ACE-D Aim 3 Clinical Cognitive Trial to Enhance Translation in Depression

The investigators will conduct a parallel-group, double-blind randomized trial at Stanford Bay Area and Chicago sites, identifying 162 participants across Stanford University and the University of Illinois Chicago with a prominent clinical cognitive signature (C+) and relative absence of the signature (C-). If you are eligible and choose to participate based off of your answers on the screening survey, the investigators will call you on the number you have provided to verify participants' responses and answer any additional questions you may have about the study. The first screening visit will consist of obtaining participants' informed consent to participate in the study, completing cognitive testing, answering questions about participants' thoughts and feelings, and providing information about participants' medical and psychiatric history. If participants are deemed eligible at this phase, the investigators will ask participants to come in for an in-person medical screening (up to 2 hours). This in-person medical screen visit will consist of getting your vitals taken (heart rate/blood pressure), undergoing a blood draw, and providing a urine sample. Additionally, people who are or suspect they may become pregnant throughout the course of the study will be given a pregnancy test. If a participant is deemed eligible after the medical screen, the investigators will ask participants to come in for another in-person visit (2 hours) that would involve a non-invasive brain scan. Participants will then be randomized to receive guanfacine plus sertraline or placebo plus sertraline for an 8 week treatment phase. Starting week 1 and for every week during the 8-week treatment phase, participants will complete nightly medication log surveys, passive sampling with the BiAffect application, and conduct cognitive testing. Additionally, starting week 1 and every week thereafter, participants will attend a virtual physician visit. At the end of week 8, the investigators will conduct an MRI visit that resembles the initial MRI visit. Participants will be unblinded over weeks 9-10 to arrange for the participants' transition out of the trial.