What to Do When Clozapine Response Is Inadequate? Augmentation Strategies

Abstract

Background: Clozapine is the most effective medication for treatment-refractory schizophrenia (TRS); however, only 40% of people will meet response criteria.\n\nObjectives: We conducted a systematic review and meta-analysis of the global literature on strategies for clozapine augmentation.\n\nMethods: PubMED, PsycInfo, Embase, Cochrane Database, Chinese Biomedical Literature Service System and China Knowledge Resource Integrated Database were systematically reviewed for randomized control trials of augmentation strategies for people with clozapine-resistant schizophrenia. We undertook pairwise meta-analyses of within-class interventions.\n\nFindings: A total of 46 studies of 25 interventions were included. The most effective augmentation agents for total psychosis symptoms were aripiprazole (standardized mean difference (SMD) −0.48; 95% confidence interval (CI) −0.89 to −0.07); fluoxetine (SMD −0.73; 95% CI −0.97 to −0.50); and sodium valproate (SMD −2.36; 95% CI −3.96 to −0.75). For negative symptoms, memantine may be effective (SMD −0.56; 95% CI −0.93 to −0.20). Many results included poor quality studies. Electroconvulsive therapy was highly promising.\n\nConclusions: On the basis of the limited available data, aripiprazole, fluoxetine and sodium valproate have the best evidence for use as augmentation agents for total psychosis symptoms. However, these conclusions are tempered by generally short follow-up periods and poor study quality.