Psychopharmacology (2011) 216:475–484 DOI 10.1007/s00213-011-2242-3
ORIGINAL INVESTIGATION
Effectiveness of maintenance treatments with atypical and typical antipsychotics in stable schizophrenia with early stage: 1-year naturalistic study Xiaofeng Guo & Maosheng Fang & Jinguo Zhai & Bo Wang & Chuanyue Wang & Bin Hu & Xueli Sun & Luxian Lv & Zheng Lu & Cui Ma & Tiansheng Guo & Shiping Xie & Elizabeth W. Twamley & Hua Jin & Jingping Zhao
Received: 16 November 2010 / Accepted: 18 February 2011 / Published online: 3 March 2011 # Springer-Verlag 2011
Abstract Rationale The relative effectiveness of the atypical antipsychotic drugs and conventional agents in patients with early-stage schizophrenia has not been comprehensively determined. Objectives The aim of our study was to evaluate the efficacy and safety of seven antipsychotic drugs for the maintenance treatment in patients with early-stage schizophrenia.
Methods In a 12-month open-label, prospective observational, multicenter study, 1,133 subjects with schizophrenia or schizophreniform disorder within 5 years of onset were monotherapy with chlorpromazine, sulpiride, clozapine, risperidone, olanzapine, quetiapine, or aripiprazole. The primary measure was the rate of treatment discontinuation for any reason. Secondary outcomes included measures for clinical and functional outcomes and tolerability.
Clinical Trials.gov Identifier: NCT00654576 Guo and Fang contributed equally to the study. X. Guo : M. Fang : J. Zhai : J. Zhao (*) Institute of Mental Health, the Second Xiangya Hospital, Central South University, 139 Renmin Middle Road, Changsha 410011 Hunan, People’s Republic of China e-mail:
[email protected] M. Fang Mental Health Center, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China B. Wang Chongqing Mental Health Center, Chongqing, China C. Wang Beijing Anding Hospital Affiliated to Capital Medical University, Beijing, China B. Hu Psychiatric Hospital of Jiangxi Province, Nanchang, China X. Sun Mental Health Center of West China Hospital, Sichuan University, Chengdu, China
L. Lv Mental Hospital of Henan Province, Xinxiang, China Z. Lu Shanghai Mental Health Center, Shanghai, China C. Ma Guangzhou Brain Hospital, Guangzhou, China T. Guo Hunan Brain Hospital, Changsha, China S. Xie Nanjing Brain Hospital, Nanjing Medical University, Nanjing, China E. W. Twamley : H. Jin Department of Psychiatry, University of California, San Diego, USA
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Results The percentage of patients discontinued treatment within 12 months was 41.4% for chlorpromazine, 39.5% for sulpiride, 36.7% for clozapine, 40.2% for risperidone, 39.6% for olanzapine, 46.9% for quetiapine, and 40.2% for aripiprazole, a nonsignificant difference (p=0.717); there were no significant differences among these seven treatments on discontinuation due to relapse, intolerability, patient decision, or nonadherence (all p values≥0.260). Extrapyramidal symptoms were more prominent in chlorpromazine and sulpiride treatment groups. Anticholinergic side effects were most common with clozapine and chlorpromazine. Weight gain was most common with olanzapine and clozapine. Conclusions The efficacy of seven antipsychotic medications for the maintenance treatment appeared similar in early-stage schizophrenia. With regard to the high dropout rate and side effects, special programs are needed to keep efficacy and safety of antipsychotics maintenance treatment for schizophrenia with early stage Keywords Antipsychotic . Schizophrenia . Safety
Introduction Treatment of schizophrenia usually involves the long-term administration of antipsychotic drugs. However, long-term therapy with antipsychotics is generally associated with the lack of efficacy, poor patient compliance, and a range of adverse effects including acute extrapyramidal symptoms, tardive dyskinesia, weight gain, and sedation. These adverse effects can interfere with long-term adherence to maintenance drug therapy (Lieberman et al. 2003a). Atypical antipsychotic drugs have been proven lower risk of extrapyramidal symptoms, but higher risk of metabolic adverse events (Marder et al. 2003;Leucht et al. 2009a, b). The effectiveness of long-term therapy with typical and atypical antipsychotics in schizophrenia is not well understood, but some recent studies had sought to provide objective evidence in real-world settings. One study comparing haloperidol and risperidone in stable outpatients found advantages in preventing relapse for risperidone (Csernansky et al. 2002). The Schizophrenia Outpatient Health Outcomes study shows that patients on clozapine and olanzapine have a lower risk of relapse and patients on olanzapine have a higher chance of remission than typical antipsychotics (Haro et al. 2006). Results of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) have been found no differences in drug discontinuation rates between typical and atypical drug in chronic schizophrenia patients (Lieberman et al. 2005). Comparison of atypicals in first episode of psychosis found atypical antipsychotics (quetiapine, risperidone, and olanzapine) had equal effectiveness in first episode schizophrenia
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(McEvoy et al. 2007). The new result of European FirstEpisode Schizophrenia Trial showed all atypical antipsychotics better than haloperidol in loss of retention on drug (Kahn et al. 2008). Schizophrenic patients require long-term antipsychotic maintenance treatment, but studies of maintenance treatment with antipsychotic drugs in the early stage of stable schizophrenia are scarce, especially some typical antipsychotics (e.g., chlorpromazine and sulpiride) and clozapine used widely in developing countries(Si et al. 2004; Mao et al. 2007). Patients with early-stage schizophrenia are likely to be more sensitive to drugs than are those with chronic ones. Moreover, trials of drugs in chronic patients were usually conducted in highly selected samples, so findings have no external validity. We undertook an open-label, prospective observational, multicenter study to determine if any of seven antipsychotics (chlorpromazine hydrochloride, sulpiride, clozapine, risperidone, olanzapine, quetiapine fumarate, and aripiprazole) maintenance treatment was more effective in stable outpatients with schizophrenia or schizophreniform disorder, and whether atypical antipsychotics had an advantage over typical antipsychotics. We selected these antipsychotics because over 90% of schizophrenia patients in China were prescribed one of these antipsychotics (Si et al. 2004).
Methods Participants The study was conducted between January 2005 and October 2007 at ten clinical sites in China (six university clinics and four province mental health agencies). Study participants were enrolled from outpatient psychiatric clinics and included in the study if they met the following criteria: (1) were age 16–50 years; (2) met the Diagnostic and Statistical Manual, Fourth Edition (DSM-IV) criteria for schizophrenia or schizophreniform disorder within the past five years, as assessed with the Structured Clinical Interview for DSM-IV, Research Version; (3) lived with family members who could be involved in the patients’ care; (4) had relatively stable improvement (Positive and Negative Syndrome Scale (PANSS) (Kay et al. 1987) total scores were≤60); (5) treated with only one of the following seven oral antipsychotics: chlorpromazine, sulpiride, clozapine, risperidone, olanzapine, quetiapine, or aripiprazole for at least 8 weeks, provided that the dose had remained stable during the 4 weeks before screening. Patients were excluded if they were: (1) prescribed two or more antipsychotics or long-acting injectable antipsychotics; (2) had treatment-refractory illness according to Kane’s criteria (Kane et al. 1988), as evidenced by continued psychosis
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despite two previous trials of conventional neuroleptics at dosages of at least 1,000 mg of chlorpromazine equivalents a day for at least 6 weeks; (3) pregnant or breastfeeding; (4) diagnosed with a serious and unstable medical condition; or (5)participating in other therapy programs. Study design This was a 12-month open-label, naturalistic, flexible-dose, multicenter study of antipsychotic medications used for treatment of early course of schizophrenia. Patients initiated or switched to one of study antipsychotic drugs before screening were potential candidates for the study. If patients entered a stabilization period and met our study criteria, they were invited to participate in this 12-month maintenance treatment study. The study was approved by the institutional review board at each site, and a written informed consent was obtained from the patients and their legal guardians. Interventions Since all patients were on maintenance treatment, we encouraged clinicians to try to keep patients on the same medication for 3 to 6 months in order to gauge treatment efficacy and minimize early discontinuation. However, medications could be changed at any time during the course of the study if the change was clinically warranted. If a patient’s medication was stopped or switched, patients were classified as discontinued and terminated from the study. No further assessments were required for these patients. During the 12-month follow-up study, the daily doses of antipsychotics was set: chlorpromazine hydrochloride 200 to 800 mg, sulpiride 200 to 1,200 mg, clozapine 100 to 450 mg, risperidone 1.5 to 6 mg, olanzapine 5 to 20 mg, quetiapine fumarate 200 to 750 mg, and aripiprazole 5 to 30 mg. Mood stabilizers, benzodiazepines, antidepressants, and anticholinergic medications were permitted, and daily doses of all medications were recorded throughout the study. Outcome measures All subjects were assessed monthly by the study psychiatrists and every 2 weeks by a research assistant who had instructions to contact the psychiatrist if medication discontinuation, relapse or other problems were suspected. The primary outcome measure was rate of treatment discontinuation or change and time to treatment discontinuation. Our criteria for treatment discontinuation or change were somewhat broader than those of the CATIE study (Lieberman et al. 2005) and included: (1) clinical relapse/ hospital admission, (2) patient’s refusal or lost to follow-up,
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(3) noncompliance or changing initial antipsychotic, and (4) intolerability. When investigators recorded more than one reason for discontinuation, we ranked the reasons: clinical relapse/hospital admission, intolerability, noncompliance or changing initial antipsychotic, and other reasons. Clinical relapse was defined by any one of the following (Csernansky et al. 2002): (1) psychiatric hospitalization, (2) an increase in the level of psychiatric care (e.g., from clinic visits to day treatment) and a 25% or more increase in the PANSS total score (or 10 points if the initial score was 40 or less), (3) a Clinical Global Impressions (CGI) Scale score of “much worse” or “very much worse” (Guy 1976a), (4) deliberate self-injury, (5) emergence of clinically significant suicidal or homicidal ideation, or (6) violent behavior resulting in significant injury to another person or significant property damage. Secondary outcomes further assessed treatment effectiveness by measuring symptom severity (PANSS) and CGI, insight (Insight and Treatment Attitudes Questionnaire (ITAQ) McEvoy et al. 1989), treatment adherence (appointment compliance), and social function on the Global Assessment Scale (GAS) Guy 1976b; Endicott et al. 1976).The physical examination and the effect of antipsychotic treatment on weight gain were recorded regularly. The tolerability and adverse events was assessed by Treatment Emergent Symptom Scale (Guy 1976c) and the Simpson–Angus Extrapyramidal Signs Scale (Simpson and Angus 1970). Data collected at baseline and after 3, 6, 9, and 12 months of study participation, as well as the treatment discontinuation. All interviewers trained and received reassessments of inter-rater reliability based on videotaped demonstration interviews. Agreement among the raters was high for the PANSS, CGI (Pearson’s correlation coefficient=0.78 to 0.86) at baseline, and every 6 months. Statistical analyses All analyses were conducted with the Statistical Package for Social Sciences, version 15.0 (SPSS Inc, Chicago, Illinois). Assuming a treatment discontinuation rate at 12-month follow-up, of 50% in patients receiving firstgeneration antipsychotic drugs and 40% in patients receiving second-generation antipsychotic drugs, 136 patients per treatment group were needed, on the basis of a two-tailed test with α=5% and 1-β=80%. Therefore, we planned to enroll 150 patients per group. The seven treatment regimens were compared at baseline for continuous parameters with a six degree of freedom analysis of variance (ANOVA) test. Groups were compared for baseline categorical outcomes with Pearson’s Chi-square (χ2) test, Kruskal–Wallis H test, or Fisher’s exact test.
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The primary outcome measure was analyzed using Pearson’s χ2 test and Kaplan–Meier survival analysis (comparing the treatment groups with a log-rank test), considering all eligible patients. The continuous (secondary) outcome measures used the intention-to-treat population included all eligible patients with at least one follow-up test. Missing data of patients discontinuing were replaced by the last-observation carriedforward. Changes within groups were analyzed using Within-sample t tests (paired t tests). Treatment regimens were compared for change from baseline for PANSS, CGIS, ITAQ, and GAS total scores at 12 months using an analysis of covariance (ANCOVA) with adjustment for the baseline value. Other categorical outcomes were compared with the use of Pearson’s χ2 test or Fisher’s exact test. Partitions of χ2 methods were performed comparing the data between each treatment group if overall χ2 p value were more than 0.05. We adjusted the alpha levels in the following way, α*=α/[k(k-1)/2+1]=0.05/[7*(7–1)/2+1]= 0.0023, according to Brunden (Brunden 1972) and Bortz (Bortz et al. 1990).
Results
The mean age of eligible subjects was 26.1 years (SD, 7.7), 45.6% were female, and most patients had a diagnosis of schizophrenia (85.0%; Table 1). There were no significant differences among treatment groups in age, sex, education, marital status, diagnostic composition, number of episodes, duration of illness, psychopathology scores, or duration of study drug treatment before screening (all p values≥0.059). Differences in socioeconomic status among groups was found (p
