The BIomarker Guided Study for Depression (BIG)

• ClinicalTrials.gov Identifier: NCT04181736
• Recruitment Status: Recruiting
• First Posted: November 29, 2019
• Last Update Posted: December 2, 2022
• Sponsor: Stanford University
• Information provided by (Responsible Party): Laura Hack, Stanford University

Study Description

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

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. The 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 2 to 3 screening visits (screening visit 2 and 3 can be combined) in order to enroll in the study. During the first visit, participants will go over informed consent, be administered a clinical interview and complete cognitive testing.
3. The second visit will be a medical screen in order to ensure participants are safe to continue and will include blood samples, medical history, vitals and a urine drug test and can be combined with visit three, detailed in step 4 below.
4. If the participant meets medical and cognitive criteria, scans for functional MRI will be undertaken at another study visit (or in combination with the medical screen) at the CNI on the Stanford campus. All MRI scans, including the optional MRI scan at week 6, will last 1.5 hours. If a participant's task-evoked activity in the DLPFC falls within the highest or lowest quartiles derived from a large data set of healthy volunteers, the participant will be able to proceed with medication
5. Participants will be randomized to either receive active medication treatment with guanfacine or placebo in a double blinded fashion. Randomization will be generated using a random number generator computer program. The probability for random assignment to each treatment is 50% chance randomized to active treatment with guanfacine and 50% chance randomized to placebo. A prescription lasting a period of 4 weeks will be sent to the Stanford Psychiatry Department from Mariner pharmacy. The pharmacist will provide a research coordinator in the lab with the randomization information, but this research coordinator will not be involved in patient interaction. The packaging of the medication itself will not identify drug or otherwise, but have an ID only.
6. At weeks 1, 3 and 5 when subject is not seen by the study MD, the participant will be monitored by an appropriately trained clinical research coordinator. All subjects will have an fMRI scan during week 4 and an optional week 6 fMRI scan. During in-person visits and phone monitoring, participants will be assessed for changes to physical health and treatment physical side-effects, anthropometrics and vital signs, changes to current medications (other than GIR), compliance to GIR treatment, alcohol and drug use abstinence compliance, birth control usage compliance and likelihood of pregnancy (female participants of child bearing potential), mood changes (QIDS-SR), suicidality (C-SSRS), clinical global impression severity (CGI-S) and improvement (CGI-I), Barratt Impulsiveness Scale (BIS). We will also have participants complete the following cognitive measures described below on a weekly basis during the treatment period in the form of an online battery (aka Webneuro): Choice reaction time, emotion test, digit span, GoNoGo, Verbal Interference, CPT, and Maze.

DETAILS

1. Participants: Volunteers will be aged 18-65 years old. The effect size of guanfacine vs. placebo on ADHD symptoms, including symptoms of inattention, has been estimated to be between 0.43 and 0.86. Using the most conservative of these values (0.43) and assuming an alpha of 0.05 with 4 groups, a total of 64 patients will be needed to provide a power of 80%. This would result in 32 subjects in each of the highest and lowest quartile groups of DLPFC activity.
2. Randomization: Participants will undergo fMRI scanning using tasks described below, including the N-back Working Memory Task. A region of interest (ROI) analysis will be performed using our established methods, to identify BOLD- dependent signal change in the DPLPC (right, left). Beta values for each ROI will be extracted for each subject and used to determine eligibility for the study. If a subject falls with the extreme quartiles of either the right or left DLPFC or both, this individual be randomized in a double blind fashion into one of two groups: placebo or guanfacine.
3. Suicidal thoughts or psychotic symptoms: Established procedures are in place for direct and immediate referral and intervention when suicidality and/or psychosis are identified.
4. Participants wishing to participate in this study will be screened with a psychiatric interview, an in-person physical exam (height, weight, vital signs, systems assessment, general appearance), medical history (history of disorders, diseases and allergies), lab tests (hematology: hemoglobin, hematocrit, total and differential WBC count, platelet count; chemistry: sodium, potassium, chloride, CO2, glucose, creatinine, BUN/urea; liver panel: albumin, total bilirubin, direct bilirubin, AST, ALT, ALP, total protein; endocrine: TSH; pregnancy test; full urine toxicology).
5. Participants will be prescribed tabs containing either placebo or guanfacine immediate release 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. If intolerance is encountered with a dosage increase, the dosage will be reduced to the prior level for a length to be determined by the treating psychiatrist and then raised again if/when tolerated. Dosing schedule may be slowed at the discretion of the physician based on participant's reaction to the drug. Decision to terminate guanfacine treatment will be made by clinicians based on side effects or lack of response or at patient's request. Follow up care for 2 weeks will be provided and transfer of care arranged at week 6 according to patients' decisions. At 4 weeks, the blind will be broken and those taking GIR may choose to continue this medication or taper off. If patients select to continue, a fMRI scan will be offered at week 6. Abrupt discontinuation of GIR (either due to side effects or to study end) will be avoided to prevent rebound hypertension and withdrawal symptoms. Participants will be seen by the study's psychiatrists at treatment weeks 2, 4, and 6.

Study Design

• 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

Arms and Interventions

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.

Outcome Measures

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.

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Contacts

Contact: Laura M Hack, MD, PhD; 4102742582; lhack@stanford.edu

Contact: Leanne M Williams, PhD; 6507233579; leawilliams@stanford.edu

Locations

United States, California

Stanford Psychiatry; Recruiting

Palo Alto, California, United States, 94304

Contact: Rachel Hilton, MSN, PMHNP-BC (650) 723-2686 rhilton@stanford.edu

Contact: Jenna Jubeir, BS (650) 497 - 2615 jjubeir@stanford.edu

Sponsors and Collaborators

Stanford University

More Information

• Responsible Party: Laura Hack, Laura Hack MD, PhD, Clinical Instructor and Postdoctoral Fellow, Stanford University
• ClinicalTrials.gov Identifier: NCT04181736
• Other Study ID Numbers: 49147
• First Posted: November 29, 2019
• Last Update Posted: December 2, 2022
• Last Verified: December 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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:

guanfacine; dorsolateral prefrontal cortex; DLPFC; MDD; cognitive dysfunction

Additional relevant MeSH terms:

Depressive Disorder; Depressive Disorder, Major; Mood Disorders; Mental Disorders; Guanfacine; 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