Grant: Project Grant

Almost one in every two patients with schizophrenia (SCZ) are obese and patients die 15-20 years earlier than the general population from heart disease. Medications called antipsychotics are needed to treat SCZ, but they cause a lot of weight gain. Weight gain is associated with poorer quality of life, barriers to social engagement, worse medication adherence, and poorer brain function. However, available treatments for managing obesity and related problems are not adequate. A drug called metformin has support from research studies to help treat weight gain in SCZ. However, it is effective in only about 20% of people, and doctors don't know what to use next. Newer treatments for diabetes and obesity such as a class called "glucagon-like peptide-1 receptor agonists" (GLP-1RAs) can potentially help. Semaglutide is a newer, well-tolerated GLP-1RA, also found to have excellent weight-loss effects. We plan to study SCZ patients who suffer from obesity and don't lose weight on metformin, to see if adding semaglutide can help with body weight reduction and other risk factors for heart disease. Patients will first be treated with metformin for 4 months, and those who don't lose at least 5% of their body weight will enter a second study phase. At the start of this phase, they will be assigned to a weekly injection of semaglutide or placebo ("dummy"), which will be added to metformin. Participants have an equal chance of receiving semaglutide or the placebo. Neither patients, or study personnel know if placebo or semaglutide is being given. Over the next 6 months, participants will undergo body weight measurements, measures of blood sugar metabolism, an MRI scan to measure body fat changes, and tests of brain function to see if these improve with semaglutide. The goal of this study is to help develop logical and effective care pathways that can reduce the huge disparities in cardiovascular-related health that burden people already suffering with severe mental illness.