Pharmacological Interventions for the Prevention of Antipsychotic-Induced Weight Gain in People With Schizophrenia: A Cochrane Systematic Review and Meta-Analysis

Abstract

Patients with schizophrenia are burdened by higher rates of obesity, cardiovascular disease and reduced life expectancy than the general population. In addition to illness, genetic and lifestyle factors, the associated weight gain and metabolic adverse effects of antipsychotic (AP) medications are known to exacerbate and accelerate these cardiometabolic problems significantly. Given the detrimental consequences of weight gain and other metabolic disturbances, there is an urgent need for safe and effective strategies to manage these issues as early on as possible. This review summarizes the literature of adjunctive pharmacological interventions aimed at preventing AP-induced weight gain.

Objectives

To review the effectiveness of pharmacological interventions for preventing AP-induced weight gain in people with schizophrenia.

Search Methods

The Cochrane Schizophrenia Information Specialist searched Cochrane Schizophrenia’s Register of Trials on June 16, 2014, August 5, 2015, September 4, 2019, and February 10, 2021. There was no language, date, document type, or publication status limitations for inclusion of records in the register.

Selection Criteria

Randomized controlled trials (RCTs) examining any adjunctive pharmacological intervention for preventing weight gain in people with schizophrenia or schizophrenia-like illnesses who use AP medications.

Data Collection and Analysis

At least 2 review authors independently extracted data and assessed the quality of included studies. We synthesized all studies in a quantitative meta-analysis according to agent/medication class using Review Manager 5.3. Mean differences (MD) was calculated for continuous outcomes and risk ratios for dichotomous outcomes.

Main Results

Seventeen RCTs (N = 1388 participants) published between 2003 and 2020, met inclusion criteria for this review. Five studies investigated metformin, 3 topiramate, 3 H2 antagonists, 3 monoamine modulators, and 1 each investigated monoamine modulators plus betahistine, melatonin, and samidorphan. The comparator in all trials was placebo or no treatment (ie, standard care alone). Most studies inadequately reported their methods of allocation concealment and blinding of participants and personnel. The resulting risk of bias and often small sample sizes limited the overall certainty of the evidence.

Metformin had the most evidence of being effective in preventing weight gain (MD −4.03 kg, 95% CI −5.78 to −2.28; 4 studies, N = 131; low-certainty evidence) and increases in body mass index (BMI) (MD −1.63 kg/m², 95% CI −2.96 to −0.29; 5 studies, N = 227; low-certainty evidence). Other agents that may be slightly effective in preventing weight gain include H2 antagonists such as nizatidine, famotidine, and ranitidine (MD −1.32 kg, 95% CI −2.09 to −0.56; 3 studies, N = 248; low-certainty evidence) and monoamine modulators such as reboxetine and fluoxetine (MD −1.89 kg, 95% CI −3.31 to −0.47; 3 studies, N = 103; low-certainty evidence). Topiramate did not appear effective in preventing weight gain (MD −4.82 kg, 95% CI −9.99 to 0.35; 3 studies, 168 participants; very low-certainty evidence). Figure 1 displays the weight outcomes for all comparisons. For all agents, there was no difference between groups in terms of individuals leaving the study early or reports of nausea. However, the results of these outcomes are uncertain given the very low-certainty evidence.

Fig. 1.

Average endpoint/change in weight outcomes with (A) Metformin, (B) H2 Antagonists, (C) Monoamine Modulators, and (D) Topiramate.

Author’s Conclusions

This review provides evidence supporting the safe use of pharmacological interventions to prevent AP-induced weight gain. Metformin has the most evidence to support that co-initiation along with an AP may lead to lesser weight gain. This medication has no safety concerns with a very good established safety and tolerability profile. The interpretation of other agents is limited given the small number of studies and low quality of evidence. We assert that future studies that are adequately powered with larger sample sizes and longer treatment durations are necessary for establishing the true effects of these adjunctive pharmacological agents for the prevention of AP-induced weight gain in schizophrenia. Additionally, the cost-effectiveness of these pharmacological agents should be studied as well. Full details of this review are reported elsewhere.¹

Cochrane Corner

This article is based on a Cochrane Review published in the Cochrane Database of Systematic Reviews (CDSR) 2022, Issue 10, DOI: 10.1002/14651858.CD013337.pub2. (see www.cochranelibrary.com for information). Cochrane Reviews are regularly updated as new evidence emerges and in response to feedback, and the CDSR should be consulted for the most recent version of the review.

Conflict of Interest Disclosure

MH has consultant fees from Alkermes, Inc. However, she declares that she did not receive any direct payment for completion of this review. All other funding details and conflicts of interest can be found in the main Cochrane report.