Metformin for treatment of clozapine-induced weight gain in adult patients with schizophrenia: a meta-analysis

BACKGROUND: Long-term use of clozapine for individuals with schizophrenia carries a high risk for developing metabolic abnormalities, especially clozapine-induced weight gain. Previous studies suggest that metformin can decrease clozapine-induced weight gain, but the sample sizes of most of these studies are relatively small. METHODS: We identified randomized controlled trials (RCTs) published prior to December 15, 2015 about the use of metformin to treat clozapine-induced weight gain in adults with schizophrenia by searching several English-language and Chinese-language databases. Two independent researchers did the screening and data extraction. We used Revman 5.3 to conduct the meta-analyses, assessed the risk of bias (RoB), and assessed the strength of the evidence using the Cochrane Grades of Recommendation, Assessment, Development, and Evaluation (GRADE). RESULTS: Six studies with a pooled sample of 207 treatment-group patients and 207 control-group patients were included —— three double-blind, placebo-controlled RCTs and three RCTs that did not use placebo controls and were not blinded. The meta-analysis found that compared to the control condition, patients receiving metformin experienced significantly greater reductions in body weight (mean difference [MD]=-2.89 kg, 95% CI: -4.20 to -1.59 kg) and body mass index (BMI) (MD=-0.81, 95% CI: -1.16 to -0.45), but there was no significant difference between the groups in the prevalence of side effects. Based on the GRADE scale, the strength of the evidence for the change in weight outcome was ‘moderate’ and that for the change in BMI outcome was ‘high’, but the strength of evidence about differences in side effects between groups was ‘low’ or ‘very low’. CONCLUSIONS: Adjunctive treatment with metformin appears to be effective for treating clozapine-induced weight gain and elevations in BMI in adult patients with schizophrenia. However, the quality of the evidence about the safety of this treatment is low, follow-up time in the available studies is relatively short, and half of the studies did not employ blinded assessment of outcome measures. Larger studies with placebo controls that follow patients for at least 24 weeks and that make blinded assessments of a range of relevant outcome measures (weight, BMI, blood lipids, insulin resistance, etc.) are needed to confirm these results.