Once-weekly semaglutide led GLP-1 options for weight and metabolic improvements in psychiatric populations, but researchers say stronger head-to-head trials are still needed before firm clinical rankings can be made.
Review: Glucagon-like peptide-1 receptor agonists for weight management in mental illness: a network meta-analysis. Image Credit: Edugrafo / Shutterstock
In a recent comprehensive network meta-analysis published in the journal Translational Psychiatry, researchers evaluated the safety and effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for individuals with mental illness and comorbid obesity or overweight-related metabolic risk. The analysis pooled data from nine randomized controlled trials (RCTs; n = 595 patients) investigating the use of exenatide, liraglutide, and semaglutide for weight management in psychiatric populations.
Study findings revealed that once-weekly subcutaneous semaglutide showed the largest estimated effect on body weight and several metabolic markers, identifying the GLP-1 RA as a highly promising intervention for future clinical trials in psychiatric populations, although comparative rankings remain uncertain because the evidence base was small, heterogeneous, and largely indirect.
Background
Obesity has been identified as a significant clinical challenge for individuals diagnosed with psychiatric conditions, particularly schizophrenia spectrum disorders or bipolar disorder.
Studies have found that these subcohorts demonstrate metabolic risk rates substantially higher than in the general public, and have attributed this observational disparity to multiple factors, including patients’ reduced physical activity, diminished baseline motivation, and the metabolic side effects of essential antipsychotic treatments like olanzapine and clozapine.
Furthermore, follow-up investigations indicate that unwanted weight gain in psychiatric populations often cascades into multisystemic comorbidities and significantly increases patients’ risk for type 2 diabetes (T2D), cardiovascular disease (CVD), some cancers, and structural joint pain.
While typical weight management relies heavily on lifestyle changes, including diet- and physical exercise-based interventions, a growing body of evidence emphasizes that these strategies are rarely sufficient on their own. Consequently, modern medical guidelines recommend pharmacological treatment when lifestyle interventions fail to achieve an adequate response.
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a class of medications that mimic natural metabolic hormones. Initially developed to treat metabolic conditions such as diabetes and obesity, these medications have been found to offer multisystemic benefits beyond their intended use.
While emergent evidence suggests the benefits of GLP-1 RA-based interventions in psychiatric populations, their comparative benefits and comparative safety profiles within these vulnerable individuals remain largely unclear.
About the Study
The present study aimed to bridge this knowledge gap and inform future psychiatric research and clinical policy by leveraging a frequentist network meta-analysis with a random-effects model to simultaneously elucidate the safety and efficacy of multiple distinct GLP-1 RA regimens.
Study data from peer-reviewed publications were shortlisted using a custom keyword search across PubMed, Embase, and the Cochrane Library, from database inception to April 28, 2026. Title, abstract, and full text screening included only randomized controlled trials (RCTs) evaluating adults experiencing any form of mental illness combined with obesity.
The final analysis dataset comprised 9 RCTs, involving 595 human patients with a mean age of 37.8 years. Study participants were predominantly female (55.3%), with schizophrenia spectrum disorders identified as the dominant psychiatric condition (83.9%).
Drug regimens under investigation included: 1. subcutaneous exenatide administered twice daily or once weekly, 2. once-daily subcutaneous liraglutide, and 3. once-weekly subcutaneous semaglutide. Outcomes were compared with placebo or non-placebo control groups.
The study specifically evaluated participants’ primary changes in total body weight, secondary changes in body mass index (BMI) and waist circumference, comprehensive fasting plasma glucose and hemoglobin A1c (HbA1c) measures, and overall changes in schizophrenia symptom severity.
Study Findings
The study’s random-effects model revealed that once-weekly subcutaneous semaglutide and once-daily subcutaneous liraglutide were both significantly associated with greater weight reductions than the control arms. In contrast, the exenatide intervention did not statistically alter patients’ weight compared with the control arms.
Among successful interventions, once-weekly semaglutide demonstrated the greatest efficacy, with patients achieving a standardized mean difference (SMD) of -2.101 (back-transformed to a mean difference of about -15.76 kg) versus control. BMI and waist circumference evaluations mirrored these findings, demonstrating SMDs of -2.092 and -1.075, respectively.
Once-weekly semaglutide was also found to substantially lower metabolic markers, yielding SMDs of -0.902 for fasting plasma glucose and -1.051 for hemoglobin A1c. While the liraglutide intervention showed reductions in waist circumference and hemoglobin A1c levels, its efficacy was less pronounced than semaglutide’s.
Safety evaluations revealed that both semaglutide and liraglutide consumption resulted in patients reporting higher rates of gastrointestinal adverse events, including increased incidences of nausea, vomiting, and constipation. These side effects are well-documented across GLP-1 RA interventions and remain important tolerability considerations.
Encouragingly, however, neither drug was associated with significant increases in psychiatric hospitalizations or overall psychiatric symptom scores, supporting further safety evaluation in future clinical trials in psychiatric populations.
Conclusions
The present study is one of the first to empirically compare the safety and efficacy of GLP-1 RA regimens for weight management in pharmacological psychiatric interventions. The results indicate that once-weekly subcutaneous semaglutide may be the preferred treatment option due to its largest estimated effect in reducing body weight and improving selected metabolic abnormalities for patients with obesity and comorbid mental illness.
However, the authors caution against clinical interpretation of these findings, emphasizing that additional clinical trials are required to establish safe dosages, determine comparative efficacy, and assess long-term outcomes.