วารสารสมาคมจิตแพทย์แห่งประเทศไทย
Journal of the Psychiatrist Association of Thailand
ISSN: 0125-6985
บรรณาธิการ มาโนช หล่อตระกูล
Editor: Manote Lotrakul, M.D.

บทคัดย่อ

วัตถุประสงค์ เพื่อเปรียบเทียบความแตกต่างในด้านประสิทธิภาพและการยอมรับระหว่างยารักษาโรคจิตชนิดผิดพวกและยารักษาโรคจิตชนิดดั้งเดิม โดยทำการวิเคราะห์จากบทความที่ได้ตีพิมพ์ในวารสารทางวิชาการ, เป็นการศึกษาชนิดควบคุม และมีการสุ่มตัวอย่างในผู้ป่วยจิตเภทผู้ใหญ่

วิธีการศึกษา ผู้นิพนธ์ได้ค้นหาบทความที่เกี่ยวข้องกับการศึกษาชนิดควบคุมและมีการสุ่มตัวอย่างของยาolanzapine, risperidone และ quetiapine จาก MEDLINE โดยใช้วิธีการของ intention-to-treat และได้ค้นหาอัตราการตอบสนองและอัตราการออกจากการวิจัยในผู้ป่วยที่ได้รับการรักษาด้วยยารักษาโรคจิตชนิดผิดพวกเปรียบเทียบกับผู้ป่วยที่ได้ยารักษาโรคจิตชนิดดั้งเดิม

ผลการศึกษา พบว่ามี 15 รายงานที่เข้าเกณฑ์ในการวิเคราะห์ได้ประกอบด้วยการศึกษาในยา risperidone 10 เรื่อง, olanzapine 3 เรื่อง และ quetiapine 2 เรื่อง ในการเปรียบเทียบกับยารักษาโรคจิตชนิดดั้งเดิมขนาดของ effect sizes (95% confidence intervals) ของอัตราการตอบสนองและอัตราการออกจากการวิจัยของผู้ป่วยที่ได้รับยารักษาโรคจิตชนิดผิดพวกเท่ากับ 1.38 (1.05 ถึง 1.82) และ 0.70 (0.53 ถึง 0.92) ตามลำดับ

สรุป ยารักษาโรคจิตชนิดผิดพวกมีประสิทธิภาพสูงกว่าและได้รับการยอมรับมากกว่ายารักษาโรคจิตชนิดดั้งเดิม อย่างไรก็ตาม เนื่องจากยาเหล่านี้มีราคาแพง แพทย์จึงควรคำนึงถึงสภาพทั่วไปและความต้องการของผู้ป่วยก่อนที่จะสั่งใช้ยาดังกล่าว

วารสารสมาคมจิตแพทย์แห่งประเทศไทย 2542;44(2): 147-155.

คำสำคัญ olanzapine, quetiapine, risperidone, การทดลองชนิดควบคุมและสุ่มตัวอย่าง มหวิเคราะห์ ยารักษาโรคจิต

* ภาควิชาจิตเวชศาสตร์ คณะแพทยศาสตร์ มหาวิทยาลัยเชียงใหม่ อ. เมือง จ. เชียงใหม่ 50200

Efficacy and Acceptability of Atypical Antipsychotics

Manit Srisurapanont, M.D.*
Narong Maneeton, M.D.*

 Abstract

Objective To compare the differences of efficacy and acceptability between atypical and classical antipsychotics, we conducted a meta-analysis of published, randomized-controlled trials carried out in adult patients with schizophrenia.

Methods By using MEDLINE, we comprehensively searched papers relevant to randomized-controlled trials of olanzapine, risperidone, and quetiapine. In each study, the response and dropout rates of patients treated with an atypical antipsychotic and those treated with a classical antipsychotic were extracted on an intention-to-treat basis.

Results Fifteen studies included in this meta-analysis were 10 risperidone, 3 olanzapine, and 2 quetiapine trials. In comparison to classical antipsychotics, the response-rate effect size (95% CI) and the drop-out effect size (95% CI) of atypical antipsychotics were 1.38 (1.05 to 1.82) and 0.70 (0.53 to 0.92), respectively.

Conclusions Atypical antipsychotics are more effective and more acceptable than classical antipsychotics in treating schizophrenic patients. However, due to the high cost of drugs, physicians should take patients’ circumstances and wishes into account in prescribing atypical antipsychotics.

J Psychiatr Assoc Thailand 1999; 44(2): 147-155.

Key words : olanzapine, quetiapine, risperidone, randomized-controlled trial, meta-analysis, antipsychotic agents

* Department of Psychiatry, Chiang Mai University Faculty of Medicine, Amphur Muang, Chiang Mai, 50200 Thailand.

 Introduction

Antipsychotics are a group of drugs used for treating psychotic disorders.¹ The discovery of a classical antipsychotic called chlorpromazine in the 1950’s was instrumental in the treatment of schizophrenia. Due to its effectiveness, chlorpromazine has changed our clinical practice for treating schizophrenic patients. Instead of using only psychosocial treatment and institutionalization, classical antipsychotics have played an important role in treating schizophrenia.

After the discovery of chlorpromazine, the development of antipsychotics progressed slowly. The availability of other classical antipsychotics did not have much impact on our clinical practice. Pharmacodynamically, all of them block the postsynaptic dopamine type 2 receptors.^{2, 3} Clinically, most of them are equally effective for treating schizophrenic patients.⁴

Although the effectiveness of classical antipsychotics is well established, a few limitations are of concern. First, due to a variety of mechanism of actions conventional antipsychotic drugs cause several adverse effects such as extrapyramidal side effects, sedation, orthostatic hypotension, and antimuscarinic side effects. Second, at least 20%-30% of schizophrenic patients do not respond or only partially respond to conventional antipsychotic drugs. Last, although conventional antipsychotic drugs are effective for positive symptoms (e.g., delusions, hallucinations), they are only partially effective for negative symptoms (e.g. blunted affect, social withdrawal). Because of these limitations, several attempts have been made to develop a more effective and more acceptable antipsychotic.

Recently, several atypical antipsychotics are available such as clozapine, risperidone, olanzapine and quetiapine. These drugs have been defined as antipsychotic drugs with low propensity both to induce extrapyramidal side effects and to increase serum prolactin level.⁵ Pharmacodynamically, these antipsychotics block both 5-HT₂ and D₂ receptors. Clinically, they are more effective than classical antipsychotics in the relief of schizophrenic negative symptoms.

In clinical practice, some guidelines recommend both classical and atypical antipsychotics as first-line drugs for schizophrenia.^{6, 7} Due to several advantages of atypical antipsychotics and the recommendations, it is likely that physicians will increasingly prescribe these agents. In doing so, it is important for a clinician to know the clinical differences between atypical and classical antipsychotics.

To compare the differences of efficacy and acceptability between atypical and classical antipsychotics, we conducted a meta-analysis of published, randomized-controlled trials carried out in adult schizophrenic patients. The atypical antipsychotics included in the analysis were olanzapine, risperidone, and quetiapine. Clozapine was excluded because it has been used differently from others. While it is very effective for treating treatment-resistant schizophrenia, it also causes the serious side effect of drug-induced agranulocytosis.

Methods

We started performing MEDLINE search (from 1966 to October 1998) by using the following strategy: olanzapine or quetiapine or risperidone and schizophrenia. The search was then limited to randomized controlled trials only. Finally, we included only papers presenting the data relevant to the response and/or dropout rates of adult psychotic patients into the analysis. Owing to the failure of electronic searches to detect all relevant references, we also examined the reference lists of identified papers but found no other published paper relevant to this issue. Since multiple publications from a single study can lead to bias in several ways,⁸ we selected only one paper presenting the best details of each trial.

In each study, the response and dropout rates of patients treated with an atypical antipsychotic and those treated with a classical antipsychotic were extracted on an intention-to-treat basis. The number of patients randomized to each treatment group was considered as the total number of patients.

The data of all trials with a flexible dose design were included in the analysis. For trials where several fixed doses of atypical antipsychotic drugs were given, only the data from patients treated with recommended doses were included. The recommended doses were as follows: i) 5-15 mg/day of olanzapine, ii) 150-750 mg/day of quetiapine, and iii) 2-16 mg/day of risperidone.

The odds ratio with 95% confidence interval (CI) was computed for each rate comparison.^{9, 10} Since a fixed-effect model of pooling data is easy to interpret,¹¹ at first, the effect sizes with 95% CIs of pooled data comparing the response and dropout rates were calculated by using Peto’s method.¹² However, if the Chi-square tests showed significant heterogeneity between study results (p < 0.05), a random-effect model of odds ratio would be used as recommended by Egger et al.¹³

Regarding the interpretation, the response-rate effect size higher than 1 was considered to be in favor of atypical antipsychotics. The dropout-rate effect size lower than 1 was considered to be in favor of atypical antipsychotics.

Results

The MEDLINE search found 63 articles relevant to the randomized-controlled trials of atypical antispychotics. The fifteen studies included in this meta-analysis were 3 olanzapine trials,^14-16 10 risperidone,^17-26 and 2 quetiapine trials.^{27, 28} Beasley et al., did not present the exact numbers of responders or the respond rates.¹⁵ And Borison et al., did not present the exact numbers of dropouts or the dropout rates.¹⁷ The total numbers of patients given olanzapine, risperidone, or quetiapine were 3,562. One thousand four hundred and eighty-one patients were given classical antipsychotics. Apart from 62 patients in the study of Ceskova et al.,²⁰ all patients met the DSM-III-R diagnostic criteria for schizophrenia.²⁹ The study duration of all trials, except one,²⁶ was between 6 and 12 weeks. Table 1 shows the characteristics of each study.

(Please insert table 1 here)

By using a fixed-effect model of Peto’s method to compute the pooled response and dropout rates, the heterogeneity of study results were found (Chi-square = 31.37, df = 13, p = 0.003 and Chi-square = 36.97, df = 13, p = 0.0004, respectively). Therefore, a random-effect model of odds ratio was used to compute the pooled response and dropout rates.

Table 2 shows the response rates, the response-rate odds ratios (95% CIs), and the response-rate effect size (95% CI) computed by using a random-effect model. In comparison to classical antipsychotics, the response-rate effect size (95% CI) of atypical antipsychotics was 1.38 (1.05 to 1.82).

(Please insert table 2 here)

Table 3 shows the dropout rates, the dropout-rate odds ratios (95% CIs), and the dropout-rate effect size (95% CIs) computed by using a random-effect model. In comparison to classical antipsychotics, the dropout-rate effect size (95% CI) of atypical antipsychotics was 0.70 (0.53 to 0.92).

(Please insert table 3 here)

Discussion

Regarding the response-rate effect size, the lower end of 95% CI that was higher than 1 suggests significant superiority of atypical antipsychotics to classical antipsychotics. Regarding the dropout-rate effect size, the upper end of 95% CIs was lower than 1. This result suggests that atypical antipsychotics are significantly more acceptable than classical antipsychotics.

The more effectiveness and more acceptability of atypical antipsychotics should be considered as another major progress of the schizophrenic drug treatment. Support for using atypical antipsychotics as first-line drugs for schizophrenia is indicated by the cost-effectiveness,³⁰ and the effectiveness and acceptability of the drugs. However, other factors outside of the evidence should be used to make a clinical decision. As mentioned by Haynes & Haines, the patients’ circumstances and wishes should be taken into account in making any clinical decisions.³¹ In this case, the abilities of patients and their family to afford the high cost of drugs need serious consideration.

Some limitations should be considered in interpreting the results of this analysis. First, since the patients included in this meta-analysis are general adult schizophrenic patients, the results should not be generalized to schizophrenic patients with special characteristics, for example, treatment-resistant schizophrenia, and late-onset schizophrenia. Second, results were obtained from trials with a study duration of 4-12 weeks. Therefore, this meta-analysis does not determine the long-term outcomes of those three agents. As we have already mentioned, to avoid the problem of multiple publications from single studies, we excluded some results of a long-term study.³² This long-term study were carried out in patients who had participated in an included short-term study.¹⁴

In conclusion, atypical antipsychotics are more effective and more acceptable than classical antipsychotics in treating schizophrenic patients. However, due to the high cost of treatment, physicians should take patients’ circumstances and wishes into account in prescribing atypical antipsychotics.

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Table 1 Characteristics of the trials included in the meta-analysis of response and dropout rates between atypical antipsychotics and classical antipsychotics

^a H = haloperidol; M = methotrimeprazine; O = olanzapine; P = perphenazine; Q = quetiapine; R = risperidone; Z = zuclopenthixol.

^b BPRS = Brief Psychiatric Rating Scale; CGI = Clinical Global Impression Scale; PANSS = Positive and Negative Syndrome Scale for Schizophrenia.

^c The data of patients taking were not included in the analysis.

Table 2 The response rate, the response-rate odd ratio (95% CI) of each comparison, and the efficacy effect size (95% CI) of each pooled data computed by using a random-effect model.

^a H = haloperidol; O = olanzapine; P = perphenazine; Q = quetiapine; R = risperidone; Z = zuclopenthixol.

^b N/A = not available.

Table 3 The dropout rate, the dropout-rate odd ratio (95% CI) of each comparison, and the acceptability effect size (95% CI) of each pooled data computed by using a random-effect model.

^a H = haloperidol; O = olanzapine; P = perphenazine; Q = quetiapine; R = risperidone; Z = zuclopenthixol.

^b N/A = not available.