Dapagliflozin Versus Metformin for the Management of Antipsychotic-Induced Weight Gain: A Pragmatic Pilot Randomized Controlled Trial

This is an open-label, pragmatic, parallel-group pilot randomized controlled trial comparing dapagliflozin with metformin for the management of antipsychotic-induced weight gain. The study will be conducted at the Department of Behavioral Medicine, Sultan Qaboos University Hospital, University Medical City, Muscat, Oman.

Antipsychotic-induced weight gain is a common and clinically important adverse effect of antipsychotic treatment. It may contribute to reduced treatment adherence, poorer quality of life, and increased cardiometabolic risk. Metformin is commonly used to manage antipsychotic-associated weight gain, but its use may be limited by gastrointestinal adverse effects, dose titration, and pill burden. Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, has demonstrated weight-reducing and metabolic benefits in other clinical populations, but its role in antipsychotic-induced weight gain remains insufficiently studied.

Participants will be randomized in a 1:1 ratio to receive either dapagliflozin plus a common lifestyle program or metformin plus a common lifestyle program. The trial will use a pragmatic PROBE-style design, with open-label treatment allocation and blinded outcome assessment and statistical analysis where feasible. Randomization will use a computer-generated sequence with allocation concealment.

The study is designed as a pilot trial to assess feasibility, tolerability, adherence, safety, and preliminary estimates of treatment effect to inform a future definitive trial. Standardized procedures will be used for participant follow-up, medication review, safety monitoring, and data collection. Adverse events and treatment tolerability will be monitored throughout the study, and serious adverse events will be reported according to institutional and ethics committee procedures.

Data will be collected by trained study personnel and entered into an electronic database with procedures to support completeness and accuracy. Analyses will be primarily descriptive and exploratory, consistent with the pilot nature of the trial, and will be used to refine assumptions for a future larger randomized controlled trial.

Inclusion criteria

• Patients aged ≥16 years
• Diagnosis according to DSM-5 criteria, including:

Schizophrenia spectrum and other psychotic disorders, as summarized in the DSM-5 chapter Schizophrenia Spectrum and Other Psychotic Disorders, excluding:

Substance/medication-induced psychotic disorder Psychotic disorder due to another medical condition Catatonia associated with another mental disorder Catatonic disorder due to another medical condition Unspecified catatonia Bipolar and related disorders, as summarized in the DSM-5 chapter Bipolar and Related Disorders Depressive disorders, as summarized in the DSM-5 chapter Depressive Disorders Obsessive-compulsive and related disorders, as summarized in the DSM-5 chapter Obsessive-Compulsive and Related Disorders Other psychiatric conditions for which antipsychotic treatment is clinically indicated, as judged by the investigator Other conditions where antipsychotics are indicated

• Receiving stable antipsychotic treatment for ≥3 months prior to enrollment
• Evidence of antipsychotic-induced weight gain (AiWG), defined as:

• ≥7% increase in body weight from baseline following initiation of antipsychotic treatment, or
• BMI >25 kg/m² with clinically established antipsychotic-associated weight gain
• Able to understand and comply with study procedures, as judged by the investigator
• Able to provide written informed consent. For participants aged 16-17 years, assent and/or guardian consent will be obtained according to local ethics committee requirements.

Exclusion criteria

• Diabetes mellitus
• Diagnosed patients of polycystic ovarian syndrome (PCOS)
• Renal impairment defined as estimated glomerular filtration rate (eGFR <45 mL/min/1.73 m²)
• Significant hepatic disease or other serious or unstable medical conditions that, in the opinion of the investigator, would make participation unsafe
• Pregnant or breastfeeding females
• Current use of metformin, dapagliflozin, or another sodium-glucose cotransporter 2 inhibitor.
• Use of weight-loss medications or participation in structured weight-loss programs within the past 3 months
• Recurrent genitourinary infections (if dapagliflozin is used)
• Use of non-antipsychotic medications known to cause clinically significant weight gain, including but not limited to selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), mirtazapine, tricyclic antidepressants, valproate, lithium, corticosteroids, sedating antihistamines, or other medications as judged by the investigator
• Unstable psychiatric condition or active substance use disorder that may impair the ability to adhere to study procedures, as judged by the investigator