Abstract
Background
Weight gain and obesity are common problems encountered by patients with schizophrenia. This is partially attributable to use of second-generation antipsychotics that are associated with weight gain and other metabolic disturbances. The significance of this prevalence and its impact on premature mortality and morbidity requires better consensus on its management. The objective of this review is to determine the effects of adjunctive pharmacological interventions aimed at reducing weight gain in schizophrenia.
Methods
We searched the Cochrane Schizophrenia Group’s Trials Register which is based on regular searches of CINAHL, BIOSIS, AMED, EMBASE, PubMed, MEDLINE, PsycINFO, and registries of clinical trials. Inclusion criteria consisted of all randomized controlled trials examining any adjunctive pharmacological intervention for weight loss in patients with schizophrenia or schizophrenia-like illnesses. The primary outcome of each study had to be body weight or a weight related measure. We reliably selected, quality assessed, and extracted data from studies. As endpoint and change data was combined in the analysis, mean differences (MD) of the change from baseline were calculated using Review Manager 5.3.
Results
Sixty-one randomized controlled trials met inclusion criteria for this review (pooled n = 3328). Metformin is effective in bringing about modest weight loss (Weight: MD -3.40 kg, 95% CI -4.63 to -2.16; participants = 731; studies = 12; BMI: MD -1.39, 95% CI -1.94 to -0.85; participants = 879; studies = 13). Heterogeneity was reduced by dividing populations into first episode psychosis (FEP) and chronic populations, where FEP patients appeared to benefit most from early metformin intervention (Weight: MD -5.18 kg, 95% CI -6.22 to -4.14; BMI: MD -1.87 kg/m2, 95% CI -2.19 to -1.56; participants = 214; studies = 3) as compared to chronic patients (Weight: MD -2.22 kg, 95% CI -3.07 to -1.37; participants = 517; studies = 9; BMI: MD -1.18 kg/m2, 95% CI -1.89 to -0.48; participants = 665; studies = 10). However, ethnicity could be a confounder for the apparent effect of illness stage, as all first episode metformin intervention studies were conducted in patients with Chinese ethnicity. Metformin as a treatment for weight gain may be associated with additional adaptive changes in fasting insulin levels and insulin resistance. The frequency of adverse effects did not differ between metformin and placebo groups. Moreover, glucagon-like peptide agonists (GLP-1RAs), such as liraglutide and exenatide, were also effective in reducing weight (Weight: MD -3.95 kg, 95% CI -7.08 to -0.83; participants = 165; studies = 3; BMI -1.26 kg/m2, 95% CI -2.21 to -0.30; participants = 165; studies = 3; waist circumference: MD -3.25, 95% CI -5.93 to -0.57; participants = 165, studies = 3). The frequency of adverse effects did not differ between GLP-1RA and placebo groups. Topiramate 200 mg was also effective for weight reduction (Weight: MD=-6.61 kg, 95% CI -9.62 to -3.61; BMI: MD=-2.72, 95% CI -3.25 to -2.20; participants = 181, studies = 3).
Discussion
This review highlights the promise of pharmacological interventions for decreasing weight gain associated with antipsychotic use. Of the drugs studied, metformin has the most evidence and was most effective in bringing about modest weight loss. Topiramate and GLP-1RA also have accumulating evidence supporting efficacy in reducing weight. Interpretation for other agents is limited by the small number of studies, sample size, and short study duration. Future studies that are adequately powered, with longer treatment duration, will be needed in evaluating the efficacy and safety of interventions for managing weight gain further.
Preventing weight gain more important than weight loss and more realistic to study in cohorts than in randomized controlled trials