Neuropsychiatric Effects of Glucagon-Like Peptide-1 Receptor Agonists in Schizophrenia-Spectrum Disorders: A Systematic Review

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Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.

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Abstract

People with schizophrenia-spectrum disorders die 15-20 years prematurely, predominantly from cardiovascular disease, and antipsychotic-induced weight gain is a major, partly iatrogenic contributor to this excess mortality. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are potent weight-lowering agents that are increasingly used as metabolic adjuncts in this population, and preclinical evidence has suggested that they may also exert central, potentially pro-cognitive effects. However, their effects on psychiatric symptoms, cognition, and quality of life have not previously been systematically synthesized. We therefore conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement. Four databases (MEDLINE/PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, and Web of Science) were searched on 20 July 2026 for randomized controlled trials (RCTs) comparing any GLP-1RA with placebo, usual care, or an active comparator, added to antipsychotic treatment, in adults with schizophrenia-spectrum disorders. The primary outcome was psychiatric symptom severity, while secondary outcomes were cognition and quality of life or functioning. Reports were de-duplicated at the trial level using trial registration records, and risk of bias was assessed for each outcome domain using the revised Cochrane Risk of Bias tool for randomized trials (RoB 2). Because outcome measures were heterogeneous and variance data were largely unavailable, meta-analysis was not feasible, and findings were synthesized narratively according to the direction of effect. Eight reports representing four RCTs evaluating exenatide, liraglutide, and semaglutide (333 participants randomized) were included. No trial demonstrated a statistically significant effect on psychiatric symptom severity as measured by the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression-Severity (CGI-S) scale, or the six-item Positive and Negative Syndrome Scale (PANSS-6). Likewise, neither of the two trials that assessed cognition, including one in which cognitive performance was the primary outcome, demonstrated a pro-cognitive effect. Quality-of-life outcomes were also largely unchanged, except for improved physical quality of life in the largest trial (36-Item Short Form Health Survey version 2 (SF-36v2) Physical Component Summary: +3.75, 95% confidence interval (CI) 1.52 to 5.98; P = .001), which a companion mediation analysis indicated was largely attributable to weight loss. Mental quality of life and functioning showed no significant improvements. Most outcome-domain assessments were judged to have some concerns regarding risk of bias, with none rated as high risk, and the certainty of the evidence was low to moderate. Overall, in adults with schizophrenia-spectrum disorders receiving antipsychotic treatment, GLP-1RAs showed no evidence of benefit or harm for psychiatric symptoms or cognition. Improvements in quality of life were limited to physical health and appeared to be mediated by weight loss rather than direct psychotropic effects. These findings support the role of GLP-1RAs as cardiometabolic therapies in this population, with no signal of psychiatric destabilization. Larger, adequately powered RCTs with neuropsychiatric primary outcomes, longer follow-up, harmonized outcome measures, and complete reporting of variance data are needed.

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