GLP-1 Receptor Agonists for Antipsychotic Weight Gain: What the Evidence Shows
What You Will Learn
- How GLP-1 receptor agonists (GLP-1RAs) perform against antipsychotic-induced weight gain (AIWG) in patients with severe and persistent mental illness (SPMI), including the first RCT data in clozapine-treated schizophrenia
- Why traditional weight management strategies frequently fail in SPMI, and where GLP-1RAs fit relative to current first-line pharmacotherapy (metformin)
- The safety and tolerability profile of GLP-1RAs in this population, including psychiatric symptom signal (or the absence of one)
- The access gap, cost-effectiveness data, and policy levers that determine whether any of this translates to real patients
TL;DR: Semaglutide produced 13.88% mean weight loss versus 0.42% with placebo in the first RCT of a GLP-1 agonist in clozapine-treated schizophrenia, without worsening psychotic symptoms, but the trial enrolled only 31 participants and most large GLP-1RA trials explicitly excluded patients with SPMI.
Abstract
Patients with severe and persistent mental illness (SPMI) experience significant metabolic side effects from antipsychotic medications, including antipsychotic-induced weight gain (AIWG). This contributes to a high prevalence of obesity, insulin resistance, and type 2 diabetes in this population, ultimately reducing life expectancy. Traditional weight management strategies, such as behavioural interventions, are often less feasible in this group. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), initially developed for type 2 diabetes, have shown promise in addressing AIWG by reducing weight, improving metabolic parameters, and offering potential neuroprotective and psychiatric benefits. Evidence supports the efficacy of GLP-1RAs in managing AIWG, with studies demonstrating substantial reductions in weight and body mass index without exacerbating psychiatric symptoms. However, access to these medications remains limited due to high costs and restrictive healthcare policies. Expanding access to GLP-1RAs could bridge a critical gap in care for patients with SPMI, improving both physical and mental health outcomes. Future research should focus on evaluating long-term efficacy and cost-effectiveness, particularly in the Canadian healthcare context, to inform policy changes and optimize treatment strategies.
Source: Jacobson S, Margolese N, Margolese HC. GLP-1 Receptor Agonists as a Novel Solution for Antipsychotic-Induced Weight Gain in Severe and Persistent Mental Illness. The Canadian Journal of Psychiatry / La Revue Canadienne de Psychiatrie. 2025;1–7.
DOI: 10.1177/07067437251386626
PubMed: Not yet indexed at time of publication
Open Access: Yes (SAGE, CC license)
Study at a Glance
| Design | Perspective article synthesizing RCT, cohort, systematic review, and preclinical data on GLP-1RAs for AIWG in SPMI |
| Primary Population of Interest | Adults with severe and persistent mental illness (SPMI), particularly schizophrenia and schizoaffective disorder, receiving second-generation antipsychotics (especially clozapine and olanzapine) |
| Anchor RCT (COaST) | N = 31; once-weekly semaglutide 2.0 mg vs. placebo; 36 weeks; clozapine-treated schizophrenia |
| Primary Endpoint (COaST) | Weight loss at 36 weeks |
| Key Finding | Semaglutide: 13.88% mean weight loss vs. 0.42% placebo (P < 0.0001); no worsening of psychotic symptoms; no change in clozapine or norclozapine plasma levels |
Study Snapshot: Key Statistics
| Study / Data Source | Intervention | N | Duration | Weight Outcome | Psychiatric Safety |
|---|---|---|---|---|---|
| COaST (Siskind et al., 2025) | Semaglutide 2.0 mg/wk vs. placebo | 31 | 36 wks | −13.88% vs. −0.42% (P < 0.0001) | No psychosis worsening; clozapine levels unchanged |
| Canadian Case Series (Prasad et al., 2023) | Semaglutide (metformin non-responders) | 12 | 12 months | Mean −8.67 kg (P = 0.04); 41.6% lost >7% body weight | No serious AEs reported |
| Bak et al. Systematic Review (2024) | Liraglutide vs. exenatide for AIWG | Multiple studies | 12–24 wks | Liraglutide: −4.70 kg (P < 0.001); Exenatide: −2.48 kg (P = 0.07) | No worsening of psychiatric symptoms |
| Breit & Hubl Systematic Review (2025) | GLP-1RAs in patients on second-generation antipsychotics | 36 studies | Variable | Consistent reductions in weight, BMI, waist circumference, fasting glucose, HbA1c | Improved depressive symptoms and global functioning in some studies |
| Xie et al. VA Cohort (2025) | GLP-1RAs vs. other antihyperglycemics | 1,960,067 | Real-world | Not primary focus | Lower risk: substance-related disorders, suicidal ideation/self-harm, psychotic disorders, dementia, seizures |
| STEP 1 (Wilding et al., 2021) | Semaglutide 2.4 mg/wk (no SPMI) | 1,961 | 68 wks | −14.9% vs. −2.4%; 86.4% achieved ≥5% WL | Not assessed (SPMI excluded) |
| SURMOUNT-1 (Jastreboff et al., 2022) | Tirzepatide 5–15 mg/wk (no SPMI) | 2,539 | 72 wks | Up to −20.9% (15 mg); −15.0% (5 mg) | Not assessed (SPMI excluded) |
Study Facts
| Authors | Samantha Jacobson MSc, Noah Margolese MSc, Howard C. Margolese MD CM MSc FRCPC |
| Institutions | Faculty of Medicine, Université de Sherbrooke; Department of Psychiatry, McGill University Health Centre |
| Journal | The Canadian Journal of Psychiatry / La Revue Canadienne de Psychiatrie |
| Year | 2025 (Epub ahead of print) |
| DOI | 10.1177/07067437251386626 |
| Article Type | Perspective (narrative synthesis) |
| Intervention | GLP-1 receptor agonists (semaglutide, liraglutide, exenatide, tirzepatide) as adjuncts for AIWG in SPMI |
| Comparator | Placebo, metformin, other antihyperglycemics, and other GLP-1RAs depending on referenced study |
| Primary Endpoint (COaST) | Percent body weight change at 36 weeks |
| Key Results | COaST: −13.88% vs. −0.42% (P < 0.0001); Canadian case series: −8.67 kg mean (P = 0.04); Liraglutide for AIWG (Bak): −4.70 kg (P < 0.001) |
| Adverse Events | GI effects predominate (nausea, vomiting, diarrhoea); transient and mild-to-moderate; no serious AEs in case series; tolerability consistent across referenced trials |
| Funding | None declared for this article |
| Conflicts of Interest | H.C. Margolese: advisory boards/speaker bureaus for AbbVie, Bausch Health, BI, HLS, Janssen, Newron, Otsuka, Lundbeck, Teva; funded research from AIFred, MGH Foundation, Newron, SyneuRx. Jacobson and N. Margolese: none declared. |
What Researchers Actually Did
Jacobson, N. Margolese, and H.C. Margolese authored a perspective article in The Canadian Journal of Psychiatry synthesizing available evidence on GLP-1 receptor agonists as a treatment for antipsychotic-induced weight gain (AIWG) in patients with severe and persistent mental illness (SPMI). The authors drew on seven major GLP-1RA RCTs in obesity and type 2 diabetes (STEP 1, 3, 4, 5, 8; SUSTAIN-3; SURMOUNT-1), the COaST trial (the first RCT of semaglutide specifically in clozapine-treated schizophrenia), a Canadian case series of semaglutide in metformin non-responders, two systematic reviews focused on GLP-1RAs in antipsychotic-treated populations, a large US Veterans Affairs cohort study (Xie et al., N = 1,960,067), and preclinical murine data on liraglutide’s antipsychotic-like effects. They also reviewed Canadian cost-effectiveness and access data.
The article was not designed to generate new primary data. Its purpose was to synthesize existing literature, contextualize GLP-1RA evidence within the SPMI treatment landscape, identify gaps in SPMI-specific research, address pharmacokinetic concerns (particularly the interaction between GLP-1RA-delayed gastric emptying and oral antipsychotic absorption), and make a policy argument for expanded access within the Canadian healthcare system. The COaST trial serves as the primary source of SPMI-specific RCT data throughout the synthesis.
Key Findings: Primary Outcomes
- COaST (clozapine-treated schizophrenia, N = 31, 36 weeks): Semaglutide 2.0 mg once-weekly produced mean weight loss of 13.88% versus 0.42% with placebo (P < 0.0001). Clinically significant weight loss was achieved by 93.3% (≥5%) and 66.7% (≥10%) of semaglutide-treated participants.
- Canadian case series (metformin non-responders, N = 12, 12 months): Mean weight loss of 8.67 ± 9.0 kg (P = 0.04); 41.6% of patients lost more than 7% body weight. No serious adverse events were reported.
- Bak et al. systematic review (liraglutide for AIWG in schizophrenia/schizoaffective disorder, 12–24 weeks): Liraglutide reduced weight by a mean of 4.70 kg (95% CI: −4.85 to −4.56; P < 0.001) and BMI by 1.52 kg/m² (95% CI: −1.83 to −1.22; P < 0.001). Exenatide reduced weight by 2.48 kg (95% CI: −5.12 to +0.64; P = 0.07) and BMI by 0.82 kg/m² (95% CI: −1.56 to −0.09; P = 0.03).
- Breit & Hubl systematic review (36 studies, second-generation antipsychotics): GLP-1RAs (liraglutide, semaglutide, exenatide) were consistently associated with reduced body weight, BMI, waist circumference, fasting glucose, and HbA1c. GLP-1RAs were not associated with worsened psychiatric symptoms.
- STEP 1 (general obesity, N = 1,961, 68 weeks): Semaglutide 2.4 mg once-weekly produced 14.9% mean weight loss versus 2.4% with placebo; 86.4% achieved ≥5% weight loss. SPMI patients were excluded.
- SURMOUNT-1 (general obesity, no diabetes, N = 2,539, 72 weeks): Tirzepatide 15 mg once-weekly produced 20.9% (−22.5 kg) mean weight loss; tirzepatide 5 mg produced 15.0%. SPMI patients were excluded.
Key Findings: Secondary Outcomes and Additional Data
- Clozapine pharmacokinetics (COaST): Semaglutide did not alter clozapine or norclozapine plasma levels, an important safety signal given clozapine’s narrow therapeutic window.
- Psychiatric symptom signal (Breit & Hubl, 36 studies): Some studies within this review reported improved depressive symptoms, quality of life, and global functioning scores in GLP-1RA-treated patients. The authors caution that causality has not been established.
- Substance use and psychiatric risk reduction (Xie et al. VA cohort, N = 1,960,067): GLP-1RA use was associated with lower hazard ratios for alcohol use disorder (HR 0.89, 95% CI 0.86–0.92), cannabis use disorder (0.88, 0.83–0.93), stimulant use disorder (0.84, 0.78–0.91), and opioid use disorder (0.87, 0.82–0.92). Associations were also observed for reduced suicidal ideation/self-harm (HR 0.90, 0.86–0.94), bulimia (0.81, 0.77–0.84), and other psychotic disorders (0.82, 0.76–0.89).
- Neuroprotective associations (Xie et al.): GLP-1RA use was associated with reduced risk of seizures (HR 0.90, 0.85–0.95), neurocognitive disorders (0.95, 0.93–0.97), dementia (0.92, 0.88–0.97), and Alzheimer’s disease (0.88, 0.78–0.99). These are associations, not demonstrated causal effects.
- Antipsychotic adherence (systematic review cited in paper): A meta-analysis (De et al., 2024) found that AIWG is a significant driver of antipsychotic discontinuation. The authors argue, by extension, that reducing AIWG with GLP-1RAs may improve adherence, though this pathway has not been tested directly in SPMI RCTs.
- Preclinical signal (Dixit et al., murine model): Liraglutide demonstrated antipsychotic-like effects in a mouse model of psychosis; this effect was not seen with the DPP-4 inhibitor sitagliptin, which does not cross the blood-brain barrier. The authors frame this as preliminary and requiring cautious interpretation.
- STEP 4 (maintenance, 68 weeks): Continuing semaglutide versus switching to placebo yielded −7.9% vs. +6.9% additional weight change (Δ −14.8%, P < 0.001), with associated reductions in waist circumference (−9.7 cm) and systolic blood pressure (−3.9 mmHg).
Adverse Events and Safety Profile
Across all referenced studies, the predominant adverse effects are gastrointestinal. In the Bak et al. systematic review of GLP-1RAs for AIWG in schizophrenia/schizoaffective disorder, nausea was reported in 38.1% of liraglutide-treated and 40.8% of exenatide-treated patients. Vomiting occurred in 25.3% (liraglutide) and 19.8% (exenatide); diarrhoea in 13.3% (liraglutide) and 31.5% (exenatide). Exenatide also increased LDL cholesterol by 0.70 mmol/L, which was not observed with liraglutide.
In the general obesity trials, semaglutide showed fewer treatment discontinuations due to adverse events (13.5%) compared to liraglutide (27.6%) in STEP 8, despite comparable GI side-effect rates. Gastrointestinal events with tirzepatide in SURMOUNT-1 were predominantly mild-to-moderate and peaked during dose escalation. Xie et al. identified increased risks associated specifically with tirzepatide, including hypotension, syncope, arthritic disorders, nephrolithiasis, interstitial nephritis, and drug-induced pancreatitis.
For the COaST trial specifically, the tolerability profile was consistent with prior GLP-1RA data: mild gastrointestinal effects were the most common adverse event, and no serious adverse events were reported in the semaglutide arm. The Canadian case series similarly reported only mild, transient gastrointestinal side effects with no serious events in 12 patients over 12 months.
A clinically meaningful caution raised by the authors: GLP-1RAs delay gastric emptying, which theoretically could alter absorption of oral medications including antipsychotics. While this effect has been modeled or observed for cardiovascular and anticoagulant agents, no studies to date have evaluated this interaction with oral antipsychotics. This is an explicitly identified gap.
Discontinuation of GLP-1RAs is followed by weight regain, attributed to hormonal imbalances, beta-cell dysfunction, and disrupted central appetite regulation. This implies indefinite use to sustain benefit, an important consideration in a population already carrying significant medication burden.
Statistical Approach and Rigor
This is a perspective article, not a primary study. It does not report original statistics. The strength of its claims rests entirely on the quality of the studies it cites. The COaST trial (N = 31) is the only SPMI-specific RCT included; it is double-blind and randomized but severely und
Read This Paper Through Nine Different Lenses
The same evidence can produce very different conclusions depending on the question being asked. Explore this study through multiple physician-guided interpretive frameworks.
Overview
GLP-1 receptor agonists (GLP-1RAs) offer a promising solution for antipsychotic-induced weight gain (AIWG) in severe and persistent mental illness (SPMI). The COaST trial demonstrated significant weight loss with semaglutide without worsening psychiatric symptoms, highlighting the potential of GLP-1RAs to improve metabolic health in this population.
However, access remains limited due to high costs and restrictive healthcare policies. Future research should focus on long-term efficacy and cost-effectiveness to inform policy changes and optimize treatment strategies for SPMI patients.
- GLP-1RAs reduce weight without exacerbating psychotic symptoms.
- Semaglutide produced 13.88% mean weight loss in clozapine-treated schizophrenia.
- Access is limited by high costs and restrictive policies.
Patient Takeaway
For patients with severe and persistent mental illness (SPMI) on antipsychotic medications, GLP-1 receptor agonists (GLP-1RAs) offer a new approach to managing weight gain. Studies have shown that GLP-1RAs can lead to significant weight loss without worsening psychiatric symptoms.
However, access to these treatments is currently limited due to high costs and restrictive healthcare policies. Patients should discuss the potential benefits and risks with their healthcare providers to determine if GLP-1RA therapy is right for them.
- GLP-1RAs can lead to significant weight loss.
- No worsening of psychiatric symptoms reported.
- Access limited by high costs and restrictive policies.
Clinician’s POV
Clinicians treating patients with severe and persistent mental illness (SPMI) on antipsychotics can consider GLP-1 receptor agonists (GLP-1RAs) as a novel treatment option for managing weight gain. The COaST trial demonstrated significant weight loss with semaglutide without exacerbating psychiatric symptoms.
However, access to these treatments is limited by high costs and restrictive healthcare policies. Clinicians should be aware of the potential benefits and risks when considering GLP-1RA therapy for their patients.
- GLP-1RAs reduce weight without worsening psychotic symptoms.
- Semaglutide produced 13.88% mean weight loss in clozapine-treated schizophrenia.
- Access is limited by high costs and restrictive policies.
A Skeptical Read
While GLP-1 receptor agonists (GLP-1RAs) have shown promise in reducing antipsychotic-induced weight gain (AIWG) without worsening psychiatric symptoms, some skepticism remains regarding their long-term efficacy and cost-effectiveness. The COaST trial demonstrated significant weight loss with semaglutide, but the study was small.
Further research is needed to confirm these findings in larger populations and to evaluate long-term outcomes. Clinicians should consider GLP-1RA therapy as a promising option while remaining cautious about its broader implications.
- GLP-1RAs reduce weight without worsening psychotic symptoms.
- Semaglutide produced 13.88% mean weight loss in clozapine-treated schizophrenia.
- Further research needed for long-term efficacy and cost-effectiveness.
Study Critic
Critics of GLP-1 receptor agonists (GLP-1RAs) may point to the limited number of studies in patients with severe and persistent mental illness (SPMI) and the high costs associated with these treatments. The COaST trial demonstrated significant weight loss with semaglutide, but it was a small study.
Access to GLP-1RA therapy is also restricted by healthcare policies, which may limit its availability for patients who could benefit from it. Critics argue that more research and policy changes are needed to address these issues.
- Limited studies in SPMI.
- High costs associated with GLP-1RAs.
- Access restricted by healthcare policies.
Compared to Past Research
The use of GLP-1 receptor agonists (GLP-1RAs) in managing antipsychotic-induced weight gain (AIWG) represents a significant evolution in treatment approaches. Traditional methods, such as behavioral interventions, have often been less feasible for patients with severe and persistent mental illness (SPMI).
GLP-1RAs, initially developed for type 2 diabetes, have shown promise in addressing AIWG by reducing weight and improving metabolic parameters without exacerbating psychiatric symptoms. This shift highlights the ongoing development of targeted therapies for complex conditions like SPMI.
- Traditional methods less feasible for SPMI.
- GLP-1RAs initially developed for type 2 diabetes.
- Show promise in addressing AIWG without worsening psychiatric symptoms.
Practical Considerations
Implementing GLP-1 receptor agonists (GLP-1RAs) in the treatment of antipsychotic-induced weight gain (AIWG) requires careful consideration of practical factors. Clinicians should assess patient eligibility, considering factors such as medication interactions and cost.
Given the high costs and restrictive healthcare policies surrounding GLP-1RA therapy, patients may need to navigate insurance coverage and financial assistance programs. Collaborative care models involving dietitians and mental health professionals can also support successful implementation.
- Assess patient eligibility carefully.
- Consider medication interactions and cost.
- Collaborate with other healthcare providers.
Future Directions
The future of GLP-1 receptor agonists (GLP-1RAs) in managing antipsychotic-induced weight gain (AIWG) hinges on ongoing research and policy changes. Further studies are needed to evaluate long-term efficacy, cost-effectiveness, and the impact of GLP-1RA therapy on psychiatric symptoms in larger populations with severe and persistent mental illness (SPMI).
Policy changes that address access and affordability will be crucial for expanding the use of GLP-1RAs. Collaboration between researchers, clinicians, and policymakers can help bridge the gap in care for SPMI patients.
- Ongoing research needed on long-term efficacy.
- Evaluate cost-effectiveness and impact on psychiatric symptoms.
- Policy changes to address access and affordability.
Misreadings & Bad-Faith Takes
There are several common misconceptions about GLP-1 receptor agonists (GLP-1RAs) and their role in managing antipsychotic-induced weight gain (AIWG). One misconception is that GLP-1RAs worsen psychiatric symptoms, but studies have shown no exacerbation of psychotic symptoms with these treatments.
Another common misreading is that GLP-1RA therapy is widely available and affordable. In reality, access to these treatments is limited by high costs and restrictive healthcare policies. It is important to clarify these misconceptions to ensure accurate understanding and appropriate use of GLP-1RAs in clinical practice.
- GLP-1RAs do not worsen psychiatric symptoms.
- Access to GLP-RA therapy is limited by high costs.
- Clarify misconceptions about GLP-1RA efficacy and availability.
Have thoughts on this? Share it:
What are GLP-1 receptor agonists?
GLP-1 receptor agonists (GLP-1RAs) are medications initially developed for type 2 diabetes that have shown promise in managing antipsychotic-induced weight gain.
How effective are GLP-1RAs in reducing AIWG?
In the COaST trial, semaglutide produced a mean weight loss of 13.88% compared to 0.42% with placebo in clozapine-treated schizophrenia patients.
Do GLP-1RAs worsen psychiatric symptoms?
No, studies have shown that GLP-1RAs do not exacerbate psychotic symptoms and may even improve depressive symptoms and global functioning in some cases.
What are the safety concerns with using GLP-1RAs in SPMI?
The predominant adverse events are gastrointestinal effects, which are generally mild to moderate. Semaglutide did not alter clozapine or norclozapine plasma levels.
How does AIWG impact antipsychotic adherence?
Antipsychotic-induced weight gain is a significant driver of antipsychotic discontinuation, suggesting that reducing AIWG could improve treatment adherence.
Are GLP-1RAs cost-effective for SPMI patients?
The cost-effectiveness data and policy levers determining access to GLP-1RAs in the Canadian healthcare system are still being evaluated.
What is the role of GLP-1RAs in neuroprotection?
GLP-1RA use has been associated with reduced risk of seizures, neurocognitive disorders, dementia, and Alzheimer’s disease, though causality is not established.
How do GLP-1RAs compare to metformin in treating AIWG?
GLP-1RAs have shown greater efficacy in weight loss compared to metformin, particularly in patients who are non-responders to metformin.
What future research is needed on GLP-1RAs for SPMI?
Future studies should focus on long-term efficacy, cost-effectiveness, and the impact of GLP-1RAs on psychiatric symptoms in larger populations with SPMI.
Can GLP-1RAs be used in conjunction with other antipsychotics besides clozapine?
While the COaST trial focused on clozapine, other studies have shown benefits of GLP-1RAs in patients treated with second-generation antipsychotics like olanzapine.
