Obesity is a global public health concern, often co-occurring in patients with severe mental illnesses. The impact of psychotropic drugs-induced weight gain is augmenting the disease burden and healthcare expenditure. However, predictors of psychotropic drug-induced weight gain and the efficacy of anti-obesity drugs remain underexplored. This study aims to develop a machine learning algorithm to predict both psychotropic drugs-induced weight gain and metabolic changes, and the potential of anti-obesity drugs. We plan to enroll 300 patients with severe mental illnesses, including schizophrenia, bipolar disorder, and major depressive disorder. In Phase 1, the study will predict weight gain and metabolic changes after the psychotropic treatment. Data on demographics, lifestyle, medical history, psychological factors, anthropometrics, and laboratory results will be collected at baseline and re-evaluated 24 weeks post-treatment. Participants classified as obese (body mass index ≥ 25 kg/m²) or overweight (body mass index of 23-24.9 kg/m²) at the 24-week follow-up will proceed to Phase 2, which focuses on predicting the promise of anti-obesity drugs. The study participants will receive anti-obesity medications for 24 weeks, and the same variables from Phase 1 will be reassessed. A machine learning model will be developed to predict both psychotropic drug-induced weight gain and anti-obesity medications that will be effective. The algorithm will be tailored to each patient to guide clinicians in personalizing psychiatric and obesity treatment plans. The clinical trial is registered with the Clinical Research Information Service, part of the WHO International Clinical Trials Registry Platform (approval number: KCT0009769).