Psychiatry Research ()

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Psychiatry Research
journal homepage: www.elsevier.com/locate/psychres

Supplementary guanfacine hydrochloride as a treatment of attention

decit hyperactivity disorder in adults: A double blind, placebocontrolled study
Max E. Buttereld a,n, Jaime Saal b, Benjamin Young b, Joel L. Young b,c,d
a

Point Loma Nazarene University, 3900 Lomaland Drive, San Diego 92016, CA, USA
Rochester Center for Behavioral Medicine, 441 S Livernois Rd #205, Rochester Hills 48307, MI, USA
c
Wayne State University School of Medicine, 540 E Caneld St, Detroit 48201, MI, USA
d
William Beaumont Hospital, 3601 W. Thirteen Mile Road, Royal Oak 48073, MI, USA
b

art ic l e i nf o

a b s t r a c t

Article history:
Received 15 July 2015
Received in revised form
5 December 2015
Accepted 14 December 2015

The purpose of this study was to examine the efcacy of an extended release guanfacine hydrochloride
supplement relative to a placebo supplement in adults (1962) with ADHD and a sub-optimal response
to a stimulant-only treatment program. The study's primary outcome measures were the Attention
Decit Hyperactivity Disorder Rating Scale and the Clinical Global Impression Severity. Twenty-six
adults who met criteria for attention decit hyperactivity disorder and sub-optimal functioning were
randomly assigned to supplement their existing psychostimulant treatment regimen with either a titrated dose (16 mg) of extended release guanfacine hydrochloride or a matching placebo for a 10-week
trial. The data were analyzed with standard mixed model analysis of variance procedures, and participants in both the investigational agent group and the placebo group showed statistically signicant
improvement in their symptoms and functioning over the course of the trial. The treatments did not
differ in terms of their efcacy, safety, or tolerability. Although these results do suggest that both
treatments were associated with clinical improvement, the possible impacts of socially desirable responding and regression to the mean on these results are discussed.
& 2015 Elsevier Ireland Ltd. All rights reserved.

Keywords:
Attention decit hyperactivity disorder
Guanfacine hydrochloride
Placebo effect
Regression to the mean

1. Introduction
In recent years, adults with Attention Decit Hyperactivity
Disorder (ADHD) have begun to seek diagnostic consultation with
greater frequency, but there has only recently been widespread
interest in the developmental trajectories of patients with ADHD
(Wilens et al., 2002). Although evidence certainly suggests that
many children who have ADHD today will continue to need
treatment when they reach adulthood (Kessler et al., 2005), the
efcacy of treatment modalities across the lifespan is not yet fully
understood (Mannuzza et al., 1998; McGough and Barkley, 2004;
Murphy and Barkley, 1996). Today, the majority of FDA-approved

Abbreviations: ADHD, Attention Decit/Hyperactivity Disorder; ADHD RS, Attention Decit Hyperactivity Disorder Rating Scale; ASEX, Arizona Sexual Experience Questionnaire; CGII, Clinical Global Impression ScaleImprovement; CGIS,
Clinical Global Impression ScaleSeverity; C-SSRS, Columbia Suicide Severity Rating Scale; FSI, Fatigue Symptom Inventory; HAM A, Hamilton Anxiety Inventory;
HAM D, Hamilton Depression Rating Scale; RCBM, Rochester Center for Behavioral Medicine; PSQI, Pittsburgh Sleep Quality Index
n
Corresponding author.
E-mail address: mbutter@pointloma.edu (M.E. Buttereld).

pharmacological interventions for adults with ADHD are psychostimulant medications, but they can be sub-optimal treatments
for a non-trivial subset of the treatment population (Barkley, 2006;
Murphy and Gordon, 2006)
For children and adolescents, a safe and effective alternative to
stimulants involves combining non-stimulants with stimulants,
but it remains unclear whether adult populations could benet
from such regimen (Michelson et al., 2003). One combination that
has proven to be effective with children with ADHD is the addition
of extended release guanfacine hydrochloride (GH) to their existing psychostimulant regimen (Strange, 2008). GH is a selective
alpha-2A agonist that is currently FDA-approved as a supplementary therapy to stimulants for the treatment of ADHD) in
children and adolescents ages 617, but it has not been well researched as a treatment for ADHD in an adult population. The
purpose of this trial was to study GH as a supplementary therapy
to stimulants for the treatment of ADHD in adults age 18 and
above. Specically, the primary objective was to examine the efcacy of a GH supplement relative to a placebo supplement in
adults with ADHD who were experiencing sub-optimal response
to their current stimulant-only treatment program.
Half of participants in this present study were randomly

http://dx.doi.org/10.1016/j.psychres.2015.12.017
0165-1781/& 2015 Elsevier Ireland Ltd. All rights reserved.

Please cite this article as: Buttereld, M.E., et al., Supplementary guanfacine hydrochloride as a treatment of attention decit
hyperactivity disorder in adults: A double.... Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.12.017i

M.E. Buttereld et al. / Psychiatry Research ()

assigned to the GH condition, in which their existing stimulant

medication was paired with 1, 2, 3, 4, 5, or 6 mg of GH. The remaining participants were assigned to a placebo condition in which
their existing stimulant medication was paired with a placebo.
Participants' functioning was assessed pre-treatment, during treatment, and at the end of the study with two primary outcome
measures: the Attention Decit Hyperactivity Rating Scale (ADHD
RS) with adult prompts and the Clinical Global ImpressionSeverity
(CGIS). The ADHD RS was included because it is a well-validated,
widely-used assessment of ADHD symptoms (Zhang et al., 2005).
The CGI was included because it is a well-validated, widely-used
assessment of the impact of patients global functioning (Forkmann
et al., 2011; Guy, 2000). The secondary objective of this study was
conduct a safety and tolerability analysis using the Arizona Sexual
Experience Questionnaire, the Fatigue Symptom Index, the Pittsburgh Sleep Quality Index, the Hamilton Anxiety Inventory, the
Hamilton Depression Rating Scale, and standard physiological
measures of overall health (e.g., weight, blood pressure, etc.).
1.1. Hypotheses
It was hypothesized that participants in the GH group would
show lower ADHD RS and CGI S scores over time than would
those in the placebo group. It was also hypothesized that those in
the GH group would show no differences over time from those in
the placebo group on the safety and tolerability measures.

2. Methods
The study was conducted at the Rochester Center for Behavioral
Medicine (RCBM), a research and treatment center in suburban
Detroit, MI, USA. RCBM actively participates in clinical care and new
medication investigations. Clinical trials include multi-centered
national trials and single site, investigator-initiated studies. The
research unit is led by a board-certied psychiatrist and supported
by an experienced team of clinical coordinators. Study medications
were obtained from Shire's Investigator Sponsored Trial Operations
Ofce. The Western Institutional Review Board (WIRB) oversaw the
study and guided informed consent procedures.
2.1. Patient population
Study participants were recruited from local advertisements and
the clinic's existing patient population. Participants (N26) ranged
in age from 1962 (M 37.54, SD 12.22). Fourteen participants
were female, and 12 were male. Twenty-two (84.6%) were Caucasian, three (11.5%) were African-American, and one (3.8%) was listed
as other. A screening period of up to 30 days was used to determine the participants' eligibility to participate in the study and to
engage in the appropriate washout of any excluded medications.1
1
All investigational medications, tricyclic antidepressants, STRATTERAs, antipsychotics, neuroleptics, psychostimulants (other than entry dened use of VYVANSE, CONCERTAs, RITALIN, FOCALIN, and/or ADDERALL) were prohibited. These included sympathomimetics, appetite suppressants, modanil,
cough/cold preparations containing stimulants, other medications containing amphetamine, clonidine and guanfacine, monoamine oxidase inhibitors, anticonvulsant medications, any antibiotics with a CNS effect were prohibited. Any
herbal preparations that have CNS effect, affect cognitive performance, and/or affect BP, HR, or prolong QT/QTc interval were also prohibited. Medications known to
be CYP3A4/5 inducers or inhibitors that may interact with GH were prohibited. The
use of any new CYP3A4/5 inhibitors or inducers after Visit 1 was prohibited unless
use was planned for the duration of the study, and a stable dose had been established for at least 14 days prior to Visit 1. In those cases the treatment was to be
given concomitantly throughout the study, with no planned changes in use.

2.2. Inclusion criteria

All participants had a current ADHD diagnosis derived from the
diagnostic criteria for adult ADHD (inattentive, hyperactive/impulsive, or combined subtypes), as specied in the Diagnostic and
Statistical Manual of Mental Disorders, Fourth Edition Text Revision (APA, 2000). These criteria were assessed by psychiatric
intake and use of appropriate symptom checklists. Participants
were required to be on a current treatment regimen of stimulant
medications at the time of the screening interview, and all who
were selected had reported a lengthy pharmaceutical treatment
history for ADHD (years to decades). Their current primary ADHD
medications included Vyvanse (n 9, Mdose 56.67 mg), Adderall
XR (n 8, Mdose 31.88 mg), Adderall (n 6, Mdose 15.83 mg), Ritalin (n 2, Mdose 15 mg), and Concerta (n 1, Mdose 81 mg).
Each participant presented at Visit 1 with a sub-optimal response
to their treatment regimen. Sub-optimal response was dened by
the participant's dissatisfaction with his/her clinical progress, a
Visit 1 baseline score of greater than or equal to 28 using the
ADHD RS, or a CGI S score greater than or equal to 4 at Visits 1.
In addition to these hypothesis-specic inclusion criteria, more
general inclusion criteria were also specied. Participants, in the
opinion of the investigator, must have been able to understand
and comply with protocol requirements, including assessments,
prescribed dosage regimens, and discontinuation of concomitant
medications. Participants were able to provide written, personally
signed and dated informed consent to participate in the study in
accordance with the International Conference on Harmonisation,
Good Clinical Practice Guideline E6, and applicable regulations
before completing any study related procedures. They demonstrated a typical level of intellectual functioning without evidence
of signicant general intellectual decit, and they were able to
swallow intact tablets. Finally, women were required to have a
negative urine pregnancy test at Visit 1, and they agreed to use
medically accepted means of contraception during the study.
2.3. Exclusion criteria
Participants with severe comorbid psychiatric diagnoses (e.g.,
Axis I disorders such as mood disorders, anxiety disorders, posttraumatic stress disorder, obsessive compulsive disorder, etc.)
were excluded, as were participants with a history of psychosis,
pervasive developmental disorders, severe Axis II disorders or
severe substance dependence. The determination of participants'
comorbidities was made subjectively through clinical interview
and objectively through the Adult Self-Report Inventory-4. Participants were also excluded if they had a chronic or an acute
medical condition or illness that could have been negatively affected by the study medication. Those with a history of hypothyroidism, hypertension, or a resting systolic blood pressure
4140 mmHg or diastolic blood pressure 490 mmHg were ineligible. Participants who were directly afliated with the study
team, and those who were receiving treatment with an unregulated medication or had participated in a clinical trial within
30 days prior to screening, were also excluded. Individuals could
not participate if they weighed less than 30 kg or more than
120 kg at the time of informed consent.
2.4. Study design
This was a randomized, single-center, double-blind, placebocontrolled study. Participants were recruited within the Rochester
Center for Behavioral Medicine (RCBM) clinic and the Detroit
metropolitan area through outreach to professionals involved in
the treatment of adult ADHD, advertisements in local newspapers
and circulars, and internet social networking sites. At the

Please cite this article as: Buttereld, M.E., et al., Supplementary guanfacine hydrochloride as a treatment of attention decit
hyperactivity disorder in adults: A double.... Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.12.017i

M.E. Buttereld et al. / Psychiatry Research ()

screening visit potential participants were informed of the study

protocol and educated about the Informed Consent. Upon signing
the Informed Consent, psychiatric intake, medical history and inclusion and exclusion checklists were obtained. Vital signs and
urine pregnancy test (in females) were collected. Vitals signs at
screening included height, weight, supine and standing blood
pressure (three minutes between time at rest, supine, and standing BP measurements), heart rate, and oral temperature. The Arizona Sexual Experience Questionnaire (ASEX), the Fatigue
Symptom Inventory (FSI), the Pittsburgh Sleep Quality Index
(PSQI), the Hamilton Anxiety Inventory (HAM A), and the Hamilton Depression Rating Scale (HAM D) were all then
administered.
During Visit 2, eligible participants were randomly assigned
with randomization software to either the investigational product
or a matching placebo. The treatment assignments were unknown
by the principal investigator, the study coordinator, and by the
participants. Dosing began the morning following Visit 2. Participants returned to the study site on a weekly (and later, bi-weekly)
basis for evaluation of their ADHD symptoms and for possible side
effects. Table 1 shows the visit calendar.
2.5. Dosing
The investigational product was extended-release guanfacine
hydrochloride (GH), available in 1, 2, 3, or 4 mg tablets and
matching placebo. They were provided directly by the manufacturer to assist in studying blinding procedures. Dosing began
Table 1
Visit calendar.
Visit
Week

Procedure
Informed consent
Inclusion/exclusion checklist
Medical history/current conditions
Physical exam
Psychiatric Intake (including ASRI)
ADHD diagnosis verication
Record past/current medications
Vital signs/blood pressure
CGI S
CGI I
ADHD RS with adult prompts
FSI
PSQI
HAM A
HAM D
ASEX
Randomization
Medication dispensed
Medication accountability
AE recording
Discussion of aftercare plan
Follow-up off GH (in-ofce)
Urine Pregnancy Test
C-SSRS

















2
0

3
1

4
2

5
3

6
4

7
6

8
8

9
10
10 12










the morning following Visit 2, and all participants began the study
on 1 mg of GH or matching placebo. They were titrated to their
optimal dose based on their tolerance and response to the investigational product (Table 2). Fig. 1 depicts the doses of GH from
visits 28. Beginning in Visit 9, all participants completed a
2-week down titration prior to the nal in ofce follow up visit
(Table 3). Dosing was monitored for compliance from Visits 39,
and mean compliance ranged from 98% to 100% (SD 07%) during
that time period. Participants also continued their pre-existing
dose of stimulant medication, which remained stable throughout
the course of the study.
2.6. Assessments
2.6.1. Primary outcome measures
The primary outcomes measures were the Attention Decit
Hyperactivity Disorder Rating Scale (ADHD RS) and the Clinical
Global Impression Severity (CGI S). The ADHD RS is a widely
used measure of current ADHD symptoms (Zhang et al., 2005), and
the CGI is a widely used measure of clinical impressions (Forkmann et al., 2011; Guy, 2000). They were chosen because they are
both well-validated, simple assessments of ADHD and its impact
on patients' lives.
2.6.2. Secondary outcome measures: tolerability and safety
The secondary outcome measures were the ASEX, FSI, PSQI,
HAM A, and HAM D. Their purpose was to assess any possible
impact of the investigational agent on sexual functioning, fatigue,
sleep quality, anxiety, and mood. They were chosen because they
are well-validated, simple assessments. In addition, heart rate,
blood pressure and temperature were also measured and
compared.
2.7. Statistical procedures
Change in participants' levels of functioning on the primary and
secondary outcome measures over the course of the trial was assessed with two-tailed, parametric 2 (time)  2 (treatment group)


































































































Fig. 1.. GH Dosing in Visits 28.

Table 2
Dose titration schedule.
Visit
Week

2
0

3
1

GH Dose N/A 1 mg 1 mg or
2 mg

4
2

5
3

6
4

7
6

8
8

1 mg, 2 mg
or 3 mg

1 mg, 2 mg,
3 mg or 4 mg

1 mg, 2 mg, 3 mg, 4 mg or

5 mg (4 mg 1 mg)

1 mg, 2 mg, 3 mg, 4 mg, 5 mg

(4 mg 1 mg) or 6 mg
(4 mg 2 mg)

1 mg, 2 mg, 3 mg, 4 mg, 5 mg

(4 mg 1 mg) or 6 mg
(4 mg 2 mg)

Please cite this article as: Buttereld, M.E., et al., Supplementary guanfacine hydrochloride as a treatment of attention decit
hyperactivity disorder in adults: A double.... Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.12.017i

M.E. Buttereld et al. / Psychiatry Research ()

Table 3
Dose discontinuation schedule.

Table 5
The effect of GH vs. on tolerability.

Last GH Dose
Dispensed (mg)

Week 10,
Day 14 (mg)

Week 10,
Day 57 (mg)

Week 12,
Day 14 (mg)

Week 12,
Day 57 (mg)

1
2
3
4
5
6

0
1
2
3
4
5

0
0
1
2
3
3

0
0
0
1
1
1

0
0
0
0
0
0

Table 4
The effect of GH vs. placebo on clinical impression and ADHD symptoms.
Visit 1
M (SD)
CGI S

Visit 9
M (SD)

Visit 1
M (SD)

4.38

(0.51)

3.54

(0.78)

0.85

Placebo

4.46

(0.66)

3.46

(1.05)

1.00

Total

4.42

(0.58)

3.50

(0.91)

0.93

ADHD RS Guanfacine 35.92

(6.37)

24.08

(9.12)

11.85

Placebo

35.23

(6.60)

24.31

(10.94)

10.92

Total

35.58

(6.36)

24.19

(9.86)

11.39

[0.36,
1.33]
[0.57,
1.49]
[0.60,
1.25]

[7.24,
16.45]
[5.54,
16.30]
[8.10,
14.67]

mixed-model Analyses of Variance (ANOVA). Time was a repeated

measures-variable, and treatment group was a between-subjects
variable. This method for analysis was chosen because it allowed
for assessment of change from Visit 1 to Visit 9, as well as differences between treatment groups. A cut-off p-value of 0.05 was
used, and Cohen's d, a standard measure of effect size, was used to
compare the magnitude of the differences between groups and
across time.

3. Results
3.1. Primary outcome measures: ADHD RS and CGI S
Contrary to our central hypothesis, the analyses revealed no
main effect of treatment group and no time  group interaction for
either assessment, indicating that the between-subjects effect of
GH on these primary outcome measures was statistically indistinguishable from placebo over the course of the trial, Fs o1,
p 40.50. Collapsing across treatment groups, however, the repeated-measures component of the analysis demonstrated that
participants' scores improved signicantly from Visit 1 to Visit
9 on both the CGI S [F(1, 24)33.88, po 0.001, d 1.21] and the
ADHD RS [F(1, 24) 49.06, p o0.001, d 1.24] (Table 4).
3.2. Secondary outcome measures: hemodynamic assessments
The hemodynamic data were supine measures of pulse, systolic
blood pressure, and diastolic blood pressure. Because there were
three separate hemodynamic measures, the standard Bonferroni
correction for multiple comparisons (p/3) was used to adjust the
cut-off p value to 0.017. The data were analyzed with a 3 (time:
Visit 1 vs. Visit 9 vs. Visit 10)  2 (treatment group: placebo vs. GH)
mixed-model ANOVA. Visits 1, 9 and 10 were included in the
analysis to examine change in hemodynamic functioning both at

Improvement
[95% CI]

HAM A Guanfacine 12.85

Placebo
9.62
Total
11.23

(6.89)
(4.31)
(5.87)

9.23
5.15
7.19

(6.21)
(2.48)
(5.08)

3.62 [0.21, 7.02]

4.46 [1.49, 7.44]
4.04 [1.94, 6.14]

HAM D Guanfacine
Placebo
Total

8.62
6.69
7.65

(4.68)
(2.78)
(3.90)

5.31
2.46
3.88

(4.75)
(1.71)
(3.79)

3.31 [0.14, 6.48]

4.23 [1.93, 6.53]
3.77 [1.94, 6.14]

PSQI R

Guanfacine

9.38

(5.01)

6.69

(5.63)

Placebo

8.08

(3.66)

6.00

(3.22)

Total

8.73

(4.35)

6.35

(4.51)

2.69 [  1.24,
6.63]
2.08 [  0.01,
4.16]
2.39 [0.32,
4.45]

Improvement
[95% CI]

Guanfacine

Visit 9
M (SD)

FSI

ASEX

Guanfacine 46.54

(18.74)

45.85

(28.24)

Placebo

40.77

(25.28)

35.00

(26.46)

Total

43.65

(21.00)

40.42

(27.38)

Guanfacine

14.92

(3.86)

15.69

(4.63)

Placebo

15.69

(6.51)

14.38

(5.90)

Total

15.31

(5.26)

15.04

(5.23)

0.69 [  12.92,
14.30]
5.77 [  9.10,
20.64]
3.23 [  6.16,
3.96]
 0.77 [  2.21,
0.67]
1.31 [  1.91,
4.53]
0.27 [  1.42,
1.96]

the end of treatment (Visit 9) as well as post-titration (Visit 10).

The analysis revealed that pulse rates tended to increase over the
course of the trial, irrespective of treatment group (Visit 1:
M77.58, SD 12.23; Visit 2: M 79.96, SD 11.76; Visit 3:
M84.15, SD 12.33), [F(2, 48) 6.55, p .003]. No other signicant statistical differences were observed between treatment
groups, across time, or in the time treatment interaction effects
(ps 4.017). Taken together, these results suggest that participants
in both groups completed the trial with statistically indistinguishable pulse rates and blood pressure, and they showed similar changes in pulse rate and blood pressure over time.
3.3. Secondary outcome measures: tolerability and safety
Signicant adverse events were not encountered in this study,
and no participants discontinued the study due to them. The most
common treatment-emergent adverse events included: fatigue
(GH: 30.8%, placebo 61.5%) dry mouth (GH: 38.5%, placebo 23.1%),
irritability (GH: 15.4%, placebo 23.1%), headache (GH: 15.4%, placebo 23.1%), and increased appetite (GH: 7.7%, placebo 15.4%).
The analyses revealed no signicant main effects or interactions on the Arizona Sexual Experience Questionnaire or the Fatigue Symptom Index (Fs o2, ps o0.20). Participants in both
treatment groups did show statistically signicant improvement
from Visit 1 to Visit 9 on the Pittsburgh Sleep Quality Index [F(1,
24)5.45, p 0.028, d 0.54], Hamilton Anxiety Inventory [F(1,
24)15.137, p 0.001, d 0.74], and the Hamilton Depression
Rating Scale [F(1, 24)17.55, po 0.001, d 0.98] (Table 5).
Further probing revealed that the GH group did not differ from
the placebo group on sleep quality, and there was no time X
treatment agent interaction (Fs o1, ps 40.50). However, the GH
group did show signicantly more depression [F(1, 24) 4.34,
p 0.048, d 0.82] and marginally more anxiety [F(1, 24) 4.20,
p 0.052, d 0.80] than did the placebo group, but because there

Please cite this article as: Buttereld, M.E., et al., Supplementary guanfacine hydrochloride as a treatment of attention decit
hyperactivity disorder in adults: A double.... Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.12.017i

M.E. Buttereld et al. / Psychiatry Research ()

were again no time X treatment agent interactions (Fs o1,

ps 40.50), this appears to have been the result of pre-existing
differences between the groups that were not controlled by the
random assignment of participants to initial treatment groups.
Taken together, these secondary analyses conrm our secondary
hypothesis that GH shows levels of safety and tolerability that
were statistically similar to placebo over time.

4. Discussion
Somewhat contrary to our principal hypothesis, all participants
in this trial showed a statistically signicant level of clinical improvement in their ADHD symptoms and general functioning over
time, regardless whether GH or placebo was added to their existing treatment regimen. Although it may seem somewhat unusual that both groups showed considerable improvement in their
symptoms, there are several possible explanations. The rst is the
placebo effect. A variety of studies have demonstrated that placebos appear to have some impact on ADHD symptoms, but it has
been suggested that this could be due to the fact that participants'
(or caregivers and/or medical professionals) beliefs about their
treatment lead them to reinterpret ambiguous symptoms, causing
them to ignore or downplay symptoms that they previously found
troubling (Waschbusch et al., 2009). In addition, the participants
were aware they were participating in a clinical trial, and they may
have been motivated to be helpful to the researchers, thus further
downplaying their symptoms. Previous work in other elds (e.g.,
social psychology) has demonstrated that this type of socially
desirable responding is often noted in studies where participants
know they are being observed and are aware of the researchers'
general hypotheses (Crowne and Marlowe, 1960).
An additional reason that improvement may have been noted
in both treatment groups over time is because of the nature of
symptomology under investigation here. In particular, volunteers
for this study were individuals whose treatments were not optimally effective when the study began. There are a variety of reasons that psychostimulants might not be working optimally for a
given individual, but the severity of clinical disorders does tend to
vary considerably over time (Barnett et al., 2005). Often referred to
as regression to the mean (RTM), it has been proposed as one
possible reason (among many) that symptoms for clinical disorders have been known to vary across time in the same population (Yudkin and Stratton, 1996). To wit, the participants used here
were distressed enough by their poor response to their existing
treatment that they were willing take an experimental treatment
for their problems. It may therefore be reasonable to expect that
the natural progression of their condition could cause their
symptoms to return to a more typical level over time.
In terms of our secondary hypothesis, both GH and placebo
were also similar in their safety and tolerability over time. Interestingly, participants in the GH group even reported fewer treatment emergent adverse events (TEAE) due to fatigue than did
those in the placebo group, and no participants reported a TEAE
due to somnolence. Although such TEAEs are often found among
children and adolescents being treated with a GH and stimulant
regimen, it may be that GH, which is commonly used in adults to
treat hypertension, beneted participants' overall cardiovascular
health and thereby reduced their overall levels of fatigue. It did not
appear, however, that any reduction in fatigue or sleep problems
was due to treatment group, however, because no between-group
differences were observed on the FSI or PSQI. With that in mind,
though, future studies may wish to investigate these possibilities
further.

4.1. Limitations
This study does have a number of limitations that warrant
further discussion. First, the study was relatively small (N 26),
and it was conducted at only a single site. Future research should
be conducted at multiple sites and include greater numbers of
participants to assess whether increased statistical power would
change the pattern of change detected here. It is noteworthy,
however, that statistically signicant differences were observed
despite the small sample size. Another relatively important limitation was the make-up of the participant sample, which was
drawn from an existing patient population (and advertisements)
in one suburban location. The participants were largely Caucasian,
middle class, and motivated to attend treatment. Future research
on this topic should likely endeavor to include a larger sample size
and wider range of possible participants.
4.2. Conclusion
Taken together, the results of this study are both encouraging
and somewhat perplexing. On one hand, a very desirable outcome
was achieved: patients with a sub-optimal level of response to
their existing stimulant treatment regimen improved signicantly
over the course of the trial. On the other hand, this improvement
could not be denitively linked to GH or to placebo. It may be that
the additional clinical observation undergone by all participants
was enough to improve their symptoms, but it may also be that
the act of observation simply caused them to reinterpret their
symptoms or change the way they reported them. At the very
least, these results suggest that further research is necessary to
explore this phenomenon, and they do indicate that GH may be a
safe and tolerable supplement to an existing psychostimulant
treatment for adults with ADHD. Overall, however, ADHD remains
a high prevalence condition without a universal treatment, and the
present research demonstrates that further clinical investigations
continue to be necessary to help those struggling with ADHD to
achieve optimal functioning.

Conict of interest
Max E. Buttereld: none
Jaime Saal: none
Benjamin Young: none
Joel L. Young: Speaker's Bureau: Forest Laboratories, Otsuka,
Shire, Takeda/Lundbeck and Teva Grants/Research Support: Alcobra, Daiichi Sankyo, Eli Lilly and Company, Forest Laboratories,
Otsuka, Pzer, Shir, and Sunovion.

Study sponsorship: Shire

Employees of Shire did not design or conduct the study nor
were they involved in the interpretation of data.

Contributors
Max E. Buttereld served as the statistical analyst, trial design
consultant, and lead writer. He also prepared the manuscript for
publication.
Jaime Saal assisted with study design, protocol development,
and manuscript preparation
Benjamin Young assisted with data collection and trial
administration
Joel L. Young served as the principal and primary investigator

Please cite this article as: Buttereld, M.E., et al., Supplementary guanfacine hydrochloride as a treatment of attention decit
hyperactivity disorder in adults: A double.... Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.12.017i

M.E. Buttereld et al. / Psychiatry Research ()

of the clinical trial. He reviewed manuscript drafts and approved

the nal copy submitted for publication.

Clinical trials registry identier

NCT02141113.

Study name
A Double-Blind, Randomized, Placebo-Controlled, Single-Center, Dose Optimization Study Evaluating the Efcacy and Safety of
Guanfacine Hydrochloride in Combination with Psychostimulants
in Adults Aged 1865 Years with a Diagnosis of Attention-Decit/
Hyperactivity Disorder

Acknowledgments
We gratefully acknowledge the valuable contributions provided
by the clinical and research support staff at the Rochester Center
for Behavioral Medicine.

References
American Psychiatric Association, 2000. Diagnostic and Statistical Manual of
Mental Disorders: DSM-IV-TR. APA, Washington, DC.
Barkley, R.A., 2006. Attention Decit Hyperactivity Disorder: A Handbook for

Diagnosis and Treatment, 3rd ed. Guilford Press, New York.

Barnett, A.G., van der Pols, J.C., Dobson, A.J., 2005. Regression to the mean: what it
is and how to deal with it. Intern. J. Epidemiol. 34, 215220.
Crowne, D.P., Marlowe, D., 1960. A new scale of social desirability independent of
psychopathology. J. Consult. Psychol. 24, 349354.
Forkmann, T., Scherer, A., Boecker, M., Pawelzik, M., Jostes, R., Gauggel, S., 2011. The
clinical global impression scale and the inuence of patient or staff perspective
on outcome. BMC Psychiatry 11, 83.
Guy, W., 2000. Clinical Global Impressions Scale (CGI). In: Rush, A.J. (Ed.), Handbook
of Psychiatric Measures. American Psychiatric Association, Washington, DC,
pp. 100102.
Kessler, R.C., Berglund, P., Demler, O., Jin, R., Walters, E.E., 2005. Lifetime prevalence
and age-of-onset distribution of DSM-IV disorders in the national comorbidity
survey replication. Arch. Gen. Psychiatry 62, 593602.
Mannuzza, S., Klein, R., Bessler, A., Malloy, P., LaPadula, M., 1998. Adult psychiatric
status of hyperactive boys grown up. Am. J. Psychiatry 155, 493498.
McGough, J.J., Barkley, R.A., 2004. Diagnostic controversies in adult ADHD. Am. J.
Psychiatry 161, 19481956.
Murphy, K., Barkley, R.A., 1996. ADHD in adults: comorbidities and adaptive impairments. Compr. Psychiatry 37, 393401.
Murphy, K.R., Gordon, M., 2006. Assessment of adults with ADHD. In: Barkley, R.A.
(Ed.), Attention Decit Hyperactivity Disorder: A Handbook for Diagnosis and
Treatment, 3rd ed. Guilford Press, New York, pp. 425452.
Michelson, D., Adler, L., Spencer, T., Reimherr, F., West, S., Allen, A., et al., 2003.
Atomoxetine in adults with ADHD: two randomized, placebo-controlled studies. Biol. Psychiatry 53, 112120.
Strange, B.C., 2008. Once-daily treatment of ADHD with guanfacine: patient implications. Neuropsychiatr. Dis. Treat. 4 (3), 499506.
Waschbusch, D.A., Pelham, W.E., Waxmonsky, J., Johnston, C.J., 2009. Dev. Behav.
Pediatrics 30 (2), 158168.
Wilens, T.E., Biederman, J., Spencer, T.J., 2002. Attention decit/hyperactivity disorder across the lifespan. Ann. Rev. Med. 53, 113131.
Yudkin, P., Stratton, I., 1996. How to deal with regression to the mean in intervention studies. Lancet 347 (8996), 241.
Zhang, S., Faries, D.E., Vowles, M., Michelson, D., 2005. ADHD Rating Scale IV:
psychometric properties from a multinational study as a clinician-administered
instrument. Int. J. Methods Psychiatr. Res. 14, 186201.

Please cite this article as: Buttereld, M.E., et al., Supplementary guanfacine hydrochloride as a treatment of attention decit
hyperactivity disorder in adults: A double.... Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.12.017i