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T95

ROLE OF GLP-1 RECEPTOR AGONISTS IN MANAGING ANTIPSYCHOTIC-RELATED METABOLIC DYSFUNCTION AND WEIGHT GAIN

Abdul Khan — Areeba Nisar1, Mustafa Alam2, Saba Saleem1, Muhammad B. Memon1, David Abram1, Misbah Alam1, Faisal Suba1 1Valley Health System, 2Alam Medical Research

2026 ASCP Annual Meeting

Background

Patients receiving antipsychotic medications for severe and persistent psychiatric illness frequently experience significant metabolic side effects, including weight gain, insulin resistance, and type 2 diabetes. Glucagon-like peptide 1 (GLP1) receptor agonists have shown promising results in addressing antipsychotic-induced weight gain (AIWG) and improving metabolic outcomes. This literature review evaluated the effects of GLP-1 receptor agonists on weight loss and metabolic changes in patients with AIWG.

Methods

A systematic literature search was conducted on PubMed using the following keywords: (“Glucagon-Like Peptide 1 Receptor Agonists”) AND (“Antipsychotic Agents”) AND (“Obesity”), with filters applied for the past 20 years to include clinical trials (randomized and open) and meta-analyses. The search yielded 10 relevant studies. Data from all included studies were reviewed to address changes in body weight, and metabolic changes among patients with AIWG treated with GLP-1 receptor agonists.

Results

Of the 10 studies identified, two clinical trials evaluated semaglutide (HISTORI and COaST). The HISTORI trial included patients with schizophrenia on second-generation antipsychotics and obesity. The trial demonstrated that semaglutide reduced body weight by 9.21 kg (95% CI, −11.68 to −6.75) and significantly decreased HbA1c levels (P < .001) compared to placebo. The COaST trial enrolled patients receiving clozapine with < 5% baseline weight change; the semaglutide group achieved a statistically significant weight reduction of 13.88% (P < .0001). The HISTORI trial also showed improvement in quality of life by 3.75 points on the SF-36v2 (95% CI, 1.52–5.98; P = 0.001). Data on earlier GLP-1 receptor agonists, including exenatide and liraglutide, demonstrated mixed results. Exenatide trials showed either no significant weight change or weight loss comparable to placebo (P = 0.98). Liraglutide studies demonstrated improvements in glucose tolerance (P < 0.001), reductions in body weight (−5.3 kg; 95% CI), systolic blood pressure (−4.9 mm Hg; 95% CI), and visceral fat (−250.19 g; 95% CI). Only one study evaluated weight change one year after liraglutide discontinuation, showing a return to baseline weight. The most commonly reported adverse effects were gastrointestinal, including nausea, vomiting, and diarrhea.

Conclusion

GLP-1 receptor agonists, particularly newer agents such as semaglutide, are a promising and effective option for managing AIWG and metabolic dysfunction in patients requiring long-term antipsychotic therapy. These agents may play an important role in comprehensive care by decreasing the metabolic side effects of antipsychotics. However, larger randomized trials with longer follow-up are needed to better define long-term safety, durability of weight loss, and maintenance strategies after GLP-1 receptor agonists discontinuation.