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.

Study at a Glance

Study Snapshot: Key Statistics

Study Facts

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

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