Systematic Review and Meta-analysis of Pharmacological Interventions for Weight Gain from Antipsychotics and Mood Stabilizers

Abstract

Pharmacological treatments for serious mental illness (SMI) can cause weight gain and adverse metabolic effects. Many second generation antipsychotics and mood stabilizers appear to be particularly problematic in this regard. Several studies have investigated interventions for antipsychotic-induced, or less commonly mood stabilizer -induced, weight gain. Both lifestyle and pharmacological interventions have demonstrated effectiveness. We systematically review randomized controlled trials of pharmacological interventions for weight gain related to these medications. We conducted a meta-analysis of clinical trials for the most studied agents to estimate mean weight loss: metformin (2.93 kg, 95% C.I. 0.97-4.89, p=0.003), H(2) antagonists (1.78 kg (95% C.I. -0.50-4.06, p=0.13), topiramate (3.95 kg 95% C.I. 1.77-6.12, p=0.0004), and norepinephrine reuptake inhibitors (1.30 kg (95% C.I. -0.06-2.66, p=0.06). Among the studied options for antipsychotic-related weight gain, metformin has the strongest evidence base and may improve vascular risk factors beyond obesity. The use of topiramate is also supported by the literature and may improve psychotic symptoms in those refractory to treatment. A marginal benefit is seen with norepinephrine reuptake inhibitors, and any vascular benefits from such weight loss may be counteracted by increases in blood pressure or heart rate. Pharmacological therapies may offer benefits as a means of supplementing the effects of lifestyle changes for weight loss. However, the existing evidence provides little evidence of specificity for pharmacological therapies to antipsychotic-induced weight gain and has not studied any connection between benefits and reduced incidence of diabetes mellitus or any vascular outcomes.

Figure 1. Causes of Excess Death in Serious Mental Illness

Vascular disease is the leading cause of excess mortality in bipolar disorder and schizophrenia. Data for figure aggregated from similarly designed studies in Sweden by Osby et al. Archives of General Psychiatry 2001 and Osby et al. Schizophrenia Research 2000.

Figure 2. Meta-analysis of metformin for antipsychotic-related weight gain

The forest plot summarizes the results of 7 randomized, double-blind, placebo controlled trials of metformin. The overall effect supports the use of metformin for this indication with a mean difference of 2.93 kg (95% C.I. 0.97–4.89 I²=91%) difference in weight loss with metformin over placebo.

Figure 3. Meta-analysis of H₂ antagonists for antipsychotic-related weight gain

The forest plot summarizes the results of 5 randomized, double-blind, placebo controlled trials of nizatidine (4) or famotidine (1). The overall effect fails to support this indication with a non-significant mean difference of 1.78 kg (95% C.I. −0.50–4.06, I²=94%) between active treatment and placebo. Exclusion of the famotidine study does not substantially change these results.

Figure 4. Meta-analysis of topiramate for antipsychotic-related weight gain

The forest plot summarizes the results of 4 randomized, double-blind, placebo controlled trials of topiramate. The overall effect supports the use of topiramate for this indication with a mean difference of 3.95 kg (95% C.I. 1.77–6.12, I²=86%) in weight loss with topiramate over placebo. Exclusion of the Narula et al. 2010 study of incident users reduced the heterogeneity with an estimate of the mean difference in weight loss of 2.98 kg (95% C.I. 1.83–4.14, I²=33%).

Figure 4. Meta-analysis of topiramate for antipsychotic-related weight gain

The forest plot summarizes the results of 4 randomized, double-blind, placebo controlled trials of topiramate. The overall effect supports the use of topiramate for this indication with a mean difference of 3.95 kg (95% C.I. 1.77–6.12, I²=86%) in weight loss with topiramate over placebo. Exclusion of the Narula et al. 2010 study of incident users reduced the heterogeneity with an estimate of the mean difference in weight loss of 2.98 kg (95% C.I. 1.83–4.14, I²=33%).

Figure 5. Meta-analysis of norepinephrine reuptake inhibitors for antipsychotic-related weight gain

The forest plot summarizes the results of 3 randomized, double-blind, placebo controlled trials of reboxetine (2) or atomoxetine (1). A non-significant effect is observed for this class of agents with a mean difference of 1.30 kg (95% C.I. −0.06–2.66, p=0.06, I²=56%) in weight loss between norepinephrine reuptake inhibitors and placebo.