The BIomarker Guided (BIG) Study for Depression

Phase 4

Completed

Conditions: Major Depressive Disorder

Interventions: Drug: Guanfacine Tablets

Registration Number: NCT04181736

Lead Sponsor: Stanford University

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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 28

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 & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Guanfacine Treatment Group	Guanfacine Tablets	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.

Primary Outcome Measures

Name	Time	Method
Change in Cognitive Control Circuit Function Z-score	pre-treatment, 8 weeks	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.

Secondary Outcome Measures

Name	Time	Method
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	Possible HDRS-17 scores range from 0 (no depression) to 52 (severe depression).
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	Possible QIDS-SR scores range from 0 (no depression) to 27 (severe depression).
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	Possible HDRS-17 scores range from 0 (no depression) to 52 (severe depression).
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	Possible QIDS-SR scores range from 0 (no depression) to 27 (severe depression).
Change in Depression Scores on the 17-item Hamilton Depression Rating Scale (HDRS-17)	baseline, 2 weeks, 8 weeks	Possible HDRS-17 scores range from 0 (no depression) to 52 (severe depression).
Change in Depression Scores on the Quick Inventory of Depressive Symptoms-Self Report (QIDS-SR)	pre-treatment, 2 weeks, 4 weeks, 6 weeks, 8 weeks	Possible QIDS-SR scores range from 0 (no depression) to 27 (severe depression).
Change in the Satisfaction With Life Scale (SWLS) Score	pre-treatment, 2 weeks, 8 weeks	Possible scores on the SWLS range from 5 (extreme dissatisfaction) to 35 (extreme satisfaction).
Change in the World Health Organization Quality of Life - Brief (WHOQOL-BREF) Scale Scale Score	pre-treatment, 2 weeks, 8 weeks	Scores on the WHOQOL-BREF are transformed to a scale of 0 (poor quality of life) to 100 (excellent quality of life).
Change in the Columbia-Suicide Severity Rating Scale (C-SSRS) Ideation Score	pre-treatment, 8 weeks	Possible scores on the C-SSRS ideation range from 0 (no suicidal ideation) to 5 (high suicidal ideation).
Change in Cognitive Control Behavioral Performance Z-score	pre-treatment, 8 weeks	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.