Clozapine and Olanzapine can cause severe metabolic side effects, increasing cardiovascular risk. Glucagon-like peptide-1 (GLP-1) receptor agonists, primarily approved for use in patients with type 2 diabetes, may counter these effects by promoting weight loss, improving glucose metabolism, and enhancing cardiovascular health, offering a promising approach for managing antipsychotic-related metabolic complications. We conducted a literature review using the search terms "clozapine OR olanzapine AND GLP-1 agonist," "schizophrenia AND GLP-1 agonist," "antipsychotic AND GLP-1 agonist," and "psychosis AND GLP-1 agonist" on PubMed and Google Scholar. This search initially yielded 172 articles. We focused on clinical trials or case reports investigating the use of GLP-1 agonists in conjunction with Olanzapine or Clozapine. Our final selection included two clinical trial studies, one case report, and a retrospective study. In a case report, a schizophrenic patient on Clozapine treated with liraglutide experienced a reduction in glycated hemoglobin (HbA1c ), from 10% to 6.5% over 14 months, along with a total weight loss of 7.7 kg (8.7% body weight reduction) after two years, and decreased insulin requirements. In a retrospective study reviewing 16 obese patients with schizophrenia treated with liraglutide, of whom 14 were on Clozapine, significant reductions in body weight, waist circumference, body mass index (BMI), and plasma glucose levels were observed over 16 weeks (< 0.001). A randomized clinical trial with 103 patients, with diagnoses within the schizophrenia spectrum disorders, who have been treated with Olanzapine or Clozapine, and liraglutide, showed significant improvement in glucose tolerance when compared to placebo (< 0.001), with 63.8% of liraglutide-treated patients achieving normal glucose tolerance versus 16.0% in the placebo group. Additional benefits included significant reductions in body weight, waist circumference, blood pressure, visceral fat, and low-density lipoprotein (LDL) cholesterol levels. In another outpatient study with 28 participants randomized to receive subcutaneous, extended-release exenatide in one arm, or standard of care in the other arm for 24 weeks, six participants in the exenatide group achieved more than 5% weight loss, compared to just one in the usual care group (= 0.029). The exenatide group experienced significantly greater mean weight loss compared to the usual care group (= 0.015). Additionally, the exenatide group showed a more substantial reduction in BMI (= 0.019) and improved glycemic control, with significant reductions in fasting glucose (= 0.036) and glycated hemoglobin (= 0.004) compared to the usual care group. This review underscores the need for future studies that involve the use of GLP-1 agonists in conjunction with Clozapine or Olanzapine. Although results from preliminary studies are promising, there is a need for more randomized controlled clinical trials to validate these findings, assess long-term efficacy, and develop clinical guidelines. P P P P P P P
