AMISULPRIDE VERSUS RISPERIDONE IN THE TREATMENT

AMISULPRIDE VERSUS RISPERIDONE IN THE TREATMENT OF SCHIZOPHRENIC PATIENTS: A DOUBLE-BLIND PILOT STUDY IN TAIWAN Tzung J. Hwang, 1 Shin-Min Lee, 2 Hsiao-Ju Sun, 3 Hsin-Nan Lin, 1 Shih-Jen Tsai, 4 Ying-Chiao Lee, 4 and Ying-Sheue Chen 4 Background and Purpose: The atypical antipsychotics, amisulpride and risperidone, have different receptor affinity characteristics. Although the relative efficacy of both drugs compared to conventional antipsychotics is well established, it remains unclear how the efficacy of amisulpride compares with risperidone. There have been no controlled studies comparing amisulpride to risperidone in Asian patients. The purpose of this study was to compare the efficacy and safety of amisulpride with that of risperidone in Taiwanese schizophrenic patients. Methods: Patients with productive positive symptoms (n = 48) were enrolled into this double-blind, randomized pilot study for 6 weeks. Patients received either amisulpride (400 800 mg/day) or risperidone (4 8 mg/day). Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression (CGI), Social and Occupational Functioning Assessment Scale (SOFAS), and patients subjective responses to treatment were assessed during the trial period. Adverse events were recorded at each follow-up visit. Results: At the end of the trial, the mean dosage was 630 ± 134 mg/day and 6.88 ± 1.54 mg/day for amisulpride and risperidone, respectively. There was no significant difference in the reduction of the PANSS total score (amisulpride -24.1 versus risperidone -28.4, p = 0.999), the PANSS positive subscale score (amisulpride -6.8 versus risperidone -8.3, p = 0.467), the PANSS negative subscale score (amisulpride -5.6 versus risperidone -6.4, p = 0.999), or the CGI score between the two groups. The extrapyramidal symptom ratings, the improvement in the SOFAS (amisulpride 11.1 versus risperidone 10.0) and the subjective response (amisulpride 82% versus risperidone 83%) were comparable. No serious adverse events were recorded in either treatment group. There was a statistically significant body weight gain in the risperidone group. In contrast, there was a statistically, though not clinically, significant reduction of blood pressure and heart rate in the amisulpride group. Conclusions: This study suggests that amisulpride is as effective as risperidone in the treatment of patients with schizophrenia. Both drugs were well tolerated, but had different side effect profiles. Key words: Amisulpride; Risperidone; Schizophrenia; Double-blind study; Antipsychotic agents J Formos Med Assoc 2003;102:30-6 Amisulpride is a unique substituted benzamide with selective affinity to D 2 and D 3 receptors. Animal studies have shown that at low dose it blocks presynaptic dopamine autoreceptors and enhances dopamine release, whereas at high dose, it preferentially blocks postsynaptic dopaminergic receptors in the limbic region as compared to those of the striatum. 1,2 These findings are consistent with results of human clinical trials. Compared with conventional antipsychotics, amisulpride (400 to 800 mg/day) has been shown to have comparable efficacy for the treatment of positive symptoms, 3,4 better efficacy for the treatment of negative symptoms, and less propensity to induce extrapyramidal symptoms (EPS). 5,6 At lower dose (50 to 300 mg/day), amisulpride was shown to improve predominantly negative symptoms in patients with schizophrenia. 7 9 Thus, it bears the clinical features of so-called atypical antipsychotics, but with its own specific mechanism involving mainly dopaminergic receptors. Risperidone, a widely used atypical antipsychotic, is an antagonist at both dopaminergic D 2 and serotonergic 5HT 2 receptors. Compared with conventional antipsychotics, it has been shown to be equally effective in the treatment of positive symptoms, 10 12 1 Department of Psychiatry, National Taiwan University Hospital, Taipei; 2 Department of General Psychiatry, Pali Psychiatric Center, Taipei county; 3 Department of Psychiatry, Taoyuan Psychiatric Center, Taoyuan county; 4 Department of Psychiatry, Veterans General Hospital-Taipei, Taipei, Taiwan. Received: 6 June 2002 Revised: 7 July 2002 Accepted: 1 October 2002 Reprint requests and correspondence to: Dr. Ying-Sheue Chen, Department of Psychiatry, Veterans General Hospital- Taipei, No. 201, Shih-Pai Road, Sec. 2, Taipei 11217, Taiwan. 30 J Formos Med Assoc 2003 Vol 102 No 1

Amisulpride Versus Risperidone in Schizophrenia more effective in the treatment of negative symptoms, 13 and less likely to induce EPS in patients with schizophrenia. 11,12 Although the efficacy of both amisulpride and risperidone has already been compared to conventional antipsychotics, it remains unclear how amisulpride compares with risperidone. To our knowledge, there has been only one study directly comparing amisulpride and risperidone, 14 and no such studies have been done in Asian patients with schizophrenia. The purpose of this study was to compare amisulpride to risperidone to evaluate their efficacy and safety in patients with schizophrenia in Taiwan. Methods Study design The study was designed as a double-blind, randomized, multicenter study comparing the efficacy and safety of amisulpride versus risperidone in schizophrenic patients. Patients were observed for a placebo run-in (washout) period of 3 to 6 days to evaluate their enrollment eligibility, and then were randomly allocated to receive either amisulpride or risperidone for 6 weeks. The study protocol was approved by the Joint Institutional Review Board, Taiwan. Patients Patients were recruited from 4 centers in northern Taiwan. The enrollment criteria required patients to be 18 65 years old and to fulfill DSM IV 15 criteria for schizophrenia, with productive symptom [scoring 4 or above for at least 2 of the 7 positive symptoms in the Positive and Negative Symptom Scale (PANSS) and with a PANSS total score between 60 and 120] at the screening visit and day 0 (i.e. the day when patients took the first dose of trial drugs). Patients having the following conditions were excluded from the study: 1) history of allergy or hypersensitivity to risperidone, benzamides, procyclidine, or benzodiazepines; 2) significant neurological diseases such as stroke, Parkinson s disease or epilepsy; 3) significant organic brain syndrome; 4) history of severe medical diseases such as cardiovascular, respiratory, renal or liver disease; 5) pregnancy, lactation, or intention to become pregnant; 6) recent abuse of psychoactive drugs or alcohol; and 7) placebo responders, i.e. patients whose PANSS positive scores reduced by 40% or more during the placebo run-in period. Written informed consent was obtained from every patient prior to entry into the trial after explanation of the procedure and possible side effects. Efficacy, EPS, and other evaluations Efficacy and safety evaluations were done on days 0, 7, 14, 21, 28, and 42. The primary efficacy measure was the total score of the PANSS, which was assessed using a Chinese version of the PANSS (the PANSS- CH) with demonstrated reliability. 16 The secondary efficacy measures were: the subscale scores of the PANSS, the PANSS-derived BPRS (Brief Psychiatric Rating Scale) total scores, and the Clinical Global Impression (CGI) scores. 17 Other efficacy measures included the Social and Occupational Functioning Assessment Scale (SOFAS), 15 and a scale assessing patients subjective responses to treatment. EPS were evaluated with the Extrapyramidal Syndrome Rating Scale (ESRS). 18 All investigators participated in a oneday video training session of the rating procedures before the study started. The inter-rater reliability on PANSS was satisfactory (0.7 1.0 for all items) after training. Study procedures At least 6 days prior to day 0, patients were assessed and screened by participating psychiatrists for eligibility according to the above-mentioned criteria. Medical history was taken, and physical and laboratory examinations were done, including hematology, blood chemistry, urinalysis, and electrocardiography (ECG). PANSS, PANSS-derived BPRS, and CGI scale ratings were evaluated. A patient s spontaneous complaints were recorded. Eligible patients were then admitted and entered a placebo run-in (washout) period for 3 to 6 days. Those receiving a depot injection were required to have a minimal washout period equivalent to the previous injection interval. After washout, on day 0, patients were randomly assigned to receive amisulpride (400 800 mg/day) or risperidone (4 8 mg/day) for 6 weeks. Risperidone doses were titrated from 1 mg/day to 4 mg/day during the first 6 days to avoid acute adverse effects, while amisulpride remained at 400 mg/day. Subsequently, both drugs were titrated according to clinical response at the discretion of the investigators. In accordance with the double-blind nature of the study, both drugs were provided in identical sealed capsules. Psychopathology (PANSS, BPRS, CGI), ESRS, and physical examination were assessed, and patient s spontaneous complaints or clinical findings of adverse events were recorded on days 0, 7, 14, 21, 28, and 42. Adverse events were coded by the WHO-Adverse Reaction Terminology (WHO-ART) coding system and were tabulated by body system. Blood and urine examinations were performed on days 14 and 42. A follow-up ECG was performed on day 42. The SOFAS was used to evaluate the individual s level of social and occupational functioning on day 0 and day 42 J Formos Med Assoc 2003 Vol 102 No 1 31

Table 1. Demographic and baseline characteristics of the intent-to-treat population. Amisulpride (n = 22) Risperidone (n = 25) p value Male/female 9 /13 11 /14 0.832 Age [yr, mean (SD)] 36.3 (9.2) 34.1 (9.9) 0.366 Schizophrenia subtype, no. (%) 0.349 Paranoid 11 (50.0) 11 (44.0) Disorganized 5(22.7) 4 (16.0) Undifferentiated 6(27.3) 10 (40.0) Duration of illness [yr, mean (SD)] 13.3 (8.4) 13.4 (8.6) 0.923 Body weight [kg, mean (SD)] 64.6 (14.4) 63.9 (13.2) 0.695 (or at the time of premature withdrawal). Patients subjective responses were also assessed at day 7 and day 42, using a semi-structured interview by asking How does the medication agree with you? ; Did it make you feel calmer? ; Did it affect your thinking? ; and Do you think this would be the right medication for you?. Responses were rated on a seven-point (-3 to +3) euphoric/dysphoric scale. Concomitant medications were restricted unless clinically necessary. Statistical analysis The main analysis was carried out on the intent-totreat population using the Last Observation Carried Forward (LOCF) technique. Because of the limited sample size, non-parametric analyses were used. The main analysis was a Friedman two-way analysis of variance (treatment group and center) for between group analyses in efficacy parameters (PANSS, BPRS, CGI, SOFAS, subjective response) and safety parameters (ESRS, vital signs, body weight). Wilcoxon signed rank test was applied for within group analyses. Ordinal qualitative variables were examined using Cochran-Mantel-Haenszel test (with ridit transformation of the variables), with adjustment for center effect. Statistical significance was declared if the two-sided p value was less than 0.05. All statistical analyses were performed using SAS statistical software. Results From October 01, 1999 to June 30, 2000, a total of 48 patients with schizophrenia were enrolled. There were 23 and 25 patients in the amisulpride and risperidone groups, respectively. One patient in the amisulpride group had multiple somatic complaints during the placebo run-in phase and withdrew himself from the trial at day 6; the patient was excluded for efficacy data analyses due to lack of any efficacy measure after active medication. Of the remaining 47 patients, two in the amisulpride group failed to complete the entire 6-week trial. In one this was due to adverse events; the other was found not to meet the washout criteria of abstinence for antipsychotic medication injection after inclusion. Demographic data of the two groups in the intentto-treat population are summarized in Table 1. There were no significant differences in baseline characteristics between the two groups. In the amisulpride group, the mean dose was unchanged after day 28 (630 ± 150 mg/day at day 28 and 630 ± 134 mg/day at day 42), while the mean dose was increased slightly after day 28 (6.56 ± 1.58 mg/day at day 28 and 6.88 ± 1.54 mg/day at day 42) in the risperidone group. Efficacy The PANSS total score and three subscores over the 6-week trial are shown in Table 2. At the end of the trial, there were significant changes in both groups, but no significant differences between the two groups in the PANSS total scores and the three subscores. The proportions of patients with more than 20% score reduction in the PANSS total scores were calculated, and no significant difference between the two groups was observed (68% with amisulpride versus 76% with risperidone, p = 0.745). Changes in the BPRS total scores and the CGI score are also shown in Table 2. Similarly, there were significant changes within each group, but no statistical differences between these two groups. When the categories of very much improved and much improved were grouped as a single responder category, there were no significant differences in the number and percentage of responders between the amisulpride and risperidone groups (41% versus 60%, respectively, p = 0.196). There was no significant difference in the scores of SOFAS between the two groups at the end of the trial (Table 2). The assessments of patients subjective response were also comparable. Approximately 75% of all patients expressed a positive subjective response to treatment after day 7. At day 42, 82% and 83% of patients expressed good subjective response in the amisulpride and risperidone groups, respectively. Safety During the trial period, no serious adverse events were recorded based on patients spontaneous 32 J Formos Med Assoc 2003 Vol 102 No 1

Table 2. Changes in PANSS, BPRS, CGI, and SOFAS scores of the intent-to-treat population. Amisulpride Versus Risperidone in Schizophrenia Amisulpride (n = 22) Risperidone (n = 25) p value Mean SD Mean SD PANSS Total score Day 0 93.1 11.5 89.9 14.1 Day 42 minus Day 0-24.1 17.2-28.4 18.8 0.999 PANSS positive subscale Day 0 23.6 3.3 23.8 3.6 Day 42 minus Day 0-6.8 6.0-8.3 6.1 0.467 PANSS negative subscale Day 0 24.5 5.8 22.6 6.2 Day 42 minus Day 0-5.6 4.5-6.4 4.8 0.999 PANSS general psychopathology Day 0 45.0 6.0 43.5 7.4 Day 42 minus Day 0-11.6 9.4-13.7 10.0 0.626 BPRS Day 0 52.5 5.9 51.1 7.9 Day 42 minus Day 0-14.9 10.7-17.7 11.5 0.922 CGI Day 0 4.7 0.6 4.6 0.7 Day 42 minus Day 0-1.1 1.2-1.1 1.0 0.975 SOFAS Day 0 36.2 8.3 38.8 9.9 Day 42 minus Day 0 11.1 13.9 10.0 14.5 0.214 PANSS = Positive and Negative Syndrome Scale; BPRS = Brief Psychiatric Rating Scale; CGI = Clinical Global Impression severity of illness; SOFAS = Social and Occupational Functioning Assessment Scale. reports or investigators examinations. The overall incidence of treatment-related adverse events was 65.2% (15/23) and 64.0% (16/25) for patients in the amisulpride and risperidone groups, respectively, and the difference was not statistically significant (p = 0.931). When the incidence of each adverse event was compared, none was shown to be significantly different between the 2 groups. The adverse events recorded in more than 5% of patients are listed in Table 3. The most frequent adverse events were insomnia (17.3%) and constipation (17.3%) in the amisulpride group, and akathisia (16%), tremo (12%), and constipation (12%) in the risperidone group. At the end of the trial, there were no significant between-group or within-group changes in the global assessment of parkinsonism, tardive dyskinesia, or total scores of BAS, except that the risperidone group had a significant within-group reduction in the global assessment of parkinsonism (day 0: 1.4 ± 1.0, day 42: 0.9 ± 0.8, p < 0.05). The number of patients using antiparkinsonian drugs, β-blockers, anxiolytics, and hypnotics was 7 (30.4%), 1 (4.3%), 6 (26.1%), and 16 (70%), respectively, in the amisulpride group; and 11 (44%), 4 (16%), 12 (48%), and 19 (76%), respectively, in the risperidone group. There were borderline to significant differences between the two groups in the use of antiparkinsonian drugs, β-blockers, and anxiolytics (Fisher s exact test: p = 0.06, 0.008, and 0.002, respectively). Regarding the vital signs, there were no significant differences between the 2 groups at the end of the trial (Table 4). The amisulpride group had significant within-group reduction (p < 0.01), while the risperidone group had borderline reduction (p < 0.07), in both supine systolic blood pressure (SBP) and diastolic blood pressure (DBP). The amisulpride group had significant within-group reduction (p < 0.04), while the risperidone group had a non-significant increase in supine heart rate (HR) [Table 4]. These changes in vital signs were judged as clinically insignificant. Mean body weight in the risperidone group was significantly increased at the end of the trial (Table 4), but there were no significant differences in this variable between the 2 groups. Three cases with normal baseline ECG had abnormal but clinically insignificant changes at the end of the study. Two cases were in the amisulpride Table 3. Treatment-emergent adverse events occurring in at least 5% of patients. Adverse event Amisulpride Risperidone n % n % Akathisia 2 8.6 4 16 Muscle rigidity 0 0 2 8 Tremor 2 8.6 3 12 Dizziness 0 0 2 8 Agitation 2 8.6 0 0 Insomnia 4 17.3 2 8 Constipation 4 17.3 3 12 SGPT increase 2 8.6 0 0 Palpitation 0 0 2 8 Headache 1 4.3 2 8 SGPT = serum glutamic pyruvic transaminase J Formos Med Assoc 2003 Vol 102 No 1 33

Table 4. Changes in vital signs and body weight measurement of the intent-to-treat population. group (non-specific ST-T changes and left ventricular hypertrophy criteria), and one in the risperidone group (sinus tachycardia). There were no cases with prolonged QTc (QTc > 500 ms) at the end of the trial in either group. Blood and urine examinations showed that there were no clinically significant changes in either group, and no patient was withdrawn from the study due to laboratory abnormalities. Discussion This double-blind pilot study showed that there were no significant differences in efficacy between amisulpride and risperidone in schizophrenic patients. Both drugs were effective in the treatment of positive and negative symptoms of schizophrenia, and all subjective responses and functional outcomes indicated that the drugs were comparable. The result is consistent with a previous report with a direct comparison design, 14 and other indirect comparison studies. 3,4,12,19 There was an initial significant decline in the total scores of the PANSS, BPRS, and CGI at Day 7 in both groups, and the decline continued till the end of the trial. However, it is interesting to note that the mean dose did not change after Day 28 in the amisulpride group, while there was mild dose escalation in the risperidone group. This implies that amisulpride 630 mg/day was clinically equivalent to risperidone 6.56 6.88 mg/day in the 6-week trial. This estimate is close to that in the fixed-dose design of the study by Peuskens et al, in which amisulpride 800 mg/day was equivalent to risperidone 8 mg/day. 14 The finding is also consistent with a previous report that amisulpride 400 800 mg/day is the most efficacious dose in the treatment of schizophrenia. 4 Previous studies showed a trend in favor of greater improvement in negative symptoms in the PANSS negative scale in patients receiving amisulpride, 6,14 but we did not find such a trend in this study. Possible relevant factors included differences in comparison Amisulpride (n = 22) Risperidone (n = 25) p value Mean SD Mean SD Systolic blood pressure Day 0 112.4 14.3 113.8 14.7 Day 42 minus Day 0-7.6* 13.2-5.9 16.4 0.613 Heart rate Day 0 80.9 12.9 78.8 11.0 Day 42 minus Day 0-6.1* 14.5 1.7 13.1 0.898 Body weight Day 0 63.8 14.2 63.6 13.4 Day 42 minus Day 0 0.1 3.3 1.6* 2.8 0.209 *p < 0.05 for the within-group comparison between day 0 and day 42; p values for the changes between groups at day 42. doses and concomitant medications, and a smaller sample size in our study. In the study of Peuskens et al, the dosages were relatively high (800 mg/day of amisulpride and 8 mg/day of risperidone), and the percentage of concomitant antiparkinsonian drugs was 30% in the amisulpride group and 23% in the risperidone group. In our study, the dosages were moderate, and the percentage of concomitant antiparkinsonian drugs in the amisulpride group (30%) was significantly lower than in the risperidone group (44%). Both drugs were well tolerated in this trial. There were no severe adverse events, a relatively low incidence of adverse events, and only rare withdrawal from the trial due to adverse events. Scores on different dimensions of EPS also did not increase significantly during the trial, indicating that neither amisulpride nor risperidone induced marked EPS at these dose ranges. This is consistent with previous experiences with these drugs. 6,20 There was a significant reduction in the rating of parkinsonism in the risperidone group at the end of the trial, which might be related to the dose employed, concomitant medications or the small sample size. In this trial, the risperidone group had significant body weight gain at the end of the study, which is commonly associated with the use of risperidone, 21,22 but not amisulpride. 5,22 There was no QTc prolongation or arrythmogenic effect for either drug, which is consistent with recent reviews. 23,24 Theoretically, amisulpride has a low autonomic neurocardiac risk due to its action at dopamine D 2 and D 3 receptors rather than at cholinergic or adrenergic receptors. 25,26 However, albeit judged to be clinically insignificant, there were statistically significant reductions of supine SBP, DBP and HR in the amisulpride group at the end of the trial. A large pooled analysis on safety profiles of amisulpride 27 showed that a trend towards a decrease in HR (defined as sitting or supine HR 50 beats/min and a decrease versus baseline 15 beats/min) occurred in 1% of amisulpride recipients, and a trend towards decreased 34 J Formos Med Assoc 2003 Vol 102 No 1

Amisulpride Versus Risperidone in Schizophrenia blood pressure (sitting or supine SBP 90 mm Hg and a decrease versus baseline of 20 mm Hg, or any sitting or supine DBP of 50 mm Hg and a decrease versus baseline of 15 mm Hg) in 7% of amisulpride recipients, 7% of risperidone recipients, 4% of haloperidol recipients, and 4% of placebo recipients. Therefore, our findings may be explained by the small sample size. But these cardiovascular findings in this group of relatively young patients deserve attention because they may imply a possible difference in racial response. Suspected evidence for racial differences was found in the required doses for antiparkinsonian drugs. In the European study by Peuskens et al, 14 antiparkinsonian medications were initiated in 30% of patients taking amisulpride 800 mg/day and 23% taking risperidone 8 mg/day. In our study, antiparkinsonian medications were initiated in 30% of patients taking amisulpride (mean dose 630 mg/day) and 44% taking risperidone (mean dose 6.88 mg/day). In both trials, antiparkinsonian medications were not to be initiated unless antipsychotic-induced extrapyramidal symptoms emerged. While receiving a lower mean dose of antipsychotics, the patients in our study showed greater need for antiparkinsonian medications, regardless of which antipsychotic agent they received. These findings suggest that there are racial differences in response to the atypical antipsychotics. This observation is supported by other studies which show that, although the condition is rare among Caucasians, as many as 20% of Chinese and Japanese are poor metabolizers via the cytochrome P450 enzymes. 28 Compared with Caucasian individuals, Chinese have been found to have 30% to 50% higher plasma levels of clozapine 29 and 10% to 50% higher levels of haloperidol. 30 Therefore, our results and some reports 31,32 suggest that caution should be used with atypical antipsychotic agents in view of the potential for racial and individual differences in drug response. Further large-scale studies with blood level measurement need to be done in order to produce more definitive conclusions regarding the clinical implications of these variations in atypical antipsychotic drug disposition. At present, vital signs should be monitored when amisulpride is prescribed, especially in the elderly. There are several limitations in this study. The sample size is not large enough for definitive conclusions to be reached based on this trial, and the trial duration is too short to evaluate long-term effects of the drugs. The absence of a placebo control group limits the findings regarding efficacy and safety, although inclusion of a placebo study arm was precluded because of ethical considerations. The value of the study is that it provides a direct comparison of atypical antipsychotics in an Asian population. Such studies are under-represented in the literature. ACKNOWLEDGMENTS: The project was supported by funding from the Fujisawa Taiwan and a grant NTUH 90s1004 to Dr. Hwang. We wish to thank the participating psychiatrists from the collaborative hospitals for data collection, and Dr. G. Bartzokis for advice on the paper. References 1. 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