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The BIomarker Guided Study for Depression (BIG)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04181736
Recruitment Status : Recruiting
First Posted : November 29, 2019
Last Update Posted : December 2, 2022
Information provided by (Responsible Party):
Laura Hack, Stanford University

Brief Summary:
The diagnosis of major depression relies on patient reports, and two patients with the same diagnosis might share only one symptom. Thus, a single mechanism is unlikely to underlie a broad descriptive diagnosis such as major depression. Our approach is anchored by a neural circuit taxonomy that proposes distinct biotypes of depression derived from functional magnetic resonance imaging (fMRI) (Williams et al., 2016). In this study, we aim to target a putative type of major depression that arises from dysfunction in cognitive control neural circuitry with a drug called guanfacine.

Condition or disease Intervention/treatment Phase
Major Depressive Disorder Drug: Guanfacine Pill Drug: Placebo Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 64 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: We will randomize participants to one of two groups, treatment or placebo. Participants will have the option to proceed to an open label phase, post-treatment.
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description: Participants, Care Providers, and Investigators will be blinded throughout the course of the study to avoid bias.
Primary Purpose: Treatment
Official Title: Precision Mental Health: Evaluating Biotype-guided Interventions for Depression
Actual Study Start Date : July 1, 2022
Estimated Primary Completion Date : December 31, 2024
Estimated Study Completion Date : December 31, 2024

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Guanfacine Treatment Group
Participants will be prescribed tabs containing guanfacine immediate release (GIR) to be taken for 4 weeks and will be monitored by one of the study psychiatrists. Subjects randomized to GIR will start with 0.25mg GIR upon waking and increase by 0.25mg every other day with a goal dose of 2mg.
Drug: Guanfacine Pill
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.

Placebo Comparator: Placebo Group
Participants will be prescribed tabs containing placebo to be taken for 4 weeks and will be monitored by one of thestudy psychiatrists. Subjects randomized placebo will be asked to follow the same pill regimen as subjects randomized to treatment.
Drug: Placebo
Placebo masked to mirror the treatment drug dose regimen.

Primary Outcome Measures :
  1. Change in dorsolateral prefrontal cortex (DLPFC) activity [ Time Frame: 4 weeks, 6 weeks ]
    Activity as evoked by the N-back working memory task

Secondary Outcome Measures :
  1. Change in digit span task performance [ Time Frame: 4 weeks, 6 weeks ]
    Total number of correct trials in the forward digit span task where each incremental span length has two trials- at least one of which needs to be recalled correctly to progress

  2. Change in maze task performance [ Time Frame: 4 weeks, 6 weeks ]
    Time taken to successfully complete the maze without error twice consecutively [for subjects who time out- i.e.- take more than 5 minutes- this score is interpolated from their performance up until that point]

  3. Change in verbal memory recognition task performance [ Time Frame: 4 weeks, 6 weeks ]
    Verbal memory total immediate recall trials

Other Outcome Measures:
  1. Change in Barratt Impulsiveness Scale (BIS) score [ Time Frame: 4 weeks, 6 weeks ]
    A questionnaire designed to assess the personality/behavioural construct of impulsiveness--total score and attention items only.

  2. Change in Hamilton Depression Rating Scale 17-item (HAMD) score [ Time Frame: 4 weeks, 6 weeks ]
    Clinician rated 17-item overall depression severity score.

  3. Change in Clinical Global Impression of Improvement (CGI-I) [ Time Frame: 4 weeks, 6 weeks ]
    Clinician rated global measure of the degree of improvement from initial assessment in overall illness severity.

  4. Change in Clinical Global Impression of Severity (CGI-S) [ Time Frame: 4 weeks, 6 weeks ]
    Clinician rated global measure of subject overall illness severity.

  5. Change in Quick Inventory of Depressive Symptoms-Self Report (QIDS-SR) [ Time Frame: 4 weeks, 6 weeks ]
    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.

  6. Change in Columbia-Suicide Severity Rating Scale (C-SSRS) [ Time Frame: 4 weeks, 6 weeks ]
    A scale designed to quantify the severity of suicidal ideation and behavior.

  7. Change in World Health Organization Quality of Life (WHOQoL) scale [ Time Frame: 4 weeks, 6 weeks ]

    A 26-item questionnaire that measures quality of life out of 100 in the following domains:

    physical health, psychological health, social relationships, and environment.

  8. Change in Depression, Anxiety, and Stress Scale (DASS) [ Time Frame: 4 weeks, 6 weeks ]
    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.

  9. Change in Emotion Regulation Questionnaire (ERQ) [ Time Frame: 4 weeks, 6 weeks ]
    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.

  10. Change in Beck Depression Inventory (BDI) [ Time Frame: 4 weeks, 6 weeks ]
    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.

  11. Change in Beck Anxiety Inventory (BAI) [ Time Frame: 4 weeks, 6 weeks ]
    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.

  12. Change in Penn State Worry Questionnaire (PSWQ) [ Time Frame: 4 weeks, 6 weeks ]
    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.

  13. Change in Mood and Anxiety Symptom Questionnaire (MASQ) [ Time Frame: 4 weeks, 6 weeks ]
    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.

  14. Change in Sheehan Disability Scale (SDS) [ Time Frame: 4 weeks, 6 weeks ]
    A 3-item self-report questionnaire that measures functional capacity in work/school, social life, and family life on a scale of 0-10.

  15. Change in PTSD Checklist - Civilian Version (PLC-C) [ Time Frame: 4 weeks, 6 weeks ]
    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.

  16. Change in Ruminative Responses Scale (RRS) [ Time Frame: 4 weeks, 6 weeks ]
    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.

  17. Change in Snaith-Hamilton Pleasure Scale (SHAPS) [ Time Frame: 4 weeks, 6 weeks ]
    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).

  18. Change in Fagerstrom Nicotine Dependence Survey (FNDS) [ Time Frame: 4 weeks, 6 weeks ]
    A short 6-item instrument used for assessing the intensity of physical nicotine addiction.

  19. Change in Satisfaction With Life Scale (SWLS) [ Time Frame: 4 weeks, 6 weeks ]
    A short, 5-item instrument designed to measure global cognitive judgments of satisfaction with one's life.

  20. Change in Health Productivity Questionnaire (HPQ) [ Time Frame: 4 weeks, 6 weeks ]
    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).

  21. Change in Brief COPE [ Time Frame: 4 weeks, 6 weeks ]
    A multidimensional coping inventory to assess the different ways in which people respond to stress.

  22. Change in NIDA-Modified Alcohol, Smoking, and Substance Involvement Screening Test (NM-ASSIST) [ Time Frame: 4 weeks, 6 weeks ]
    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.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • 18-65 years of age (inclusive)
  • DLPFC activity in the upper or lower quartile as compared to a normative sample
  • Working memory performance <= 1 SD below the mean of a normative sample on the Verbal Memory, Digit Span, or Maze tasks.
  • Score > 14 on the Hamilton Depression Rating Scale 17
  • Meet 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 ideation representing imminent risk, defined by a score of > 8 on the MINI Plus International Neuropsychiatric Schedule, or by clinician judgement
  • Lifetime history of medical illness or injury that may compromise cognitive functioning or interfere with assessments (including neurological disorders such as seizures or stroke, Parkinson's disease, dementia, mild 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
  • 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
  • History of DSM-5 bipolar disorder (I, II, not otherwise specified), eating disorder, ADHD, schizophrenia, schizoaffective disorder, or psychosis not other specified (current or lifetime)
  • History of DSM-5 alcohol or substance use disorder criteria within the last 12 months
  • Meeting criteria for current DSM-5 PTSD or OCD
  • 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 of the prescribed drug prior to first scan.
  • General medical condition, disease or neurological disorder that is deemed by the study physicians to be unsafe for GIR treatment (kidney or liver impairment, hypotension, bradycardia, history of syncope, or family history of cardiac events)
  • 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
  • Current use of a strong CYP3A4 inhibitor or inducer

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04181736

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Contact: Laura M Hack, MD, PhD 4102742582
Contact: Leanne M Williams, PhD 6507233579

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United States, California
Stanford Psychiatry Recruiting
Palo Alto, California, United States, 94304
Contact: Rachel Hilton, MSN, PMHNP-BC    (650) 723-2686   
Contact: Jenna Jubeir, BS    (650) 497 - 2615   
Sponsors and Collaborators
Stanford University
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Responsible Party: Laura Hack, Laura Hack MD, PhD, Clinical Instructor and Postdoctoral Fellow, Stanford University Identifier: NCT04181736    
Other Study ID Numbers: 49147
First Posted: November 29, 2019    Key Record Dates
Last Update Posted: December 2, 2022
Last Verified: December 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Keywords provided by Laura Hack, Stanford University:
dorsolateral prefrontal cortex
cognitive dysfunction
Additional relevant MeSH terms:
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Depressive Disorder
Depressive Disorder, Major
Mood Disorders
Mental Disorders
Antihypertensive Agents
Adrenergic alpha-2 Receptor Agonists
Adrenergic alpha-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs