Cognitive impairments contribute significantly to psychosocial dysfunction in major depressive disorder (MDD) and respond poorly to conventional antidepressants, yet selective treatments targeted to these impairments are lacking. Our previous research identified a distinct subgroup of depression called "cognitive biotype+" that comprises 27% of depressed patients and is characterized by pre-treatment global cognitive impairments and dysfunction in the cognitive control neural circuit. In this study, we evaluated the medication guanfacine immediate release (GIR), an alpha 2A receptor agonist, as a novel treatment for selectively improving cognitive control circuit function, performance on cognitive testing, and clinical measures the cognitive biotype+ subgroup.

The flow of procedures and study visits is as follows:

1. Recruitment and screening: Participants experiencing depressive symptoms and not taking any psychiatric medications as determined by a 5 half-life wash out period will be recruited from the community, including students and employees at Stanford. Recruitment will come primarily from Facebook ads, which will use only IRB approved material. A flyer will also be physically posted on boards in public locations in order to include a variety of sources for the study.
2. Individuals will need to participate in 3 screening visits in order to enroll in the study. During the first visit, participants will review informed consent, be administered a clinical interview, and be sent instructions for completing cognitive testing at home.
3. If eligibility after this initial screening visit, the second visit will be a medical screen in order to ensure participants are safe to take GIR and will include standard blood tests, medical history, vitals, and a urine drug test.
4. If the participant meets medical and cognitive criteria, functional magnetic resonance imaging (fMRI) scans will be undertaken at another study visit at The Stanford Center for Cognitive and Neurobiological Imaging (CNI). Using a participant's task-evoked activity in the dorsolateral prefrontal cortex (dLPFC) and performance on objective cognitive testing, we will apply thresholds using established healthy norms to select participants within the cognitive biotype+ group.
5. Participants will receive GIR for a period of 8 weeks sent to their place of residence from Mariner pharmacy.
6. Participants will be seen in-person or virtually by a study clinician at weeks 2, 4, 6, 8, and 10 and an appropriately trained clinical research coordinator at weeks 1, 3, 5, 7, and 9. All subjects will have an fMRI scan after 6-8 weeks of taking GIR. During in-person visits and virtual monitoring, we will assess participants for the following: changes to symptoms, function, and suicidality, adherence to GIR, changes to concomitant medication(s), adverse events (AEs), birth control usage compliance, likelihood of pregnancy (female participants of childbearing potential), and vital signs if appropriate.
7. If participants wish to continue GIR and their psychiatrist or PCP is willing to prescribe this, they will continue with their current dose for weeks 9 and 10. If they prefer to stop taking GIR and/or they do not have a provider who is willing to continue GIR, the participant will be tapered off the medication.

Inclusion Criteria:

• 18-69 years of age (inclusive)
• Go-NoGo fMRI task-evoked dLPFC ≤ - 0.5 SD below the mean of normative sample
• Behavioral cognitive control performance ≤ - 0.5 SD below the mean of normative sample on a Maze, Digit Span, and/or Verbal Interference (Stroop) task administered using WebNeuro
• Score ≥ 14 on the 17-item Hamilton Depression Rating Scale-17 (HDRS-17)
• Meets DSM-5 diagnostic criteria for current, past, or recurrent nonpsychotic major depressive disorder established by MINI Plus
• Medication naïve to guanfacine
• Fluent and literate in English, and show non-impaired intellectual abilities to ensure adequate comprehension of the task instructions
• Written, informed consent
• fMRI scanning eligibility, including no evidence of any form of metal embedded in the body (e.g., metal wires, nuts, bolts, screws, plates, sutures), as these produce artifacts when brain imaging. All potential subjects will need to successfully complete the screening forms at the Stanford Center for Cognitive and Neurobiological Imaging (CNI).

Exclusion Criteria:

• Presence of suicidal ideations representing imminent risk, defined by a score of > 8 on the MINI-Plus, or by clinician judgement
• Lifetime history of medical illness or injury that may compromise cognitive functioning or interfere with assessments as deemed by the study physician (such as neurological disorders such as seizures or stroke, Parkinson's disease, dementia, or traumatic brain injury)
• Severe impediment to vision, hearing, and/or hand movement likely to interfere with ability to complete the assessments, or are unable and/or unlikely to follow the study protocols
• Pregnant, breastfeeding or unwilling or unable to use adequate birth control throughout the study
• Loss of consciousness for > 10 minutes during lifetime
• Any contraindication to being scanned in the 3.0T scanner at the CNI such as having a pacemaker or implanted device that has not been cleared for scanning at 3.0 Tesla
• Previous or current DSM-5 bipolar disorder (I, II, not otherwise specified) or psychosis
• Meets criteria for DSM-5 alcohol or substance use disorder within the last 12 months
• Meets criteria for current DSM-5 PTSD, OCD, or eating disorder
• Concurrent participation in other intervention or treatment studies
• Current use of psychotropic medications. If their usual treating physician is supportive, participants who are currently on psychotropics that can be safely tapered may be tapered off to participate but participant must wait 5 half-lives prior to first scan
• Current use of a strong CYP3A4 inhibitor or inducer (macrolide/ketolide antibiotics [clarithromycin, telithromycin], azole antifungals [itraconazole, ketoconazole, posaconazole, voriconazole], protease inhibitors [atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ombitasvir, paritaprevir, ritonavir, saquinavir], ceritinib, cobicistat, and idealisib), or inducer (apalutamide, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, lumacaftor-ivacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin)
• Hypotension as defined by SBP ≤ 90 and/or DBP ≤60 on 2 of 3 separate measurements at least 5 minutes apart, bradycardia as defined by HR ≤55 on 2 of 3 separate measurements at least 5 minutes apart
• General medical condition, disease, or neurological disorder as reported by participant or found on in-person screenings that is deemed by the study physicians to be unsafe for GIR treatment, including kidney or liver impairment that is deemed to be unsafe, EKG abnormalities that are deemed to be unsafe, or cardiovascular disease deemed to be unsafe.
• History of sudden cardiac death in first degree relatives
• Positive drug screen for any substance deemed by the study physician to be unsafe for use with GIR in combination with other information obtained during screening

Participants who completed at least 6 weeks of guanfacine.

10 weeks (8 weeks treatment plus 2 week follow-up)