Efficacy of second-generation antipsychotics in patients at ultra-high risk and those with first-episode or multiepisode schizophrenia

Supervisor : dr Sabar P Siregar, Sp KJ

Neuropsychiatric Disease and Treatment 2013 Washida et al, publisher and license Dove Medical Press Ltd.

Introduction
Patients will have a better prognosis with a shorter period from the onset of illness to intervention and early detection before disease progression may have a good influence on the prognosis.

Second-generation antipsychotics are effective for preventing or delaying progression to psychosis

Their use is restricted as first-line pharmacotherapy

AIM

Aim: to examine the speed of response, doses, and safety of treatment with secondgeneration antipsychotics (SGAs) in patients at ultra-high risk (UHR) compared to those with schizophrenia.

Methods
A 12-week open-label, prospective study of SGAs was performed in Ultra-High Risk (UHR) patients and those with first-episode schizophrenia (FES) and multi-episode schizophrenia (MES).

The subjects:
1430 years old; recruited @ Zikei Hospital, Okayama, Japan.

Observed:
December 1st, 2006 - December 1st, 2011.

The clinical rating scales:

Global Assessment of Functioning (GAF) Positive and Negative Syndrome Scale (PANSS) Clinical Global Impression-Severity scale (CGI-S).

Subjects
Schizophrenia

First-episode schizophrenia (FES) Multi-episode schizophrenia (MES)

Ultra-High Risk (UHR)

Attenuated positive symptom state Brief intermittent psychotic state Genetic risk and deterioration state

Subjects
Exclusion criteria No consent was obtained; Pregnancy; IQ under 70; Neurological disorder and drug dependence; Mood disorders; Pervasive developmental disorders; Personality disorders Patients with UHR and FES had not been prescribed any other antipsychotics for more than 2 weeks before the start of the study.

Treatments
UHR SGAs* Antidepressants* Benzodiazepines* Anticholinergic (min. Dosages) Supportive psychotherapy Occupational therapy FES SGAs* Anticholinergic (min. Dosages) Supportive psychotherapy Occupational therapy MES SGAs* Anticholinergic (min. Dosages) Supportive psychotherapy Occupational therapy

Clinical evaluation: after 4, 8, and 12 weeks of treatment. If treatment was ended before 12 weeks, an evaluation was performed at the end point. * Note: Main Agent

Informed consent was obtained from each patient.

Approved by the medical ethics committee of Zikei Hospital.

For patients who were minors, the consent of one or more guardians was also obtained.

MEDICAL ETHICS

Statistical Analysis
2 and Fishers exact test
Differences in ratios among the three groups.

Friedman test
Differences in data over time within groups.

KruskalWallis test
Differences among the three groups at each time.

SteelDwass test
Comparison among the three groups at each time.

MannWhitney U test
Differences in the doses of antipsychotic drugs at individual time points within groups. P < 0.05 was considered to be significant in all analyses.

BASELINE CHARACTERISTICS
A total of 72 patients (48 subjects were inpatients) were registered at Zikei Hospital, but only 61 (UHR = 17, FES = 23, MES = 21) were included as subjects because only cases treated with an antipsychotic drug as the main agent were eligible for this study.

Results

GAF

GAF score improved significantly in the UHR, FES, and MES groups after 12 weeks GAF score were higher in UHR at 4 weeks after initiation of therapy . The lowest improvement after therapy was in MES group

PANSS

Significant improvements in all three groups Highest improvement shown in UHR group compared to the FES and MES group

CGI - S

UHR patients clearly had significantly better early improvement compared with patients with schizophrenia

Dose of SGA
The modal doses in the UHR group required for improvement was significantly lower than that in two other groups MES group received the highest doses among three groups.

Switching of SGAs and Adverse Events

70% in the FES 44% in the UHR

70% in the MES

The rates for switching due to poor efficacy

67% in the UHR

70% in the MES

The rates for switching due to adverse events

50% in the FES

 Each group was prescribed anticholinergic agents the FES group had a significantly higher frequency of EPSs compared with the other two groups.
Adverse events other than EPSs included somnolence and fatigue in all three groups.

Discussion
We examined
UHR response doses safety SGA

Schizophrenia

UHR patients showed significantly faster and greater improvement compared to those with FES and MES
CAARMS UHR patients are defined as those with mild symptoms of schizophrenia

 The CGI-S is a rating scale that can be used after evaluation with GAF and PANSS. The CGI-S result showed that UHR patients had already reached a good level after 4 weeks with greater improvement at this time point compared with the other two groups

Thus, this is the first study to show faster improvement of functions and global impressions in UHR patients compared to those with FES and MES after treatment with SGAs, based on the GAF and CGI-S

SGAs as the main agent in this study

UHR

FES & MES

Minimun recommended dose

Within the limits of the recommended doses

Result = UHR patients have a faster response to lower doses of SGAs compared to patients with schizophrenia

Switching of SGAs was performed at a rate of almost 50% in all patients

UHR Adverse events = 67% Poor response = 44%

FES and MES Adverse events = Poor response =

good response of UHR patients to SGAs

both a poor response and adverse events led to switching in the FES and MES groups

Anti cholinergic agents were permitted in the study, including preventive prescription before appearance of EPSs.

UHR group showed the most improvement of functions and global impressions and the lowest incidence of EPSs

SGAs can be administered safely in UHR patients by proper choice of the dosage and use of anti cholinergic agents

EPSs occured in one subject (6%) in th UHR group during the 12week study period.

if UHR patients are prescribed SGAs at higher doses that necessary to improve symptoms safety can be compromised and adverse event may reach level observed in the FES group.

SGAs caused less EPSs compared than first-generation antipsychotics (FGAs), and FGAs may increase the incidence of EPSs in UHRs patients.

 Based on age, MES group tended to be higher than in the FES higher.

The slightly higher age in the MES group may cause the slow improvement of functions and global impressions.

Other adverse events : a. Somnolence b. Fatigue

A meta-analysis showed that risperidone, quetiapine, olanzapine, and aripiprazole frequently caused somnolence as an adverse event.

All SGAs have some inhibitory effects on receptors relate to sedation, such as histamine or 1 receptor

 In a double-blind comparative study of olanzapine and placebo in UHR patients, McGlashan et al found a significant improvement in those treated with olanzapine from 8 weeks and a faster response to olanzapine compared to placebo.

Similarly, SGAs have been shown to be significantly more effective than placebo in comparative studies in UHR patients from 8 to 12 weeks of treatment, with no difference in safety.

Thus, the short-term advantage of SGAs in UHR patients is clear

Antipsychotics are appropriate for use if immediate improvement is needed.

However, the efficacy and safety of SGAs for false positive cases remains uncertain.

Conclusion

The studies showed that UHR patients had higher sensitivity and a faster response to a lower dose of SGAs, compared to patients with FES or MES.

We suggest that SGAs can be safely prescribed to UHR patients with extremely mild positive symptoms but with serious acting out.

The efficacy and safety of SGAs in these patients was shown by giving minimizing dose and using anticholinergic drugs.

Journal ID PICO Valid Important

Acceptabl e

CRITICAL APPRAISAL

Journal identity

Journal ID
PICO

The study come from : Department of Psychiatry, Kawasaki Medical Graduate School, Kurashiki, Japan; Zikei Hospital, Okayama, Japan. Medical Staff: Kenji Washida Toshihiko Takeda Toshiaki Habara Soichiro Sato Takuro Oka Masuo Tanaka Yusaku Yoshimura Shozo Aoki

Valid Important Acceptable

Journal ID
PICO

Published by Dove Medical Press, Neuropsychiatric Disease & Treatment Section, on June 18th 2013 Available at: http://dx.doi.org./10.2147/NDT.S45697

Valid Important Acceptable

 Titles

Journal ID
PICO

Efficacy of second-generation antipsychotics in patients at ultra-high risk and those with firstepisode or multi-episode schizophrenia Positive:
Clearly shows that variables that were investigated Bold written There is no abbreviation

Valid Important

Negative:
No location No time Without a capital letter at the beginning of the word More than 12 words (20 words)

Acceptable

Journal ID
PICO

Consist of 5 sections Aim Methods Results Conclusion Keywords > 250 words

Valid Important Acceptable

Journal ID
PICO

Positive:
Participant of study is clear, followed by the inclusion and exclusion criteria Analysis tools mentioned clearly Measurable outcomes are clear Technique sampling is randomized
Valid Important Acceptable

Negative:
None

Journal ID
PICO

Positive Tables are presented in accordance with the international journal writing format (without the vertical and horizontal lines in a) with no serial number and table title and description of the contents of the table - Negative :

Valid Important

Theres no explanation about what type of drug that used to switched to SGA

Acceptable

Journal ID
PICO

Positive There are advantages of the mentioned research results that have been achieved There is an emphasis if the results of the research will be applied There are suggestions for future research

Valid Important Acceptable

Negative : There was no significant indicator to measure the response of therapy (should be using three indicators)

PICO ANALYSIS
POPULATION

PICO

Patient aged 14 30 years olds who were UHR group, first-episode schizophrenia (FES) and multi-episode schizophrenia (MES) who visited Zikei Hospital, Okayama, Japan from December 1st, 2006 to December 1st, 2011.

Valid Acceptable

INTERVENTION
Treatment by using SGAs as the main agent for UHR, FES, and MES.

PICO
COMPARATION
The speed of response, the safety of using SGAs in patient with UHR and those with FES or MES in 12 weeks.
Valid

OUTCOME
The UHR group have a better and safely response to SGAs in minimal dosage compare to patient with schizophrenia.

Acceptable

VALID EVIDENCE
QUESTIONS Is the allocation of patients in the study randomized?
Is patient observation done quite long and complete? Are all patients in the randomized, analyzed? Whether patients and physicians remain blind in doing therapy, apart from the therapy being tested?

Valid

YES
YES NO NO
Acceptable

APPLICABILITY OF TEST
QUESTIONS Is there a difference in our patients when compared with that found in previous studies so that the results can not be applied to our patients? Whether such therapy may be applied to our patients? Does the patient have a potential beneficial or detrimental treatment or when the program implemented?

Accept able

NO, because there is no previous studies.

YES Profitable

CONCLUSION
Clinical study is valid
1

Clinical study is applicable

Prodromal or Ultra-High Risk (UHR) States

Attenuated positive symptom state: Non-psychotic, pre-delusional unusual thought content; prehallucinatory perceptual abnormalities; or subthreshold disorganization of speech. Brief intermittent psychotic state: Psychotic symptoms emerging in the recent past that are too brief to meet criteria for psychotic disorder. Symptoms present at least several minutes per day at least once per month. Genetic risk and deterioration state: Genetic risk for psychosis (first degree relative with any psychotic disorder, affective or nonaffective; and/or patient has schizotypal personality disorder) plus a loss of social or work capacity, or both, in past month.