Zotepine versus placebo in the treatment of schizophrenic patients with stable primary negative symptoms: a randomized double-blind multicenter trial

Abstract

Background: In contrast to traditional antipsychotic medication, newer, the so called atypical antipsychotic drugs promise to reduce primary negative symptoms in both, acute and chronic schizophrenia and improve quality of life. Zotepine, a D (2)5HT (2A) antagonist, was compared to placebo in this clinical trial to address these issues.

Methods: In an adaptive, 8-week multicenter, double-blind, randomized, parallel group study, efficacy and tolerability as well as influence on quality of life of zotepine and placebo were compared in 80 schizophrenic patients (53 % males, age 41 +/- 11 years) who experienced stable primary negative symptoms. Efficacy was assessed using the PANSS (primary outcome criterion: PANSS negative score), CGI, and MADRS; safety was controlled by EPS (Simpson-Angus Scale), TDRS and adverse events. Quality of life was evaluated with the SF-36 health questionnaire.

Results: After eight weeks of treatment with an average dose of 131 +/- 49 mg/day of zotepine, no superior efficacy of zotepine compared to placebo with respect to the PANSS subscale "negative symptoms could be demonstrated. Although patients receiving zotepine showed a pronounced reduction (per protocol set: -7.8 +/- 5.8) during treatment, it was not statistically different from a marked placebo response (-6.5 +/- 5.8). Similar small but not significant differences between zotepine and placebo were found in other subscales of the PANSS, the CGI and the MADRS. With regards to the quality of life assessment, patients under zotepine showed better results in the physical component scale and psychological well-being scale. In general, zotepine was well tolerated and there was no excess of extrapyramidal symptoms compared to placebo.

Conclusions: Zotepine was not superior to placebo in reducing the severity of stable primary negative symptoms in schizophrenic patients in this trial. The main reasons for this finding were a high placebo response in a selected population, a probably too low dose of zotepine, and a short study period. However, several findings show clinical benefit of zotepine therapy in efficacy and quality of life.