- 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 effcacy in strictly defned 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 insuffcient, clinicians commonly add a second antipsychotic, although robust evidence to justify this practice, with regard to the potential benefts 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 schizo-phrenia unresponsive, at a criterion level of persistent symptom severity and impaired social function, to an adequate trial of clozapine monother-apy. Interventions comprised clozapine augmentation over 12 weeks with amisulpride or placebo. Participants received 400 mg of amisulpride or one matching placebo capsule for the frst 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 (defned 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 fnding was statistically signifcant. 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 signifcant differences between the active and placebo groups was limited. Conclusion: The risk-beneft of amisulpride augmentation of clozapine for schizophrenia that has shown an insuffcient response to a trial of clozap-ine 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 beneft 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 identifed for the amisulpride-clozapine combination may partly refect 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.