Efficacy and safety of glucagon-like peptide-1 receptor agonists in patients with schizophrenia spectrum disorders treated with antipsychotics: a meta-analysis

Background

Metabolic disturbances, including weight gain and impaired glucose metabolism, are highly prevalent among patients with schizophrenia spectrum disorders treated with antipsychotics, particularly second-generation agents such as clozapine and olanzapine. These adverse effects contribute to increased cardiometabolic risk, reduced quality of life, and premature mortality. Despite their clinical relevance, effective and well-tolerated strategies to mitigate antipsychotic-associated metabolic dysfunction remain limited. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated robust metabolic benefits in the general population; however, available evidence regarding their efficacy and safety in patients with schizophrenia spectrum disorders remains inconclusive.

Aims

To evaluate the efficacy and safety of GLP-1 RAs as adjunctive treatment for antipsychotic-associated metabolic disturbances in patients with schizophrenia spectrum disorders.

Methods

We conducted a systematic review and meta-analysis of randomised controlled trials comparing GLP-1 RAs with placebo in patients with schizophrenia spectrum disorders receiving antipsychotic treatment, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Scopus, and Web of Science were systematically searched from inception to January 2026. Outcomes included changes in body weight, body mass index, waist circumference, glycated haemoglobin, fasting plasma glucose, high-density lipoprotein, low-density lipoprotein, triglycerides, blood pressure, and adverse events. Random-effects models were used to calculate pooled estimates, expressed as standardised mean differences (SMD) or risk ratios (RR) with 95% confidence intervals (CI). Heterogeneity was assessed using the I² statistic. The risk of bias was evaluated using the revised Cochrane risk of bias tool for randomised trials (RoB 2).

Results

Eight randomised controlled trials including 523 participants were identified. GLP-1 RAs were associated with significant reductions in body weight (SMD −1.17; 95% CI −1.68 to −0.65), body mass index (SMD −1.14; 95% CI −1.80 to −0.47), waist circumference (SMD −0.82; 95% CI −1.25 to −0.39), glycated haemoglobin (SMD −0.99; 95% CI −1.35 to −0.64), and fasting plasma glucose (SMD −0.77; 95% CI −1.07 to −0.47) compared with placebo. No significant effects were observed for high-density lipoprotein, low-density lipoprotein, triglycerides, or blood pressure. There were no significant differences in psychiatric symptom severity between groups (SMD −0.14; 95% CI −0.40 to 0.12). GLP-1 RAs were generally well tolerated, with no differences in overall discontinuation rates or serious adverse events compared with placebo. Gastrointestinal adverse events, including nausea, vomiting, diarrhoea, and constipation, were more frequent, whereas no differences were observed in psychiatric adverse events, hospitalisations, or other safety outcomes. Subgroup analyses suggested greater effects among patients treated with clozapine or olanzapine and for semaglutide compared with exenatide.

Conclusions

GLP-1 RAs significantly improve weight and glycaemic outcomes in patients with schizophrenia spectrum disorders treated with antipsychotics, without evidence of psychiatric deterioration. These findings support their potential role as an adjunctive strategy for managing antipsychotic-associated metabolic disturbances in this population. The observed benefits appear more pronounced in patients receiving antipsychotics with a high metabolic burden, such as clozapine and olanzapine, and with more potent agents such as semaglutide. Nevertheless, the relatively small number of trials, heterogeneity across studies, and limited long-term data warrant further large-scale studies to confirm durability of effects and safety.

References

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