Objective <p>Patients prescribed second-generation antipsychotics (SGA) are at risk of antipsychotic induced weight gain (AIWG). The objective was to estimate weight changes after prescription of incretin-based weight loss medications by category of expected AIWG: high (olanzapine, clozapine), intermediate (risperidone, quetiapine, paliperidone) and low (e.g., asenapine, aripiprazole).</p> Methods <p>We conducted a retrospective cohort study using electronic health records (June 2021–December 2023) from Epic Cosmos for adults (≥18 years) without diabetes, prescribed SGA, and eligible for incretin-based weight loss medications. We studied changes in weight (kg) and the probability of at least 5% weight loss after 6 months of prescription of incretin-based medications by categories of AIWG.</p> Results <p>The analytic sample (<i>n</i> = 66,574) were aged 51.9 years (SD: 17.7), with average BMI of 39.5 kg/m² (SD: 7.7). Those prescribed incretin-based medications lost −2.17 kg (95% CI: −2.49, −1.84), and were 1.71 (95% CI: 1.63, 1.80) times more likely to achieve 5% weight loss, relative to those who didn’t receive prescriptions. Weight loss was greater among those prescribed SGAs of low AIWG (−3.02 kg, 95% CI: −3.29, −2.74), relative to those prescribed high AIWG (−1.33 kg, 95% CI: −2.04, −0.62).</p> Conclusions <p>Semaglutide and tirzepatide induce weight loss among those prescribed SGAs, with lower effectiveness in those prescribed higher AIWG SGAs.</p>