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 Participants will be withdrawn from the study if they experience treatment-emergent mania, severe depression, suicidality, or other safety concerns.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.

Inclusion criteria

• Men or women between 18 to 65 years old.
• Patients with a SCID IV confirmed diagnosis of bipolar disorder (BDI or BDII) or schizoaffective bipolar type (SZA-BD).
• Women with a negative pregnancy test 48 hours before study entry (obesity phenotyping visit).
• Patients with a negative urine drug screen except for allowable drugs.
• Patients with a BMI ≥ 30 kg/m2 or a BMI ≥ 27 kg/m2 plus one medical comorbidity (e.g., type 2 diabetes, hypertension, dyslipidemia, obstructive sleep apnea)
• Patients must be undergoing mood stabilizer treatment but may also receive concurrent antidepressant or anxiolytic therapy.
• Patients must be on a stable regimen of a mood stabilizer, with no changes to the medication, for at least one month prior to study enrollment.
• Continuation of mood-stabilizing treatment is preferred but not required; the decision should be made in collaboration with the participant's primary mental health provider.

Exclusion criteria

• Abdominal bariatric surgery: Gastric bypass surgery (Roux-en-Y), Adjustable gastric band (Lap band), and Gastric sleeve surgery (Sleeve gastrectomy).
• Positive history of chronic gastrointestinal diseases, or systemic disease that could affect gastrointestinal motility, such as diabetic gastroparesis; or use of medications that may alter gastrointestinal motility and appetite.
• Positive history of chronic gastrointestinal diseases that could affect gastrointestinal absorption such as inflammatory bowel disease (IBD), celiac disease, small intestinal bacterial overgrowth (SIBO), etc; or use of medications that may alter gastrointestinal absorption.
• Significant untreated psychiatric dysfunction.
• Hypersensitivity to any of the study medications.
• Contraindications to the FDA-approved medications: Phentermine-Topiramate Extended Release; Oral naltrexone extended-release/bupropion extended-release (NBSR; Contrave®, Mysimba™); and Semaglutide (Weygovy™).
• Inability to provide informed consent: participants who are on involuntary commitment, conservatorship or under a legal guardian.
• Patients with active hypomania or mania (YMRS ≥ 20 points)
• Patients with active psychosis (YMRS item 8 ≥ 6 points)
• Patients with active suicide ideation (MADRS item 10 ≥ 4 points)
• Patients with any medication changes (mood stabilizers) without advisement of study clinicians or clinical provider.
• Patients with active bulimia (purging) or anorexia (severe restriction)
• Patients with a history of bulimia (purging behaviors) or anorexia (severe dietary restriction) within the 12 months preceding study enrollment will be excluded
• Current drug and/or alcohol use disorders (except nicotine)
• Patients with a positive toxicology screening (except cannabis)
• Positive toxicology screen for cannabis and a cannabis use disorder by CUDIT-R.
• Participants who use cannabis for recreational or medicinal purposes and fail the toxicology screen can potentially be included in the study only if they take the CUDIT-R and score a 12 or less.
• Patients unwilling to complete the full phenotyping day on its current form (i.e. patients avoiding gluten meal or adhering to a vegan diet).