The purpose of this study is to understand how a psychotropic medication called guanfacine affects brain network functioning in humans, and how this function interacts with cognitive impairments in people experiencing depressive symptoms.

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.

Inclusion Criteria:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

1. Provision of signed and dated informed consent form

2. Stated willingness to comply with all study procedures and lifestyle considerations (see Section 5.3) and availability for the duration of the study

3. Male or female

4. Age 18-60 years

5. Fluent and literate in English

6. Meets DSM-5-TR diagnostic criteria for MDE (major depressive episode), and criteria for current or recurrent nonpsychotic MDD using the Mini International Neuropsychiatric Interview (MINI Plus)79

7. A total score of 10 or higher on the PHQ-8 at initial screening, including:

   a. Endorsement of anhedonia, as indexed by a response of "more than half the days" or "nearly every day" to Item 1 ("Little interest or pleasure in doing things") or endorsement of persistent negative mood, as indexed by a response of "more than half the days" or "nearly every day" to Item 2 ("Feeling down, depressed, or hopeless")

8. Meets criteria for cognitive dysfunction (C+ subgroup) or absence of cognitive dysfunction (C- subgroup) based on results from computerized behavioral testing of cognitive control performance (WebNeuro) and from fMRI scanning using the Go/No-Go task.

Exclusion Criteria:

An individual who meets any of the following criteria will be excluded from participation in this study:

1. Presence of one or more of the following conditions established via the participant's medical record and confirmed using the MINI Plus:

   • bipolar disorder (I, II, not otherwise specified, current or lifetime)
   • psychosis (current or lifetime)
   • moderate to severe alcohol or substance use disorders (current)
   • post-traumatic stress disorder (PTSD; current)
   • obsessive compulsive disorder (OCD; current or lifetime)
   • attention deficit hyperactivity disorder (ADHD; current or lifetime)
   • eating disorders (ED; current)

2. Suicidality with active plan

3. Severe impediment to vision, hearing, and/or hand movement

4. Current or lifetime history of medical illness or brain injury that may interfere with assessments

5. Pregnant, breastfeeding, or unwilling or unable to use adequate birth control throughout the study (females of child-bearing potential only)

6. 3.0T MRI scanner contraindications (e.g., metal in the body, claustrophobia)

7. Concurrent participation in other intervention studies

8. Current use of psychotropic medications contraindicated by guanfacine or sertraline

9. General medical condition or disorder that is deemed by study physicians to be unsafe for GIR as reported by patient or found on medical screening. This may include:

   • Cardiac-related exclusions:

     • Resting heart rate (HR) < 55 beats per minute (bradycardia)
     • Systolic blood pressure (SBP) < 90 mmHg or diastolic blood pressure (DBP) < 60 mmHg (hypotension)
     • Current symptoms suggestive of cardiac dysfunction based on clinician assessment (e.g., persistent chest pain, palpitations, dizziness, fainting)

   • Renal-related exclusions:

     • eGFR < 60 mL/min/1.73 m²
     • Current symptoms suggestive of kidney dysfunction based on clinician assessment

   • Hepatic-related exclusions:

     • ALT > 2× ULN
     • AST > 2× ULN
     • Current symptoms suggestive of liver dysfunction based on clinician assessment

   • Thyroid-related exclusions:

     • TSH outside normal laboratory reference range
     • Current symptoms suggestive of thyroid dysfunction based on clinician assessment

10. Use of substance deemed by the study physician to be unsafe for use with guanfacine

11. Current use of a strong CYP3A4 inhibitor (e.g., ketoconazole) or inducer (e.g., carbamazepine) that, in the judgment of the study clinician, may alter guanfacine plasma concentrations and cannot be safely discontinued for the duration of the study.

12. Unwillingness to verify biotype classification via fMRI

13. Unwillingness or inability to use a computer or access a computer for assessments.