Potential Role of the Triple Receptor Agonist Retatrutide in Antipsychotic-Associated Metabolic Dysfunction Among Clozapine- and Olanzapine-Treated Schizophrenia Spectrum Disorders: A Narrative Review and Theoretical Framework.

Antipsychotic-associated metabolic dysfunction contributes substantially to cardiometabolic morbidity and premature mortality in schizophrenia spectrum disorders, with the greatest burden among patients treated with clozapine and olanzapine. This review focuses on patients with schizophrenia spectrum disorders receiving these two agents, in whom the relevant psychiatric evidence is concentrated. Existing pharmacological interventions, including metformin and glucagon-like peptide-1 receptor agonists (GLP-1RAs), produce clinically meaningful but often incomplete benefits. Retatrutide (LY3437943) is a once-weekly triple agonist of the GLP-1, glucose-dependent insulinotropic polypeptide (GIP), and glucagon receptors that produced a mean body-weight reduction of 24.2% at 48 weeks under the efficacy estimand in a Phase 2 obesity trial; company-reported Phase 3 results from four trials, not yet peer-reviewed, describe reductions of up to 28.7%. This narrative review examines the rationale for investigating retatrutide in this setting, drawing on retatrutide trials in non-psychiatric populations, the pathophysiology of antipsychotic-induced weight gain, and emerging evidence for incretin-based therapies in antipsychotic-treated populations. The glucagon component is of particular mechanistic interest because it increases basal energy expenditure, a pathway not engaged by mono- or dual agonists; whether this could partially compensate for the reduced physical activity associated with antipsychotic-related sedation is untested and is presented here solely as a hypothesis. Indirect support comes from randomized trials and meta-analyses of GLP-1RAs in clozapine- or olanzapine-treated patients, which report reductions in body weight and glycemic impairment without evidence of worsening psychotic symptoms. No trial has evaluated retatrutide in an antipsychotic-treated population. Future studies should therefore characterize gastrointestinal tolerability, potential interaction with clozapine-associated gastrointestinal hypomotility, possible effects on clozapine and olanzapine exposure, adherence and feasibility, and the dysesthesia observed in retatrutide trials, which was dose-related in most but not all trials. Dedicated randomized controlled trials are needed to determine the efficacy and safety of retatrutide in patients with schizophrenia spectrum disorders receiving clozapine or olanzapine.