Amisulpride augmentation of clozapine for treatment-refractory schizophrenia: The amicus study

Abstract

Background: In around a third of people with schizophrenia, the illness responds poorly to standard treatment with antipsychotic medication. Clozapine is the only antipsychotic medication with robust evidence for efficacy in strictly defined treatment-resistant schizophrenia, but even then, an adequate response is seen in only 30%–60% of patients. When a trial of clozapine proves to be insufficient, clinicians commonly add a second antipsychotic, although robust evidence to justify this practice, with regard to the potential benefits and risks, is lacking.

Methods: The AMICUS study was a multicentre, double-blind, individually randomized, placebo-controlled trial with follow-up at 12 weeks. Eligible participants were people aged 18–65 years with treatment-resistant schizophrenia unresponsive, at a criterion level of persistent symptom severity and impaired social function, to an adequate trial of clozapine monotherapy. Interventions comprised clozapine augmentation over 12 weeks with amisulpride or placebo. Participants received 400 mg of amisulpride or one matching placebo capsule for the first 4 weeks, after which there was a clinical option to titrate the dosage of amisulpride up to 800 mg or 2 matching placebo capsules for the remaining 8 weeks.

Results: A total of 68 participants were randomized. Compared with the participants assigned to placebo, those receiving amisulpride had a greater chance of being a responder (defined as a 20% or more reduction in total score on the Positive and Negative Syndrome Scale by the 12-week follow-up: OR: 1.17, 95% CI: 0.40–3.42) and a greater improvement in negative symptoms, although neither finding was statistically significant. Amisulpride was associated with a greater side effect burden, including cardiac side effects. The trial under-recruited and, therefore, the power of statistical analysis to detect significant differences between the active and placebo groups was limited.

Conclusion: The risk-benefit of amisulpride augmentation of clozapine for schizophrenia that has shown an insufficient response to a trial of clozapine monotherapy is worthy of further investigation in larger studies. The design of future trials of such a treatment strategy should take into account that any modest benefit with the clozapine-amisulpride combination may be delayed beyond the 4–6 week follow-up considered adequate for acute psychotic episodes. The size and extent of the side effect burden identified for the amisulpride–clozapine combination may partly reflect the comprehensive assessment of side effects in this study. It has implications for the safety and tolerability monitoring of clozapine augmentation with a second antipsychotic in clinical and research settings.-