Original article 143 Ziprasidone and amisulpride effectively treat negative symptoms of schizophrenia: results of a 12-week, double-blind study Jean-Pierre Olié a, Edoardo Spina b, Stephen Murray c and Ruoyong Yang c We compared the efficacy of ziprasidone and amisulpride in the treatment of negative symptoms and overall psychopathology in subjects who had chronic schizophrenia with predominantly negative symptoms. This multicentre, 12-week, double-blind study randomly assigned subjects with predominantly negative-symptom schizophrenia [i.e. Positive and Negative Syndrome Scale (PANSS) Negative Subscale score Z 6 points greater than Positive Subscale score] to ziprasidone (40 80 mg b.i.d.; n = 60) or amisulpride (50 100 mg b.i.d.; n = 63). The primary efficacy variable was the change from baseline in PANSS Negative Subscale score. Secondary efficacy variables included change in scores for PANSS Total, Global Assessment of Functioning, Brief Psychiatric Rating Scale derived from PANSS Total and Core, Clinical Global Impression (CGI) Severity and CGI Improvement. For the change in PANSS Negative Subscale score, a ratio to assess the equivalence of the treatment groups was calculated from the least squares mean changes from baseline, with equivalence claimed if the lower limit of the 95% confidence interval of the ratio exceeded 0.60. Mean daily dose, adjusted for differential numbers of subjects and differential days between visits, was 118.0 mg for ziprasidone and 144.7 mg for amisulpride. Mean PANSS Negative Subscale scores improved over the 12-week treatment period for intent-to-treat subjects, evaluable subjects (subjects with Z 4 weeks of double-blind treatment and no protocol deviations) and completers in both treatment groups. Ziprasidone demonstrated efficacy comparable to amulsipride in improving negative symptoms and global psychopathology. The groups demonstrated comparable improvements in secondary efficacy variables. Both agents were generally well tolerated, with comparably low incidences of movement disorders. In subjects with negative symptom prominent schizophrenia, ziprasidone in mean daily doses of 118 mg was equivalent to amisulpride in mean daily doses of 148 mg in ameliorating negative symptoms and comparable in improving overall psychopathology and global illness severity. Int Clin Psychopharmacol 21:143 151 c 2006 Lippincott Williams & Wilkins. International Clinical Psychopharmacology 2006, 21:143 151 Keywords: amisulpride, double-blind study, efficacy, negative symptoms, PANSS, schizophrenia, ziprasidone a Department of Mental Health and Therapy, Sainte-Anne Hospital, Paris, France, b Department of Clinical and Experimental Medicine and Pharmacology, Section of Pharmacology, University of Messina, Centers of Mental Health, Messina, Italy and c Pfizer Inc., New York, New York, USA. Correspondence and requests for reprints to Jean-Pierre Olié, Saint Anne Hospital, Department of Mental Health, SHU Catchment Area, 141r Cabanis, 75014 Paris, France. Tel: + 33 014565 8452; fax: + 33 014565 8160; E-mail: olie@chsa.broca.inserm.fr Received 6 August 2005 Accepted 8 September 2005 Introduction Historically, the positive symptoms of schizophrenia, such as delusions, paranoia, hallucinations, conceptual disorder, and disorganized speech, have been the primary focus of antipsychotic therapy. However, negative symptoms, which include diminished social drive and emotional range, alogia, anhedonia and avolition, are increasingly viewed as critical targets for treatment (Moller et al., 1994) because their severity may predict functional and social outcomes (Ho et al., 1998). Conventional antipsychotic drugs, such as chlorpromazine and haloperidol, control positive symptoms but are less effective against negative symptoms. Moreover, these agents are commonly associated with extrapyramidal symptoms (EPS) (i.e. akathisia, dystonia, parkinsonism, and tardive dyskinesia), which may contribute to secondary or induced negative symptoms. Patients treated with conventional antipsychotics may also experience sedation and cognitive impairment. Atypical antipsychotic drugs are less likely than conventional agents to induce EPS, and appear to possess superior efficacy with regard to negative symptoms. As a consequence, they are increasingly being used as first-line treatment in schizophrenia. However, distinct tolerability issues have emerged. Some atypicals have been associated with weight gain, with olanzapine and clozapine exhibiting the greatest liability (Allison et al., 1999). Olanzapine has also been associated with alterations in the lipid profile (Osser et al., 1999; Meyer, 2001) and with disturbances in glucose metabolism, including new onset diabetes (Biswasl et al., 2001; Gianfrancesco et al., 2002; Koro et al., 2002). 0268-1315 c 2006 Lippincott Williams & Wilkins
144 International Clinical Psychopharmacology 2006, Vol 21 No 3 Ziprasidone, a benzisothiazolylpiperazine, is an atypical antipsychotic that has demonstrated efficacy in multiple symptom domains in schizophrenia (Gunesekara et al., 2002). In short-term, placebo-controlled clinical trials, ziprasidone improved the positive, negative and affective symptoms of schizophrenia, with improvement observed within 1 week of treatment initiation (Keck et al., 1998; Daniel et al., 1999) and, in a 1-year trial, reduced the risk of relapse (Arató et al., 2002). Ziprasidone has shown efficacy comparable to that of haloperidol in the treatment of positive symptoms and a higher rate of negative-symptom response (Hirsch et al., 2002). Shortterm and long-term studies have demonstrated efficacy comparable to that of olanzapine (Simpson et al., 2002, 2004) and risperidone (Addington et al., 2004). Ziprasidone possesses a unique tolerability profile. Both the incidence of extrapyramidal side-effects and scores on movement disorder rating scales were lower than those for haloperidol in stable schizophrenic outpatients (Hirsch et al., 2002). In both short-term (Simpson et al., 2002) and longterm treatment (Simpson et al., 2002), ziprasidone was associated with significantly less weight gain than olanzapine, with favourable effects on lipid profiles and neutral effects on glucose metabolism. In a comparison with risperidone, ziprasidone had a lower movement disorder burden score, less weight gain and a lower incidence of prolactin elevation (Addington et al., 2004). Amisulpride is an atypical antipsychotic of the benzamide class that has shown efficacy in subjects with acute psychoses or predominantly negative-symptom schizophrenia (Curran and Perry, 2001; Leucht et al., 2002). Although unavailable in the USA, amisulpride is widely used in Europe, where comparative studies involving antidepressants have established its efficacy in depressive disorders (Lecrubier et al., 1997; Cassano and Jori, 2002; Muller et al., 2002). Other comparative studies have shown it to be as effective overall in schizophrenia as olanzapine (Martin et al., 2002) but superior to haloperidol (Carriere et al., 2000) and risperidone (Peuskens et al., 1999) with respect to negative symptoms. The primary objective of our study was to compare the efficacy of ziprasidone and amisulpride in the treatment of negative symptoms in schizophrenic subjects with predominantly negative symptomatology. We also compared the efficacy of ziprasidone and amisulpride in the treatment of general psychopathology and global illness severity, and evaluated the safety and tolerability of the two agents. Methods Study design and subjects This randomized, double-blind, parallel-group, flexibledose phase III study enrolled outpatients from 26 centres in Western Europe. Subjects included men and women aged 18 64 years with a primary DSM-III-R diagnosis of chronic schizophrenia and an indication for maintenance therapy with antipsychotic medication. All patients provided their informed consent. Women either were not of child-bearing potential or were practicing contraception. Individual baseline scores on the Negative Subscale of the Positive and Negative Syndrome Scale (PANSS) had to exceed the PANSS Positive Subscale by Z 6 for inclusion in the study. Exclusion criteria included acute exacerbation of schizophrenia or psychosis 12 weeks before screening, a history of psychosurgery, or any severe medical illness. Treatment protocol Subjects underwent a minimum 3-day run-in period for screening procedures, including both psychiatric and medical evaluations. Subsequently, those who fulfilled the PANSS Negative Subscale criteria at baseline evaluation were randomized in a 1 : 1 ratio to receive ziprasidone (40, 60, or 80 mg b.i.d.) or amisulpride (50 or 100 mg b.i.d. or 50 mg a.m. and 100 mg p.m.). Doses were administered in three capsules after feeding and approximately 12 h apart. Subjects randomly assigned to ziprasidone were started on 20 mg b.i.d.; after 2 days, the dosage was increased to 40 mg b.i.d. At the discretion of the investigator, the dosage could be increased to 60 mg b.i.d. from week 2 onwards or to 80 mg b.i.d. from week 3 onwards. The starting dosage for amisulpride was 50 mg b.i.d. This could be increased to 150 mg per day from week 2 onwards and to 100 mg b.i.d. from week 3 onwards, according to clinical response. The minimum interval between dosage titration steps was 1 week. Permitted concomitant medications were lorazepam for agitation and temazapam for insomnia. Anticholinergics and propranolol were gradually withdrawn (25% dosage reduction per week) but were reinstated, if needed, at the discretion of the investigator. Evaluation of efficacy The primary efficacy variable was change from baseline in the PANSS Negative Subscale score. A relative efficacy ratio for change from baseline was used to measure the difference between amisulpride and ziprasidone in change from baseline. This method was chosen rather than absolute difference from baseline because the treatment effect of amisulpride compared to placebo on the PANSS Negative Subscale was not known. Previous placebo-controlled studies (Danion et al., 1999; Curran and Perry, 2001) with amisulpride have used the Scale for Assessment of Negative Disorders, rather than PANSS, to assess the effect of amisulpride on negative symptoms. Secondary efficacy variables were changes from baseline in the PANSS Total score, the Clinical Global Impression Severity (CGI S) and Improvement (CGI I)
Ziprasidone and amisulpride for negative symptoms of schizophrenia Olié et al. 145 scores, the Brief Psychiatric Rating Scale derived from PANSS (BPRSd) Total and Core scores, and the Global Assessment of Functioning (GAF) score. PANSS and CGI S were assessed at screening and then again with CGI I at baseline and weeks 4, 8 and 12 (or early termination). BPRSd Total and Core were assessed at baseline and weeks 4, 8 and 12 (or early discontinuation). GAF was assessed at baseline and week 12 (or early termination). A responder was defined as having at least a 20% decrease in PANSS Negative Subscale score at the last observation relative to baseline. A CGI responder was defined as having an observed score of 1 2 on the CGI I scale at last observation. Responder rates for each criterion were calculated for the two treatment groups. Responder rates based on 30%, 40% or 50% decrease in PANSS Negative scores were also calculated. Safety and tolerability evaluation Abnormal movements and EPS were assessed by the Simpson Angus Rating Scale, the Barnes Akathisia Scale and the Abnormal Involuntary Movement Scale (AIMS). The Barnes Akathisia Scale included one objective, two subjective and one global assessment of akathisia symptoms. The AIMS evaluation included seven items assessing tardive dyskinesia. Tests were performed at baseline and weeks 6 and 12 (or early discontinuation). The Movement Disorder Burden Score (MDBS) (Brook et al., 2005) was used to quantify overall discomfort from movement disorder adverse events occurring during the study or within 6 days of treatment cessation. All observed or volunteered adverse events were recorded regardless of suspected causal relation to the study drugs. Treatment-emergent adverse events were defined as those that were not present at baseline or those that were present at baseline but increased in severity following study drug treatment. Electrocardiogram (ECG) changes and abnormal laboratory test results that gave rise to a change of study drug dosage were recorded. Body weight measurements and ECGs were obtained at screening and week 12. Clinical laboratory tests, including blood cell counts, blood biochemistry and urinalysis, were performed at baseline and weeks 4 and 12. Analysis groups The safety population included all randomized subjects with at least one dose of study medication. The intent-to-treat (ITT) population included all randomized subjects who had a baseline and at least one post-baseline efficacy evaluation, regardless of whether protocol inclusion/exclusion criteria were met. The evaluable subjects population comprised randomized subjects who had Z 4 weeks of double-blind treatment and no major protocol deviations or violations. The Completers population comprised randomized subjects who completed the 12-week study period. Statistical analysis Efficacy analyses were performed for the ITT population, evaluable subjects, and completers. The primary inference on the comparison of treatment effects was based on the evaluable subjects population. Analyses of safety were based on the safety population. P < 0.05 (two-sided) was considered statistically significant. Statistical tests and estimates of treatment effects were based on least squares means derived from an analysis of covariance model, with baseline value as the covariate and fixedeffect terms for treatment, country, and centre nested within country. P-values and confidence intervals (CI) for differences in responder rates between the two treatment groups were obtained using normal approximation to the binomial with continuity correction. A ratio to assess the equivalence of the treatment groups was calculated from the least squares mean changes from baseline. Equivalence of the two groups was claimed if the lower limit of the 95% CI based on Fieller s Theorem of the ratio exceeded 0.60. The 0.60 ratio guarantees that the difference between ziprasidone and amisulpride will be smaller than the difference between amisulpride and placebo. The differences between amisulpride and placebo in other clinical trials (Curran and Perry, 2001) have been approximately 50 55%. The selection of a 0.60 ratio also complies with the ICH guideline on equivalence margin. Although many equivalence studies use a 90% CI, a 95% CI was chosen for this study because it is considered a more stringent level (i.e. more difficult to claim equivalence). Abnormal movement scores were summarized as the percentage of subjects with a postbaseline change. Results Subject characteristics Of the 143 subjects screened, 123 were randomized and received at least 1 dose of study medication (Fig. 1). All were white, with a mean age of 39 years (Table 1) and a primary diagnosis of schizophrenia. The mean number of previous hospitalizations was greater for the amisulpride group (7.3 ± 9.8) than for the ziprasidone group (4.3 ± 7.5), whereas the mean duration of most recent hospitalization was greater for subjects treated with ziprasidone (4.0 ± 12.4 months) than for those treated with amisulpride (1.6 ± 2.7 months). Neither difference was statistically significant. In the 3 months before study entry, use of anticholinergic drugs for parkinsonism was slightly higher in the ziprasidone group (53%) than in the amisulpride group (49%). During the study, 35% of ziprasidone-treated
146 International Clinical Psychopharmacology 2006, Vol 21 No 3 Fig. 1 Subjects discontinued (n = 18) Ziprasidone group (n =60) Ziprasidone completers (n = 42) Subjects screened for entry (n = 143) Subjects randomized (n = 123) Amisulpride group (n = 63) Amisulpride completers (n =50) Subjects discontinued (n = 13) Disposition of subjects. Table 1 Baseline subject characteristics Ziprasidone Amisulpride Male Female Total Male Female Total No. of subjects randomized 41 19 60 38 25 63 Age range (year) 21 53 21 65 21 65 22 58 24 48 22 58 Mean age (year) 37.3 43.8 39.4 39.2 36.7 38.2 Mean weight (kg) 76.3 65.3 75.4 66.6 PANSS Negative Subscale score 31.03 29.00 Subject groups (n) Safety 60 63 ITT 59 63 Evaluable 50 53 Completers 42 50 ITT, Intent-to-treat population. subjects and 21% of the amisulpride-treated subjects required anticholinergic therapy. Treatment Dosing Starting dosages (ziprasidone, 40 mg b.i.d., titrated from 20 mg b.i.d. for 2 days; amisulpride, 50 mg b.i.d.) were increased in two steps to a maximum of 80 mg b.i.d. for ziprasidone and 100 mg b.i.d. for amisulpride. The mean daily dose, adjusted for differential numbers of subjects and differential days between visits, was 118.0 mg for ziprasidone and 144.7 mg for amisulpride. The median duration of treatment (84 days) and the number of subjects receiving > 28 days of study drug (amisulpride group: 57/63, 90.5%; ziprasidone group: 50/60, 83.3%) were comparable for the two treatment groups. Discontinuations Thirty-one subjects were discontinued from the study. Twelve subjects (20%) in the ziprasidone group and four
Ziprasidone and amisulpride for negative symptoms of schizophrenia Olié et al. 147 Table 2 Changes in primary efficacy variable (baseline to last visit, all populations) Variable/population Treatment group LS (adjusted) mean change (95% CL) a Difference between groups (95% CL) b, P-value Ratio of adjusted mean change Lower limit of 95% CI for ratio PANSS Negative Intent-to-treat Ziprasidone (n =59) 6.1 ( 7.8, 4.3) 0.81 ( 1,47, 3.10), P = 0.48 0.88 0.60 Amisulpride (n = 63) 6.9 ( 8.5, 5.3) Evaluable Ziprasidone (n = 50) 6.9 ( 8.6, 5.2) 1.16 ( 1.09, 3.41), P = 0.31 0.86 0.62 Amisulpride (n = 53) 8.1 ( 9.7, 6.5) Completers Ziprasidone (n = 42) 9.1 ( 10.5, 7.7) 0.81 ( 2.66, 1.03), P = 0.38 1.10 0.89 Amisulpride (n = 50) 8.3 ( 9.5, 7.0) a All within-group changes P < 0.001, univariate t-test. Confidence interval (CL) based on least squares (LS) (adjusted) mean change as fit by an analysis of covariance model with (fixed) effects for treatment, country and centre (nested within country), and baseline covariate. b Amisulpride Ziprasidone. CI, Confidence interval. Table 3 Changes in secondary efficacy variables (baseline to last visit, all populations) Variable/population Treatment group n LS (adjusted) mean change Difference between groups (95% CL) a (95% CL), P-value Ratio of adjusted mean change Lower limit of 95% CI for ratio PANSS Total Intent-to-treat Ziprasidone 59 11.9 ( 16.9, 6.9) 2.78 ( 3.72, 9.27), P = 0.40 0.81 0.45 Amisulpride 63 14.6 ( 19.3, 10.0) Evaluable Ziprasidone 50 14.1 ( 19.0, 9.2) 2.53 ( 3.80, 8.86), P = 0.43 0.85 0.53 Amisulpride 53 16.6 ( 21.2, 12.1) Completers Ziprasidone 42 19.9 ( 24.3, 15.4) 0.50 ( 6.37, 5.38), P = 0.87 1.03 0.75 Amisulpride 50 19.4 ( 23.4, 15.4) CGI S Intent-to-treat Ziprasidone 59 0.6 ( 0.9, 0.3) 0.11 ( 0.27, 0.48), P = 0.58 0.86 0.45 Amisulpride 63 0.7 ( 1.0, 0.5) Evaluable Ziprasidone 50 0.7 ( 1.0, 0.4) 0.11 ( 0.27, 0.49), P = 0.56 0.86 0.48 Amisulpride 53 0.8 ( 1.1, 0.5) Completers Ziprasidone 42 1.0 ( 1.3, 0.8) 0.15 ( 0.53, 0.23), P = 0.43 1.17 0.78 Amisulpride 50 0.9 (1.2, 0.6) BPRSd Total Intent-to-treat Ziprasidone 59 5.2 (8.0, 2.4) 2.08 ( 1.55, 5.71), P = 0.26 0.71 0.32 Amisulpride 63 7.3 ( 9.9, 4.6) a All within-group changes P < 0.001, univariate t-test. Confidence limit (CL) based on least squares (LS) (adjusted) mean change as fit by an analysis of covariance model with (fixed) effects for treatment, country and centre (nested within country), and baseline covariate. CI, Confidence interval. (6%) in the amisulpride group were discontinued for reasons thought to be treatment related [11 (nine in the ziprasidone group, two in the amisulpride group) because of insufficient clinical response and five (three and two, respectively)] because of treatment-emergent adverse events). Other reasons for study discontinuation included adverse events not considered treatment related (n =2) and withdrawal of consent (n = 9). Efficacy assessments PANSS Negative Subscale PANSS Negative Subscale score, the primary efficacy variable, improved for both treatment groups over the 12-week study, with all three populations in each treatment group demonstrating significant improvement from baseline to endpoint (P < 0.001) (Table 2). There were no statistically significant differences between treatments in any of the populations. Both treatments demonstrated equivalent effects (defined as the lower limit of the CI of the ratio exceeding 0.60) on the PANSS Negative Subscale in the ITT population (ratio 0.88, lower limit of CI 0.60), the evaluable subjects population (ratio 0.86, lower limit of CI 0.62) and the completers population (ratio 1.10, lower limit of CI 0.89). Secondary efficacy variables Subjects in all three populations in both treatment groups improved from baseline to endpoint in the secondary efficacy variables of PANSS Total, CGI S, BPRSd Total and Core and GAF scores (P < 0.05) (Table 3). Changes in secondary efficacy variables did not differ significantly between treatment groups in any of the populations. As with the primary efficacy variable, equivalence between treatment groups for secondary efficacy variables was defined as the lower limit of the CI of the ratio exceeding 0.60. Equivalence between treatments was demonstrated in the completers population for PANSS Total (ratio 1.03, lower limit of CI 0.75), CGI S (ratio 1.17, lower limit of CI 0.78), BPRSd Total (ratio 0.95, lower limit of CI 0.66) and GAF (ratio 1.31, lower limit of CI 0.84) (Table 3). Clinical response Clinical response for the various efficacy measures was defined as at least a 20% decrease in score from baseline to last visit. For the PANSS Negative Subscale score, the primary efficacy variable, response rates in the ITT population were 56% in the ziprasidone group and 62% in the amisulpride group [95% confidence limit (CL) between-group difference in percentage responders was
148 International Clinical Psychopharmacology 2006, Vol 21 No 3 Table 4 Clinical response rates in intent-to-treat and evaluable subjects populations Decrease in PANSS Negative Subscale score, n (%) [95% CL] a CGI Improvement 1 or 2 at last observation 20% 30% 40% 50% Intent-to-treat subjects Ziprasidone (n = 59) 33 (55.9) [21.8, 13.1] 25 (42.4) [19.7, 15.6] 15 (25.4) [12.0, 18.6] 5 (8.5) [13.5, 8.4] 24 (40.7) Amisulpride (n =63) 39 (61.9) [21.8, 13.1] 29 (46.0) [19.7, 15.6] 15 (23.8) [12.0, 18.6] 8 (12.7) [13.5, 8.4] 29 (46.0) Evaluable subjects Ziprasidone (n = 50) 31 (62.0) [27.7, 8.4] 22 (44.0) [26.2, 12.4] 13 (26.0) [17.6, 16.8] 5 (10.0) [13.7, 11.1] 22 (44.0) Amisulpride (n =53) 39 (73.6) [27.7, 8.4] 28 (52.8) [26.2, 12.4] 15 (28.3) [17.6, 16.8] 7 (13.2) [13.7, 11.1] 27 (50.9) a For between-group difference in percentage responders. CL, Confidence limit; PANSS, Positive and Negative Syndrome Scale; CGI, Clinical Global Impression. 21.8, 13.1]. The respective response rates were 62% and 74% in the evaluable subjects population (95% CL 27.7, 8.4) (Table 4). There were no statistically significant between-drug differences in response rates in either group. The number and proportion of responders and the difference in response rates decreased for both groups as the criterion was made more stringent (e.g. 30%, 40% and 50% decreases in PANSS Negative Subscale score from baseline to last visit). Response rates for evaluable subjects are shown in Fig. 2. Response rates based on a change in CGI I score of 1 or 2 from baseline were 41% and 46% for ziprasidone and amisulpride subjects, respectively, in the ITT population, and 44% and 51%, respectively, in the evaluable subjects population (Table 4). Tolerability and safety Movement disorders By a factor > 2, a higher percentage of subjects in both groups showed an overall decrease in abnormal movement disorder scores (Simpson Angus, Barnes Akathisia and AIMS) at last visit versus baseline than showed an increase (Table 5). Mean MDBS scores (0.14 for ziprasidone-treated subjects and 0.03 for amisulpridetreated subjects) did not differ significantly. Adverse events Of the 123 subjects in the safety population, 72 (58.5%) experienced an adverse event during the study or within 6 days of treatment cessation. Adverse events considered by the investigators to be related to study drug and leading to study discontinuation (three subjects in the ziprasidone group, two subjects in the amisulpride group) included severe behavioural disorders, anxiety, delusions, asthenia, EPS and insomnia in differing combinations. Treatment-emergent adverse events occurred in 36 (60%) ziprasidone subjects and 34 (54%) amisulpride subjects (Table 6). Adverse events most commonly affected the nervous system, the digestive system and the body as a whole. One subject in each group had a serious adverse event judged by the investigator to be related to the study drug. The ziprasidone subject had Fig. 2 Subjects meeting response criteria (%) 80 70 60 50 40 30 20 10 0 Ziprasidone Amisulpride 20% 30% 40% 50% Responder rates for Positive and Negative Syndrome Scale Negative Subscale: evaluable subjects. worsening schizophrenia, EPS and avolition; the amisulpride subject, severe anxiety and asthenia. Events in both subjects resolved. Treatment-emergent adverse events occurring in Z 5% of the safety population are shown in Table 7. Laboratory events The most frequent clinically significant abnormality in blood chemistry was an increase ( Z 1 + ) in ketones, observed in 11.1% and 3.3% of subjects on ziprasidone and amisulpride, respectively. No other laboratory abnormalities occurred in Z 4% of subjects. Median values for haematology parameters, liver and renal function tests, electrolytes, thyroxine and thyroid-stimulating hormone did not change significantly from baseline. There were no clinically significant changes in QT c or QRS intervals with any dosage in either treatment group. No subject in either treatment group experienced a QT c interval Z 450 ms. A clinically significant weight increase ( > 7% of body weight) occurred in more amisulpride subjects (17.9%) than ziprasidone subjects (8.8%). The rate of clinically significant weight decrease ( > 7% of body weight) was similar in the two groups (7.0% with ziprasidone and 5.4% with amisulpride).
Ziprasidone and amisulpride for negative symptoms of schizophrenia Olié et al. 149 Table 5 Abnormal movement disorder scores in intent-to-treat population Parameter Ziprasidone subjects showing (%) Amisulpride subjects showing (%) n Increase Decrease No change n Increase Decrease No change Simpson Angus 58 10.3 53.4 36.2 57 8.8 52.6 38.6 Barnes Akathisia 58 8.6 17.2 74.1 58 3.4 10.3 86.2 AIMS 57 17.5 14.0 68.4 58 15.5 22.4 62.1 AIMS, Abnormal Involuntary Movement Scale. Table 6 Treatment-emergent adverse events Adverse events summary, safety population Ziprasidone (n = 60) Amisulpride (n = 63) No. % No. % Total 36 60 34 54.0 Serious events 1 1.7 3 4.8 Nervous system 29 48.3 21 33.3 Digestive system 11 18.3 14 22.2 Body as a whole 14 23.3 15 23.8 Clinically significant 12 21.8 7 11.7 laboratory abnormalities Discontinuations due to adverse events 3 5.0 4 6.3 Table 7 Treatment-emergent adverse events occurring in Z 5% of the safety population Event Subjects (%) Ziprasidone (n = 60) Amisulpride (n = 63) Insomnia 16.7 14.3 Extrapyramidal syndrome 10.0 1.6 Anxiety 8.3 6.3 Dizziness 6.7 0 Akathisia 5.0 3.2 Somnolence 3.3 9.5 Headache 13.3 4.8 Asthenia 8.3 3.2 Vomiting 6.7 7.9 Dry mouth 6.7 1.6 Nausea 5.0 4.8 Discussion In this 12-week study, both ziprasidone (in total daily doses of 80 160 mg) and amisulpride (in total daily doses of 100 200 mg) demonstrated significant improvement in antipsychotic symptoms from baseline in subjects with chronic schizophrenia characterized by negative-symptom predominance. Response rates for negative-symptom improvement, defined as at least a 20% decrease in PANSS Negative Subscale score, were similar for ziprasidone- and amisulpride-treated subjects. Both ziprasidone and amisulpride were well tolerated, with few subjects discontinuing treatment because of adverse events. Although ziprasidone was associated with a higher rate of EPS than amisulpride, the percentage of subjects showing an overall decrease in movement disorder scores was considerably higher in both groups than the percentage showing an increase. No subject receiving either drug had prolongation of the QT c interval above 450 ms, and there was no clinically significant mean change (increase or decrease) in weight in either treatment group over the 12-week study period. Several studies have established the efficacy of amisulpride in controlling the negative symptoms of schizophrenia (Boyer et al., 1995; Danion et al., 1999; Loo et al., 1997; Rein and Turjanski, 1997) at dosages comparable to those used here. Our study provides evidence of the efficacy of ziprasidone with respect to negative symptoms. The efficacy of ziprasidone in this regard was also demonstrated in a 28-week study of outpatients with stable schizophrenia (Hirsch et al., 2002). In that study, ziprasidone not only proved superior to haloperidol in controlling negative symptoms, but was also associated with a lower liability for EPS. In addition to acute symptom improvement, long-term symptom control is important for schizophrenic patients with a preponderance of negative symptomatology because full remission is less likely if primary negative symptoms become an enduring feature of psychosis (Carpenter et al., 1988). In a recent 1-year placebocontrolled study of hospitalized subjects with chronic, stable schizophrenia, ziprasidone was associated with a statistically significant improvement in the PANSS Negative Symptom Subscale score. Importantly, treatment with ziprasidone was also shown to significantly lower the probability of relapse compared to placebo (Arató et al., 2002). The present study was not designed to compare treatment efficacy with respect to the positive symptoms of schizophrenia, and subjects in our study did not have acute exacerbation of schizophrenia. Although amisulpride in dosages of 100 mg per day is effective in improving the negative symptoms of schizophrenia (Boyer et al., 1994; Danion et al., 1999), dosages Z 400 mg per day are considered optimal for controlling acute schizophrenia (Burns and Bale, 2001). However, the incidence of EPS with amisulpride is dose-related, increasing to 37% at 600 800 mg per day (Curran and Perry, 2001). Ziprasidone has demonstrated efficacy against both acute and chronic schizophrenia in negative and positive symptom domains within the same dosage range (i.e. 120 160 mg per day), and has a favourable
150 International Clinical Psychopharmacology 2006, Vol 21 No 3 tolerability profile with respect to movement disorders at those dosages. Possible limitations of our study include an apparent disparity in subjects baseline characteristics and differences in discontinuation rates between the two treatment groups. Although subjects in the current study were generally well matched with respect to history of psychiatric illness, the mean number of previous psychiatric hospitalizations was greater in the amisulpride-treated group (trend towards significance versus ziprasidone). This might suggest that subjects randomized to amisulpride were more ill at baseline than those randomized to ziprasidone. However, given the vast number of baseline parameters that were collected and analysed, a finding of borderline significance in one baseline parameter should be not regarded as either surprising or necessarily clinically relevant. Although there was a higher rate of discontinuation due to insufficient clinical response in the ziprasidone than the amisulpride group, this was likely due to protocoldefined dosage limitations in our study. A dosage of 80 mg b.i.d. has previously been shown to improve the negative symptoms of schizophrenia (Daniel et al., 1999). However, our subjects did not achieve this dosage until day 21, which may have affected clinical response. In a pooled analysis of placebo-controlled trials, discontinuation rates for ziprasidone were lower within the first 14 days of treatment initiation in subjects who received 60 80 mg b.i.d. (5.2%) than in those who received 20 40 mg b.i.d. (11.5%) (Murray et al., 2003). The mean decrease from baseline in BPRS Total scores within the first 14 days of treatment initiation was greater in subjects who received 60 mg b.i.d. ( 3.14; P < 0.05 versus placebo) or 80 mg b.i.d. ( 5.62; P r 0.001) than in those who received 20 mg b.i.d. ( 1.51; P = NS) or 40 mg b.i.d. ( 0.62; P = NS) (Murray et al., 2003). Furthermore, flexible-dose trials of ziprasidone versus olanzapine or haloperidol in which ziprasidone was titrated from 80 mg/day to 160 mg/ day over several days had lower rates of discontinuation due to inadequate clinical response than a trial versus risperidone in which titration of ziprasidone occurred over 2 weeks (8.8%, 10.7%, and 14.8% in the trials versus olanzapine, haloperidol and risperidone, respectively) (Murray et al., 2003). In our study, both ziprasidone and amisulpride showed equivalence in improving negative symptoms. In three identically designed 6-week, open-label switch studies, ziprasidone was associated with significant improvement in PANSS Negative Subscale scores in subjects switched from conventional agents (P < 0.01), olanzapine (P < 0.01) and risperidone (P < 0.0001). Improvement was sustained during the continuation phase of the studies (P < 0.05 versus baseline in those switched from olanzapine, P < 0.01 in those switched from conventionals and P < 0.001 in those switched from risperidone) (Schooler et al., 2003). Ziprasidone dosing in these studies was 80 mg per day for 2 days, followed by 40 160 mg per day through week 6 (Weiden et al., 2003) and the continuation phase (overall median 215 days) (Schooler et al., 2003). A limitation of our own study may thus be suboptimal dosing of ziprasidone (i.e. the adjusted mean daily dose was 118 mg, which is lower than the currently recommended optimal dosage of Z 60 mg b.i.d.) (Murray et al., 2003). Similarly, the literature cites amisulpride dosages of 50 300 mg per day as appropriate to significantly reduce the negative symptoms of schizophrenia (Curran and Perry, 2001). In the present study, the adjusted mean daily dose of amisulpride was 144.7 mg. 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