GLP-1 Agonists for antipsychotic-induced weight gain

CaseMaria, a 42-year-old female patient living with schizophrenia, has been stable on clozapine for five years. Clozapine has been transformative, allowing her to gain control of her psychotic symptoms and return to her job. However, she has gained more than 20 kg since starting clozapine. Despite efforts at lifestyle modification and receiving metformin 1000 mg twice daily, she feels increasingly ashamed of her appearance and struggles with low mood related to the weight gain. Her mental health team wonders if a glucagon-like peptide 1 receptor agonist (GLP-1 RA) could be a suitable adjunct for Maria to address the metabolic consequences of her antipsychotic treatment.BackgroundAntipsychotics are the foundation of treatment for schizophrenia and other psychotic disorders.1 Clozapine remains the gold standard for treatment-resistant schizophrenia, but its benefits come at the cost of profound metabolic risk.1,2 Other second-generation antipsychotics, including olanzapine, risperidone, paliperidone and quetiapine, are also well known to cause obesity, dyslipidemia, hypertension and type 2 diabetes.2 These adverse effects not only drive excess morbidity and mortality, but also contribute distress and subsequently to poor medication adherence.2Lifestyle interventions, such as exercise and nutrition education, can modestly reduce antipsychotic-induced weight gain (AIWG), but these effects are often not clinically significant and these interventions may be difficult to sustain or access.2,3 Metformin is the best studied pharmacologic adjunct for antipsychotic-induced weight gain, although weight loss is modest (approximately 3 kg).2,3 Other medications, such as topiramate or orlistat, may reduce weight but are limited by significant adverse effects.3 Historically, management of AIWG has been reactive. However, a 2025 guideline now recommends starting metformin concurrently with antipsychotic therapy as a preventive strategy, and initiating GLP-1 RAs according to their approved indications.2GLP-1 RAs, initially marketed for type 2 diabetes, are increasingly used in obesity management given their dual effects on glycemic control and weight reduction.2,3 GLP-1 signalling regulates satiety, slows gastric emptying and improves glycemic control.4 Clozapine and other antipsychotics may impair GLP-1 pathways, creating a biologic rationale for using GLP-1 RAs in this population.3 With multiple GLP-1 RAs now available in Canada (i.e., liraglutide, semaglutide, dulaglutide), as well as a combined GLP-1 RA and gastric inhibitory polypeptide (GIP) analog (i.e., tirzepatide), their role in antipsychotic-associated metabolic complications is a growing clinical consideration.3,5Evidence summaryAn increasing number of studies have investigated the use of GLP-1 RAs to reduce weight in individuals receiving antipsychotics.6-14 A 2016 review summarized 13 articles on the potential use of GLP-RAs in individuals living with schizophrenia and a single case report describing successful weight loss with liraglutide in a patient receiving clozapine.6 Preclinical findings and data from nonpsychiatric populations discussed in the article identified GLP-1 RAs as a promising strategy to mitigate clozapine-associated weight gain and diabetes.6Emerging evidence has specifically evaluated the use of GLP-1 RAs in patients with psychotic disorders receiving antipsychotic therapy. The CODEX trial (2018), a 24-week open-label randomized controlled trial (RCT), found that exenatide (no longer marketed in Canada) led to significantly greater weight loss compared with usual care in clozapine-treated patients (5.29 kg versus 1.12 kg, p=0.015), with improvements in fasting glucose and glycated hemoglobin (A1C).7 Six of 14 patients on exenatide achieved a > 5% weight loss compared to one receiving usual care (p=0.019).7A 2019 systematic review and meta-analysis pooling three trials (n=164; exenatide once weekly–2 studies, liraglutide once daily–1 study) found that 16 weeks of GLP-1 RA treatment resulted in a mean weight loss of 3.71 kg more than controls, with greater benefit in clozapine/olanzapine users (-4.7 kg) compared with other antipsychotics (-1.5 kg).8 The number needed to treat for a ≥ 5% weight loss was 3.8. Nausea was the most frequent adverse event (number needed to harm approximately 3.8).8 A 2024 systematic review included five RCTs and one cohort study.9 Mean weight loss was 2.48 kg with exenatide and 4.7 kg with liraglutide. Importantly, GLP-1 RAs did not worsen psychiatric symptoms. Gastrointestinal adverse effects were common but manageable.9Recent research has increasingly focused on semaglutide as a promising GLP-1 RA for managing AIWG. In a case series of 12 patients who had not responded to metformin, weight reductions of 4.56–8.67 kg over three to 12 months were reported with injectable semaglutide (0.71 +/- 0.47 mg/weekly), with good tolerability.10 Similarly, in a prospective nonrandomized cohort, oral semaglutide produced a mean weight loss of 4.5 kg over 16 weeks, versus 2.9 kg in the metformin group, with improvements in body mass index and waist circumference.11 The differences in weight loss between the semaglutide and metformin groups were not statistically significant.11In a larger Danish cohort of 154 patients with schizophrenia and prediabetes, weekly semaglutide injections reduced A1C by 0.46% and body weight by 9.2 kg over 30 weeks, accompanied by improvements in physical quality of life and no worsening of psychiatric symptoms.12 Additionally, in the COaST trial (2025), clozapine-treated patients receiving semaglutide achieved a 13.88% reduction in body weight at 36 weeks compared with minimal change in the placebo group (0.42%).13 No differences in clozapine concentrations or psychotic symptoms were observed.13 Lastly, a retrospective cohort study published in 2025 aimed to estimate the weight changes after semaglutide or tirzepatide prescriptions in patients taking antipsychotics. Those prescribed incretin-based medications lost 2.17 kg (95% CI: −2.49 to −1.84), and were 1.71 (95% CI: 1.63 to 1.80) times more likely to achieve 5% weight loss, relative to those who did not receive prescriptions.14Key takeaways and practical considerationsGLP-1 RAs consistently demonstrate clinically meaningful reductions in weight and improvements in glycemic control among patients with AIWG, particularly those receiving clozapine or olanzapine. Psychiatric stability is maintained across studies, and gastrointestinal side effects including nausea, vomiting and diarrhea are generally manageable. Despite these encouraging results, access to GLP-1 RAs is constrained by high cost and coverage restrictions to diabetes or obesity indications, highlighting the need for advocacy in populations with severe mental illness.3Back to the patient caseFor Maria, the addition of a GLP-1 RA represents a promising next step after limited benefit from lifestyle interventions and metformin. Semaglutide has shown efficacy in weight reduction and glycemic control, with demonstrated safety in patients living with schizophrenia and receiving clozapine. While drug coverage remains a barrier in some jurisdictions, pharmacist advocacy and patient-centred care planning could help overcome this. Addressing Maria’s weight gain may not only improve her physical health but also restore self-confidence and quality of life, supporting continued adherence to clozapine and long-term psychiatric stability.SummaryGLP-1 RAs are an exciting therapeutic option for mitigating AIWG. Evidence supports meaningful reductions in body weight and improved metabolic outcomes, without compromising psychiatric stability. Pharmacists are uniquely positioned to bridge the gap between emerging evidence and clinical practice through patient education, adverse effect monitoring and advocacy for drug access. As research expands, GLP-1 RAs may soon become standard adjuncts in the management of antipsychotic-related metabolic complications.Katelyn Halpape is a clinical pharmacist at the Dube Centre for Mental Health in Saskatoon, SK, and an associate professor in the College of Pharmacy and Nutrition at the University of Saskatchewan.References:Addington D, Anderson E, Kelly M, et al. Canadian practice guidelines for comprehensive community treatment for schizophrenia and schizophrenia spectrum disorders. Can J Psychiatry 2017;62(9):662-72.Carolan A, Hynes-Ryan C, Agarwal SM, et al. Metformin for the prevention of antipsychotic-induced weight gain: guideline development and consensus validation. Schizophr Bull 2025;51(5):1193-205.Kisely S, Siskind D, Speyer H. Latest findings challenge behavioural approaches to the management of antipsychotic-induced weight gain. BJPsych Open 2025;11(3):e85.Collins L, Costello RA. Glucagon-like peptide-1 receptor agonists. In: StatPearls [Internet]. 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Acta Psychiatr Scand 2024;150(6):516-29.Prasad F, De R, Korann V, et al. Semaglutide for the treatment of antipsychotic-associated weight gain in patients not responding to metformin - a case series. Ther Adv Psychopharmacol 2023;13:20451253231165169.Campforts B, Drukker M, van Amelsvoort T, et al. Management of obesity with semaglutide or metformin in patients with antipsychotic-induced weight gain (MOSA): a non-randomised open-label pilot study. BMC Psychiatry 2024;24(1):865.Ganeshalingam AA, Uhrenholt N, Arnfred S, et al. Semaglutide treatment of antipsychotic-treated patients with schizophrenia, prediabetes, and obesity: the HISTORI randomized clinical trial. JAMA Psychiatry 2025 Sep 3:e252332.Siskind D, Baker A, Arnautovska U, et al. Efficacy and safety of semaglutide versus placebo for people with schizophrenia on clozapine with obesity (COaST): a phase 2, multi-centre, participant and investigator- blinded, randomised controlled trial in Australia. 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