The CHAT study: clozapine haloperidol aripiprazole trial

BACKGROUND Schizophrenia is a disabling mental disorder. It affects as much as 1% of the population worldwide. A proportion of one fifth to one third of patients with schizophrenia derive little or no benefit from treatment with first or second generation antipsychotics. In these treatment refractory patients, clozapine has been shown to be the treatment of choice. Unfortunately, however, approximately one third of treatment-refractory patients have persistent positive symptoms. The need to provide real-world suggestions for patients who do not have an optimal response to clozapine has prompted European and American treatment guidelines to recommend the concurrent prescription of a second antipsychotic in addition to clozapine in partially responsive patients, with no indication on which agent should be prescribed. OBJECTIVE The main clinical question to be answered by CHAT is the relative efficacy and tolerability of combination treatment with clozapine plus aripiprazole compared to combination treatment with clozapine plus haloperidol in patients with an incomplete response to treatment with clozapine over an appropriate period of time. METHODS The Clozapine Haloperidol Aripiprazole Trial (CHAT) is a prospective, multicentre, pragmatic, randomized, parallel group, superiority trial. Patients were assessed at baseline and after three, six and 12 months of follow-up. During the study, patients and clinicians were not blind to pharmacological treatments provided during the trial. However, outcome assessments based on rating scales were performed by trained assessors masked to the allocated treatment. CHAT was undertaken in compliance with Good Clinical Practice guidelines and the Declaration of Helsinki. The study protocol was approved by Italian Medicine Agency (Agenzia Italiana del Farmaco) and received ethical approval in each participating site. All phases of CHAT were recorded following the Consolidated Standard of Reporting of Trials (CONSORT) statement. RESULTS 106 patients were enrolled in the study and randomly assigned to treatment. After three months (13.2 vs 15.1%, p = 0.780), as well as after twelve months (30.8 vs 38.0%, p = 0.442), the analysis of the primary outcome revealed no difference in the proportion of patients who discontinued treatment between the aripiprazole and haloperidol groups. CONCLUSIONS This study indicates that augmentation of clozapine with aripiprazole offers no benefit with regard to treatment withdrawal and overall symptoms in schizophrenia as compared with augmentation with haloperidol. The analysis of the 12-month data from CHAT, confirm a trend of favourable advantage in the perception of adverse effects with aripiprazole, found out at 3-month analysis.