02. Antipsychotic-Induced Weight Gain: Best Management Strategies

Text version

Antipsychotic-Induced Weight Gain: A Significant Concern

Weight gain and metabolic syndrome are two of the most concerning complications of treatment with antipsychotic agents. At least 50% of patients with schizophrenia experience weight gain with antipsychotics, and that figure is likely an underestimate.

In addition to impacts on self-image, weight gain brings with it a host of other metabolic problems, significantly increasing the risk for cardiovascular disease and contributing to the significantly decreased lifespan of patients with serious mental illness.

Studies have also shown that concerns about weight gain are one of the most common reasons why patients discontinue their antipsychotic medication. In fact, patients who gain weight are up to 13 times more likely to discontinue antipsychotics than those who don’t.

Antipsychotics and Weight Gain: A Trade-Off

Some of the most effective antipsychotics, including olanzapine and clozapine, have some of the highest rates of weight gain and metabolic effects. Weight gain has become so problematic with second-generation antipsychotics that some psychiatrists have started reevaluating whether second-generation antipsychotics are actually better for patients than first-generation antipsychotics, as the trade-off has become one of less EPS for more metabolic concerns.

Several antipsychotics, including ziprasidone and aripiprazole, were marketed as being weight neutral, but even these agents are likely to cause some degree of weight gain in antipsychotic-naïve patients. The only antipsychotic that was not associated with weight gain and may have actually caused some weight loss, molindone, is no longer widely available.

In this setting, many of our patients are desperate for solutions to antipsychotic-induced weight gain.

Management Strategies for Antipsychotic-Induced Weight Gain

Up until now, there had been a few different management strategies for patients experiencing antipsychotic-induced weight gain. For a long time, we were told to encourage patients to engage in lifestyle modifications, including dieting and exercise, but these can be extremely challenging for patients with psychosis to adhere to and often lead to only modest impact by themselves.

Metformin is probably the most widely used medication for antipsychotic-induced weight gain, but it hasn’t been widely adopted by most psychiatrists as something they would actually prescribe themselves.

Network Meta-Analysis: Comparing Treatment Options

A Cochrane systematic review and meta-analysis was done in 2023 to compare several options to placebo. The authors of the study recently published in General Hospital Psychiatry took things a step further by performing a network meta-analysis.

As they point out, this approach allows for comparisons between agents even if those comparisons were not made in the original studies, which gives it a significant advantage over a traditional meta-analysis and also allows for ranking of potential treatment options. The authors examined different doses of medications separately in order to compare dosing as well.

Medications examined in the network meta-analysis include:

• Metformin
• Topiramate
• Naltrexone
• Bupropion
• Fluoxetine
• Fluvoxamine
• Melatonin
• Amantadine
• Zonisamide
• Ranitidine
• Sibutramine, among many others

Overall, the authors compared nearly 70 specific doses of agents or combinations of agents.

Metformin and Lifestyle Modifications: The Most Effective Strategy

The major take-away from the article is that metformin 750 mg daily combined with lifestyle modifications is the most effective treatment strategy to combat antipsychotic-induced weight gain. Notably, the medication sibutramine, a tricyclic-like medication, was actually found to be more effective than metformin but has already been discontinued in most countries, including in the United States, due to cardiovascular concerns.

Topiramate 200 mg performed second best behind the combination of metformin and lifestyle modifications, followed by metformin 750 mg alone and topiramate 100 mg. Other medications like liraglutide and nizatidine were rated as having moderate effect.

One notable finding was that liraglutide actually performed best when the authors adjusted for a centering body weight, which they interpret to suggest that it might work better when started along with an antipsychotic at the beginning of treatment rather than waiting until the weight gain has occurred and attempting to counteract the weight gain.

Dosage Matters: Low-Dose Metformin Outperforms High-Dose

Because the authors examined different dosages and combinations independent from one another, they were able to determine that higher doses of metformin, which have been shown to be overall more efficacious for obesity in general, actually did not perform as well as the low-dose metformin in the study.

The authors note that this may have to do with the proposed mechanism for antipsychotic-induced weight gain, which involves both increased eating, specifically carbohydrates, and an increase in neuropeptide Y, the latter of which is counteracted by low-dose but not high-dose metformin through the release of leptin.

Topiramate: Promising Results but Cognitive Concerns

It’s notable that topiramate performed fairly well in this study and is often prescribed off-label for this indication. Unfortunately, topiramate also has very high rates of cognitive slowing, up to 33% in some studies, which is particularly detrimental in patients with schizophrenia who may already show cognitive impairment from the illness.

For this reason, many psychiatrists are reluctant to use it in patients with antipsychotic-induced weight gain despite some promising results.

Consistency with Prior Meta-Analysis

The findings here are largely consistent with the prior meta-analysis mentioned, with a few differences such as the study not finding a positive effect for zonisamide, fluoxetine, or for most H2 antihistamines. The authors attribute these differences to their more precise examination of individual agents and doses, whereas prior studies grouped drugs by class and looked at overall class effect.

Interestingly, the opposite was true for topiramate, which showed effect here at three different doses but had not shown effect in prior studies.

Take-Home Points for Clinicians

• It’s imperative that we recognize and pay attention to antipsychotic weight gain given how big a factor it is in adherence. Ask your patients about their weight gain and determine how distressing it is to them.
• If you have patients who have gained weight on antipsychotics, this study provides good evidence that the best management strategy is a combination of metformin and lifestyle changes. Metformin is a very safe medication with the main risk being very low rates of lactic acidosis.
• For patients just starting on antipsychotics who have not yet gained weight, metformin is certainly still a good option, but it seems like liraglutide could also be a reasonable agent to start in the hopes of preventing weight gain in the first place.
• If the patient has a PCP with whom they are well engaged, it would be reasonable to discuss with the PCP the possibility of them prescribing metformin. However, it’s important to recognize that for many of our patients, especially those with SMI, a psychiatrist may be the only physician they routinely see. If that’s the case, it behooves us to feel comfortable prescribing and managing metformin ourselves, as it may make the difference between adherence and non-adherence.

Abstract

Pharmacological interventions for antipsychotic-induced weight gain in schizophrenia: A network meta-analysis

Naveen Chandrashekar Hegde, M.D., Archana Mishra, M.D., Rituparna Maiti, M.D., Biswa Ranjan Mishra, M.D., Debadatta Mohapatra, M.D. & Anand Srinivasan, M.D.

Objective

Antipsychotic-induced weight gain (AIWG) is a significant but frequently neglected adverse effect of first- and second-generation antipsychotic therapy, which may lead to cardiovascular disturbances. The present network meta-analysis (NMA) was conducted to evaluate and compare the effects of available treatment options in antipsychotic-induced weight gain (AIWG).

Methods

The data was extracted from 68 relevant clinical trials after a literature search on MEDLINE/PubMed, Embase, Scopus, Cochrane databases and clinical trial registries. Random-effects Bayesian NMA was done to pool the effects across the interventions for the change in body weight from baseline. A network graph was built, a consistency model was run, node split analysis was performed, treatments were ranked as per the SUCRA score and meta-regression was done for the duration of therapy, baseline body weight and treatment strategy as the predictor variables. Finally, the results were sorted based on the certainty of evidence.

Results

The drugs showing significant reduction in body weight in order of magnitude of effect size include sibutramine 10 mg (−8.0 kg; −16. to −0.21), metformin 750 mg + lifestyle modification (−7.5 kg; −12 to −2.8), topiramate 200 mg (−7 kg; −10 to −3.4), metformin 750 mg (−5.7 kg; −9.3 to −2.1), topiramate 100 mg (−5.7 kg; −8.8 to −2.5), topiramate 50 mg (−5.2 kg; −10 to −0.57), liraglutide 1.8 mg (−5.2 kg; −10., −0.080), sibutramine 15 mg (−4.5 kg; −8.9 to −0.59), nizatidine 300 mg (−3.0 kg; −5.9 to −0.23) and metformin 1000 mg (−2.3 kg; −4.6 to −0.0046). There was no effect of duration of follow-up, baseline body weight and, preventive versus therapeutic strategy on weight reduction in AIWG.

Conclusion

Metformin 750 mg with lifestyle modification was the most effective treatment for AIWG, followed by topiramate 200 mg, metformin 750 mg, and topiramate 100 mg with moderate certainty of evidence.

Reference

Chandrashekar Hegde, N., M.D., Mishra, A., M.D., Maiti, R. M.D., Ranjan Mishra, B., M.D., Mohapatra, D., M.D. & Srinivasan, A., M.D. (2024). Pharmacological interventions for antipsychotic-induced weight gain in schizophrenia: A network meta-analysis. General Hospital Psychiatry, Volume 90, Pages 12-21.