A comparison of an atypical and typical antipsychotic, zotepine versus haloperidol in patients with acute exacerbation of schizophrenia: a parallel-group double-blind trial. Zotepine vs. haloperidol in paranoid schizophrenia: a double-blind trial. Improvement of cognitive function in schizophrenic patients receiving clozapine or zotepine: results from a double-blind study. [Effectiveness and tolerance of zotepine in a double-blind comparison with perazine in schizophrenic patients]. Comparison of efficacy of zotepine and thiothixene in schizophrenia in a double-blind study. [Zotepine versus perazine in patients with paranoid schizophrenia: a double-blind controlled trial of its effectiveness]. Zotepine in the treatment of schizophrenic patients with prevailingly negative symptoms. A double-blind trial vs. haloperidol. Zotepine versus placebo in the treatment of schizophrenic patients with stable primary negative symptoms: a randomized double-blind multicenter trial.
The atypical antipsychotic zotepine was compared to haloperidol in 126 patients suffering from acute exacerbation of schizophrenia (DSM-III-R) in a randomized, double-blind study. After 8-weeks, 150 to 300 mg zotepine improved scores on the Brief Psychiatric Rating Scale (BPRS) more than 10 to 20 mg haloperidol (-17.03 versus -13.45; 95%CI for zotepine-haloperidol -9.34/2.04). BPRS subscores and Clinical Global impressions (CGI) Severity and improvement subscales showed comparable gains, but scores on the Scale for the Assessment of Negative Symptoms (SANS) improved significantly more with zotepine (-23.82) than haloperidol (-15.15; P < .05; 95%CI for zotepine haloperidol -18.03/-0.18). Adverse events were reported by 71 percent of zotepine and 78 percent of haloperidol patients. Extrapyramidal side effect (EPMS) scores decreased with zotepine (-0.34) but increased with haloperidol (+2.32; P < .05). Seven haloperidol patients reported akathisia but no zotepine patients did (p < .05). Uric acid reductions (which appear to have no clinical consequence) and transient raised liver enzymes were recorded with zotepine. Weight increased on zotepine (2.32 kg; P < .001) and a small increase in pulse rate occurred (P < .05). Both drugs were effective in reducing positive symptoms of schizophrenia; zotepine was significantly more effective against negative symptoms and reduced EPMS. nan Clinical interest in the so-called atypical antipsychotics currently focuses on the possibility of improving the negative symptoms of schizophrenia and the cognitive dysfunction associated with the disease. While clozapine has been shown to be effective in this respect, no data are available on zotepine. We report on a double-blind randomized study designed to evaluate the impact of zotepine and clozapine on cognitive dysfunction in schizophrenia. Cognitive function was operationalized by a maze test in which patients traversed computer-displayed mazes of increasing complexity. Passage time, route, and motor errors were evaluated. 25 schizophrenic (DSM-IIIR) patients were included in each group. After washout, they were randomized on zotepine or clozapine and given up to 450 mg of substance each. Patients were followed for six weeks and evaluated weekly. We report on a subsample of 26 patients matched for baseline BPRS, SANS, and age. 13 matched healthy persons were recruited as controls. ANOVA with group and course over time as factors was used for analysis. Both clozapine and zotepine achieved a highly significant decrease in overall symptoms (BPRS) and negative symptoms (SANS). Zotepine and clozapine were equally effective. In the maze tests, motor errors in simple mazes were stable over time and differentiated schizophrenics from controls as a "trait" marker. In passage time and maze route, schizophrenics performed worse than controls. An improvement by medication was evident in both medication groups, but was more pronounced in the zotepine-treated group. The study confirms previous results on the efficacy of clozapine and zotepine in treating negative symptoms of schizophrenia. The data presented show for the first time that zotepine is efficacious in improving cognitive dysfunction, confirming this substance's value as an atypical antipsychotic. 40 inpatients suffering from a schizophrenia (ICD-9) were treated with either zotepine or perazin. The study was continued for a period of 28 days. Assessment of clinical efficacy was effected via BPRS, AMDP, CGI and SANS; tolerance was assessed by means of Simpson's scale. In addition, EEG, ECG and laboratory controls were conducted. The overall therapeutic efficacy was good, and it was not possible to distinguish one group from the other, i.e. both substances were equally effective, judged by means of the psychopathometric tools that were at our disposal. In 11 patients of the zotepine group and in 9 patients of the perazin group, slight extrapyramidal symptoms were observed. No clinically relevant changes were seen in EEG, ECG and laboratory controls in both groups. Zotepine and thiothixene were compared for clinical efficacy and safety in a double-blind trial. Using overall improvement ratings and Gorham's BPRS, zotepine rated higher improvement in motor retardation, suspiciousness, mannerisms and posturing symptoms, suggesting that it has both activating and antipsychotic activities. Thiothixene produced higher improvement ratings in symptoms such as hallucinatory behavior, somatic concerns, anxiety, guilt feelings, tension, depressive mood and uncooperativeness. As for side effects, there was a significantly lower frequency of dry mouth and insomnia with zotepine when compared with thiothixene. The lower incidence of insomnia is interesting in view of zotepine's clinical activating effects. There were no abnormal laboratory findings. The dibenzothiepine zotepine is a new potential "atypical" neuroleptic exhibiting powerful antiserotonergic and antidopaminergic properties. The efficacy of zotepine was evaluated in a double-blind controlled trial versus the tricyclic neuroleptic perazine in 41 patients suffering mainly from the paranoid-hallucinatory type of schizophrenia. The key outcome variable was the extent of mental disturbance as defined by the total score of the BPRS. Additional outcome variables were GAS and CGI. In addition, adverse reactions and extrapyramidal side effects were assessed according to the FSUCL scale and the Gerlach and AIMS rating scale, respectively. Additional variables recorded were blood pressure, heart rate and routine laboratory parameters as well as electrocardiogram and electroencephalogram. In the first two days, standard equivalent doses of both drugs were administered. Thereafter, doses were administered as required. The efficacy of both substances was compared after 7, 14 and 28 days of treatment. Both drugs showed a similar antipsychotic efficacy. Under zotepine treatment a 55% improvement of the BPRS total score was observed while perazine led to a 41% BPRS score reduction. After 7 days the zotepine group was significantly more improved than the perazine group, possibly due to a dosing effect in the perazine group. In the zotepine group, fewer adverse reactions and a better benefit/risk index were observed although the differences between the two treatment groups did not reach levels of statistical significance. There were no drug-specific abnormal laboratory findings. Thus, in the present study there was no significant difference between zotepine and perazine with respect to antipsychotic efficacy and side-effect rates. However, zotepine showed a trend to a better benefit/risk index at the end of treatment. Zotepine, a neuroleptic agent with additional 5-HT2 blocking properties, was compared with haloperidol in the treatment of schizophrenic patients with predominantly negative symptoms using a double-blind design. During the investigation period zotepine treated patients showed significant improvements in all rating instruments whereas haloperidol treated patients did not. Patients in the zotepine group developed fewer clinical side effects. The results of the presented study confirm the positive impressions gained in earlier open trials with zotepine. 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.
                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.
                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.
                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.
Zotepine may be a valuable addition to the class of atypical antipsychotic drugs. However, more data from existing studies is urgently needed to increase confidence in the findings of this review. In addition to this, new data from well planned, conducted and reported long term pragmatic randomised trials are needed. Otherwise clinical use of zotepine will be based upon speculation of short explanatory trials for everyday practice.