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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.

“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: 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.

• 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:
• 14–30 years old; recruited @ Zikei Hospital, Okayama, Japan.

• 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 .

• Mood disorders. • Pervasive developmental disorders.Subjects Exclusion criteria • • • • No consent was obtained. IQ under 70. Neurological disorder and drug dependence. • 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. Pregnancy. .

and 12 weeks of treatment. Dosages) • Supportive psychotherapy • Occupational therapy FES • SGAs* • Anticholinergic (min. If treatment was ended before 12 weeks.Treatments UHR • • • • SGAs* Antidepressants* Benzodiazepines* Anticholinergic (min. an evaluation was performed at the end point. Dosages) • Supportive psychotherapy • Occupational therapy  Clinical evaluation: after 4. Dosages) • Supportive psychotherapy • Occupational therapy MES • SGAs* • Anticholinergic (min. 8. * Note: Main Agent .

MEDICAL ETHICS . For patients who were minors. Approved by the medical ethics committee of Zikei Hospital. the consent of one or more guardians was also obtained.Informed consent was obtained from each patient.

• Mann–Whitney U test – Differences in the doses of antipsychotic drugs at individual time points within groups.05 was considered to be significant in all analyses. • Friedman test – Differences in data over time within groups.Statistical Analysis • χ2 and Fisher’s exact test – Differences in ratios among the three groups. • Steel–Dwass test – Comparison among the three groups at each time. . – P < 0. • Kruskal–Wallis test – Differences among the three groups at each time.

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

Results .


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


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

S UHR patients clearly had significantly better early improvement compared with patients with schizophrenia .CGI .

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 .

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

based on the GAF and CGI-S .• 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.

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 .

including preventive prescription before appearance of EPSs.Anti cholinergic agents were permitted in the study. 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. and FGAs may increase the incidence of EPSs in UHRs patients. 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).

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. .• Based on age.

quetiapine. such as histamine or α1 receptor . and aripiprazole frequently caused somnolence as an adverse event. Fatigue A meta-analysis showed that risperidone. All SGAs have some inhibitory effects on receptors relate to sedation. olanzapine.Other adverse events : a. Somnolence b.

McGlashan et al found a significant improvement in those treated with olanzapine from 8 weeks and a faster response to olanzapine compared to placebo. 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. the short-term advantage of SGAs in UHR patients is clear . • Similarly. Thus.• In a double-blind comparative study of olanzapine and placebo in UHR patients.

. However. the efficacy and safety of SGAs for false positive cases remains uncertain.Antipsychotics are appropriate for use if immediate improvement is needed.

.Conclusion The studies showed that UHR patients had higher sensitivity and a faster response to a lower dose of SGAs. We suggest that SGAs can be safely prescribed to UHR patients with extremely mild positive symptoms but with serious acting out. compared to patients with FES or MES. 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 .

Kurashiki. Kawasaki Medical Graduate School. Okayama. Zikei Hospital. Japan. Japan.Journal identity Journal ID PICO • The study come from : Department of Psychiatry.  Medical Staff: – Kenji Washida – Toshihiko Takeda – Toshiaki Habara – Soichiro Sato – Takuro Oka – Masuo Tanaka – Yusaku Yoshimura – Shozo Aoki Valid Important Acceptable .

on June 18th 2013 • Available at: http://dx.S45697 Valid Important Acceptable ./10. Neuropsychiatric Disease & Treatment Section.Journal ID PICO • Published by Dove Medical

• 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 • There’s 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) .

Japan from December 1st.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. 2006 to December 1st. Okayama. FES. Valid Acceptable • INTERVENTION – Treatment by using SGAs as the main agent for UHR. . 2011. and MES.

Acceptable . the safety of using SGAs in patient with UHR and those with FES or MES in 12 weeks.PICO • COMPARATION – The speed of response. Valid • OUTCOME – The UHR group have a better and safely response to SGAs in minimal dosage compare to patient with schizophrenia.

analyzed? Whether patients and physicians remain blind in doing therapy. apart from the therapy being tested? Valid YES YES NO NO 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.

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. YES Profitable . because there is no previous studies.

CONCLUSION • Clinical study is valid 1 2 • Clinical study is applicable .


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