The BIomarker Guided (BIG) Study for Depression (BIG)

Precision Mental Health: Evaluating Biotype-guided Interventions for Depression

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.

Study Overview

• Status: Completed
• Conditions: Major Depressive Disorder
• Intervention / Treatment: Drug: Guanfacine Tablets

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • California
    • Palo Alto, California, United States, 94304
      • Stanford Psychiatry

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 61 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Guanfacine Treatment Group; Participants will be prescribed tabs containing guanfacine immediate release (GIR) to be taken for 8 weeks and will be monitored by one of the study psychiatrists/nurse practitioners. Subjects will start with 0.5mg GIR nightly and increase by 0.5mg every 3 days with a goal dose of 2mg.	Drug: Guanfacine Tablets; Guanfacine immediate release, sold under the brand name Tenex among others, is a medication used to treat high blood pressure and off-label to treat attention deficit hyperactivity disorder (ADHD). It is taken by mouth and will be compounded by a pharmacy to the required doses used in this study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Cognitive Control Circuit Function Z-score	During functional magnetic resonance imaging (fMRI), the cognitive control circuit was engaged by a Go-NoGo task, and circuit activation was quantified by blood flow in three regions of interest in the brain (dorsal anterior cingulate cortex [dACC], left dorsolateral prefrontal cortex [dLPFC], and right dLPFC) and the extent of functional connectivity between them. Task-evoked activation and connectivity are expressed as Z-scores, which represent the number of standard deviations the observed value is from the mean of a healthy reference dataset (population mean = 0). There is no fixed minimum or maximum for Z-scores. Standard deviations above the mean (a positive Z-score) indicate that the observed activation or connectivity is higher than the mean of the healthy reference dataset, while standard deviations below the mean (a negative Z-score) indicate it is lower. A negative Z-score indicates a worse outcome. For this study, a Z-score of <= -0.5 indicates poor cognitive control.	pre-treatment, 8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With a Score of ≤7 on the 17-item Hamilton Depression Rating Scale (HDRS-17) at Week 8 as a Measure of Depression Remission.	Possible HDRS-17 scores range from 0 (no depression) to 52 (severe depression).	8 weeks
Number of Participants With a Score ≤5 on the Quick Inventory of Depressive Symptoms-Self Report (QIDS-SR) at Week 8 as a Measure of Depression Remission.	Possible QIDS-SR scores range from 0 (no depression) to 27 (severe depression).	8 weeks
Number of Participants With a ≥50% Reduction on the 17-item Hamilton Depression Rating Scale (HDRS-17) as a Measure of Depression Response.	Possible HDRS-17 scores range from 0 (no depression) to 52 (severe depression).	pre-treatment, 8 weeks
Number of Participants With a ≥50% Reduction From Baseline on the Quick Inventory of Depressive Symptoms-Self Report (QIDS-SR) as a Measure of Depression Response.	Possible QIDS-SR scores range from 0 (no depression) to 27 (severe depression).	pre-treatment, 8 weeks
Change in Depression Scores on the 17-item Hamilton Depression Rating Scale (HDRS-17)	Possible HDRS-17 scores range from 0 (no depression) to 52 (severe depression).	baseline, 2 weeks, 8 weeks
Change in Depression Scores on the Quick Inventory of Depressive Symptoms-Self Report (QIDS-SR)	Possible QIDS-SR scores range from 0 (no depression) to 27 (severe depression).	pre-treatment, 2 weeks, 4 weeks, 6 weeks, 8 weeks
Change in Cognitive Control Behavioral Performance Z-score	Cognitive control behavioral performance was assessed using the WebNeuro computerized battery measuring cognitive control. Test performance is expressed as a composite Z-score, representing deviations from the mean of a healthy reference dataset (population mean = 0). Composite Z-scores were calculated by averaging: Maze (trials completed, completion and path learning time, errors), Digit Span (recall span, correct trials), Verbal Interference (total errors, reaction time), and Switching of Attention (completion time, connection time, errors). For GoNoGo, only reaction times were used as data was collected in-scanner, and data for this measure was normalized to the group. Extreme scores were winsorized to a threshold of 5 standard deviations. Z-scores have no fixed range; positive scores indicate better performance, negative scores indicate worse performance. For this study, a Z-score of <= -0.5 indicates poor cognitive control performance.	pre-treatment, 8 weeks
Change in the Satisfaction With Life Scale (SWLS) Score	Possible scores on the SWLS range from 5 (extreme dissatisfaction) to 35 (extreme satisfaction).	pre-treatment, 2 weeks, 8 weeks
Change in the World Health Organization Quality of Life - Brief (WHOQOL-BREF) Scale Scale Score	Scores on the WHOQOL-BREF are transformed to a scale of 0 (poor quality of life) to 100 (excellent quality of life).	pre-treatment, 2 weeks, 8 weeks
Change in the Columbia-Suicide Severity Rating Scale (C-SSRS) Ideation Score	Possible scores on the C-SSRS ideation range from 0 (no suicidal ideation) to 5 (high suicidal ideation).	pre-treatment, 8 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Barratt Impulsiveness Scale (BIS) score	A questionnaire designed to assess the personality/behavioural construct of impulsiveness--total score and attention items only.	4 weeks, 6 weeks
Change in Hamilton Depression Rating Scale 17-item (HAMD) score	Clinician rated 17-item overall depression severity score.	4 weeks, 6 weeks
Change in Clinical Global Impression of Improvement (CGI-I)	Clinician rated global measure of the degree of improvement from initial assessment in overall illness severity.	4 weeks, 6 weeks
Change in Clinical Global Impression of Severity (CGI-S)	Clinician rated global measure of subject overall illness severity.	4 weeks, 6 weeks
Change in Quick Inventory of Depressive Symptoms-Self Report (QIDS-SR)	A 16-item self-report measure that assesses the severity of depression symptoms in the past week on a 4-point scale ranging from 0 to 3.	4 weeks, 6 weeks
Change in Columbia-Suicide Severity Rating Scale (C-SSRS)	A scale designed to quantify the severity of suicidal ideation and behavior.	4 weeks, 6 weeks
Change in World Health Organization Quality of Life (WHOQoL) scale	A 26-item questionnaire that measures quality of life out of 100 in the following domains: physical health, psychological health, social relationships, and environment.	4 weeks, 6 weeks
Change in Depression, Anxiety, and Stress Scale (DASS)	A 42-item self-report scale that assesses symptoms of depression/anhedonia, anxious arousal and generalized anxiety (stress) that are not tied to a particular diagnosis.	4 weeks, 6 weeks
Change in Emotion Regulation Questionnaire (ERQ)	A 10-item self-report questionnaire designed to assess individual differences in the habitual use of two emotion regulation strategies: cognitive reappraisal and expressive suppression.	4 weeks, 6 weeks
Change in Beck Depression Inventory (BDI)	A 21-item, self-report rating inventory that measures symptoms of depression such as hopelessness and irritability, cognitions such as guilt or feelings of being punished, as well as physical symptoms such as fatigue, weight loss, and lack of interest in sex.	4 weeks, 6 weeks
Change in Beck Anxiety Inventory (BAI)	A 21-item self-report inventory for measuring the severity of common symptoms of anxiety that the participant has had during the past week, such as numbness and tingling, sweating not due to heat, and fear of the worst happening.	4 weeks, 6 weeks
Change in Penn State Worry Questionnaire (PSWQ)	A 16-item self-report questionnaire that assesses items such as "my worries overwhelm me" and is rated on a likert scale, with scores ranging from 1 to 80.	4 weeks, 6 weeks
Change in Mood and Anxiety Symptom Questionnaire (MASQ)	A 90-item questionnaire based on the tripartite model of affective disorder which encompasses constructs of anhedonia, anxious arousal and generalized distress, equivalent to the DASS, and which has also been used in healthy and patient groups.	4 weeks, 6 weeks
Change in Sheehan Disability Scale (SDS)	A 3-item self-report questionnaire that measures functional capacity in work/school, social life, and family life on a scale of 0-10.	4 weeks, 6 weeks
Change in PTSD Checklist - Civilian Version (PLC-C)	A 17-item self-report scale that measures symptoms of PTSD in the past month on a 5-point scale ranging from 1 to 5.	4 weeks, 6 weeks
Change in Ruminative Responses Scale (RRS)	A 22-item self-report questionnaire that assesses two aspects of rumination; brooding and reflecting pondering. It is scored on a 4-point scale ranging from 1 to 4.	4 weeks, 6 weeks
Change in Snaith-Hamilton Pleasure Scale (SHAPS)	A 14-item self-report measure to determine anhedonia levels. It is scored on a 4-point scale of 1 (strongly disagree, disagree) and 0 (strongly agree, agree).	4 weeks, 6 weeks
Change in Fagerstrom Nicotine Dependence Survey (FNDS)	A short 6-item instrument used for assessing the intensity of physical nicotine addiction.	4 weeks, 6 weeks
Change in Satisfaction With Life Scale (SWLS)	A short, 5-item instrument designed to measure global cognitive judgments of satisfaction with one's life.	4 weeks, 6 weeks
Change in Health Productivity Questionnaire (HPQ)	This is a 14-item scale that assesses productivity at work, and relative and absolute levels of absenteeism from work as well as presenteeism (being at work, but unproductive due to the effects of anxiety and depressive symptoms).	4 weeks, 6 weeks
Change in Brief COPE	A multidimensional coping inventory to assess the different ways in which people respond to stress.	4 weeks, 6 weeks
Change in NIDA-Modified Alcohol, Smoking, and Substance Involvement Screening Test (NM-ASSIST)	A 15-item measure adapted from the World Health Organization (WHO) Alcohol, Smoking and Substance Involvement Screening Test, used to assess prescription medicine and illicit substance use in adults age 18 and older.	4 weeks, 6 weeks

Collaborators and Investigators

• Sponsor: Stanford University
• Investigators: Principal Investigator: Leanne M Williams, PhD, Stanford University; Principal Investigator: Laura M Hack, MD, PhD, Stanford University

Study record dates

Study Major Dates

• Study Start (Actual): September 14, 2022
• Primary Completion (Actual): January 17, 2024
• Study Completion (Actual): February 12, 2024

Study Registration Dates

• First Submitted: November 26, 2019
• First Submitted That Met QC Criteria: November 26, 2019
• First Posted (Actual): November 29, 2019

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 7, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: major depressive disorder (MDD); guanfacine; dorsolateral prefrontal cortex (dLPFC); cognitive control circuit; cognitive control behavioral performance
• Additional Relevant MeSH Terms: Mental Disorders; Behavioral Symptoms; Mood Disorders; Depression; Depressive Disorder; Depressive Disorder, Major; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Adrenergic Agents; Antihypertensive Agents; Guanfacine
• Other Study ID Numbers: 49147

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes