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 Chen4 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 negative symptoms, and less propensity to induce with selective affinity to D and D receptors. Animal extrapyramidal symptoms (EPS).5,6 At lower dose studies have shown that at low dose it blocks pre- (50 to 300 mg/day), amisulpride was shown to synaptic dopamine autoreceptors and enhances improve predominantly negative symptoms in patients dopamine release, whereas at high dose, it prefer- with schizophrenia.7–9 Thus, it bears the clinical entially blocks postsynaptic dopaminergic receptors features of so-called “atypical antipsychotics”, but with in the limbic region as compared to those of the its own specific mechanism involving mainly dopa- striatum.1,2 These findings are consistent with results Risperidone, a widely used atypical antipsychotic, Compared with conventional antipsychotics, is an antagonist at both dopaminergic D and sero- amisulpride (400 to 800 mg/day) has been shown to tonergic 5HT receptors. Compared with conventional have comparable efficacy for the treatment of positive antipsychotics, it has been shown to be equally symptoms,3,4 better efficacy for the treatment of effective in the treatment of positive symptoms,10–12 1Department of Psychiatry, National Taiwan University Hospital, Taipei; 2Department of General Psychiatry, Pali PsychiatricCenter, Taipei county; 3Department of Psychiatry, Taoyuan Psychiatric Center, Taoyuan county; 4Department of Psychiatry,Veterans General Hospital-Taipei, Taipei, Taiwan.
Received: 6 June 2002 Revised: 7 July 2002 Accepted: 1 October 2002Reprint 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.
J Formos Med Assoc 2003 • Vol 102 • No 1 Amisulpride Versus Risperidone in Schizophrenia more effective in the treatment of negative symp- Efficacy, EPS, and other evaluations
toms,13 and less likely to induce EPS in patients with Efficacy and safety evaluations were done on days 0, 7, 14, 21, 28, and 42. The primary efficacy measure Although the efficacy of both amisulpride and was the total score of the PANSS, which was assessed risperidone has already been compared to con- using a Chinese version of the PANSS (the PANSS- ventional antipsychotics, it remains unclear how CH) with demonstrated reliability.16 The secondary amisulpride compares with risperidone. To our know- efficacy measures were: the subscale scores of the ledge, there has been only one study directly compar- PANSS, the PANSS-derived BPRS (Brief Psychiatric ing amisulpride and risperidone,14 and no such studies Rating Scale) total scores, and the Clinical Global have been done in Asian patients with schizophrenia.
Impression (CGI) scores.17 Other efficacy measures The purpose of this study was to compare amisulpride included the Social and Occupational Functioning to risperidone to evaluate their efficacy and safety in Assessment Scale (SOFAS),15 and a scale assessing patients with schizophrenia in Taiwan.
patients’ subjective responses to treatment. EPS wereevaluated with the Extrapyramidal Syndrome Rating Scale (ESRS).18 All investigators participated in a one- day video training session of the rating proceduresbefore the study started. The inter-rater reliability Study design
on PANSS was satisfactory (0.7–1.0 for all items) The study was designed as a double-blind, random- ized, multicenter study comparing the efficacy andsafety of amisulpride versus risperidone in schizo- Study procedures
phrenic patients. Patients were observed for a placebo At least 6 days prior to day 0, patients were assessed run-in (washout) period of 3 to 6 days to evaluate and screened by participating psychiatrists for their enrollment eligibility, and then were random- eligibility according to the above-mentioned criteria.
ly allocated to receive either amisulpride or Medical history was taken, and physical and laboratory risperidone for 6 weeks. The study protocol was examinations were done, including hematology, approved by the Joint Institutional Review Board, blood chemistry, urinalysis, and electrocardiography (ECG). PANSS, PANSS-derived BPRS, and CGIscale ratings were evaluated. A patient’s spontaneous Patients
complaints were recorded. Eligible patients were then Patients were recruited from 4 centers in northern admitted and entered a placebo run-in (washout) Taiwan. The enrollment criteria required patients period for 3 to 6 days. Those receiving a depot to be 18–65 years old and to fulfill DSM IV15 criteria injection were required to have a minimal washout for schizophrenia, with productive symptom [scoring period equivalent to the previous injection interval.
4 or above for at least 2 of the 7 positive symptoms in After washout, on day 0, patients were randomly the Positive and Negative Symptom Scale (PANSS) assigned to receive amisulpride (400–800 mg/day) or and with a PANSS total score between 60 and 120] at risperidone (4–8 mg/day) for 6 weeks. Risperidone the screening visit and day 0 (i.e. the day when patients doses were titrated from 1 mg/day to 4 mg/day during took the first dose of trial drugs).
the first 6 days to avoid acute adverse effects, while Patients having the following conditions were amisulpride remained at 400 mg/day. Subsequently, excluded from the study: 1) history of allergy or hyper- both drugs were titrated according to clinical response sensitivity to risperidone, benzamides, procyclidine, at the discretion of the investigators. In accordance or benzodiazepines; 2) significant neurological with the double-blind nature of the study, both diseases such as stroke, Parkinson’s disease or drugs were provided in identical sealed capsules.
epilepsy; 3) significant organic brain syndrome; 4) Psychopathology (PANSS, BPRS, CGI), ESRS, and history of severe medical diseases such as cardio- physical examination were assessed, and patient’s vascular, respiratory, renal or liver disease; 5) preg- spontaneous complaints or clinical findings of adverse nancy, lactation, or intention to become pregnant; events were recorded on days 0, 7, 14, 21, 28, and 42.
6) recent abuse of psychoactive drugs or alcohol; Adverse events were coded by the WHO-Adverse and 7) placebo responders, i.e. patients whose PANSS Reaction Terminology (WHO-ART) coding system positive scores reduced by 40% or more during and were tabulated by body system. Blood and urine the placebo run-in period. Written informed consent examinations were performed on days 14 and 42. A was obtained from every patient prior to entry into follow-up ECG was performed on day 42. The SOFAS the trial after explanation of the procedure and 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
T. J. Hwang, S.M. Lee, H.J. Sun, et al Table 1. Demographic and baseline characteristics of the intent-to-treat population.
(or at the time of premature withdrawal). Patients’ abstinence for antipsychotic medication injection subjective responses were also assessed at day 7 and day 42, using a semi-structured interview by Demographic data of the two groups in the intent- asking “How does the medication agree with you?”; to-treat population are summarized in Table 1. There “Did it make you feel calmer?”; “Did it affect your were no significant differences in baseline character- thinking?”; and “ Do you think this would be the right istics between the two groups. In the amisulpride medication for you?”. Responses were rated on a group, the mean dose was unchanged after day 28 seven-point (-3 to +3) euphoric/dysphoric scale.
(630 ± 150 mg/day at day 28 and 630 ± 134 mg/day Concomitant medications were restricted unless 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.
Statistical analysis
The main analysis was carried out on the intent-to-
treat population using the Last Observation Carried The PANSS total score and three subscores over the Forward (LOCF) technique. Because of the limited 6-week trial are shown in Table 2. At the end of the sample size, non-parametric analyses were used. The trial, there were significant changes in both groups, main analysis was a Friedman two-way analysis of but no significant differences between the two groups variance (treatment group and center) for between in the PANSS total scores and the three subscores.
group analyses in efficacy parameters (PANSS, BPRS, The proportions of patients with more than 20% score CGI, SOFAS, subjective response) and safety param- reduction in the PANSS total scores were calculated, eters (ESRS, vital signs, body weight).
and no significant difference between the two groups Wilcoxon signed rank test was applied for within was observed (68% with amisulpride versus 76% with group analyses. Ordinal qualitative variables were examined using Cochran-Mantel-Haenszel test Changes in the BPRS total scores and the CGI (with ridit transformation of the variables), with score are also shown in Table 2. Similarly, there were adjustment for center effect. Statistical significance significant changes within each group, but no was declared if the two-sided p value was less than statistical differences between these two groups. When 0.05. All statistical analyses were performed using 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).
From October 01, 1999 to June 30, 2000, a total of 48 There was no significant difference in the scores patients with schizophrenia were enrolled. There were of SOFAS between the two groups at the end of the 23 and 25 patients in the amisulpride and risperidone trial (Table 2). The assessments of patients’ subjective groups, respectively. One patient in the amisulpride response were also comparable. Approximately 75% group had multiple somatic complaints during the of all patients expressed a positive subjective response placebo run-in phase and withdrew himself from the to treatment after day 7. At day 42, 82% and 83% trial at day 6; the patient was excluded for efficacy of patients expressed good subjective response in data analyses due to lack of any efficacy measure after the amisulpride and risperidone groups, respectively.
active medication. Of the remaining 47 patients, twoin the amisulpride group failed to complete the entire 6-week trial. In one this was due to adverse events; the During the trial period, no serious adverse events other was found not to meet the washout criteria of were recorded based on patients’ spontaneous 32
J Formos Med Assoc 2003 • Vol 102 • No 1 Amisulpride Versus Risperidone in Schizophrenia Table 2. Changes in PANSS, BPRS, CGI, and SOFAS scores of the intent-to-treat population.
PANSS = Positive and Negative Syndrome Scale; BPRS = Brief Psychiatric Rating Scale; CGI = Clinical Global Impression—severity of illness; SOFAS = Social andOccupational Functioning Assessment Scale.
reports or investigators’ examinations. The overall the trial (Table 4). The amisulpride group had sig- incidence of treatment-related adverse events was nificant within-group reduction (p < 0.01), while 65.2% (15/23) and 64.0% (16/25) for patients in the risperidone group had borderline reduction the amisulpride and risperidone groups, respectively, (p < 0.07), in both supine systolic blood pressure and the difference was not statistically significant (SBP) and diastolic blood pressure (DBP). The (p = 0.931). When the incidence of each adverse event amisulpride group had significant within-group was compared, none was shown to be significantly reduction (p < 0.04), while the risperidone group had different between the 2 groups. The adverse events a non-significant increase in supine heart rate (HR) recorded in more than 5% of patients are listed in [Table 4]. These changes in vital signs were judged Table 3. The most frequent adverse events were as clinically insignificant. Mean body weight in the insomnia (17.3%) and constipation (17.3%) in the risperidone group was significantly increased at the amisulpride group, and akathisia (16%), tremo (12%), end of the trial (Table 4), but there were no significant and constipation (12%) in the risperidone group.
differences in this variable between the 2 groups.
At the end of the trial, there were no significant between-group or within-group changes in the global abnormal but clinically insignificant changes at the assessment of parkinsonism, tardive dyskinesia, or end of the study. Two cases were in the amisulpride total scores of BAS, except that the risperidone grouphad a significant within-group reduction in the global Table 3. Treatment-emergent adverse events occurring in
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, -blockers, and anxiolytics (Fisher’s exact test: p = 0.06, 0.008, and 0.002, respectively).
Regarding the vital signs, there were no signifi- cant differences between the 2 groups at the end of SGPT = serum glutamic pyruvic transaminase J Formos Med Assoc 2003 • Vol 102 • No 1 33
T. J. Hwang, S.M. Lee, H.J. Sun, et al Table 4. Changes in vital signs and body weight measurement of the intent-to-treat population.
*p < 0.05 for the within-group comparison between day 0 and day 42; †p values for the changes between groups at day 42.
group (non-specific ST-T changes and left ventricular doses and concomitant medications, and a smaller hypertrophy criteria), and one in the risperidone sample size in our study. In the study of Peuskens group (sinus tachycardia). There were no cases with et al, the dosages were relatively high (800 mg/day prolonged QTc (QTc > 500 ms) at the end of the trial of amisulpride and 8 mg/day of risperidone), and in either group. Blood and urine examinations the percentage of concomitant antiparkinsonian showed that there were no clinically significant drugs was 30% in the amisulpride group and 23% changes in either group, and no patient was withdrawn in the risperidone group. In our study, the dosages from the study due to laboratory abnormalities.
were moderate, and the percentage of concomitantantiparkinsonian drugs in the amisulpride group (30%) was significantly lower than in the risperidone iscussion
Both drugs were well tolerated in this trial. There This double-blind pilot study showed that there were were no severe adverse events, a relatively low inci- no significant differences in efficacy between dence of adverse events, and only rare withdrawal amisulpride and risperidone in schizophrenic from the trial due to adverse events. Scores on dif- patients. Both drugs were effective in the treatment ferent dimensions of EPS also did not increase of positive and negative symptoms of schizophrenia, significantly during the trial, indicating that neither and all subjective responses and functional outcomes amisulpride nor risperidone induced marked EPS at indicated that the drugs were comparable. The result these dose ranges. This is consistent with previous is consistent with a previous report with a direct experiences with these drugs.6,20 There was a signifi- comparison design,14 and other indirect comparison cant reduction in the rating of parkinsonism in the risperidone group at the end of the trial, which might There was an initial significant decline in the total be related to the dose employed, concomitant medi- scores of the PANSS, BPRS, and CGI at Day 7 in both groups, and the decline continued till the end of the In this trial, the risperidone group had significant trial. However, it is interesting to note that the mean body weight gain at the end of the study, which is dose did not change after Day 28 in the amisulpride commonly associated with the use of risperidone,21,22 group, while there was mild dose escalation in the but not amisulpride.5,22 There was no QTc prolonga- risperidone group. This implies that amisulpride tion or arrythmogenic effect for either drug, which is 630 mg/day was clinically equivalent to risperidone 6.56–6.88 mg/day in the 6-week trial. This estimate is Theoretically, amisulpride has a low autonomic close to that in the fixed-dose design of the study by neurocardiac risk due to its action at dopamine Peuskens et al, in which amisulpride 800 mg/day was D and D receptors rather than at cholinergic or equivalent to risperidone 8 mg/day.14 The finding is adrenergic receptors.25,26 However, albeit judged to also consistent with a previous report that amisulpride be clinically insignificant, there were statistically 400–800 mg/day is the most efficacious dose in the significant reductions of supine SBP, DBP and HR in the amisulpride group at the end of the trial. A large Previous studies showed a trend in favor of greater pooled analysis on safety profiles of amisulpride27 improvement in negative symptoms in the PANSS showed that a trend towards a decrease in HR (defined negative scale in patients receiving amisulpride,6,14 but as sitting or supine HR ≤ 50 beats/min and a decrease we did not find such a trend in this study. Possible versus baseline ≤ 15 beats/min) occurred in 1% of relevant factors included differences in comparison 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 comparison of atypical antipsychotics in an Asian and a decrease versus baseline of ≥ 20 mm Hg, or any population. Such studies are under-represented in the sitting or supine DBP of ≤ 50 mm Hg and a decrease versus baseline of ≥ 15 mm Hg) in 7% of amisulpriderecipients, 7% of risperidone recipients, 4% of halo- ACKNOWLEDGMENTS: The project was supported by peridol recipients, and 4% of placebo recipients.
funding from the Fujisawa Taiwan and a grant NTUH Therefore, our findings may be explained by the 90s1004 to Dr. Hwang. We wish to thank the small sample size. But these cardiovascular findings participating psychiatrists from the collaborative in this group of relatively young patients deserve hospitals for data collection, and Dr. G. Bartzokis for attention because they may imply a possible dif- Suspected evidence for racial differences was found in the required doses for antiparkinsonian References
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