Antipsychotic treatment is associated with weight gain and metabolic syndrome, a constellation of metabolic risk factors associated with the development of atherosclerotic cardiovascular disease. Cardiovascular disease is the leading cause of death in patients with schizophrenia.1 The metabolic syndrome is common in patients with schizophrenia, with a prevalence of 43% in the Clinical Antipsychotic Trials of Intervention Effectiveness.2
Metformin is an anti-diabetic agent that enhances the action of insulin in the liver (and thereby decreases hepatic glucose production) and suppresses appetite. In addition to its use in type 2 diabetes mellitus, metformin is also used to treat obesity in persons who do not have diabetes by decreasing both insulin resistance and appetite. Metformin has been investigated for the treatment of antipsychotic-induced weight gain in several randomized controlled trials.
De Silva and colleagues3 conducted a meta-analysis of all randomized double-blind placebo-controlled trials of metformin in patients with DSM-IV, DSM-V, or ICD-10 schizophrenia or schizoaffective disorder. They performed a systematic search of the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE.
Trials of metformin alone or metformin plus lifestyle intervention were included. Open-label trials and observational studies were excluded. The primary outcome measure was mean change in weight. Secondary outcomes were change in BMI, fasting glucose, and the insulin resistance index.
One hundred thirty-seven studies were screened, and 12 studies comprising 743 patients met the inclusion/exclusion criteria. In most studies, metformin was dosed at 1000 mg per day. Ten studies were performed in adults, and 2 studies included children and adolescents.
The authors found that metformin was associated with significantly greater absolute weight loss (-3.3 kg) and percentage weight loss (-5.0%) than placebo. Metformin was also associated with significantly greater reduction in BMI (-1.1 kg/m2) than placebo. Fasting glucose was non-significantly reduced (-2.5 mg/dL), but the insulin resistance index was significantly reduced (-1.5) in patients treated with adjunctive metformin. Rates of discontinuation and adverse events were low in both metformin and placebo groups.
In a subgroup analysis, the pattern of results was similar in studies of adults and children and adolescents, considered separately. Importantly, the effects of metformin on weight were greater in studies of patients with first-episode psychosis (-5.9 kg) than in those of patients with chronic illness (-2.1 kg).
The bottom line
The authors found evidence that adjunctive metformin was associated with significantly greater reductions in weight, BMI, and metabolic parameters than placebo during antipsychotic treatment in patients with schizophrenia or schizoaffective disorder. Findings suggest more robust effects of metformin earlier in the course of the disorder. They concluded that metformin should have more widespread use in patients with antipsychotic-induced weight gain.
Dr. Miller is Associate Professor in the Department of Psychiatry and Health Behavior at Augusta University in Augusta, GA, and Schizophrenia Section Editor for Psychiatric Times. He reports no conflicts of interest concerning the subject matter of this article.
1. Saha S, Chant D, McGrath J. A systematic review of mortality in schizophrenia: is the differential mortality gap worsening over time? Arch Gen Psychiatry. 2007;64:1123-1131.
2. McEvoy JP, Meyer JM, Goff DC, et al. Prevalence of the metabolic syndrome in patients with schizophrenia: baseline results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial and comparison with national estimates from NHANES III. Schizophr Res. 2005;80:19-32.
3. De Silva VA, Suraweera C, Ratnatunga SS, et al. Metformin in prevention and treatment of antipsychotic induced weight gain: a systematic review and meta-analysis. BMC Psychiatry. 2016;16:341.