Lumateperone for Late-Life Depression

This study is a 10-week, randomized, double-blind, placebo-controlled clinical trial designed to evaluate the efficacy and safety of adjunctive lumateperone in older adults with treatment-resistant depression (TRD). Approximately 100 participants aged ≥60 years with unipolar, non-psychotic major depressive disorder will be enrolled across two study sites. Participants will continue their existing antidepressant medication at a stable dose throughout the study and will be randomized to receive either lumateperone or matching placebo administered adjunctively during the treatment phase. * Screening: Participants who sign consent will go through a screening process. This will involve answering questions about medical history, medications, demographics, mood and emotions as well as completing a brief cognitive test. * Baseline: If the participant is eligible from the screening visit, the participant will complete a baseline visit in our research clinic. This will involve answering questions and completing questionnaires about mood and emotions, completing tasks on an iPad to assess thinking, attention, and memory, as well as a physical exam. The physical exam will include gathering height and weight, an evaluation for potential medication side effects, a fasting blood draw to measure blood lipids and glucose, and an electrocardiogram (ECG). * Study Medication: Participants will be randomized (like flipping a coin) to take either lumateperone or placebo (sugar pill). The research team and participant will be blinded to each participant's study medication. Participants will not get to choose whether they take lumateperone or placebo. * Monitoring visits: The study team will ask participants to complete visits in the research clinic after one week, two weeks, four weeks, six weeks, and eight weeks following the baseline visit. These visits will be to assess depression symptoms, medication changes, and side effects. The study team may ask participants to complete additional visits in person or over the phone if they are needed to manage side effects or worsening in depressive symptoms. * Endpoint visit: After 10-weeks the study team will ask participants to complete an endpoint visit in the research clinic to measure the effects of lumateperone or placebo. This visit includes answering questions and completing questionnaires about mood and emotions, medication changes, and side effects. Participants will complete tasks on an iPad to assess their thinking, attention, and memory. There will also be a fasting blood draw to measure blood lipids and glucose as well as another ECG. * Extra visit (if needed): The study team may ask participants to complete one additional endpoint visit for a final assessment of symptoms.