measures: 1. Psychosis/mania 2. Suicidal events 3. Aggression events
Ritalin LA 5 DB 1 OL
Atomoxetine 20 DB 10 OL
Non-stimulant medication
Reference Bangs et al 2006 (Eli Lilly) (431) Design MetaAnalysis Level I (Aetiology) Quality Adequate Setting USA Industry Funding Yes Intervention/ Comparator Intervention ATX Comparator Placebo or no comparator Population/Study information Population: All individuals participating in RCTs for ATX Study information: 12 paediatric trials 9 adult trials Outcome measures: 1. Suicidal ideation or behaviour Results
Bangs et al 2008 (432) Design MetaAnalysis Level I (Aetiology) Quality Adequate Setting USA Industry Funding Yes
R D
Intervention ATX Comparator Placebo or MPH Study information: 14 paediatric RCTs
Population: Children and adolescents participating in clinical trials for ADHD or nocturnal enuresis.
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12 44 198 Paediatric trials (11 ADHD & 1 enuresis trial) Outcomes ATX Placebo p-value Suicidal 6/1357 0/851 0.010 ideation or behaviour Adult trials (3 ADHD & 6 major depression trials) Outcomes ATX Placebo p-value Suicidal 15/1718 ideation or behaviour Adult trials (3 ADHD trials) Outcomes ATX Suicidal 0/541 ideation or behaviour ATX vs Placebo 10/1072 0.465 Placebo 1/405 p-value 0.346 Suicidal behaviour or ideation (FDA Codes 1,2,3,4) ATX: 6/1357 (0.44%) Placebo: 0/851 (0.0%) Incidence difference: 0.52 (95% CI .12-.91) p = .010 Risk ratio: 2.49 (95% CI 0.64-9.78) p = .190 Suicidal behaviour (FDA Codes 1,2,3,) ATX: 1/1357 (0.07%) Placebo: 0/851 (0.0%) Incidence difference: 0.06 (95% CI -.07 - .19) p = .398 Risk ratio:
Placebo 259 Drug DB 383 Drug OL 125 Placebo 1443 Drug DB 2459 Drug OL 5270
0 2 0 0 4
1 0 1 4 9
0 2 0 18 49
ADHD studies were limited to individuals aged 6 17 years with a DSM-IV based diagnosis of ADHD.
Analysis 1: ATX vs Placebo No. 12 RCTs ATX; n = 1357 Placebo; n = 851 Duration: 6-18 weeks Analysis 2: ATX vs MPH
182
No. 5 RCTs ATX; n = 558 MPH; n = 464 Duration: 6-9 weeks Dose: Mean daily dose ATX; 1.3-1.6 mg/kg MPH; 0.9 1.1 mg/kg
1.19 (95% CI .049-28.96) p = .914 Suicide ideation (FDA Code 4) ATX: 5/1357 (0.37%) Placebo: 0/851 (0.0%) Incidence difference: 0.46 (95% CI .09 0.83) p = .016 Risk ratio: 2.92 (95% CI .63-13.57) p = .172 ATX vs MPH
Summary
Three meta-analyses were identified that address the association of psychiatric adverse events with ADHD medications. The FDA reviewed the ADHD medication clinical trial data to consider the association with psychiatric adverse events (430). This review included trials of preschoolers, children, adolescents and adults. 1. Extended-release MPH (Concerta): There were no psychiatric adverse events in double-blind trials. Psychosis, mania, suicidal events and aggression events were, however, reported in open label trials. 2. Immediate-release MPH (Ritalin): Psychosis, mania, suicidal events and aggression events were reported in double-blind and open label trials. 3. ATX (Strattera): Psychosis and mania events, suicidal events and aggression events were considered to be more frequent with ATX treatment than with placebo. The difference did not reach statistical significance. There were no completed suicides in ADHD trials. Mosholder (430) noted that psychosis and mania events occurred with every compound. The numbers of such events with drug treatment were small, however, no psychosis or mania events have been reported in the placebo groups. Bangs et al (431) performed a meta-analysis on available ATX clinical trial data in children and adults. The incidence of suicidal ideation was significantly greater in ATX-treated paediatric patients compared with placebo. No suicidal ideation or behaviour was identified in the small number of trials of adults taking ATX for ADHD. Bangs et al (432) conducted a meta-analysis on suicidal behaviour and ideation in 14 paediatric randomized controlled trials for either ADHD or nocturnal enuresis as documented in treatment emergent adverse events for each trial. Two comparisons were made ATX versus placebo and ATX versus MPH. As also reported in Bangs et al (431), in 12 paediatric clinical trails a comparison of ATX to placebo showed that the frequency of suicidal ideation was significantly
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Outcome measures: 1. Suicide event FDA Codes 1: completed suicide 2: suicide attempt 3: preparatory acts toward imminent suicidal behavior 4: suicidal ideation 5: self-injurious behavior, intent unknown 6: not enough information, fatal 7: self-injurious behavior, no suicidal intent 8: other: accident, psychiatric, medical 9: not enough information, nonfatal
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Suicidal behavior or ideation (FDA Codes 1,2,3,4) ATX: 1/558 (0.18%) MPH 1/464 (0.22%) Incidence difference: 0.12 (95% CI .62 0.38) p = .649 Risk ratio: 0.52 (95% CI .06-4.547) p = .556 No suicidal behaviour (FDA Codes 1,2,3,) reported in either the ATX or the MPH group.
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increased compared to the placebo group. A comparison of frequency of suicidal ideation between ATX and MPH found no difference in the incidence of suicidal ideation or behaviour between the groups. The clinical trials used for this analysis were not head to head comparisons of ATX to MPH. It is important to note that the available clinical trial data is of short to medium term in duration and long term effects are not known. Excluded studies Study FDA 2005 (433) Gelperin et al 2006 (434)
Reason for exclusion Reports the same data as an included study Post marketing safety data - no analysis possible
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ADHD medications and substance abuse

Research question 21: In individuals with ADHD, does the use of pharmacological interventions, compared to no intervention, alter the risk for later substance use or the development of substance use disorders? Selection criteria Population Inclusion criteria Individuals with ADHD diagnosed according to standard criteria; DSM-III, DSMIII-R, DSM-1V or ICD10 receiving pharmacological interventions. Comparator Individuals with ADHD diagnosed according to standard
criteria; DSM-III, DSMIII-R, DSM-1V or ICD10 receiving no pharmacological interventions or placebo. Individuals without ADHD Outcomes
Primary: Incidence of substance use disorders Secondary: Prevalence of substance use
Study design Search period Language
NHMRC defined levels of evidence (I-IV) for aetiology studies 1997 - present English
Date of search
NB: Did not include studies that only considered cigarette and/or alcohol use. Search terms MeSH: Attention deficit disorder with hyperactivity/ Addiction/ or Substance-Related Disorders/
Reference
Wilens et al 2003 (435)
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November 2007
Diagnostic tool/ Reference test Cases Individuals with ADHD treated with stimulant medication Comparison Individuals with ADHD not treated with stimulant
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Text words: adhd or addh or adhs or hyperactive$ or hyperkin$ or (attention adj deficit) (substance adj abuse) or (substance adj misuse) or (abuse adj liability) or (abuse adj potential) or substance use disorder or SUD
Results Meta-analysis results: Pooled estimate of the odds ratio: 1.9-fold reduction in risk for SUD in individuals who have taken stimulant medication. (p < .037). Individual studies: Lambert (OR: 0.47, 95%CI: 0.22-1) Biederman (OR: 3.9, 95%CI: 1.8-8.1) Huss (OR: 2.2, 95%CI: 0.99-5.1)
Incidence of substance use disorders

Also reported in (436) Design Systematic review and meta analysis
Population: Children followed up to adolescence (at least 4 years) (2 studies) Children followed up to young adulthood (3 studies) Adults (1 study) Study information: Design: Meta-analysis of 6 studies
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Level III-2 (aetiology) Quality Poor Setting Populations from United States and Germany Industry funding Yes Goksyr et al 2008 (437) Design Retrospective cohort study Level III-2 (aetiology) Quality Poor Setting Norway
medication
5 prospective longitudinal studies 1 retrospective study No. ADHD treated: n = 674 ADHD untreated: n = 360 Outcome measures: 3. SUD (present or not)
Loney (OR: 1.1, 95%CI: 0.46-2.8) Molina (OR: 4.6, 95%CI: 1.5-14.5) Barkley (OR: 0.83, 95%CI: 0.29-2.3) Odds ratio > 1 indicate protective effect of medication on SUD outcome Heterogeneity of the odds ratios of the included studies was statistically significant (p < 0.001). Age effect: Follow-up in adolescence OR: 5.8 Follow-up in adults OR: 1.4
Cases Individuals with childhood or adolescent diagnosis of ADHD treated with stimulant medication Comparison Individuals with ADHD symptoms not treated with stimulant medication
Population: 1. ADHD + Medication: Adults with a mean age of 21.6 years (1831). 2. ADHD symptoms + nomedication: Adults with a mean age of 30.8 (18-57). Study information: Design: Cross-sectional. Comparison groups defined retrospectively
Katusic et al 2005 (438) Design: Retrospective cohort study Level III-2 (aetiology) Quality Poor Setting USA Industry funding None reported
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Duration: NA Cases Individuals with ADHD Comparison Control individuals not diagnosed with ADHD. Cases Individuals with ADHD treated with stimulant medication Comparison Individuals with ADHD not treated with stimulant medication
No. ADHD treated: n=17 ADHD symptoms untreated: n=74
Outcome Measures: Substance abuse (ICD-10) Population: Birth cohort of children born between January 1, 1976 and December 31, 1982. Median age at last follow-up was 18.3 years.
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Incidence of substance abuse (yes/no) ADHD + Medication: 4/13 ADHD symptoms + no-medication: 36/37 Adults with ADHD who have been treated with stimulants in childhood and/or adolescence, had a lower incidence of substance abuse compared with individuals not previously treated with stimulants (p < 0.05). Incidence of substance abuse ADHD versus No ADHD ADHD: 83/379 (21.9%) No ADHD: 33/758 (4.4%) (U-OR: 6.2; 95% CI: 4.09.4, p<0.001) (A-OR: 6.1, 95% CI:4.09.4, p<0.001) Boys: U-OR: 6.3, 95% CI: 4.010.1, p<0.001 Girls: U-OR: 5.9, 95% CI: 2.017.0, p<0.001 ADHD+ med versus ADHD+ no med ADHD + medication: 60/295 (20.3%) ADHD + no medication: 23/84 (27.4%) (U-OR: 0.7, 95% CI: 0.41.2, p=0.170) (A-OR 0.6, 95%CI: 0.3-1.0, p=0.052) Boys:
U-OR: 0.5, 95%CI: 0.30.9, p=0.027 Girls: U-OR: 1.5, 95%CI: 0.46.1, p=0.530
ADHD diagnosed by combination; (1) meets DSM-IV criteria for ADHD; (2) positive ADHD questionnaire results; and (3) clinical diagnosis of ADHD documented. Controls were matched individually on gender and date of birth (6 months) Study information: Design: Population-based birth cohort study No. ADHD: n = 379 No ADHD: n= 758
ADHD treated: n =295 ADHD untreated: n = 84
U-OR = unadjusted odds ratio
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Duration: mean length of followup 17.2 years Outcome Measures: Substance abuse: documented alcohol /substance abuse prior to 18 years of age Population: Adults with ADHD aged between 18-55 years that met DSM-IV diagnostic criteria. Study information: Design: retrospective cohort study Duration: NA
A-OR = Adjusted odds ratio: Adjusted for; gender, year of birth, and duration of follow-up.
Faraone et al 2007 (439) Design: Retrospective cohort study Level III-2 (aetiology) Quality Adequate Setting USA Industry funding No
Cases Individuals with ADHD: No medication treatment Comparison Individuals with ADHD: Past medication treatment
No. No treatment: n=108 Past treatment: n=33 Current and past treatment: n=65
Individuals with ADHD : Current and past medication treatment
Outcome Measures: Structured Clinical Interview for DSM-IV (SCID); measured abuse and dependence Drug Use Screening Inventory (DUSI); measured prevalence
Design: Prospective cohort study Level III-2 (aetiology)
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Cases Individuals with ADHD treated with stimulant medication Comparison Individuals with ADHD not treated with stimulant medication
Population: At study inception participants were aged 6-17 years, Caucasian with ADHD diagnosed according to DSM-IIIR. Mean age at follow up was 22 years. Study information: Design: retrospective cohort study Duration: 10 year follow-up No. ADHD treated: n= 82 ADHD untreated: n = 30
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The current and past treatment group had a significantly lower incidence of life time drug dependence than the past treatment group and the no treatment group (p < 0.001). NB: Significance was lost after controlling for full ADHD versus late onset ADHD Prevalence There was no significant between group differences in the 1 month prevalence of drug use of any drug. The most commonly used drugs were cigarettes alcohol and marijuana. Incidence of substance abuse No statistically significant difference between individuals with ADHD that had been treated with stimulant medication and individuals with ADHD that were untreated. Drug abuse: hazard ratio=1.6, 95% CI=0.83.2 (p=0.23) Drug dependence: hazard ratio=1.0, 95% CI=0.42.6 (p=0.96) No significant association between the age of stimulant treatment onset and the risk for subsequent substance use disorders Drug abuse: hazard ratio=1.0, 95% CI=0.91.1 Drug dependence: hazard ratio=1.0, 95% CI=0.91.2 No significant association between the duration of stimulant treatment and the risk for substance use disorders. Drug abuse: hazard ratio=1.0, 95% CI=0.91.1 Drug dependence: hazard ratio=1.0, 95% CI=0.9-1.1 NB: Statistical analyses controlled for conduct disorder.
Life time drug dependence No treatment: 26/108 (24%) Past treatment: 10/33 (30%) Current and past treatment: 6/65 (9%)
Outcome Measures: lifetime diagnosis of DSM-IV abuse or dependence
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Prevalence of substance use

Reference Molina et al 2007 (441) Level III-2 (aetiology) Quality Adequate Setting USA Industry funding No Diagnostic tool/ Reference test Cases Individuals with ADHD randomised to four treatment groups: 1. Behavioural management 2. Medication management 3. Combined (behavioural and medication management) 4. Community care Population/Study information Population: MTA study: Study inception children aged 7-9.9 years meeting DSM criteria fro ADHD combined type. Matched controls (LNCG) drawn from the local community. Results Lifetime use of any substance 24 month outcomes ADHD: 57/486 (11.7%) No ADHD: 16/287 (5.6%) (OR 2.25, p = 0.003)* More days of prescription medication use was not significantly associated substance use (p = 0.47)
Participant retention rate was 84% at 36 months. Study information: Design: Comparative study with concurrent controls Duration: 36 months.
No. ADHD n = 487 (n = 579 at study inception) No ADHD n = 272 Outcome Measures:
Chilcoat et al 1999 (442) Level III-2 (aetiology) Quality Poor Setting USA Industry funding No
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Cases Individuals with ADHD Comparison Control individuals not diagnosed with ADHD.
Comparison Local normative comparison group (LNCG)
Child-reported substance use questionnaire
Population: Birth cohort followed up at age 6 and 11. A subset of the children were diagnosed with ADHD at 6 years old according to DSM-III criteria. Study information: Design: Longitudinal prospective cohort ADHD n =146 No ADHD n=565
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36 month outcomes ADHD: 83/478 (17.4%) No ADHD: 21/269 (7.8%) (OR 2.34, p = 0.001)* More days of prescription medication use was not significantly associated substance use (p = 0.30) Most commonly used substances; alcohol [ADHD: 8.4%; no ADHD: 2.6% (p = .005)] cigarettes [ADHD: 11.1%; no ADHD: 3.3% (p = .001)] marijuana [ADHD: 3.0%; no ADHD: 0%]
* controlled for age
Incidence of drug use by age 11 ADHD: 28.8% No ADHD: 16.6%
OR: 1.7, 95% CI: 1.1-2.7, p < 0.001
Within the ADHD group there was no significant difference in drug use for children with ADHD who were receiving stimulant medication compared to those who were untreated.
Duration: Children 11 years old. Insufficient follow up to assess risk of SUD. 717 subjects (87%) followed up. Recruitment: 628 low birth weight babies and 477 normal birth weight babies were selected from 1983-85 from lists of newborn discharges from two hospitals. Outcome Measures: Childrens self report, parent monitoring and peer drug use
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Summary Substance abuse: One meta-analysis and three primary studies were identified that addressed the question of whether treatment with medications could alter the risk for substance abuse in individuals with ADHD. Wilens et al (435) conducted a meta-analysis using data from 6 studies (5 prospective, 1 retrospective). The pooled estimate of the odds ratio indicated a significant 1.9fold reduction in risk for SUD in individuals with ADHD who have taken stimulant medication compared to individuals with ADHD who had not taken stimulant medication. The authors also identified an age effect which suggested that a greater protective effect of prior treatment in those studies that conducted the follow-up in adolescents (OR: 5.8) compared to those that conducted the follow-up in young adults (OR: 1.4). Analysis of the individual studies identified statistically significant heterogeneity of the odds ratios, which suggests that there is not a single common treatment effect across the studies. The authors also acknowledge several limitations of the metaanalysis including the small number of studies available and inherent confounding factors that may vary between studies such as severity of ADHD and the presence/absence of comorbidities. The quality of this study was rated as poor. The retrospective study described by Goksyr et al (437) involved a convenience sample of adults seeking treatment for ADHD symptoms. In this study the researchers compared the incidence of substance abuse between individuals with a childhood diagnosis of ADHD who had taken stimulant medication to individuals with symptoms of ADHD who had never taken stimulant medication. They found that adults with ADHD who had been treated with stimulants in childhood and/or adolescence, had a significantly lower incidence of substance abuse. This was a small study and the reporting of methodology was limited, making it difficult to interpret the results. The quality of this study was rated as poor. Katusic et al (438) described a retrospective study of a birth cohort whose age at the most recent follow-up was 18 years. The researchers addressed the impact of previous treatment with stimulants in a subset of the cohort that had been diagnosed with ADHD. In boys treated for ADHD there was a significant reduction in the incidence of substance abuse compared to the untreated group (p = 0.027). This protective effect was not found, however, in girls with ADHD treated with stimulant medication. The quality of this study was rated as poor.
Faraone et al (439) conducted a retrospective cohort study in adults with ADHD that were divided into three groups for comparison; no previous medication treatment, previous medication treatment and current and past medication treatment. The current and past treatment group had a significantly lower incidence of life time drug dependence than the other groups. The significance of this difference across groups was lost after controlling for full ADHD versus late onset ADHD. There was no significant between group differences in the 1 month prevalence of drug use of any drug. The quality of this study was rated as adequate. Biederman et al 2008 (440) reported on a prospective cohort study of Caucasian males diagnosed with ADHD at the 10 year follow-up point when the average age of participants was 22 years. The statistical analysis controlled for conduct disorder. There was no significant difference in the risk of substance abuse for individuals with ADHD that had been treated with stimulant medication compared to individuals with ADHD who were untreated. Similarly there was no significant association between the age of stimulant treatment onset or the duration of stimulant treatment and the risk for subsequent substance use disorders. As for the meta-analysis the results of the primary studies should be considered cautiously as there are several limitations to consider. The cohort studies participants are not randomised into comparison groups and many rely on retrospective data which may introduce bias stemming from
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deficiencies in recall. In addition, confounding factors such as ADHD severity, length of time on medication, type of medication and the presence or absence of comorbidities can impact on study outcomes and these have not been controlled for in every study. Substance use: Two studies met our inclusion criteria that looked at the impact of medication treatment for ADHD on the risk for substance use in individuals with ADHD (441, 442). Both studies also considered the prevalence of substance use in individuals with ADHD compared to a matched control group. Molina et al (441) described an analysis of the MTA study at the 24 and 36 month time points comparing individuals with ADHD who were enrolled in the MTA study with a control group without ADHD recruited from the same community. At both the 24 and 36 month time point the group with ADHD was found to have significantly higher rates of substance use than the control group. When taking treatment into consideration, the researchers found that more days of prescription medication use was not significantly associated with substance use. At the 36 month time point the children in the MTA study were aged between 11 and 13.The quality of this study was rated as adequate. Chilcoat et al 1999 (442) described a birth cohort followed up at age 6 and 11. At age 11 those diagnosed with ADHD were found to have significantly higher rates of substance use than the group without ADHD. Looking within the ADHD group the researchers found that there was no significant difference in drug use for children with ADHD who were being treated with stimulant medication compared to those who were untreated. The quality of this study was rated as poor. Excluded studies Study Mannuzza et al 2003 (443) Milberger (444) Faraone and Wilens 2003 (436) Biederman et al 2003 (445) Upadhyaya et al 2005 (446) Fischer et al 2003 (447)
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Reason for exclusion Stimulant medication prescribed for learning disorders not ADHD Does not consider impact of medication use Includes same articles and reaches same conclusion as Wilens et al 2003 Includes previously published data considered in Wilens et al 2003 Not a comparative study Description of Barkley et al 2003(230) which is considered in Wilens et al 2003
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Treatment of ADHD and comorbid substance abuse disorders

Research question 22: For individuals with ADHD and substance use disorders do pharmacological or psychosocial interventions, affect outcomes? Selection criteria Population Inclusion criteria Adolescents or adults with ADHD diagnosed according to standard
criteria; DSM-III, DSMIII-R, DSM-1V or ICD10 with comorbid SUD
diagnosed according to standard criteria; DSM-III, DSMIII-R, DSM-1V or ICD10, receiving interventions. Comparator
Individuals with ADHD and comorbid SUD not receiving interventions
Outcomes Study design Search period Language Date of search
Primary: Symptoms of ADHD or SUD
NHMRC defined levels of evidence (I-II) for intervention studies. 1997 - present English
Also excluded studies of pemoline
No studies of psychosocial interventions were identified Search terms MeSH: Attention deficit disorder with hyperactivity/ Addiction/ or Substance-Related Disorders/
Reference
Carpentier et al 2005 (448) Design RCT Level II Quality Adequate
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November 2007
Intervention/ comparator Intervention MPH Comparator placebo
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Text words: adhd or addh or adhs or hyperactive$ or hyperkin$ or (attention adj deficit) (substance adj abuse) or (substance adj misuse) or (abuse adj liability) or (abuse adj potential) or substance use disorder or SUD
Results ADHD symptoms: No significant difference in ADHD symptoms between MPH and placebo on any rating scale. SUD symptoms: Not addressed Adverse events: Significantly more side effects for MPH compared to placebo.
Adults
Population/Study information Population: Adults (mean age 31.9) receiving in-patient treatment for SUD that were diagnosed with ADHD based upon DSM-IV.
Study information: Design & duration: 8 week crossover RCT. Four treatment phases of 2 weeks each with placebo (A) and MPH (B) randomly conducted either A-B-AB or B-A-B-A.
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Setting Netherlands Industry funding Yes
No. n = 25 entry. n = 19 completion Dose: MPH: maximum daily dose 45 mg Fixed schedule of three doses a day: Day 1-3 15mg, day 4-7 30mg, day 8-14 45mg. Outcome measures: ADHD rating scale-IV Clinical observation scale Clinical global impression scale (CGI) Population: Adults aged 1860 who met DSM-IV criteria for cocaine dependence and ADHD. Recruited from cocaine dependent treatment seekers. Study information: Design & duration: 14 week parallel design RCT No. MPH: n = 53 Placebo n = 53 Dose: MPH: Max dose of 60 mg/day (40 mg am and 20 mg pm) Placebo: included 1mg Folic acid.
Levin et al 2007 (449) Design RCT Level II Quality Adequate Setting USA Industry funding No
Intervention MPH-SR Comparator Placebo NB: All participants received weekly cognitive behavioral therapy.
Levin et al 2006 (214) Design RCT Level II Quality Adequate Setting USA Industry funding No
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Intervention MPH-SR or BupropionSR Comparator Placebo NB: All participants received usual care at a methadone program including medication
Outcome measures: Adult ADHD Rating Scale (AARS) Clinical global impression scale (CGI) Targeted Adult Attention Deficit Disorder Scale (TAADS) Response (>30% reduction in ADHD symptoms and CGI <3) Urine toxicology Population: Adults aged 18-60 who met DSM-IV criteria for ADHD. Participants were recruited from methadone treatment programs and 53% met DSM-IV criteria for cocaine dependence / abuse
Study information: Design & duration: 12 weeks threearm parallel design RCT. 2-week placebo lead-in phase - 2-week dose titration - 8 weeks stable dose. No. MPH: n = 33 Bupropion: n = 32 Placebo: n = 33 Dose: Bupropion: max dose 400 mg/day MPH: max dose 80 mg/day Placebo: included 1mg Folic acid. Outcome measures: Adult ADHD Rating Scale (AARS) WenderReimherr adult attention deficit disorder scale (WRAADS) Clinical global impression scale (CGI) Proportion of weeks positive for any drug. Proportion of weeks positive for
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SUD symptoms: Urine toxicology data showed a decrease in the probability of cocaine positive urine samples during the trial for the MPH group compared to the placebo group (p = 0.001). Adverse events: No significant differences in number of reported side effects between groups. Most frequently reported side effects: headache (Placebo = 2%, MPH= 8%), gastrointestinal upset (Placebo = 4%, MPH= 8%) diarrhoea (Placebo = 9%, MPH= 2%) insomnia (Placebo = 2%,MPH= 9%). ADHD symptoms: No significant difference in ADHD symptoms between MPH, bupropion or placebo on any rating scale. SUD symptoms: No significant difference between either medication and placebo on proportion of weeks positive for any drug or opiates Adverse events: No significant differences in number of reported side effects between groups. Most frequently reported side effects: fatigue (placebo = 9%) increased sweating (MPH = 6%, Bupropion = 9%)
ADHD symptoms: No significant difference in ADHD symptoms between MPH and placebo on any rating scale.
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opiates Schubiner et al 2002 (450) Design RCT Level II Quality Adequate Setting USA Industry funding No Intervention MPH Comparator Placebo NB: All participants received twice weekly cognitive behavior therapy. Population: Adults aged 18-55 years, who met the DSM-IV criteria for cocaine dependence and ADHD. Study information: Design & duration: 13 week RCT No. MPH: n= 24 Placebo: n = 24 Dose: MPH: Max dose 90mg/day (30mg x3 over the day) ADHD symptoms: No significant difference between groups on the ADHD symptom checklist (inattentive or hyperactive symptoms). Physician-rated and self-rated efficacy indexes rated the MPH groups symptoms to be significantly improved compared to the placebo group (p < 0.05), but this outcome was not consistent across all time points.
Outcome measures: Physician-rated and self-rated efficacy indexes (7 point scale) ADHD symptom checklist Global improvement scale Tiffany cocaine craving scale Addiction Severity Index Urine analysis
Summary MPH: Four studies were identified that addressed the efficacy of MPH treatement in adults with ADHD and comorbid SUD. Carpentier et al (448) compared the use of MPH to placebo in an 8 week cross-over design RCT. The participants were individuals with ADHD recruited from an inpatient treatment centre that were being treated for various substance use disorders. No significant difference in ADHD symptoms was found between MPH and placebo. The impact of MPH on SUD symptoms or drug use was not addressed in the study. Reporting of adverse events was very limited; the authors note that there were significantly more side effects for MPH compared to placebo. The quality of this study was rated as adequate. Schubiner et al (450) conducted a 13 week parallel design RCT in adults, who met the DSM-IV criteria for both cocaine dependence and ADHD. Overall, comparison of MPH and placebo revealed no significant differences between the groups in either ADHD symptoms (ADHD symptom checklist) or SUD outcomes. Physician- and self-ratings of efficacy taken at various times did show a significant improvement in ADHD symptoms in the MPH group compared to placebo in some but not all ratings. Reporting of side effects showed that insomnia or trouble sleeping occurred more frequently in the MPH group compared to placebo. The quality of this study was rated as adequate.
Levin et al (214) employed a parallel design RCT to compare MPH to placebo in adults with ADHD recruited from methadone treatment programs for cocaine use. No significant differences in ADHD symptoms or cocaine (or other drug) use was found between the MPH and placebo groups. The number of side effects did not differ between the two groups. The quality of this study was rated as adequate. Levin et al (449) described a 14 week parallel design RCT in adults who met DSM-IV criteria for cocaine dependence and ADHD. No significant difference in ADHD symptoms was seen between the MPH and placebo groups. There was a significant decrease in the probability of cocaine positive urine samples during the trial for the MPH group compared to the placebo group. There were no significant differences in the number of reported side effects between groups. The quality of this study was rated as adequate.
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SUD symptoms: No group differences in self-reported cocaine use, urinalysis results, or cocaine craving. Adverse events: Insomnia or trouble sleeping occurred more frequently in the MPH group compared to placebo (p < 0.043)
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It is important to note that all studies considered here recruited participants from treatment centres, and as such the results may not be representative of the general community. Reporting of side effects in all studies was very limited. Bupropion: On study was identified that looked at the efficacy of bupropion treatment for adults with ADHD and comorbid SUD. In a parallel design RCT of individuals in methadone treatment programs for cocaine use, Levin et al (214) found no significant improvement in ADHD symptoms or differences in cocaine (or other drug) use in the bupropion group compared to placebo. The number of side effects did not differ between the two groups. The quality of this study was rated as adequate. Excluded studies Study Levin et al 2008 (451) King et al 1999 (452) Wilens et al 2005(453)
Reason for exclusion Not a RCT Not a RCT The majority of included studies in this meta-analysis were open label
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Medication compared to and combined with other strategies

Comparing psychosocial and pharmacological interventions
Research question 23. For individuals with ADHD, do psychosocial interventions compared to pharmacological interventions, affect outcomes? Selection criteria Population Inclusion criteria
Pharmacological interventions
Primary: Change in incidence or severity of symptoms of ADHD (including; inattention, impulsivity, hyperactivity).
Secondary: School/work achievement, quality of life, social function. Study design Search period Language NHMRC defined levels of evidence (I-IV) for intervention studies. 1997 - present English
Search date
Search terms A separate search was not performed: Pooled results of questions 9 22 were screened. Children and adolescents
Reference
King et al 2006 (196) Design Systematic Review Level I Quality Adequate Setting UK Industry funding
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Intervention/ comparator Intervention Psychosocial Intervention Comparator Medication Population/ study information 2. Firestone 1986
A separate search was not performed
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Results MPH-IR versus psychosocial intervention Hyperactivity: 3/3 studies demonstrated a significant difference in favour of MPH. Quality of life: Only 1 study looked at CGI (Klein 1997) and found a higher percentage of improved children in the MPH group Study quality: all rated as poor. Author conclusions: Few studies were included that examined a non-drug intervention in combination with MPH, DEX or ATX. Generally, the results were variable. The studies were,
Population: Children and adolescents under 18 years diagnosed with ADHD (ICD-10 or DSM-IV) Study Information: MPH-IR versus psychosocial intervention 3/8 studies identified assessed hyperactivity or quality of life 1. Brown 1986 Design: Parallel design RCT comparing MPH (20.08mg/day ) to cognitive therapy (22 sessions) No. n = 40 Age: 5.7-13.1 years Duration: 3 months
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No NB: Majority of included studies had industry funding
Design: Parallel design RCT comparing MPH (22mg/day ) to parent training No. n = 134 Age: 5-9 years Duration: 3 months 3. Klein 1997 Design: Parallel design RCT comparing MPH (1.55mg/kg/day ) to child behaviour modification plus parent & teacher training No. n = 86 Age: 6-12 years Duration: 12 weeks DEX versus psychosocial intervention One study identified but it did not assess hyperactivity or quality of life ATX versus psychosocial intervention No studies identified
however, heterogeneous regarding the type of non-drug-interventions examined and the scales used to measure outcomes.
Outcome measures: 1. Hyperactivity (using any scale that measured hyperactivity specifically) 2. Quality of Life (using Clinical Global Impression (CGI) as a proxy) MTA cooperative group 1999 (135)
MTA cooperative Group 2004 (136) Jensen et al 2007 (137)
Design Comparative study with concurrent controls Level III-2 Quality Adequate
Setting USA (MTA study) Industry funding No
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Intervention Psychosocial intervention Comparator Medication management
Population: Children aged 7-9.9 years meeting ADHD Diagnostic Interview Schedule for Children for ADHDcombined type Study information: Design: RCT (parallel design)
14 months: Behavioural treatment n = 144 Medication management n = 144 24 months: Behavioural treatment n = 139 Medication management n = 128 36 months Behavioural treatment n = 127 Medication management n = 115
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14 months: Medication management was superior to behavioural treatment in improving ADHD core symptoms; Parent rated inattention (p = 0.001) and impulsive/hyperactive (p = 0.001). Teacher rated inattention (p = 0.001) and impulsive/hyperactive (p = 0.004). No significant differences were found for measures of academic achievement and social skills. 24 months: Medication management was more effective than behavioural treatment alone. (MTA meds vs not: p < 0.0001) 36 months: No significant difference between any of the treatment groups for all outcomes. Note: Comparisons not clear cut as all subjects were followed up according to their original treatment allocation, regardless of what they chose to continue with over the course of the 36 month follow up.
Psychosocial intervention: Behavioural treatment consisting of 35 parent training sessions, 10-16 face-toface teacher consultations, 8-week allday summer treatment program, 12 weeks of half-time paraprofessional behaviourally trained aide in the classroom, daily report card Medication management: Children had an initial 28-day double-blind, placebo-controlled dose titration of MPH. For children with inadequate response to MPH there was an open titration of other medications.
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Arnold et al 2004 (138) Design Comparative study with concurrent controls Level III-2
Intervention Psychosocial intervention Comparator Medication management
Outcome measures: 1. SNAP: parent and teacher 2. Wechsler Individual Achievement Test reading score 3. Social skills rating scale (SSRS): parent and teacher Population: Children aged 7-9.9 years rigorously diagnosed with combinedtype ADHD Study information: Design: 4-arm RCT
No. Community control n=117-137 Behavioural treatment n=117-138 Duration: 9 months
Quality Poor (based on reporting in this publication) Setting USA (MTA study) Industry funding No
Psych intervention: 35 parent training sessions, 10-16 face-to-face teacher consultations, 8-week all-day summer treatment program, 12 weeks of halftime paraprofessional behaviourally trained aide in the classroom, daily report card Outcome measures: 1. SNAP-IV(ADHD/ODD): parent and teacher rated 2. Social Skills Rating System (SSRS): parent and teacher rated - Total social skills - Internalising factor Population: Children aged 6-12 years with a diagnosis of ADHD Study information: Design: Meta-analysis of RCTs with the goal of comparing effect sizes No. 26 studies
Van der Oord et al 2007 (454) Design Metaanalysis Level I Quality Poor Setting USA Industry funding No
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Intervention Psychosocial interventions Comparator MPH Combined psychosocial & MPH
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ADHD symptoms Psychosocial Parent: 0.87 (CI 0.73-1.01, p<0.01) Teacher: 0.75 (CI 0.49-1.01, p<0.01) MPH Parent: 1.53 (CI 1.23 -1.82, p<0.01) Teacher: 1.83 (CI 1.43-2.12, p<0.01) Combined Parent: 1.89 (CI 1.39-2.40, p<0.01) Teacher: 1.77 (CI 1.08-2.46, p<0.01) ODD symptoms Psychosocial Parent: 0.66 (CI 0.161.16, p<0.01) Teacher: 0.43 (CI 0.260.60, p<0.01) MPH Parent: 0.61 (CI 0.390.83, p<0.01) Teacher: 1.08 (CI 0.771.39, p<0.01) Combined Parent: 1.23 (CI 0.641.83, p<0.01) Teacher: 0.92 (CI 0.451.39, p<0.01) Social Psychosocial Parent: 0.54 (CI 0.370.70, p<0.01) Teacher: 0.71 (0.510.92, p<0.01) MPH Parent: 0.62 (CI 0.420.83, p<0.01)
9 months: Medication management was superior to behavioural management on ADHD/ODD (SNAPIV) symptoms (p < 0.0001), parent rated internalizing factor (p = 0.006) and teacher rated social skills (p < 0.001) but not teacher rated internalizing factor (p = 0.26) or parent rated social skills (p = 0.16).
ADHD symptoms Psych: parent 12 studies n = 402 Psych: teacher 11 studies n = 381 MPH: parent 15 studies n = 705 MPH: teacher 13 studies n = 588 Combined: parent 6 studies n = 242 Combined: teacher 6 studies n = 240 ODD symptoms Psych: parent 3 studies n = 167 Psych: teacher 7 studies n = 289 MPH: parent 10 studies n = 529 MPH: teacher 12 studies n = 579 Combined: parent 3 studies n = 191 Combined: teacher 5 studies n = 232 Social Psych: parent 5 studies n = 292 Psych: teacher 5 studies n = 203
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MPH: parent 3 studies n = 189 MPH: teacher 4 studies n = 199 Combined: parent 3 studies n = 191 Combined: teacher 5 studies n = 207 Academic Psych: Child 6 studies n = 274 MPH: Child 4 studies n = 216 Combined: Child 5 studies n = 227 Psych intervention: Behavioural or cognitive behavioural Outcome measures: Effect sizes
Teacher: 1.06 (CI 0.691.43, p<0.01) Combined Parent: 0.71 (CI 0.500.92, p<0.01) Teacher: 1.08 (CI 0.851.31, p<0.01) Academic Psychosocial Child: 0.19 (CI 0.030.36, p<0.05) MPH Child: 0.33 (CI 0.140.81, NS) Combined Child: 0.35 (CI 0.020.71, NS)
Fabiano et al 2007 (455) Design RCT Level II Quality Adequate Setting USA Industry funding No
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Intervention Behaviour modification MPH Combined behaviour modification & MPH Comparator Placebo Outcome measures:
Population: Children aged 5-12 years meeting DSM-IV criteria for ADHD
Study information: Design & duration: RCT (cross-over) 9 weeks total. 9 hour per day Monday to Friday. No. n = 48 (44 males 4 females)
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Author conclusions: Both MPH and psychosocial treatments are effective in reducing ADHD symptoms. Psychosocial treatment yields smaller effect sizes than either MPH or combined treatment. Psychosocial interventions did not add to MPH in reduction of ADHD and teacher rated ODD. For social behaviour and parent rated ODD symptoms psychosocial, MPH and combined interventions were equally effective. For improvement of academic function no treatment was effective. Behaviour modification only Beahviour modification (low and high intensity) was superior to no behaviour modification for all outcomes (p <0.05). There was no significant difference between the low and high intensity behaviour modification. Medication only Medication was superior to placebo for all outcomes (p <0.05). Comparing medication and behaviour medication Behaviour modification (low and high intensity) was equivalent or better than all MPH doses on measures of classroom rule violations and seatwork completion. Combined medication and behaviour medication Low intensity behaviour modifaction plus a low dose of MPH (0.15mg/kg) was equivalent to a high dose of medication.
Psychosocial intervention: 3 week blocks of either; No behaviour modification Minimal contingency management Low-intensity behaviour modification Simple behavioural techniques High-intensity behaviour modification Summer treatment program (STP): Highly structured behaviour modification using a point system with feedback, reinforcers, and daily report cards (DRCs). Medication management: MPH: 0.15 mg/kg, 0.30 mg/kg or 0.60 mg/kg three times per day Medication was randomly assigned within each child and was varied daily.
198
Frequency of rule violations Seatwork completed Iowa oppositional/defiant and inattention/overactivity rating scales Impairment rating scale (teacher/classroom)
Summary
Preschoolers: no studies met the inclusion criteria. Children: King et al (196) identified eight studies that addressed the comparison of psychosocial treatments with MPH in children, only three of which reported on hyperactivity or quality of life. Different psychosocial interventions were utilised in each of the studies. These were parent training, cognitive therapy and child behaviour modification plus parent and teacher training. Two studies found that MPH was superior to the psychosocial intervention. One study demonstrated variable results depending on the scale used to measure outcomes. No studies were assessed that compared DEX or ATX to psychosocial interventions.
The MTA study compared the use of medication with multi-modal psychosocial management. In the first report at 14 months (135), medication management was superior to behavioural treatment in the measures of ADHD core symptoms, but not in academic achievement or social skills. Arnold et al (138) also examined the outcome measures obtained at 9 months, when the behavioural management was still being intensively administered, and found equivalent results to those that had been reported for comparisons made at 14 months. At 24 months (136) the difference between the medication group and the combined group was still evident, although not as great. In the most recent assessment at 36 months (137), no significant difference was found between the effectiveness of psychosocial interventions compared to medication. As noted in the table, as the study has progressed, the subjects have been followed up according to their original treatment allocation, regardless of what treatment they chose to use, making the results of between group comparisons difficult to interpret. Fabiano et al 2007 (455) reported on classroom behaviours in a comparison between behaviour modification and medication within the setting of the summer treatment program. Behaviour modification (low and high intensity) was equivalent or better than all MPH doses on measures of classroom rule violations and seatwork completion. Overall, there is a dearth of studies directly comparing the use of psychosocial interventions and medications. The results of the existing research studies are variable. This may be explained by the variety of psychosocial interventions for ADHD that have been studied to date. Van der Oord et al (454) conducted a meta-analysis of RCTs with the goal of comparing effect sizes between MPH, psychosocial interventions and a combination of the two. The number of studies of psychosocial interventions was much less than those investigating MPH. Both MPH and psychosocial treatments are effective in reducing ADHD symptoms. Psychosocial treatment yields smaller effect sizes than either MPH or combined treatment. For ODD symptoms both psychosocial interventions and MPH generated significant improvements. However, MPH was significantly more effective than the psychosocial interventions. For social behaviour the psychosocial, MPH and combined interventions were equally effective. For academic functioning, the psychosocial interventions generated a marginally significant improvement, with no observed improvement when MPH or combined treatments were employed. The authors concluded that no treatment was effective in improving academic function.
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Adolescents: no studies met the inclusion criteria. Adults: no studies met the inclusion criteria. Excluded studies Study Dopfner et al 2004 (456) Greene et al 2001 (457) Gulley et al 2003 (458)
Reason for exclusion Compares psychosocial management with combined management (psychosocial + medication) No outcome data presented Sample size less than 10
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Combining psychosocial and pharmacological interventions

Research question 24. For individuals with ADHD, do psychosocial interventions used alongside pharmacological interventions, compared with pharmacological interventions alone, affect outcomes? Selection criteria Population Inclusion criteria Individuals with ADHD, diagnosed according to standard criteria; DSMIII, DSMIII-R, DSM-1V or ICD10 Intervention
Psychosocial interventions used at the same time as pharmacological interventions
Comparator Outcomes
Pharmacological interventions
Primary: Change in incidence or severity of symptoms of ADHD (including; inattention, impulsivity, hyperactivity).
Secondary: School/work achievement, quality of life, social function. Study design Search period Language NHMRC defined levels of evidence (I-IV) for intervention studies. 1997 - present English
Date of search
Search terms A separate search was not performed: Pooled results of questions 9 22 were screened. Combined interventions for children and adolescents
Population/ study information Results
Reference
MajewiczHefley & Carlson 2007 (459) Design: Systematic Review (studies of varied design) Level III-2 Quality Poor Setting USA
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Intervention/ comparator Intervention Combined treatment Comparator Medication alone Outcome measures: 1. Inattention 2. Hyperactivity 3. Impulsivity 4. Social Skills 5. Academic
A separate search was not performed
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Effect sizes for combined treatment: Effect size (SE) [95% CI] 1. Inattention 1.27 (.23) [0.83-1.72] 2. Hyperactivity 1.27 (.24) [0.79-1.75] 3. Impulsivity 0.91 (.17) [0.56-1.25] 4. Social Skills 0.9 (.2) [0.50-1.30] 5. Academic 0.19 (.09) [0.02-0.37] Authors conclusion: The calculated effect sizes for combined treatment on ADHD symptoms were greater than those previously reported in the literature for treatment with medication alone.
Population: Children aged 5 to 12 years with ADHD. (Diagnostic criteria for each study not reported) Study information: Design: Meta-analysis of 8 studies of varying design No. Combined: n = 308 Duration: 2-24 months
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Industry Funding No van der Oord et al 2007 (460) Design: RCT Level II Quality Poor Setting Netherlands Industry Funding Not reported
Intervention Combined treatment Comparator Medication alone
Population: Children aged 8-12 years with a diagnosis of ADHD based on DSM-IV criteria. No previous treatment with MPH. Study information: Design: Parallel design RCT with pretest/post-test measures No. Combined treatment n = 27 Medication only n = 23 Duration: 10weeks total with 5 week RCT Medication: Best dose MPH as determined by titration. Average individual dose 20.8 mg/day
No significant differences were found between the combined treatment group and the medication alone group. The addition of behavioural treatment to stimulant medication did not appear to improve outcomes over those achieved with stimulant medication alone.
Psychosocial treatment: Parent training, teacher training and child cognitive behavioural therapy (weekly 75 min sessions)
Chacko et al 2005 (461) Design RCT Level II Quality Adequate Setting USA Industry funding No
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Intervention Summer treatment program Comparator Summer treatment program plus MPH Summer treatment program plus placebo No. n = 36
Outcome measures: 1. ADHD score; Disruptive Behavior Disorder Rating Scale (DBDRS) 2. Social Skills Rating Scale (SSRS) Population: Children aged 5-6 years meeting ADHD DSM-III-R or DSMIIV criteria.
Study information: Design: cross-over design RCT Duration: 8 weeks (2 weeks STP only, 6 weeks STP plus MPH or placebo)
Psychosocial intervention: Summer treatment program (STP); 9 hours per weekday over 8 weeks. Highly structured behaviour modification program based on reinforcement. Medication management: MPH: 0.3 mg/kg or 0.6 mg/kg
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Significant difference between the two MPH groups and placebo in all point system measures and 2 of 3 classroom measures (not seatwork correct) (all p < 0.05)
Outcome measures: Point system Percentage following activity rules Non-compliance Conduct problems Negative verbalizations Classroom measures Percentage following classroom rules Percentage seatwork completed Percentage seatwork correct
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Pelham et al 2005 (462) Design: RCT Level II Quality Poor Setting USA (Summer Treatment Program) Industry Funding Yes
Intervention MPH transerdmal system (MTS) plus summer treatment program Comparator 1. MPH transerdmal system plus suspended behavior modification 2. summer treatment program
Population: Children aged 6 -12 with a diagnosis of ADHD based on DSM-IV diagnostic criteria. 10 (37%) met diagnostic criteria for oppositional/defiant disorder. 15 (56%) met diagnostic criteria for conduct disorder. Study information: Design: RCT with Cross-over design No. n = 27 Duration: 6 weeks
Both behavioural modification alone and medication alone were efficacious. The combined treatment (MPH + behavioural modification) was reported to be more effective than either treatment alone based on a comparison of effect sizes.
Medication Doses: 1. Placebo 2. 12.5 cm2 MTS 3. 25 cm2 MTS 4. 37.5 cm2 MTS. Varied daily -Monday-Thursday. Behaviour modification: Summer treatment program; Reward/cost point systems. Time-out. Daily report card. Parent training.
Suspended behaviour modification: Designed to emulate a typical classroom or camp setting. Varied weekly for 4 weeks Outcome measures: 1. ADHD symptoms a. Pittsburgh Modified b. Conners Rating Scale c. IOWA Conners Rating Scale: Inattention/Overactivity and Oppositional/Defiant subscales d. Abbreviated Conners Rating Scale 2. Academic performance; productivity & accuracy 3. Behaviour points system 4. Effectiveness and stress ratings Population: Children aged 5-12 years meeting DSM-IV criteria for ADHD
Fabiano et al 2007 (455) Design RCT Level II Quality Adequate Setting USA Industry funding No
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Intervention Behaviour modification MPH Combined behaviour modification & MPH Comparator Placebo
Study information: Design & duration: RCT (cross-over) 9 weeks total. 9 hour per day Monday to Friday. No. n = 48 (44 males 4 females) Psychosocial intervention: 3 week blocks of either; No behaviour modification Minimal contingency management Low-intensity behaviour modification Simple behavioural techniques High-intensity behaviour modification Summer treatment program (STP): Highly structured behaviour modification using a point system with feedback, reinforcers, and daily report cards (DRCs). Medication management:
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Behaviour modification only Beahviour modification (low and high intensity) was superior to no behaviour modification for all outcomes (p <0.05). There was no significant difference between the low and high intensity behaviour modification. Medication only Medication was superior to placebo for all outcomes (p <0.05). Comparing medication and behaviour medication Behaviour modification (low and high intensity) was equivalent or better than all MPH doses on measures of classroom rule violations and seatwork completion. Combined medication and behaviour medication Low intensity behaviour modifaction plus a low dose of MPH (0.15mg/kg) was equivalent to a high dose of medication.
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MPH: 0.15 mg/kg, 0.30 mg/kg or 0.60 mg/kg three times per day Medication was randomly assigned within each child and was varied daily. Outcome measures: Frequency of rule violations Seatwork completed Iowa oppositional/defiant and inattention/overactivity rating scales Impairment rating scale (teacher/classroom) Population: Children aged 7-9.9 years meeting ADHD Diagnostic Interview Schedule for Children for ADHDcombined type Study information: Design: RCT (parallel design)
MTA Cooperative group 1999 (135) MTA Cooperative Group 2004 (136) Jensen et al 2007 (137)
Intervention Combined treatment Comparator Medication management
Design Comparative study with concurrent controls Level III-2 Quality Adequate Setting USA (MTA study) Industry funding No
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Intervention Multimodal psychosocial plus MPH Comparator
14 months: Behavioural treatment n = 144 Medication management n = 144 24 months: Behavioural treatment n = 139 Medication management n = 128 36 months Behavioural treatment n = 127 Medication management n = 115
Psychosocial intervention: Behavioural treatment consisting of 35 parent training sessions, 10-16 face-toface teacher consultations, 8-week allday summer treatment program, 12 weeks of half-time paraprofessional behaviourally trained aide in the classroom, daily report card Medication management: Children had an initial 28-day double-blind, placebo-controlled dose titration of MPH. For children with inadequate response to MPH there was an open titration of other medications.
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14 months: Combined treatment and medication management did not differ significantly on any outcomes 24 months: Combined treatment and medication management did not differ significantly on any outcomes 36 months: No significant difference between any of the treatment groups for all outcomes.* Note: Comparisons not clear cut as all subjects were followed up according to their original treatment allocation, regardless of what they chose to continue with over the course of the 36 month follow up. ADHD Symptoms Significant improvement occurred in all treatments and continued over 2 years. No differences between groups. Relapse
Outcome measures: 1. Swanson, Nolan, and Pelham Rating Scale (SNAP) (Parent & Teacher) 2. DSM-IV psychopathology 3. Wechsler Individual Achievement Test (WIAT) reading score 4. Social Skills Rating System (Parent & Teacher) 5. Columbia Impairment Scale Population: Children aged 7-9 years meeting ADHD DSM-IV criteria. No conduct or learning disorder. The children were responders to MPH identified in a short term trial.
Abikoff et al 2004 (220) Abikoff et al 2004 (222)
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MPH Klein et al 2004 (463) MPH plus attention psychosocial control treatment Study information: Design: 3 arm comparative study Duration: 2 years No. n = 103
MPH n = 34 MPH + MPT n = 34 MPH + ACT n = 35
All children relapsed when after 1 year of treatment placebo replaced MPH. Days to relapse were significantly greater in the MPH+ MPT group compared to MPH (p < .04). Social skills Significant improvement occurred in all treatments and continued over 2 years. No differences between groups.
Design Comparative study Level III-2 Quality Adequate Setting USA & Canada Industry funding No
Psychosocial intervention: Multimodal psychosocial treatment (MPT); Parent training and counselling, social skills training, psychotherapy, and academic assistance
Psychosocial control: Attention control psychosocial treatment (ACT); The components were parallel to those of MPT but excluded specific remedial or therapeutic content. Medication management: MPH: Individualized dose Placebo substitution at the end of 1 year.
Van der Oord et al 2007 (454) Design Metaanalysis Level I Quality Adequate Setting Netherlands Industry funding No
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Intervention Combined psychosocial & MPH Comparator MPH No. 26 studies
Outcome measures: 1. Conners Rating Scale Parent and Teacher 2. DSM-III R checklist for ADHD, ODD, & CD symptoms 3. Childrens Global Assessment 4. Scale (C-GAS) 5. Academic and gym class observations 6. Rate of relapse 7. Social skills rating scales Population: Children aged 6-12 years with a diagnosis of ADHD Study information: Design: Meta-analysis of RCTs with the goal of comparing effect sizes
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ADHD symptoms MPH Parent: 1.53 (CI 1.23 -1.82, p<0.01) Teacher: 1.83 (CI 1.43-2.12, p<0.01) Combined Parent: 1.89 (CI 1.39-2.40, p<0.01) Teacher: 1.77 (CI 1.08-2.46, p<0.01) ODD symptoms MPH Parent: 0.61 (CI 0.390.83, p<0.01) Teacher: 1.08 (CI 0.771.39, p<0.01) Combined Parent: 1.23 (CI 0.641.83, p<0.01) Teacher: 0.92 (CI 0.451.39, p<0.01) Social MPH Parent: 0.62 (CI 0.420.83, p<0.01) Teacher: 1.06 (CI 0.691.43, p<0.01) Combined Parent: 0.71 (CI 0.500.92, p<0.01) Teacher: 1.08 (CI 0.851.31, p<0.01)
ADHD symptoms MPH: parent 15 studies n = 705 MPH: teacher 13 studies n = 588 Combined: parent 6 studies n = 242 Combined: teacher 6 studies n = 240 ODD symptoms MPH: parent 10 studies n = 529 MPH: teacher 12 studies n = 579 Combined: parent 3 studies n = 191 Combined: teacher 5 studies n = 232 Social MPH: parent 3 studies n = 189 MPH: teacher 4 studies n = 199
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Combined: parent 3 studies n = 191 Combined: teacher 5 studies n = 207 Academic MPH: Child 4 studies n = 216 Combined: Child 5 studies n = 227
Academic MPH Child: 0.33 (CI 0.140.81, NS) Combined Child: 0.35 (CI 0.020.71, NS) Author conclusions: MPH and combined treatment were equally effective in reducing ADHD symptoms.
Outcome measures: Effect sizes
Combined interventions for adults

Reference Safren et al 2005 (154) Intervention/ comparator Intervention Combined intervention Population/Study information
Design: RCT Level II Quality Poor Setting USA Industry Funding No
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Comparator Medication only Intervention Combined intervention Study information:
Population: Adults aged 18 65 diagnosed with ADHD by DSM-IV diagnostic criteria. Stable on ADHD medication. Exclusions: Psychiatric comorbidities
Study information: Design: Parallel design RCT with pretest/post-test measures No. Combined treatment n = 16 Medication only n = 15 Duration: 15 weeks Medication: Current medication and dose
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Parents and teachers rated MPH and combined treatments as equally effective in the reduction ODD symtoms. For social behaviour MPH and combined interventions were equally effective. For improvement of academic function no treatment was effective. Results Significant improvements were reported in individuals who received combined intervention compared to medication alone. Between group effect sizes; CGI: 1.4 (p < 0.002) ADHD Rating Scale: 1.2 (p < 0.01) Current Symptoms Scale: 1.7 (p < 0.0001) Adverse events: not examined Cognitive therapy appeared to enhance the response beyond that attained with medication alone. Significant improvement in CGI severity (p = 0.0002) and GAF (P = 0.01) when
Behaviour modification: Cognate behaviour therapy including 1. Psychoeducation on ADHD 2. Learning skills to decrease distractibility 3. Cognitive restructuring
Wilens et al1999 (162) Design: Case series
Outcome measures: 1. Clinical Global Impression (CGI) 2. ADHD Rating Scale 3. Current Symptoms Scale (Self report) Population: Adults with a mean age of 42 11.1 diagnosed with ADHD by DSM-III diagnostic criteria.
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Level IV Quality Poor Setting USA Industry Funding Not reported
Comparator Medication
Design: Retrospective chart review No. Combined treatment n = 22 No medication n = 4 Duration: up to 30 months Cognitive therapy and medication initiated simultaneously. Comparison made between scores at point when medication stabilized and end of Cognitive therapy intervention. Medication: Stable medication dose Psychosocial treatment: Cognitive therapy (ADHD based) Outcome measures: 1. Clinical Global Impression (CGI) 2. ADHD Rating Scale 3. Global assessment of Functioning Scale
comparing cognitive therapy plus medication to point of medication stabilization. Note: Results must be considered in light of major study limitations (retrospective design, no clear medication only group and no control)
Summary
Preschoolers: No studies were identified that considered combined interventions in preschoolers. Children and adolescents: One systematic review and 6 primary studies were identified that addressed the use of a combined intervention compared to medication alone. Majewicz-Hefley and Carlson (459) performed a meta-analysis on 8 studies that had utilised combined treatments. The authors reported that calculated effect sizes for combined treatment were greater than those previously reported in the literature for treatment with medication alone. This review included both randomised controlled trials and studies with lower levels of evidence, and was rated poor in quality. Van der Oord et al (460) found that while significant improvements were found for both the combined treatment and medication only groups, the use of combined treatment did not appear to improve outcomes over those achieved with stimulant medication alone. A summer treatment program study by Pelham et al (462) reported that combined treatment was superior to medication treatment alone. A second summer treatment program study in younger children (6-7 years) reported by Chacko et al (461) found a significant difference between the two MPH groups and placebo in all point system measures and 2 of 3 classroom measures. These results suggest that the behavioural intervention added little benefit. The direct impact on ADHD symptoms as measured via DSM criteria or related scales was not assessed.
Fabiano et al 2007 (455) reported on classroom behaviours within the setting of the summer treatment program. Behaviour modification plus low doses of MPH (0.15 mg/kg) was equivalent to a high dose of MPH (0.60 mg/kg) alone on measures of classroom rule violations and seatwork completion. Three assessments were derived from the MTA study, which included a combined intervention arm of medication and multi-modal psychosocial management, and a medication only arm. Over the course of the study, the reports at 14 months (135), 24 months (136) and 36 months (137) found no significant difference in the effectiveness of combined treatment compared to medication alone in any of the five ADHD symptom domains they assessed. As noted in the table, as the study has progressed the subjects have been followed up according to their original
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treatment allocation, regardless of what treatment they chose to use, making it difficult to compare between groups. The multimodal psychosocial treatment study (220, 222, 463) was conducted over two years in children aged 7-9 years with ADHD. Entry into the study was restricted to children who responded to MPH in a 5 week open-label treatment period. Three groups were compared; MPH alone, MPH plus multimodal psychosocial treatment and MPH plus a psychosocial treatment control. While significant improvement in ADHD symptoms and social behaviour occurred in all treatment groups and continued over 2 years, there were no differences between groups. The biggest limitation of this study is that they only included children who were known responders to MPH. As such these results cant be assumed to accurately reflect a more general population of children. Van der Oord et al (454) conducted a meta-analysis of RCTs with the goal of comparing effect sizes between MPH, psychosocial interventions and a combination of the two. There were very few studies addressing combined interventions. MPH and combined treatment were equally effective in reducing ADHD symptoms, ODD symptoms and social behaviour. Neither combined treatment nor MPH was effective for improving academic function. Effect sizes of MPH and combined treatment were not significantly different, suggesting no additive effect of psychosocial interventions.
Adults: Two primary studies were identified that found in favour of the use of combined interventions for adults with ADHD compared to medication alone. Safren et al (154) reported that the combination of medication and cognitive behavioural therapy was superior to medication alone. This study was designed as a parallel RCT. The quality rating of the study was poor as blinding was not used due to the difficulty of blinding of participants to this behavioural intervention. The study by Wilens et al (162) reported that the combined intervention of medication and cognitive therapy was greater than the use of medication alone. This retrospective study had major methodological limitations as there was no clear comparator or control group. The results must be considered cautiously.
Excluded studies Study Rostain et al 2006 (153) Weiss et al 2006 (306)
Forness et al 2006 (464)
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Reason for exclusion No comparison of combined treatment with medication treatment only. No comparison of combined treatment with medication treatment only. Review
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Management in an Education Setting

School-based interventions
Research question 25. For children and adolescents with ADHD, do school-based interventions, compared to no intervention or standard care, affect outcomes? Selection criteria Population Inclusion criteria
Children and adolescents with ADHD diagnosed according to standard criteria; DSM-III, DSMIII-R, DSM-1V or ICD10
School-based behavioural interventions No intervention or standard care
Primary: Change in the incidence or severity of symptoms of ADHD (including; inattention, impulsivity, hyperactivity)
Secondary: School achievement, quality of life, social function. Study design Search period Language
Date of search
School/ or Classrooms/ or Behavior Therapy/
Reference
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March 2008
Intervention/ comparator Intervention Academic, contingency management, or cognitive-
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Text words: adhd or addh or adhs or hyperactive$ or hyperkin$ or (attention adj deficit) behave$ therapy and school or (school adj intervention) or school-based intervention or (classroom adj intervention) or (planned adj ignoring) or (daily adj report adj card) or praise or (time adj out) or (peer adj tutor$) or (social adj skills adj training) or (summer adj treatment adj program) or (academic adj intervention) or (academic adj achievement)
Results Authors conclusions: ADHD symptoms: The assessed school-based interventions were significantly effective in enhancing
School-based interventions
Population/ Study information/ Population: school-aged children (kindergarten to year 12) described or diagnosed with one or more of the following disorders: ADD, ADHD, hyperkinetic impulse disorder,
DuPaul & Eckert 1997 (465) Design
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Systematic Review (studies of various designs) Level III-2 Quality Adequate Setting USA Industry funding No Barkley et al 2000 (466) Shelton et al 2000 (467) Design RCT Level II Quality Adequate Setting USA Industry funding No
behavioural interventions Comparator Not clear
hyperactive deficits, or attention deficits. (basis for diagnosis not reported) Study information: Design: Systematic review and metaanalysis of 63 studies. Outcome measures: 1. Behaviour measures (i.e. problem behaviour, prosocial interactions, or academic behaviour) 2. School performance measures (academic measures, behavioural measures, clinic-based tests)
classroom behaviour. Behaviour modification techniques were found to be more effective than cognitive or cognitive-behavioural strategies in improving behaviour control. Academic performance: Some positive effects of school-based interventions on academic performance were obtained, however the effects were not as robust.
Intervention 1. Parent training 2. Classroom behaviour modification techniques 3. 1 & 2 Comparator No treatment
Population: Kindergarten children with a mean age of 4.8 years. Diagnosed with ADHD based on DSMIII-R criteria Study information: Design: Parallel RCT Duration: 9 months (2 year follow-up) No. n = 158 (1. n = 39 2. n = 37 3. n = 40 no treatment n = 42) Dose: Determined by titration; 1870mg/day.
Miranda et al 2006 (468)
Design Comparative study with concurrent controls Level III-2 Quality Poor Setting Spain Industry
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Intervention Behaviour modification/ cognitive behavioural techniques carried out by teachers in the classroom. Comparator 1. Medication 2. No treatment
Outcome measures: 1. Parent rating of child behaviour a. Child behaviour checklist (CBCL) b. Homes situations questionnaire c. Normative adaptive behaviour checklist 2. Teacher rating of child behavior a. CBCL teacher report form b. School situations questionnaire c. Self control rating scale d. Social skills rating scale 3. Psychological testing 4. Clinic Behaviour observations
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ADHD symptoms: Children receiving the classroom intervention alone showed improvement in teacher rated attention (p = 0.001), aggression (p = 0.002), social skills (p = 0.001) and behaviour (p = 0.006) and parent rated normative adaptive behaviour (p = 0.002). But not on any measure of the parent rated CBCL. No improvement in academic achievement. The school based interventions were effective in the school environment but not sustained at home. Two year follow-up indicated no differences between the treated and untreated groups. ADHD symptoms: Reported benefit of classroom intervention over the control group in teacher ratings of DSM-IV hyperactivity (p < 0.001) and parent ratings of DSM-IV hyperactivity (p < 0.001) and inattention (p < 0.01).
Population: Children mean age 8 years 3 months. Diagnosed with ADHD based on DSM-IV criteria Study information: Design: pre-test/post-test measures Duration: 4 months No. No -treatment n = 16 Behaviour modification n = 17 Medication (MPH 10mg/day) n = 17 Outcome measures: 1. Conners teacher rating scale 2. IOWA Conners rating scale 3. School problem inventory 4. Child symptoms Inventory (parent rated). DSM-IV hyperactivity and DSM-IV inattention
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funding No Miranda &

Presentacion
2000 (469) Design Comparative study without concurrent controls Level III-3 Quality Adequate Setting Spain Industry funding No Miranda et al 2002 (470) Design Pseudorandomised controlled trial Level III-1 Quality Adequate Setting Spain Industry funding No Klingberg et al 2005 (471) Design: RCT Level II Quality Adequate Setting USA
Intervention Stop and think program ( 1 hour sessions twice weekly) Comparator Stop and think program plus anger control technique
Population: Children aged 9-12 years. Diagnosed with ADHD based on DSMIII criteria Study information: Design: pre-test/post-test measures Duration: 3 months (2 month follow up) No. n = 32 (16 aggressive) Stop & think n = 16 (8 aggressive) Stop & think plus anger control n = 16 (8 aggressive)
ADHD symptoms: Significant improvements in parent and teacher rated child behaviour at post-treatment testing. Parent ratings; DSM-III hyperactivity (p < 0.001), anti-social behaviour (p < 0.008), school problems (p < 0.003) internalization (p < 0.05). Teachers ratings; Coners (p < 0.001), IOWA hyperactivity (p < 0.001), IOWA aggression (p < 0.002), Learning problems (p < 0.001), antisocial behaviour (p < 0.002), Inhibition (p < 0.001), school adjustment (p < 0.005), self control (p < 0.001) and social skills (p < 0.001). No differences were found in outcomes between the two interventions.
Outcome measures: 1. Hyperactivity questionnaire adapted from the DSM-III 2. Scale of Behavioural Problems 3. Teachers Conners rating scale 4. IOWA Conners rating scale 5. School problem inventory 6. Social skills assessment teacher form 7. self control rating form Intervention Behaviour modification/ cognitive behavioural techniques carried out by teachers in the classroom. Comparator Standard classroom Population: Children mean age 8.6 years. Diagnosed with ADHD based on DSM-III criteria. low socio-economic status
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Intervention Computerbased working memory tasks with escalating difficulty Comparator Computerbased working memory tasks with only low difficulty
Study information: Design: pre-test/post-test measures Duration: 3 months (2 month follow up) No. Intervention group n = 29 Control group n = 21 Outcome measures: 1. Scale of Behavioural Problems 2. Teachers Conners rating scale 3. IOWA Conners rating scale 4. School problem inventory 5. self control rating form 6. school achievement
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ADHD symptoms: Significant benefit from intervention in measures of parent rated DSM-IV hyperactivity (p < 0.02) and teacher rated DSM-IV hyperactivity (p = 0.006), Conners (p = 0.04), IOWA hyperactivity (p = 0.05) and self control (p = 0.02). ADHD symptoms: Significant improvement in the intervention group compared to the control group for parent rated inattention (p = 0.04) and hyperactivity/impulsivity (p = 0.03). No significant improvement in teacherrated ADHD symptoms in the treatment group over the control group. Academic performance: Not reported Adverse events: No adverse events were reported by parents
Population: Children aged 7-12 years with diagnosis of ADHD (basis not reported). Not being treated with medication Study information: Design: Parallel design RCT Duration: 5 weeks (2 month followup) No. Intervention n = 27 Comparator n = 27 Outcome measures: 1. Conners Rating Scale for parents and teachers (revised short version)
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Industry Funding Yes Jitendra et al 2007 (472) Design: Comparative study without concurrent controls Level III-3 Quality Adequate Setting USA Industry Funding Meyer and Kelley 2007 (473) Design Comparative study with concurrent controls Level III-2 Quality Poor Setting USA Industry funding No
Intervention Intensive databased academic intervention (IDAI)
Population: Children with a mean age of 8.6 years with diagnosis of ADHD based on parent and teacher ratings on the ADHD rating scale IV that were experiencing problems in reading or math. Medication not excluded. Study information: Design: Pre- and post-test measures Duration: 15 months No. Intervention n = 81 Comparator n = 86 Outcome measures: 1. Reading and math tests 2. Attainment of academic goals 3. Grades
ADHD symptoms: Not reported Academic performance: No significant difference between groups. Improvement from baseline was seen in both groups for reading and math tests and attainment of academic goals (effect size 0.80). Report card grade for math in both groups showed small improvements (effect size 0.50) as did report cards for reading in the TDAI group (0.50 < effect size < 0.80).
Comparator Traditional data-based academic intervention (TDAI)
Reference
Evans et al 2005 (474)
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2. Parent monitoring of homework and study skills completion Comparator Wait-list control group Intervention/ comparator Intervention Challenging Horizons Program: behavioural interventions /social skills training. After school program run 3
Intervention 1. Selfmonitoring of homework and study skills completion
Population: Children and adolescents aged between 11 and 14 that met diagnostic criteria for ADHD based on DSM-IV, had a high score on homework problem checklist (over 19) and 3+ nights per week of homework. Medication permitted. Study information: Design: pre and post-test outcome measures Duration: 4 week treatment period No. Intervention Self - monitoring n = 14 Parent monitoring n = 14 Comparator n = 16
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ADHD symptoms: not reported Academic performance: A significant reduction in homework problems (HPC) (p < 0.0001) and increased homework turned in (p < 0.0001) was observed in the two treatment groups compared to the wait-list control group. No significant differences were seen between the treatment groups and the wait-list control groups on the CPS. No significant differences were seen between the parent-monitoring and the self-monitoring groups on any measure. Results ADHD symptoms and academic performance: Parent reports indicated benefits in academic, social, and overall functioning. There was discrepancy between parent and teacher reports. Note: no test of significance reported
Outcome measures: 1. Homework problem checklist (HPC) 2. Classroom performance survey (CPS) 3. Percent of homework turned in 4. Treatment satisfaction
Population/ Study information/ Population: Children and Adolescents aged 11-14 years. Diagnosed with ADHD based on DSM-IV criteria Study information: Design: pre-test/post-test measures Duration: 1 year No. Intervention group n = 13 Control group n = 14
Design Comparative study with concurrent controls Level III-2
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days/week Quality Poor Setting USA Industry funding No Evans et al 2007 (475) Design Comparative study with concurrent controls Comparator Community care control group Outcome measures: 1. ADHD-RS (parent & teacher rated. 2. Impairment rating scale (IRS) 3. Grade point average
Level III-2 Quality Poor Setting USA Industry funding No Frame et al 2003 (476) Design Pseudorandomised Controlled trial Level III-1 Quality Poor Setting USA Industry funding No Fabiano et al 2004 (477)
Intervention Challenging Horizons Program modified for within school hours (Participants attending schools running CHP) Comparator Community care control group (Participants attending schools not running CHP)
Population: Children and adolescents aged between 10 and 14 years. Diagnosed with ADHD based on DSMIV-TR criteria. Study information: Design: pre-test/post-test measures Duration: 3 years No. Intervention group n =42 Control group n = 37
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Intervention Twice weekly support group sessions based on the STARS curriculum of social empowerment training and responsibilities for students with ADHD as designed by the researcher Comparator No treatment Intervention Time out procedures 1. 5 min timeout 2. 15 min time-out 3. escalating & deescalating time- out
Outcome measures: 1. Behavior Assessment System for Children (BASC) 2. Disruptive Behavior Disorders Rating Scale (DBD) 3. Impairment rating scale (IRS) 4. Social skills rating system (SSRS) 5. Grade point average 6. Teacher reported classroom disruption. Population: 5th/6th grade children with a mean age of 11.4. Diagnosed with ADHD (basis for diagnosis not reported)
Study information: Design: Pseudo-randomised controlled trial with pre-test/ post-test outcomes. 4 week treatment period. No. n = 65 Outcome measures: 1. Harters Self-Perception Profile for Children
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Social skills: No significant differences between the groups were found (IRS, BASC or SSRS). Academic performance: No significant differences between the groups were found (IRS, Grades, Classroom disruption). ADHD symptoms: Effects on ADHD symptoms were not measured in this study. Self perception: Children attending the support group reported significantly increased perceptions of social acceptance (p = 0.000), physical appearance (p = 0.001), athletic competence (p = 0.25), and global selfworth (p = 0.000) when compared to children who did not participate in the support group. ADHD symptoms: No clear data for improvement in ADHD behaviours following time-out interventions due to the poor methodological quality of the study.
ADHD symptoms: Ratings on the BASC inattention scale were significantly improved in the intervention group at 3 years (Effect size 0.76). No significant differences were seen on the BASC-hyperactivity scale or the DBD hyperactivity and inattention scales.
Population: Children aged 6-12 years diagnosed with ADHD based on DSMIV Study information: Design: cross-over. All children receiving behaviour modification in a summer treatment program. Study compared 3 time out procedures. Duration: 7 weeks No. n = 71
Design Randomised cross-over trial with concurrent controls
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Level III-2 Quality Poor Setting USA Industry funding No
Comparator Response cost only
Outcome measures: 1. Normalisation: % of children in each time out condition who feel within 2 standard deviations of the normative mean for non compliance (counselor and teacher rated)
Summary One systematic review met the inclusion criteria. DuPaul and Eckert (465) reviewed 63 schoolbased interventions for ADHD with the conclusion that school-based interventions were effective in enhancing classroom behaviour, but effects on academic performance were less clear. This review had several methodological limitations and was rated as poor quality. The review did not assess the quality of each study individually and the study methodology was varied, with many studies having a small number of participants, no control group or no clear diagnostic criteria for the inclusion of participants. Eleven primary studies met our inclusion criteria. Barkley et al (466) described the use of a combination of behaviour modification techniques in the classroom by specially trained teachers in a well designed RCT. The behavioural interventions included a token system, time-out procedures, group training in social skills, and anger control and a daily school report card with home based reinforcement. When compared to the no-treatment group, children receiving the classroom intervention showed improvement in teacher-rated attention, aggression and social skills behaviour. There was no improvement in academic achievement. While the school based interventions were effective in the school environment, the changes in behaviour were not sustained at home. At the two year follow-up Shelton et al (467) found no differences between the treated and untreated groups.
Three Spanish studies also addressed multi-component classroom interventions. Miranda and Presentacion (469) assessed a Stop and think program of cognitive behavioural therapy that was aimed at increasing concentration and reflection. There were significant improvements in ADHD symptoms, school problems and antisocial behaviour measures at post-treatment testing and two month follow-up. However, there was no benefit in social adjustment or academic performance. The quality of this study was rated as adequate. The use of behaviour modification and cognitive behavioural techniques carried out by teachers in the classroom was reported in two studies. In the first study, Miranda et al (470) reported significant benefit in the ADHD symptom measures of hyperactivity and self control only. The quality of this study was rated as adequate. In the second study, Miranda et al (468) reported benefits of the classroom intervention over a no-treatment control group in measures of inattention and hyperactivity. The quality of this study was rated as poor due to limited reporting of the methodology. Klingberg et al (471) assessed the use of computer-based working memory tasks with escalating difficulty in a well designed RCT. Parent ratings of inattention and hyperactivity/impulsivity measures were improved compared to the control group. No differences were found between groups for teacher rated ADHD symptoms. The impact on academic performance was not addressed. Jitendra et al 2007 (472) compared two interventions that involved teachers working with consultants (such as school psychologists) either as usual (TDAI) or more intensively (IDAI) to
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develop interventions to target math and reading skills. Although, some improvements were seen in reading and maths for both groups, without a control group it is difficult to determine the efficacy of these programs. Meyer and Kelley 2007 (473) described a controlled study that looked at either self-monitoring or parent-monitoring of homework compared to a wait-list control group. In addition to monitoring of homework, students were given training in study strategy. Homework completion and homework problems improved significantly in both groups compared to the control group. The methodology and reporting of four primary studies was poor, making it difficult to gauge the usefulness of the programs (474-477). Excluded studies Reference Robinson et al1999 (478) Barbaresi et al1998 (479) Owens et al 2005 (480) Kapalka et al 2005(481) Miranda et al 2006 (482) van Lier et al 2004 (483) Purdie et al 2002 (484)
Gureasko-Moore et al 2006 (485) Solomonidou et al 2004 (486) Murick et al 2005 (487) Eber et al 1997 (488) Eber et al 2002 (489) Scott et al 2003 (490) Ridgway et al 2003 (491) Clarfield and Stoner (492) Codding et al 2005 (493) Evans et al 2004 (494) Habboushe et al 2001 (495) Hook et al1999 (496) Levy & Vaughn 2002 (497) Mautone et al 2005 (498) Northup et al 1999(499) Ota and DuPaul 2002 (500) Pelham et al 2005 (501) Plumer and Stoner (502) Rabiner et al 2004 (503) Reid et al 2005 (504)
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Reason for exclusion No specific diagnosis of ADHD for study participants. Outcomes not relevant to the research question. Not all children had ADHD, main diagnosis was disruptive behaviour. Outcomes not relevant to the research question. Data extracted - Not true systematic review identified primary studies to use Population based study, does not specifically address ADHD. Data-extracted - comprehensive review of all interventions relating to ADHD insufficient detail on school based interventions to be used for this research question Sample size less than 10 Sample size less than 10
Not specific to ADHD Descriptive no intervention outcomes Descriptive no intervention outcomes Descriptive no intervention outcomes Sample size less than 10 Sample size less than 10 Sample size less than 10 Sample size less than 10 No treatment outcomes reported Sample size less than 10 No treatment outcomes reported
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Sample size less than 10 Sample size less than 10 Sample size less than 10
Descriptive no treatment outcomes Sample size less than 10 No diagnosis of ADHD Meta-analysis all included studies sample size less than 10.
Peer support and mentoring

Research question 26. For children and adolescents with ADHD, do peer support, tutoring or mentoring, compared to no intervention or standard care, affect outcomes? Selection criteria Population Inclusion criteria Children and adolescents with ADHD diagnosed according to standard criteria; DSM-III, DSMIII-R, DSM-1V or ICD10 Intervention Comparator Outcomes peer support and mentoring
Primary: Change in the incidence or severity of symptoms of ADHD (including; inattention, impulsivity, hyperactivity)
Secondary: School achievement, quality of life, social function. Study design Search period Language Date of search
School/ or Classrooms/ or Behavior Therapy/
Reference
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March 2008
Intervention/ comparator Intervention Class-wide peer tutoring Comparator NA
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Text words: adhd or addh or adhs or hyperactive$ or hyperkin$ or (attention adj deficit) behave$ therapy and school or (school adj intervention) or school-based intervention or (classroom adj intervention) or (planned adj ignoring) or (daily adj report adj card) or praise or (time adj out) or (peer adj tutor$) or (social adj skills adj training) or (summer adj treatment adj program) or (academic adj intervention) or (academic adj achievement)
Results Classroom behaviour: Increases in active engagement in academic tasks along with reductions in off-task behaviour were reported. Academic performance: 50% of children were reported to have improved their academic performance.
School-based peer interventions for children

Population/Study Information Population: Children aged 6-10 years that with ADHD based on DSM-III diagnostic criteria and matched control children (gender and classroom) Study information: Design: Case-control study with pretest/post-test outcome measures
Dupaul et al1998 (505) Design: Case-control Level III-2
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Quality Poor Setting USA Industry Funding No Hoza et al 2003 (506) Design Observation al: pre and post test Level IV Quality Poor Setting USA Industry funding Not reported Strayhorn & Bickel 2002 (507) Design: Case series Level IV Quality Poor Setting USA Industry Funding No
Duration: 2 years No. Children with ADHD n = 19 Peer controls n = 10 Outcome measures: 1. Behavioral Observations of Students in Schools (BOSS) (teacher rated) 2. Academic performance (maths tests; spelling tests) Population: Children aged 5-12 with a diagnosis of ADHD by parent structured diagnostic interview and teacher rating scales Study Information: Design: Pre and Post test measures. 8 week intervention No. n = 289 (188 boys/21 girls)
Increases in active engagement in academic tasks along with reductions in off-task behaviour were reported. Note: No tests of significance were used.
Intervention Friendship intervention
Comparator None
Intervention: Behaviour modification program that included a peer Buddy System
Summary
Three studies were identified that met the inclusion criteria. The study by Hoza et al (506) made use of a buddy system that was reported to reduce negative behaviour and increase participation and adaptation. However this study had a number of methodological flaws. There was no use of standard ADHD symptom scales and the study was poorly reported, making it difficult to interpret the results. Two studies looked at the use of tutoring. DuPaul et al (505) described the use of a class-wide peer tutoring program that was reported to increase the childrens ability to actively engage in academic tasks and reduce the time spent in off-task behaviour. Half of the children in this study
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Comparator NA
Intervention Individual tutoring
Outcome measures: 1. Disruptive behaviour disorder rating scale 2. Friendship measures specifically developed for this study Population: Children with a mean age of 7.5 years. Teacher rated symptoms of ADHD on DSM-IV criteria. Study information: Design: Case series study with pretest/post-test outcome measures Duration: 15 moths No. n = 30
Intervention: 45 min tutoring sessions conducted by an adult. High frequency; 1 session per 1.6 school days. Low frequency; 1 session per 8.5 school days. Outcome measures: 1. ADHD Symptom checklist
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Note: No tests of significance reported. ADHD symptoms: Significant improvement in ADHD symptoms. Effect size [95% CI] = 0.9 [2.9, 11.8] p = .002 Academic performance: Not reported.
The Buddy System was associated with a reduction in negative behaviour, and an increase in participation and adaptation skills.
were found to have improved their academic performance. The study did not statistically test the efficacy of these outcomes and the overall quality of this study was rated as poor. The study by Strayhorn and Bickel (507) employed individual tutoring by adults and reported improvements in ADHD symptoms, but did not address academic outcomes. The quality of this study was rated as poor.
Excluded studies Reference Reason for exclusion Spencer 2006 (508) Not specific to ADHD Glomb et al 2006 (509) outcomes data reported No Tournaki et al 2003 (510) specific to ADHD Not
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Interventions in adult education settings

Research question 27. For adults with ADHD, do University/TAFE-based interventions, compared to no intervention or standard care, affect outcomes? Selection criteria Population Inclusion criteria Adults with ADHD diagnosed according to standard criteria; DSM-III, DSMIII-R, DSM-1V or ICD10. Intervention Comparator Outcomes
University/TAFE-based interventions No intervention or standard care
Primary: University/TAFE achievement, quality of life, social function. Secondary: Change in incidence or severity of symptoms of ADHD (including; inattention, impulsivity, hyperactivity).
Study design Search period Language Date of search
Treatment outcome/
Summary
No studies addressing the use of university/TAFE-based interventions for individuals with ADHD were identified.
Excluded studies Study Allsopp et al 2005 (511) Swartz et al 2005 (512) Zwart et al 2001 (513)
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March 2008
T F A
Text words: adhd or addh or adhs or hyperactive$ or hyperkin$ or (attention adj deficit) (tertiary adj education) or college or university or TAFE
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Reason for exclusion Does not present separate data for ADHD Single case report with no relevant outcomes Does not present separate data for ADHD
Complimentary and alternative management strategies

Elimination and restriction diets
Research question 28. For individuals with ADHD, do diet restrictions, compared with no intervention or standard care, affect outcomes? Selection Criteria Population Inclusion Criteria
Individuals with ADHD diagnosed according to standard criteria; DSM-III, DSMIII-R, DSM-1V or ICD10. (Extended due to the limited number of studies to included individuals with ADHD symptoms)
Diet restrictions/diet modifications
Placebo or no intervention or standard care
Primary: Change in the incidence or severity of symptoms of ADHD
(including; inattention, impulsivity, hyperactivity). Adverse events Secondary: School/work achievement, quality of life, social function. Study design
Search period Language
Date of search
Search terms MeSH: Attention deficit disorder with hyperactivity/ diet/ or diet therapy/
Reference
Schmidt et al1997 (514) Design Placebo controlled and doubleblind crossover trial. Level III-2
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1997 - present English September 2007
Intervention / Comparator Intervention Oligoantigenic diet. Comparator Diet rich in additives and artificial colours. Outcome measures:
NHMRC defined levels of evidence (I-IV) for intervention studies.
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Text words: adhd or addh or adhs or hyperactive$ or hyperkin$ or (attention adj deficit) oligoantigenic or (diet adj modification) or (diet adj restriction)
Results 12/49children in the diet group showed improvement (>25%) in behaviour for both play and test ratings. 2/49 children in the diet group showed deterioration for both play and test ratings. Improvement (>25%) was found in the diet group (n = 22, 45%) of the 49 children in the test situation and in 21 children (43%) in the play situation
Preschoolers and children
Population/Study information Population: Children aged 6-12 with a Diagnosis of ADHD and/or conduct disorder (DSM III & ICD-10)
Study information: Design & duration: Diet regimes lasted 9 days and ADHD symptoms were assessed day 3 and day 8. No. n = 49
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Quality Poor Setting Germany Industry funding No Bateman et al 2004 (515) Design Challenge: Placebo controlled and doubleblind crossover trial. Level III-2 Quality Adequate Setting UK
1. Conners Abbreviated Parent Teaching questionnaire (classroom observation. 2. Behaviour checklist designed for this study filled in by blinded observers when children were either playing or undertaking tests (Paired associate learning task and continuous performance task). Intervention Artificial colouring and sodium benzoate free diet. Challenge sodium benzoate & artificial food colourings supplement to a mixed fruit drink Comparator Placebo Population: Children aged 3-4 years from the general population
Note: Results poorly reported
Study information: Design & duration: 1 week challenge with a 1 week washout between each; 1. placebo 2. 45 mg of sodium benzoate and 20 mg artificial food colourings No. n = 397
Outcome measures: 1. Mean daily parent behaviour rating (EAS & Weiss-Werry-Peters) 2. Psychologist tests.
Industry funding No McCann et al 2007 (516) Design RCT Cross-over design. Level II Quality Adequate Setting UK Industry funding No
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Intervention Artificial colouring and sodium benzoate free diet. Challenge sodium benzoate & artificial food colourings supplement to a mixed fruit drink Comparator Placebo (mixed fruit drink)e
Population: Children aged 3 years and children aged 8/9 years from the general population Study information: Design and duration: 3 year olds received a 1 week random order challenge with a 1 week washout between each; 1. Placebo 2. Mix A: 45 mg of sodium benzoate and 20 mg artificial food colourings 3. Mix B: 45 mg of sodium benzoate and 30 mg of artificial food colourings
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3 year olds who consumed more than 85% of juice with no missing data; n = 79 Mix A versus placebo; significant increase in hyperactivity (effect size 032 [95% CI 005060], p = 002) Mix B versus placebo; no significant increase in hyperactivity 8/9 year olds who consumed more than 85% of juice with no missing data; n = 91 Mix A versus placebo; significant increase in hyperactivity (effect size 012 [95% CI 002023], p = 0023) Mix B versus placebo; significant increase in hyperactivity (effect size 017 [95% CI 007028], p = 0001)
Improved behaviour reported by parent (Weiss-Werry-Peters scale) (p < 0.001) but not by psychologist testing.
8/9 olds received a 1 week random order challenge with; 1. Placebo 2. Mix A: 45 mg of sodium benzoate and 24.98 mg artificial food colourings 3. Mix B: 45 mg of sodium benzoate and 62.4 mg of artificial food colourings No. 3 year olds n = 153 8/9 year olds n = 144 Outcome measures: 1. hyperactivity based on aaggregated
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scores of observed behaviours and ratings by teachers and parents Pelsser et al 2008 (517) Design Comparative study with concurrent controls Level III-2 Quality Adequate Setting Netherlands Industry funding No Intervention Restricted elimination diet Population: Children aged 3.8-8.5 years with ADHD diagnosed according to DSM-IV criteria. Number of clinical responders in the intervention group was significantly larger than in the control group. Parent ratings: Intervention 11/15 Control 0/12 Teacher ratings: Intervention 7/10 Control 0/7
Comparator Waiting-list control group
Study information: Design & duration: 9 weeks total. 2 week baseline diet 5 week elimination diet or waiting period
Elimination diet: rice, turkey, lamb, vegetables, fruits margarine vegetable oil, tea, pear juice and water No. n = 27 Intervention n = 15 Control n = 12
Summary
Four primary studies were identified that addressed the use of restriction diets for the treatment of ADHD/hyperactivity. These studies focused on preschoolers and children. No trials involving adolescents or adults were identified. Schmidt et al (514) addressed the use of the oligoantigenic diet in children with ADHD. This poor quality study had several limitations in study design and reporting that make the results difficult to interpret. Improved behaviour was reported in approximately 50% of participants. The remaining studies, Bateman et al (515) and McCann et al (516) addressed the impact of artificial food colourings on hyperactivity. These studies were of adequate quality. They were conducted with children drawn from the general population and were not specific for children with ADHD. Short term challenge (one week) with sodium benzoate and artificial food colourings was found to moderately increase hyperactivity, but not in all groups. Overall, insufficient data is available from the literature to draw conclusions on the use of restriction diets for the treatment of ADHD. Further research is required using standardised and validated outcome measures in RCTs with a parallel design. Excluded studies Study Schab et al 2004 (518)
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Outcome measures: 1. Clinical response: decline in symptom scores by 50% or more. 2. Conners Scale (Parent and teacher) 3. ADHD DSM-IV Rating Scale 4. Diagnostic interview ODD symptoms
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ODD symptoms were significantly decreased in the intervention group compared to the control group.
Reason for exclusion Meta-analysis broad inclusion criteria for studies and no data specific to ADHD
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Fatty acid supplements

Research question 29. For individuals with ADHD, does diet supplementation with fatty acids, compared with placebo or standard care, affect outcomes? Selection criteria Population Inclusion criteria Individuals with ADHD diagnosed according to standard criteria; DSM-III, DSMIII-R, DSM-1V or ICD10. (Extended due to the limited number of studies to included individuals with ADHD symptoms) Fatty acid supplements Placebo
Primary: Change in the incidence or severity of symptoms of ADHD (including; inattention, impulsivity, hyperactivity). Adverse events.
Secondary: School/work achievement, quality of life, social function. Study design Search period Language Date of search NHMRC defined levels of evidence (I-IV) for intervention studies. 1997 - present English May 2007
Search terms MeSH: Attention deficit disorder with hyperactivity/ fatty acids/
Reference
Hirayama et al 2004 (519) Design RCT Level II Quality Adequate Setting Japan
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Intervention/ comparator Intervention EFA (EPA & DHA) Population/ study information Comparator Placebo (olive oil)
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Text words: adhd or addh or adhs or hyperactive$ or hyperkin$ or (attention adj deficit) fatty acids or Omega$ or Omega-3 or Omega-6 or EPA or Eicosapentaenoic or DHA or docosahexaenoic acid or EFA or essential fatty acids
Results No significant benefit from EFA supplements compared to placebo.
Children
Population: Children 6-12 years. 32/40 were diagnosed with ADHD based on DSM-IV criteria. 8 suspected of having ADHD. Stimulant medication permitted. Study information: Design and duration: 8 week parallel design RCT No. n= 40 Dose: EFA supplied in food: EPA100 mg/day DHA 514 mg/day
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Industry funding Yes Richardson & Puri, 2002 (520) Design RCT Level II Quality Good Setting Ireland Industry funding No Sinn & Bryan 2007 (521) Design Intervention EFA (EPA & DHA) Comparator Placebo (palm oil) Intervention EFA (EPA & DHA) Comparator Placebo (olive oil)
Outcome measures: 1. DSM-IV criteria rated by parent and teachers Population: Children 8-12 years with ADHD symptoms but no official diagnosis Study information: Design and duration: 12 week parallel design RCT No. active drug n = 22 placebo n = 19 Significant benefit of EFA over placebo on 2 of 7 CPRS-L Sub-scale measures; Anxious/shy (p = 0.04), cognitive problems (p = 0.01) and 1
of 7 CPRS-L Global scales; Conners index (p = 0.01)
Dose: EFA supplement EPA 480mg/day DHA 186 mg/day
Outcome measures: 1. CPRS-L for seven subscales of
individual ADHD features and seven global scales of ADHD.
Population: Children aged 7-12 with ADHD symptoms but no official diagnosis Study information: Design and duration: 15 week parallel design
psuedorand omised controlled trial

Level III-1 Quality Adequate Setting Australia
Industry funding Yes Stevens et al 2003 (522) Design RCT Level II Quality Adequate Setting USA Industry funding Yes
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Intervention EFA (EPA & DHA) Comparator Placebo No. Placebo n = 15 Active drug n = 18 Outcome measures:
No. n = 109 Placebo n = 27 Active drug n = 36 Active drug plus multivitamin n = 41 Dose: EFA supplement EPA 558 mg/day DHA 174 mg/day
Outcome measures: 1. Conners parent rating scales (CPRS) 2. Conners teacher rating scales (CTRS) Population: Children aged 6-13 with ADHD symptoms but no official diagnosis Study information: Design and duration: 16 week parallel design
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Significant benefit in 9 of 14 parent reported ADHD measures (CPRS). No benefit in teacher reported ADHD measures (CTRS). Variable (effect size, p-value) Cognitive problems/ Inattention (0.52, p < 0.01) Hyperactivity (0.17, p < 0.05) ADHD index (0.59, p < 0.01) Global: restless/ impulsive (0.45, p < 0.01) DSM-IV inattentive (0.39, p < 0.01) DSM-IV hyperactive/ impulsive (0.61, p < 0.01) DSM-IV total (0.20, p < 0.01) Oppositional (0.49, p < 0.01) Anxious/shy (0.43, p < 0.01) Significant benefit on 1 of 16 ADHD measures (DBD Attention; p = 0.03).
Dose: EFA supplement EPA 80 mg/day DHA 480 mg/day
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Voigt et al 2001 (523) Design RCT Level II Quality Good Setting USA Industry funding No
Intervention EFA (DHA) Comparator Placebo
1. Conners Abbreviated Symptom Questionnaire (ASQ) 2. Disruptive Behaviour Disorders (DBD) Rating Scale 3. Conners Continuous Performance Test (CPT) 4. Woodcock-Johnson Psychoeducational Battery-Revised (WJ-R) Population: Children aged 6-12 with a diagnosis of ADHD based on DSM-IV criteria. All receiving stimulant medication 6-12 years 16 week trial N = 54
No significant benefits of EFA compared to placebo
Study information: Design and duration: 16 week parallel design No. Placebo n = 32 Active drug n = 31
Dose: EFA supplement DHA 345 mg/day
Summary
Five placebo controlled trials were identified that addressed the use of EFA for the treatment of ADHD. The treatment trials to date have involved children 6-13 years of age and no trials have been conducted in adolescents or adults with ADHD. The efficacy of fatty acid supplementation in the treatment of ADHD remains uncertain. Two trials found no improvements (519, 523) and three trials showed benefits in only a sub-set of ADHD related measures (520-522). No trials reported any serious adverse events.
The inconsistencies in the findings may simply be the result of differences in study design such as inclusion criteria, dosage levels or type of EFA used. In addition, the studies did not take into account confounding factors such as adherence to treatment or the inclusion of individuals being treated with medication. It is also important to note that a formal diagnosis of ADHD was made in only two studies. Excluded studies Study Joshi et al 2006(524) Richardson et al 2005 (525) Stordy et al 2000 (526)
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Outcome measures:
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Reason for exclusion Not placebo controlled Did not directly address ADHD or ADHD symptoms
Did not directly address ADHD or ADHD symptoms
Chiropractic
Research question: 30. For individuals with ADHD, does chiropractic, compared with no intervention or standard care, affect outcomes? Selection criteria Population Inclusion criteria Individuals with ADHD diagnosed according to standard criteria; DSM-III, DSMIII-R, DSM-1V or ICD10. (Extended due to the limited number of studies to included individuals with ADHD symptoms) Intervention Comparator Outcomes Chiropractic
Primary: Change in the incidence or severity of symptoms of ADHD (including; inattention, impulsivity, hyperactivity). Adverse events
Secondary: School/work achievement, quality of life, social function. Study design Search period Language Date of search NHMRC defined levels of evidence (I-IV) for intervention studies. 1997 - present (Extended due to limited number of studies) English
Search terms
MeSH: Attention deficit disorder with hyperactivity/ chiropractic/ or manipulation, chiropractic/
Summary
No studies addressing the use of chiropractic treatment for the management of ADHD were identified. The literature in the area is limited to a small number of case reports. Excluded studies Study Goff et al 2000 (527)
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July 2007
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Text words: adhd or addh or adhs or hyperactive$ or hyperkin$ or (attention adj deficit) chiroprac$
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Reason for exclusion Did not recruit individuals with ADHD
Behavioural optometry
Research question 31. For individuals with ADHD, does behavioural optometry, compared with no intervention or standard care, affect outcomes? Selection criteria Population Inclusion criteria Individuals with ADHD diagnosed according to standard criteria; DSM-III, DSMIII-R, DSM-1V or ICD10 Intervention Comparator Outcomes Behavioural optometry
Secondary: School/work achievement, quality of life, social function. Study design Search period Language Date of search NHMRC defined levels of evidence (I-IV) for intervention studies. 1997 - present English
Search terms MeSH: Attention deficit disorder with hyperactivity/ Optometry/
Summary
No studies addressing the use of behavioural optometry for the treatment of ADHD were identified.
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July 2007
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Text words: adhd or addh or adhs or hyperactive$ or hyperkin$ or (attention adj deficit) (behave$ adj optometry) or (vision adj therapy) or (eye adj exercise) or (vision adj therapy)
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Biofeedback
Research question 32. For individuals with ADHD, does biofeedback, compared with no intervention or standard care, affect outcomes? Selection criteria Population Inclusion criteria Individuals with ADHD diagnosed according to standard criteria; DSM-III, DSMIII-R, DSM-1V or ICD10 Intervention Comparator Outcomes
Biofeedback (also called neurofeedback)
Placebo or waitlist control or standard care
Primary: Change in the incidence or severity of symptoms of ADHD (including; inattention, impulsivity, hyperactivity). Side effects
Search Terms MeSH: Attention deficit disorder with hyperactivity/ biofeedback/ or Electroencephalography/
Reference Riccio & French, 2004 (528) Design Systematic Review Level IV Quality Adequate Setting
R D
Intervention/ comparator Intervention Neurofeedback Comparator Waitlist control or standard care
July 2007
T F A
Text words: adhd or addh or adhs or hyperactive$ or hyperkin$ or (attention adj deficit) biofeedback or neurofeedback or neurotherapy or EEG or electroencephalo$ or (slow adj cortical adj potentials)
Results 17/18 studies reported positive outcomes following neurofeedback treatment. Authors conclusions: These outcomes must be interpreted with caution as the majority of the reports were case based and/or had major methodological limitations (few used a control group; no studies used randomised assignment or a combination of outcome measures). No adverse events were reported.
Population: Children with ADHD Study Information: Design: Systematic review of 18 studies of various design (4 comparative studies with concurrent controls (III-2), 3 comparative studies with historical controls & 11 case series (IV))
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USA Industry Funding No Strehl et al 2006 (529) Design Case series with pretest/post-test outcomes Level IV Quality Adequate Setting Germany Industry funding No.
Intervention Neurofeedback Comparator NA
Population: Children aged 8- 13 years with a diagnosis of ADHD based on DSM-IV criteria. Stimulant use permitted Study information: Design: pre-test/post-test measures No. n =23 Duration: 6 months Neurofeedback treatment: 30 Neurofeedback sessions. Self regulation training of slow cortical potentials. Visual and auditory feedback.
Heinrich et al 2004 (530)
Design Psuodorando mised controlled trial Level III-1 Quality Adequate Setting Germany Industry Funding No
R D
Intervention Neurofeedback Comparator Waitlist control
Outcome measures: 1. DSM-IV questionnaires for parents and teacher; 2. Eyberg Child Behavior Inventory 3. German translation of Conners Rating Scale 4. Kindl-Questionnaire for Measuring Health-Related Quality of Life in Children and Adolescents, parents and childrens version 5. Testbatterie zur Aufmerksamkeitspru fung, (test battery that measures attention) 6. German version of the Wechsler Intelligence Scale for Children Population: Children aged 7-13 years with a diagnosis of ADHD based on DSM-IV criteria. Concurrent use of stimulant medication was permitted. Study information: Design: Parallel design with pretest/post-test measures Duration: 3 weeks No. Neurofeedback n = 13 Waitlist control n = 9
T F A
No clear benefit on parent rated DSM-IV criteria. Significant improvement of parent rated ADHD symptoms for children receiving neurofeedback treatment compared to the control group (p < 0.05). No adverse events were reported.
Children showed significant improvement on multiple outcome measures following neurofeedback training. Eyberg questionnaire (p = 0.02 ), Conners Rating Scale (p = 0.03). Teacher rated inattention (p = 0.032), hyperactivity (p = 0.003), impulsivity (p = 0.034), and social behavior (p = 0.02).
Neurofeedback treatment: Children played a computer game, with tasks to change the colour of an object, by modulating their electrical brain activity. Training lasted 3 weeks, with 25 training sessions lasting 50 minutes. In each training sessions 120 tasks were performed. Outcome measures: 1. Parent rated German measurement
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scale relating to ADHD Monastra et al 2002 (531) Design Comparative study will concurrent controls Level III-2 Quality Adequate Setting USA Industry Funding No Intervention Clinical care plus Neurofeedback Comparator Clinical care Population: Children aged 7-19 years with a diagnosis of ADHD based on DSM-IV criteria. Study information: Design: Parallel design with pretest/post-test measures Duration:1 year No. Clinical care plus Neurofeedback n = 51 Clinical care n = 49 Significant improvement in attention and hyperactivity reported for children receiving neurofeedback treatment compared to the control group for both parent and teacher ratings of hyperactivity and inattention (all p < 0.001). No adverse events were reported.
Fuchs et al 2003 (532)
Design Comparative study will concurrent controls Level III-2 Quality Adequate Setting Germany Industry Funding No
R D
Intervention Neurofeedback Comparator Medication (MPH)
Neurofeedback treatment: Weekly attention training sessions (3040 minutes). Visual and auditory feedback, with reinforcement by a points system. Child achieving 20 points could cash this in for $15. Generally achieved within 3-4 sessions. ECG feedback sessions conducted until child exhibited a degree of cortical slowing demonstrated on a scan (34-50 sessions) Clinical care: MPH 5mg for one week and then reviewed and changed as needed. Parents training (10 sessions). School consultation
Outcome measures: 1. Attention Deficit Disorders evaluation scale (Parent/ teacher rated) Population: Children aged 8-12 years with a diagnosis of ADHD based on DSM-IV criteria. Study information: Design: Parallel design with pretest/post-test measures Duration:12 weeks No. Clinical care plus Neurofeedback n = 22 Medication n = 12
T F A
Improvement found on the TOVA, the speed and accuracy measures of the d2 Attention Endurance Test as well as teacher and parent ratings of behaviour (Conners) for both the neurofeedback group (parents; p < 0:001, teachers; p = 0.002 ) and the medication group (parents; p < 0:007, teachers; p = 0.005 ). No differences between groups were found. No adverse events were reported.
Neurofeedback treatment: Children played a computer game, such as pacman-type maze games, by modulating their electrical brain activity. Three sessions per week lasting 30-60 minutes. Visual and auditory feedback. Medication: MPH on school days. Individualised dose. Outcome measures 1. Test of Variable of Attention (TOVA) 2. Computerised visual continuous
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Rossiter, 2004 (533) Design Comparative study with concurrent controls Level III-2 Quality Adequate Setting USA Industry funding No. NB Private clinic with study subjects paying researchers fee for service)
Intervention Neurofeedback Comparator Medication
performance task (d2 Attention Endurance Test) 3. IOWA-Conners Behavior Rating Scale Population: Children and adolescents with a mean age of 16.6 (12.7) years with a diagnosis of ADHD based on DSM-IV criteria. Study information: Design: Parallel design with pretest/post-test measures Duration: 3.5 months No. Neurofeedback; home n = 17, office n = 14 Medication n = 31
Neurofeedback treatment: Neurofeedback sessions lasting 30-36 minutes 3- 5 times a week for 3.5 months. Visual and auditory feedback. Medication: Stimulant treatment; MPH or DEX. Individualised dose.
Summary
One systematic review and 5 primary studies were identified that addressed the use of neurofeedback in the treatment of ADHD. Riccio and French (528) reviewed 18 studies, 17 of which reported benefits from biofeedback in the treatment of ADHD. Riccio and French (528) highlighted the flaws with the identified literature, including the predominance of case studies and the dearth of studies utilising a control group, randomised assignment of participants or a combination of outcome measures. The need for more empirical documentation through well deigned RCTs was stressed.
The 5 primary studies published since Riccio and Frenchs review (528) are level III and IV studies rated as being adequate in quality. No RCTs were identified. The case-series conducted by Strehl et al (529) with no control group found that the children displayed improvements on multiple measures, but there was no clear benefit when parent-rated DSM-IV criteria were used. Heinrich et al (530) reported significant improvement in parent ratings in the biofeedback group compared to a waitlist control group. Only one rating scale was used, and participants were permitted stimulant medication which may have confounded results. The remaining two studies compared biofeedback treatment to medication. Monastra et al (531) looked at the use of neurofeedback as part of a combined treatment strategy that also included medication and psychosocial interventions. When neurofeedback was included in the treatment, inattention and hyperactivity were improved compared to the control group. The remaining studies compared neurofeedback to stimulant medication. Fuchs et al (532) reported improvements in both the neurofeedback and the medication treatment groups, however, no differences between groups were identified. Rossiter (533) reported improvement in both the neurofeedback group and the
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R D
Outcome measures: 1. Test of Variable of Attention (TOVA) 2. Behavior Assessment System for Children (BASC) 3. Brown Attention Deficit Disorder Scales
T F A
Differences between neurofeedback and medication and groups were not statistically significant. No adverse events were reported.
Significant improvement found for the neurofeedback group with the Brown (p < 0.001) and BASC (p < 0.001); hyperactivity (p < 0.001), attention problems (p < 0.001), externalizing problems (p < 0.001), and Internalizing Problems (p < 0.001) scales, and behavioral symptoms index (p < 0.001). Improvement was also seen in the neurofeedback group on TOVA measures of attention, impulse control, processing speed, and variability in attention (all p < 0.001).
medication group on three subscales of the TOVA. Again no differences were found between the groups. No studies reported adverse events. However, it is not clear that any of the studies sought to measure adverse events. Excluded studies Study Beauregard & Levesque 2006 (534) Boyd et al1998 (535) Carmody et al 2000 (536) Cho et al 2002 (537) Heywood & Beale 2003 (538) Martin et al 2005 (539) Tinius et al 2000 (540)
Reason for exclusion No clinical data relevant to research question Sample size less than 10 Sample size less than 10 Participants did not have a diagnosis of ADHD Sample size less than 10 Sample size less than 10 Participants had comorbid diagnosis
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Homeopathy
Research question 33. For individuals with ADHD, does homeopathy, compared with no intervention or standard care, affect outcomes? Selection criteria Population Inclusion criteria Individuals with ADHD diagnosed according to standard criteria; DSM-III, DSMIII-R, DSM-1V or ICD10 Intervention Comparator Outcomes Homeopathy
Search terms MeSH: Attention deficit disorder with hyperactivity/ MeSH: homeopathy/
Search strategy for studies of children and adolescents: As a systematic review was identified no primary studies were sought. Children and adolescents
Results Two studies reported a benefit from homeopathy compared to placebo (Straus; PSQ P= 0.01, Frei; CGI-P P=0.048) One study found no differences between groups (Jacobs; CGI-P). Study quality: Straus: poor. Frie: good. Jacobs: good Adverse events: 3/3 studies reported
Reference
Atlunc et al 2007(541) Design Systematic Review Level I Quality Adequate
R D
July 2007
Intervention/ comparator Intervention Homeopathy Comparator Placebo Population/ study information No. n = 125
T F A
Text words: adhd or addh or adhs or hyperactive$ or hyperkin$ or (attention adj deficit) Text words: homeopath$, homopath$
233
Population: Children aged 0-19 with ADHD (diagnosis criteria not described) Study information: Design: Systematic review of 3 RCTs Straus 2000 Jacobs 2005 Frei 2005
Setting UK Industry funding Not reported
Outcome measures: 1. Conners Parent symptom questionnaire (PSQ) 2. Conners Global Index-Parent CGI-P
on adverse events. Jacobs & Straus: reported no adverse events. Frie: 4/62 participants withdrew due to adverse effects; increasing tics (1), behavioural disorders (2), reactive depression (1). Authors conclusions: Insufficient evidence to make clinical recommendations
Summary
The research articles identified that address the use of homeopathy for ADHD are primarily case reports, and there is a dearth of controlled trials. No studies were found that addressed the use of homeopathy in adults. In a broad systematic review of the use of homeopathy in child and adolescent conditions, Atlunc et al (541) reviewed three double-blind, placebo controlled randomised clinical trials where the participants had a diagnosis of ADHD. Two of these studies reported a benefit from homeopathy and one study found no differences between the use of homeopathy and placebo. Overall, the small number of participants in these trials and the varying results mean that at present there is insufficient evidence to draw a conclusion about the use of homeopathy as a therapy for ADHD. While homeopathy treatments are generally held to be safe (542) it is important to note that in one of the three trials, adverse events led to the withdrawal of 4 out of 62 participants. Further research is needed with larger numbers of participants in all population groups.
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Cerebellar therapy
Research question 34. For individuals with ADHD, do cerebellar therapies, compared with no intervention or standard care, affect outcomes? Selection criteria Population Inclusion criteria Individuals with ADHD diagnosed according to standard criteria; DSM-III, DSMIII-R, DSM-1V or ICD10 Intervention Comparator Outcomes Cerebellar therapies
Primary: Change in incidence or severity of symptoms of ADHD
(including; inattention, impulsivity, hyperactivity). Adverse events.
Secondary: School/work achievement, quality of life, social function. Study design Search period Language Date of Search NHMRC defined levels of evidence (I-IV) for intervention studies. 1997 - present English
Reference
Rutherford et al 2006 (543) Design Case series Level IV Quality Poor Setting UK Industry funding Yes
R D
July 2007
Intervention/ comparator Intervention Exercises designed to stimulate the cerebellum. 510 minutes twice daily Comparator None
Preschoolers, children, adolescents and adults

Population/Study information Population: Individuals of any age with a diagnosis of ADHD based on DSM-IV criteria Study information: Design: case series Duration: 6 months No. n = 895 (698 under 16 years 193 over 16 years) Outcome measures: 1. DSM-IV Hyperactivity/impulsivity symptoms (counted) 2. DSM-IV Inattention symptoms (counted) Results
T F A
Text words: adhd or addh or adhs or hyperactive$ or hyperkin$ or (attention adj deficit) Dore Program or cerebel$ therap$ or DDAT
Hyperactivity/impulsivity symptoms: pre-post test effect size = 2.6 Inattention symptoms: pre-post test effect size = 3.32 Note: no p-values reported
235
Summary
One primary study was identified that addressed the use of exercises designed to stimulate cerebellum in individuals with ADHD. The study included both children and adults. This study was a poster presentation and not a peer reviewed publication. The study had several limitations in design and reporting. Most importantly the study lacked a control group and did not use objective outcome measures and the results must be interpreted with caution. No unwanted side effects were reported. Further research of higher quality is required utilising well designed RCTs. Excluded studies Study Reynolds and Nicolson 2003 (544) Reynolds et al 2007 (545) Roderick and Nicholson 2007 (546)
Reason for exclusion Does not recruit subjects with ADHD specifically and no data is reported separately Does not recruit subjects with ADHD specifically and no data is reported separately Commentary. No data on ADHD.
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Excerise, meditation and relaxation

Research question 35. For individuals with ADHD, does sport or exercise, compared with no intervention or standard care, affect outcomes? Selection criteria Population Inclusion criteria Individuals with ADHD diagnosed according to standard criteria; DSM-III, DSMIII-R, DSM-1V or ICD10 Intervention Comparator Outcomes Sport, exercise, yoga
Search terms MeSH: Attention deficit disorder with hyperactivity/ sports/ or physical exercise/ or exercise therapy/
Reference
Harrison et al 2004 (547)
Design Observation al study Level IV Quality Adequate Setting Australia
R D
July 2007
Intervention/ comparator Intervention Sahaja Yoga Meditation Population/ study information Comparator Pre-treatment No. n = 48 total 31/48 on medication
T F A
Text words: adhd or addh or adhs or hyperactive$ or hyperkin$ or (attention adj deficit) (exercis$ adj therapy) or yoga or sport$ or massage or relax$
Results Significant improvement in ADHD symptoms (p < 0.001) improvement in behavioral symptoms (This effect was not influenced by medication)
Population: School-age children ADHD diagnosis. Medication permitted Study information: Design: pre test/post test outcome measures Duration: 6 weeks
Intervention: Yoga Meditation. Program consisted of twice weekly 90 minute clinics
237
Industry funding No HernandezReif et al 2001 (548) Design Case series pre and post test design Level IV Quality Adequate Setting USA Industry funding No Jensen & Kenny 2004 (549) Design Case-series Level IV Quality Poor Setting Australia Industry funding No
Intervention Tai Chi Comparator Pre-treatment
Outcome measures: 1. Parent rated questionnaires Connors parent-teacher questionnaire Population: Adolescents with a mean age 14.5 years and a DSM IV diagnosis of ADHD Study information Design : Duration: 5 weeks No. n = 13 Intervention: Tai Chi postures taught twice a week over 5 weeks
Improvement in symptoms of 5/6 subscales anxiety, conduct, daydream, emotion, hyperactive (all p < 0.001)
Outcome measures: 1. Conners Teaching Rating Scale
Intervention 1. yoga 2. cooperative games and activities Comparator Pre-treatment
Population: Children aged 8-13 years with a DSM IV diagnosis of ADHD. Medication permitted Study information: Design: Pre-test/post-test outcomes Duration: 20 weeks No. Yoga n = 11 Cooperative n = 8
Field et al 1998 (550) Design Case-series Level IV Quality Poor Setting USA Industry
R D
Intervention Massage therapy Comparator Relaxation therapy
Intervention: Yoga: 20 weekly 1 hour sessions once a month of yoga
Outcome measures: 1. Conners Teaching rating scale 2. Conners Parent rating scale
T F A
Yoga group: significant improvement on 5 subscales of the CPRS: Oppositional (p = .003); Global Index Emotional Liability (p = .001); Global Index Total (p = .001); Global Index Restless/Impulsive (p = .008) and ADHD Index (p = .019). Cooperative group: Significant improvement on three subscales of the CPRS: Hyperactivity (p = .004); Anxious/Shy (p = .028) and Social Problems (p = .034). Both groups demonstrated significant improvements in: Perfectionism (y: p = .032, c: p = .028); DSMIV Hyperactive/ Impulsive (y: p = .036, c: p = .016) and DSM-IV Total (y: p = .024, c: p = .016) No between group comparisons reported. Massage therapy group but not the relaxation therapy group rated themselves as happier and fidgeted less. Teacher reports indicated more time ob tasks and lower levels of hyperactivity in the massage therapy group compared to the relaxation therapy group. Depression and empathy were not altered in either group.
Population: Adolescents mean age 14.6 years with a DSM-III-R diagnosis of ADHD.
Study information: Design: Pre-test/post-test outcomes Duration: 2 weeks No. n = 28 Massage n = 14 Relaxtion n = 14 Intervention: Massage therapy: 15 minute massage after school for 10 consecutive school days
238
funding No
Relaxation therapy: 15 minute relaxation sessions after school for 10 consecutive school days Outcome measures: 1.Happy face scale 2. Fidgeting (observer rated) 3. Depression scale / empathy scale 4. Conners Rating Scale (teacher rated) Population: Children and adolescents mean age 13 years with a DSM-IV diagnosis of ADHD. Study information: Design: Pre-test/post-test outcomes Duration: 4 weeks No. n = 30 Massage n = 15 Relaxtion n = 15
Khilnani et al 2003 (551) Design Case-series Level IV Quality Adequate Setting USA Industry funding No
Intervention Massage therapy Comparator Wait-list control group
Intervention: Massage therapy: 20 minute massage twice per week
Summary
Five primary studies were identified that addressed the use of sport, exercise or relaxation techniques for the treatment of ADHD. The included studies were disparate in the type of intervention used and in the design and quality of the study. The studies focused on children and adolescents and no trials directed towards preschoolers or adults were identified. There was some evidence of clinical benefit for the studies of yoga (547, 549), Tai Chi (548) and massage therapy (550, 551). However, further research is required with larger numbers of participants in RCTs. No adverse events were reported in any of the studies. Excluded studies Study Ekeland et al 2004 (552) Marjorel et al 2004 (553) Lopez-Williams et al 2005 (554) Reitman et al 2005 (555) Tantillo et al 2002 (556)
R D
Outcome measures: 1.Happy face scale 2. Childrens Pain/Fear Thermometer Rating Scale (modified) 3. Conners Rating Scale (teacher rated)
T F A
Massage group reported feeling happier and improved on the pain/fear thermometer.
Reduction in hyperactivity (p < 0.01), anxiety (p <0.01) and day dreaming/inattention (p < 0.05) in the massage group compared to the control group.
Reason for exclusion Systematic review no subjects with ADHD Sample size less than 10 Exploratory study Treatment outcomes not measured No relevant outcomes reported
239
Sensory integration interventions

Research question 36. For individuals with ADHD, do sensory diets / sensory integrative treatments, compared with no intervention, affect outcomes? Selection criteria Population Inclusion criteria Individuals with ADHD diagnosed according to standard criteria; DSM-III, DSMIII-R, DSM-1V or ICD10 Intervention Comparator Outcomes
Sensory diets / sensory integrative treatments No intervention or standard care
Search terms MeSH: Attention deficit disorder with hyperactivity/ Occupational therapy/
Reference Chu et al 2007 (557) Design Case series Level IV Quality Poor Setting UK Industry funding
R D
Intervention/ comparator Intervention Occupational therapy Comparator None Population/ study information No. n = 20
June 2008
Children
T F A
Text words: adhd or addh or adhs or hyperactive$ or hyperkin$ or (attention adj deficit) Sensory diet or sensory modulation or sensory integration or sensory integrative treatment
Results Eleven children showed statistically significant improvement on the total ADHD rating scale by either the parent or teacher (p<0.05). Two children were rated as significantly improved by both the parent and the teacher.
Population: Children with ADHD aged between 5 and 11 years diagnosed by a child psychiatrist or paediatrician. Study information: Design and duration: Case series using pre-test/post-test outcome measures. 12 weekly sessions.
Intervention: Combination of the following; Parent education. Behavioural management and sensory diet program for home and school. Adaptation of classroom environment
240
None
and routine. Other treatments for specific problems such as handwriting or social skills. Outcome measures: ADHD Rating Scale-IV. Home and school versions.
Summary
One study was identified that utilised occupational therapy with a sensory integration approach for the management of children with ADHD. This small study of 20 children found improvement in ADHD symptoms in 11 of the 20 participants based on either parent or teacher reports. This preliminary study did not include a control group and was not blinded and as such the results should be interpreted with caution. Further research is required with larger numbers of participants in RCTs. Excluded studies Study Stratton et al 1998 (558)
Reason for exclusion Case study of one person
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ADHD and Society

ADHD and driving
Research question 37: For individuals with ADHD, does the use of interventions (pharmacological, psychosocial or other), compared with no intervention, improve driving performance? Selection criteria Population Inclusion criteria
Intervention
Pharmacological interventions, psychosocial interventions, other forms of management.
Comparator Outcomes
Placebo or no-intervention
Primary: Change in the incidence of driving accidents, driving fatalities or driving offences
Study design Search period Language
Date of search
Search terms MeSH: Attention deficit disorder with hyperactivity/ Accidents, Traffic/ or Automobile Driving/
Notes: Search strategy for studies with stimulant medications: As a systematic review was identified no primary studies were sought. Adolescents and adults
Results Effect sizes (Cohens d) varied from 0.00 1.86 for various driving outcomes.
Reference
Jerome et al 2006 (559) Design SR Level III-2 Quality
R D
November 2007
Intervention/ comparator Intervention Stimulant (MPH/OROS MPH/ATX) Comparator Placebo/No medication/ regular
T F A
Text words: adhd or addh or adhs or hyperactive$ or hyperkin$ or (attention adj deficit) driving fatal$ or driving accident or driving offence or drive$.ab or driving performance or driving risk
242
Population/Study information Population: Adults/adolescents with ADHD and adults with no-ADHD diagnosis, age range 16-55 years
Study information: Design & Duration: SR (13 observational studies) No. varied Dose: 10 or 20mg MPH (where stated)
Poor Setting Canada Industry funding None stated Barkley & Cox 2007 (560) Design SR Level III-2 Quality Poor Setting USA Industry funding None stated Barkley et al 2007 (561) Design RCT Level II Quality Adequate Setting USA Industry funding Yes Cox et al 2006 (562) Design RCT Level II Quality Poor Setting USA Industry funding None stated
MPH/seAMPH ER
Intervention Stimulant (MPH IR/OROS MPH) Comparator Placebo/MPH IR/MAS XR
Outcome measures: Driving: Outcomes Behaviour Performance Knowledge Anger Population: teenagers/adults aged 1765 years with ADHD (one study included community controls)
Study information: Design & Duration: SR (included 5 controlled studies) No. varied Dose: varied - MPH 10mg, 10-20mg, 30-120mg; OROS MPH 0.74mg/kg, 18-144mg/day, 72mg; MAS XR 30mg Outcome measures: Driving performance (simulator/road course)
R D
Intervention Manual transmission Comparator Automatic transmission
Population: adults aged 21-65 years clinically diagnosed with ADHD (DSM-IV criteria)
Study information: Design & Duration: 4-week RCT No. n=18 (crossover) Dose: up to 1.2 mg/kg daily Outcome measures: Safe Driving Behavior Survey Driving Anger Scale (DAS) Simulator driving behavior scale Global simulator performance evaluation
T F A
Self-report measures revealed a substantial effect (p<0.05) of medication on ADHD symptoms, impairment ratings, and ratings of driving behavior in natural settings. No beneficial effects were evident, however, on ratings of others on these same parameters or on the actual simulator driving scores. ADHD adolescents subjectively rated they were more attentive to driving while in the manual transmission mode (F = 6.50, p = .016). This was consistent across time (F = 0.05, p = .82). Objective driving simulator data showed that overall driving performance was better, less impaired, with manual transmission (F = 4.95, p = .03). IDS while driving an automatic transmission was similarly more impaired at both 20:00 and 23:00 (F = 0.01, p = .96).
Results varied between studies however all five studies found significant improvement in various measures of driving with medication.
Population: male drivers aged 17-21 years, with a diagnosis of ADHD based on parent rating on the DuPaul ADHD Rating Scale-IV, the Diagnostic Interview Schedule for Children (DISC-IV) and the Standardized Interview for Adult ADHD Study information: Design & Duration: single day single blind crossover trial No. n=10 (crossover) Dose: not relevant
Outcome measures: Atari Research Driving Simulator (composite impaired driving score (IDS))
243
Summary
Two systematic reviews addressed the impact of MPH on driving performance in adolescents and adults (559, 560). Five small RCTs were considered. Four of the five used a virtual reality driving simulator and one used on-road testing. MPH was found to improve driver performance on driving simulator tests in all studies. Further studies are needed to support these outcomes, especially with larger sample sizes. One of the studies on MPH included in the systematic reviews found that driving performance worsened later in the day when MPH-IR was used (559, 560). This contrasted with MPH-ER, where performance was improved at all driving test time points throughout the day. One small cross-over trial compared treatment with ATX to placebo in adults and reported improved self ratings of driving performance but not observer rating or test score in simulated driving exercises (561). One study was identified that considered the use of a manual transmission compared to an automatic transmission in adolescents. Improved driving performance was seen when using a manual transmission in simulated driving exercises (562).
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Australian Guidelines On Attention Deficit Hyperactivity Disorder

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Australian Guidelines On Attention Deficit Hyperactivity Disorder

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Australian Guidelines on Attention Deficit Hyperactivity Disorder (ADHD)

List of research questions

Literature review methods

Table 1. Search methods and databases

Table 3. Number of articles at each step for each question.

163 113 17 392 97 Q9-10 screened Q9-10 screened 533

131 97 12 363 82 289

Assessment and diagnosis

Individuals without ADHD

Diagnostic utility: predictive value and sensitivity & specificity

Search Period Language

MeSH: Attention deficit disorder with hyperactivity/

NHMRC I-IV for diagnostic studies 1997 - present considered

Recruitment: Clinic attendees and community

Children and adolescents

Recruitment: Patients referred from outpatient clinic

No. n=218 (controls n=35 ADHD n=183)

Recruitment: Clinic referrals consecutive sample

Fabiano et al 2006 (12) Design Diagnostic case-control

study Level III-3 Setting USA Industry funding

Considers 4 studies, only study 1 relevant and reported here.

Biederman et al 2008 (14)

Design Diagnostic crossclassification Level III-1 Quality Poor

Setting USA Industry funding Yes

GAF = 0.44 Correlation between 99-item CBS and SAS = 0.55

Retrospective recall of childhood ADHD symptoms

Informant ratings (professional or family)

Level of consensus between raters. Predictive value of selfreports.

Study Design Search Period Language Date of Search

NHMRC I-IV for diagnostic studies 1997 - present considered English

MeSH: Attention deficit disorder with hyperactivity/

Outcome Measures: Retrospective self-reports of ADHD symptoms at each followup.

Barkley et al 2002 (28)

Diagnostic tool Questionnaire based on DSM-IV criteria Reference test None

Duration: Single rating of retrospective perceptions

Parent and teacher reports

Study Design Search Period Language Date of Search

MeSH: Attention deficit disorder with hyperactivity/

Children and adolescents

Gomez et al 2007 (40)

Design Diagnostic crossclassification Level III-2 Setting Australia Industry funding No

Mitsis et al 2000 (41)

Design Diagnostic crossclassification Level III-2 Setting Not stated

Recruitment: Random community sample from eight primary schools

No. N = 213 (104 boys, 109 girls)

Study information: Design: Cross-classification Duration: Single rating

Recruitment: Sample of convenience (children with behavioural problems

Diagnostic tool ADHD-RS-IV (Parent and teacher rated)

Comparison Parent and teacher agreement

Comparison Parent and teacher agreement

Sherman et al 1997 (44)

Design Diagnostic crossclassification Level III-2

Setting USA Industry funding Funding source not stated

Parent and teacher agreement

Tripp et al 2006 (47)

Design Diagnostic case-control Level III-3

Recruitment: Children from an urban primary school system

Setting New Zealand Industry

Parent and teacher agreement

Study information: Design: Diagnostic yield Duration: single rating

Self and third-party reports

Adolescents and adults with ADHD assessed by self-report

Study Design Search Period Language