The BIomarker Guided (BIG) Study for Depression

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