The BIomarker Guided (BIG) Study for Depression

NCT04181736 | Completed Phase 4 Results FDA Drug

• 1 other identifier: 49147
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Major Depressive Disorder

Keywords

guanfacine; dorsolateral prefrontal cortex (dLPFC); major depressive disorder (MDD); cognitive control circuit; cognitive control behavioral performance

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (10)

• 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.

  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.

  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.

  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.

  pre-treatment, 8 weeks

• Change in Depression Scores on the 17-item Hamilton Depression Rating Scale (HDRS-17)

  baseline, 2 weeks, 8 weeks

Study Arms (1)

Guanfacine Treatment Group

EXPERIMENTAL

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

Interventions

Guanfacine Tablets DRUG

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.

Guanfacine Treatment Group

Eligibility Criteria

• Age: 18 Years - 69 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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

Sponsors & Collaborators

• Stanford University: lead

Study Sites (1)

Stanford Psychiatry

Palo Alto, California, 94304, United States

Location

MeSH Terms

Conditions

Depressive Disorder, Major

Interventions

Guanfacine

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Guanidines; Amidines; Organic Chemicals; Phenylacetates; Acids, Carbocyclic; Carboxylic Acids

Results Point of Contact

• Title: Laura Hack, MD, PhD
• Organization: Stanford University

lhack@stanford.edu

650-724-7478

Study Officials

• Laura M Hack, MD, PhD

  Stanford University

  PRINCIPAL INVESTIGATOR

• Leanne M Williams, PhD

  Stanford University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Laura Hack MD, PhD

Study Record Dates

• First Submitted: November 26, 2019
• First Posted: November 29, 2019
• Study Start: September 14, 2022
• Primary Completion: January 17, 2024
• Study Completion: February 12, 2024
• Last Updated: March 20, 2025
• Results First Posted: March 20, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)