Individualized Pharmacological Approach to Obesity in Patients With Bipolar Disorder

This is a single-site, open-label, non-randomized interventional pilot study evaluating a phenotype-guided pharmacological approach to obesity in adults with bipolar disorder (BD). The study aims to assess the distribution of obesity phenotypes and the efficacy, safety, and tolerability of individualized anti-obesity pharmacotherapy in this population. A total of 100 participants with BD and comorbid obesity will be enrolled and stratified into one of four obesity phenotypes: Hungry Brain (abnormal satiation), Hungry Gut (abnormal postprandial satiety), Emotional Hunger (emotional eating), and Slow Burn (low resting energy expenditure). Participants will undergo comprehensive obesity phenotyping, including indirect calorimetry, gastric emptying scintigraphy, DEXA scans, ad libitum buffet meal testing, and validated behavioral questionnaires. Based on phenotype classification, participants will receive one of the following FDA-approved anti-obesity medications (AOMs): phentermine-topiramate ER (Qsymia®), semaglutide (Wegovy®), or naltrexone-bupropion ER (Contrave®). Participants with the Slow Burn phenotype will receive behavioral and lifestyle interventions only. All participants will engage in a 12-week virtual behavioral intervention program led by a multidisciplinary team, including a psychologist and a registered dietitian. The program includes weekly group sessions focused on nutrition, physical activity, cognitive restructuring, and relapse prevention. A comprehensive data safety monitoring plan (DSMP) is in place, including bi-monthly reviews by a multidisciplinary team. Adverse events (AEs) and serious adverse events (SAEs) will be monitored and reported per institutional and federal guidelines. Participants will be withdrawn from the study if they experience treatment-emergent mania, severe depression, suicidality, or other safety concerns. The statistical analysis plan includes descriptive statistics, repeated measures models, and subgroup analyses by phenotype and BD subtype. Missing data will be handled using multiple imputation or maximum likelihood methods. No formal multiplicity adjustments will be applied due to the exploratory nature of the study. This study addresses a critical gap in obesity treatment for individuals with serious mental illness by integrating precision medicine with psychiatric care. The findings will inform future randomized controlled trials and contribute to the development of personalized obesity interventions in psychiatric populations.