02. Antipsychotic-Induced Weight Gain: Are GLP-1 Agonists Effective?

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GLP-1 Agonists for Antipsychotic Weight Gain

In this Quick Take today, we’re going to look at an important aspect of care for people treated with an antipsychotic — the issue of managing the so-called antipsychotic-induced weight gain with the help of a new class of weight loss medications called GLP-1 agonists. In order to help us think through this issue together, we will be looking at a recent review by Bak and Campforts from the Netherlands published in Acta Psychiatrica Scandinavica.

Why Weight Gain Matters Clinically

Before getting to the review, let me make a few remarks about why this review is clinically important. Weight gain is a side effect of pretty much any antipsychotic, with the possible exception of ziprasidone. Most patients simply do not want to gain weight and they will stop their medication at the first hint of weight gain or they will refuse to even consider starting an antipsychotic when you review side effects with them and when you mention weight gain, as you should by the way.

Unfortunately, most of our patients with schizophrenia spectrum disorders need an antipsychotic to stabilize their illness and maintenance treatment is an unfortunate reality to avoid a psychotic relapse once stabilized. Almost all patients will gain some weight during maintenance treatment.

So we need to figure out what to do about that. Apart from the aforementioned cosmetic or psychological aspect, I should say, weight gain comes with a host of medical morbidities and mortality ranging from:

• Obstructive sleep apnea
• Hypertension
• Diabetes
• Death from cardiovascular disease

Evolution of Weight Management Strategies

In my career of over 25 years in Clinical Psychiatry, I remember the days when weight gain became a prominent management issue with the introduction of the second-generation antipsychotics in the mid-1990s.

Initially, a lot of effort was spent on recommending monitoring and figuring out how to implement so-called guideline concordant monitoring. The usual recommendation in response to weight gain was diet and exercise, which as you may know from personal experience is not a terribly effective strategy.

The next step was prophylactic treatment with metformin, not necessarily to lose weight but to reduce the metabolic risks, specifically diabetes. Eventually, metformin actually became, I think, a standard approach that was included in guidelines, particularly for patients who needed metabolically high-risk antipsychotics like olanzapine or clozapine. Unfortunately, metformin is not a weight loss drug, and we did not really solve the issue of weight gain per se.

Introduction to GLP-1 Agonists

Fast-forward and unless you have been under a rock, you may have heard about a fairly new class of medications, so-called GLP-1 (glucagon-like peptide 1) agonists which mimic the action of the peptide hormone, GLP-1, and that causes at times dramatic weight loss. GLP-1 helps regulate blood sugar, and the GLP-1 agonists were initially developed and approved for the treatment of type 2 diabetes.

Their mechanism of action is complex and involves peripheral and central actions. It includes:

• Delaying gastric emptying, which promotes satiety
• A central mechanism to reduce hunger
• Increased insulin secretion
• Decreased glucagon secretion

The overall result is that people are less hungry, they lose weight and their blood sugar control improves.

Review Findings and Limitations

On to the review, which is really straightforward. The authors looked for pretty much any form of published trial or cohort study that involved weight gain from antipsychotics and treatment with a GLP-1 agonist. They then performed a systematic review and meta-analysis.

The catch was meager. They ended up with:

• Only six studies total
• 269 patients combined
• Three RCTs of exenatide (approved in US in 2005)
• Two RCTs and one cohort study using liraglutide

They basically found some weight loss with GLP-1 agonists while maintaining psychiatric stability, with a non-significant suggestion that liraglutide is perhaps more effective than exenatide.

Future Research Directions

Keep an eye out for publications of semaglutide, since there are several trials ongoing and close to finishing up or already finished that should be published soon. It is a fast-moving field, and we now have dual and triple agonists that work beyond GLP-1 agonism in regulating weight and metabolic parameters, and they seem even more potent.

We also need research to understand:

• Differences in response to GLP-1 agonists depending on the antipsychotic
• What happens when you stop the intervention
• How to best combine medication with other interventions for maximum benefit

Clinical Role for GLP-1 Agonists

The review is accompanied by an invited editorial that poses the question if there is a role for GLP-1 receptor agonists for the treatment of antipsychotic-induced weight gain. I agree with the answer that the authors are giving. Yes, there is a role, particularly for people on clozapine.

Unless weight gain and the metabolic risks are managed well in this cohort of patients, people have a very high risk of dying prematurely from cardiovascular disease, in part due to our iatrogenic contribution. It’s us that causes at least an aspect of the weight gain that people are experiencing.

Clinical Bottom Line

This is my clinical bottom line for today. When you prescribe antipsychotics, particularly olanzapine and clozapine, you and your clinic need to develop strategies to track and importantly to proactively manage the expected weight gain.

This may involve:

• Getting up to speed with GLP-1 agonists so you can prescribe them yourself
• Initially working with “adult supervision” from Primary Care or Internal Medicine colleagues
• Understanding drug-drug interactions (delayed gastric emptying can affect psychiatric drug absorption)
• At minimum, coordinating with patient’s PCP to assess GLP-1 agonist eligibility

Balancing Research and Implementation

To finish this Quick Take, let me add one concern about the call for more research that authors reflexively add to their research publications. I do the same. There is of course always the need for more research, including studying any new medication in particular subgroups like psychiatric patients and understanding its long-term efficacy and safety.

In psychiatric patients, we need to be sure that medical interventions do not inadvertently destabilize them psychiatrically, particularly from medications that affect the CNS like the GLP-1 agonists do. They have a central mechanism of action in addition to the peripheral one.

However, I do not think we can wait and lose a decade of new research that I suspect will basically confirm what we know today, that GLP-1 agonists are highly effective medications for weight loss including for people who gain their weight from antipsychotics. This review already points out, I think points that out fairly clearly. Therefore, we should close the research to implementation gap now while pushing ahead with more research in parallel.

I’m not arguing for you to be a cowboy or a loose cannon, but there is a potential opportunity cost that your patient pays if you are too conservative and if you wait too long with a promising new treatment. Last thought, weight management requires a team approach. You cannot do it alone, but be part of the team.

Abstract

Glucagon-like peptide agonists for weight management in antipsychotic-induced weight gain: A systematic review and meta-analysis

Maarten Bak, M.D.; Bea Campforts, M.D.; Patrick Domen, M.D.; Therese van Amelsvoort, M.D.; Marjan Drukker, M.D.

Introduction

Managing body weight in patients with antipsychotic-induced weight gain (AIWG) is challenging. Besides lifestyle interventions, pharmacological interventions may contribute to weight loss. This systematic review and meta-analysis evaluated the effect on weight loss and adverse effects of glucagon-like peptide-1 (GLP-1) agonists in patients with AIWG.

Materials and Methods

Following PRISMA guidelines, we performed a meta-analysis of blinded and open-label randomised controlled trials (RCTs), non-randomised controlled trials and cohort studies that evaluated treatment with GLP-1 in patients with AIWG, regardless of psychiatric diagnosis. PubMed, Embase, PsycINFO and Cochrane Library databases were searched. Primary outcome measures were changes in body weight and BMI. Secondary outcomes were changes in adverse effects and severity of psychopathology due to GLP-1 agonists.

Results

Only data for exenatide and liraglutide could be included, that is, five RCTs and one cohort study. For exenatide the mean weight loss was −2.48 kg (95% Confidence Interval (CI) −5.12 to +0.64; p = 0.07), for liraglutide the mean weight loss was −4.70 kg (95% CI −4.85 to −4.56; p < 0.001). The mean change in BMI was −0.82 (95% CI −1.56 to −0.09; p = 0.03) in the exenatide groups and −1.52 (95% CI −1.83 to −1.22; p < 0.001) in the liraglutide groups. Exenatide and liraglutide did not adversely affect psychopathology. The most common adverse events were nausea, vomiting, and diarrhoea.

Conclusion

The GLP-1 agonists exenatide and liraglutide are promising drugs for inducing weight loss in patients with AIWG. The adverse effects are acceptable, and the addition of GLP-1 does not increase the severity of psychopathology. However, more research is needed.

Reference

Bak, M. M.D.; Campforts B., M.D.; Domen, P. M.D.; van Amelsvoort, T. M.D.; Drukker, M. M.D. (2024). Glucagon-like peptide agonists for weight management in antipsychotic-induced weight gain: A systematic review and meta-analysis. Acta Psychiatrica Scandinavica, Volume150, Issue6, December 2024. Pages 516-529