ACE-D Aim 3 Clinical Cognitive Trial to Enhance Translation in Depression (ACE-D)

Accelerating Cognition-guided Signatures to Enhance Translation in Depression Aim 3: Clinical Cognitive Trial

The purpose of this study is to understand how a psychotropic medication called guanfacine affects brain network functioning in humans, and how this function interacts with cognitive impairments in people experiencing depressive symptoms.

Study Overview

• Status: Recruiting
• Conditions: Depression
• Intervention / Treatment: Drug: Guanfacine; Drug: Sertraline

Detailed Description

The investigators will conduct a parallel-group, double-blind randomized trial at Stanford Bay Area and Chicago sites, identifying 162 participants across Stanford University and the University of Illinois Chicago with a prominent clinical cognitive signature (C+) and relative absence of the signature (C-).

If you are eligible and choose to participate based off of your answers on the screening survey, the investigators will call you on the number you have provided to verify participants' responses and answer any additional questions you may have about the study.

The first screening visit will consist of obtaining participants' informed consent to participate in the study, completing cognitive testing, answering questions about participants' thoughts and feelings, and providing information about participants' medical and psychiatric history.

If participants are deemed eligible at this phase, the investigators will ask participants to come in for an in-person medical screening (up to 2 hours). This in-person medical screen visit will consist of getting your vitals taken (heart rate/blood pressure), undergoing a blood draw, and providing a urine sample. Additionally, people who are or suspect they may become pregnant throughout the course of the study will be given a pregnancy test.

If a participant is deemed eligible after the medical screen, the investigators will ask participants to come in for another in-person visit (2 hours) that would involve a non-invasive brain scan. Participants will then be randomized to receive guanfacine plus sertraline or placebo plus sertraline for an 8 week treatment phase.

Starting week 1 and for every week during the 8-week treatment phase, participants will complete nightly medication log surveys, passive sampling with the BiAffect application, and conduct cognitive testing. Additionally, starting week 1 and every week thereafter, participants will attend a virtual physician visit. At the end of week 8, the investigators will conduct an MRI visit that resembles the initial MRI visit. Participants will be unblinded over weeks 9-10 to arrange for the participants' transition out of the trial.

• Study Type: Interventional
• Enrollment (Estimated): 162
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Leyla Boyar, BA; Phone Number: 6504989326; Email: ljboyar@stanford.edu
• Study Contact Backup: Name: Isabelle Wydler Clinical Research Coordinator, BA; Phone Number: 6507364393; Email: iwydler@stanford.edu

Study Locations

• United States
  • California
    • Palo Alto, California, United States, 94305
      • Recruiting
      • Stanford Psychiatry and Behavioral Sciences Department
  • Illinois
    • Chicago, Illinois, United States, 60607
      • Recruiting
      • University of Illinois at Chicago
      • Contact: Jun Ma, PhD
      • Principal Investigator: Jun Ma, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

1. Provision of signed and dated informed consent form
2. Stated willingness to comply with all study procedures and lifestyle considerations (see Section 5.3) and availability for the duration of the study
3. Male or female
4. Age 18-60 years
5. Fluent and literate in English
6. Meets DSM-5-TR diagnostic criteria for MDE (major depressive episode), and criteria for current or recurrent nonpsychotic MDD using the Mini International Neuropsychiatric Interview (MINI Plus)79

7. A total score of 10 or higher on the PHQ-8 at initial screening, including:

   a. Endorsement of anhedonia, as indexed by a response of "more than half the days" or "nearly every day" to Item 1 ("Little interest or pleasure in doing things") or endorsement of persistent negative mood, as indexed by a response of "more than half the days" or "nearly every day" to Item 2 ("Feeling down, depressed, or hopeless")

8. Meets criteria for cognitive dysfunction (C+ subgroup) or absence of cognitive dysfunction (C- subgroup) based on results from computerized behavioral testing of cognitive control performance (WebNeuro) and from fMRI scanning using the Go/No-Go task.

Exclusion Criteria:

An individual who meets any of the following criteria will be excluded from participation in this study:

1. Presence of one or more of the following conditions established via the participant's medical record and confirmed using the MINI Plus:

   • bipolar disorder (I, II, not otherwise specified, current or lifetime)
   • psychosis (current or lifetime)
   • moderate to severe alcohol or substance use disorders (current)
   • post-traumatic stress disorder (PTSD; current)
   • obsessive compulsive disorder (OCD; current or lifetime)
   • attention deficit hyperactivity disorder (ADHD; current or lifetime)
   • eating disorders (ED; current)
2. Suicidality with active plan
3. Severe impediment to vision, hearing, and/or hand movement
4. Current or lifetime history of medical illness or brain injury that may interfere with assessments
5. Pregnant, breastfeeding, or unwilling or unable to use adequate birth control throughout the study (females of child-bearing potential only)
6. 3.0T MRI scanner contraindications (e.g., metal in the body, claustrophobia)
7. Concurrent participation in other intervention studies
8. Current use of psychotropic medications contraindicated by guanfacine or sertraline

9. General medical condition or disorder that is deemed by study physicians to be unsafe for GIR as reported by patient or found on medical screening. This may include:

   • Cardiac-related exclusions:

     • Resting heart rate (HR) < 55 beats per minute (bradycardia)
     • Systolic blood pressure (SBP) < 90 mmHg or diastolic blood pressure (DBP) < 60 mmHg (hypotension)
     • Current symptoms suggestive of cardiac dysfunction based on clinician assessment (e.g., persistent chest pain, palpitations, dizziness, fainting)

   • Renal-related exclusions:

     • eGFR < 60 mL/min/1.73 m²
     • Current symptoms suggestive of kidney dysfunction based on clinician assessment

   • Hepatic-related exclusions:

     • ALT > 2× ULN
     • AST > 2× ULN
     • Current symptoms suggestive of liver dysfunction based on clinician assessment

   • Thyroid-related exclusions:

     • TSH outside normal laboratory reference range
     • Current symptoms suggestive of thyroid dysfunction based on clinician assessment
10. Use of substance deemed by the study physician to be unsafe for use with guanfacine
11. Current use of a strong CYP3A4 inhibitor (e.g., ketoconazole) or inducer (e.g., carbamazepine) that, in the judgment of the study clinician, may alter guanfacine plasma concentrations and cannot be safely discontinued for the duration of the study.
12. Unwillingness to verify biotype classification via fMRI
13. Unwillingness or inability to use a computer or access a computer for assessments.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sertraline + Placebo; We will conduct a parallel-group, double-blind randomized trial at Stanford Bay Area and Chicago sites, identifying 160 participants with a prominent clinical cognitive signature (C+) and relative absence of the signature (C-). We will enrich for C+, the signature of interest, at a 2:1 ratio. Participants will be randomly assigned to receive guanfacine (shown to ameliorate cognitive control deficits in our preliminary data) plus sertraline or placebo plus sertraline.	Drug: Sertraline; Sertraline is a well-tolerated FDA-approved antidepressant that is among the most widely prescribed medications for depression.
Experimental: Sertraline + Guanfacine; We will conduct a parallel-group, double-blind randomized trial at Stanford Bay Area and Chicago sites, identifying 160 participants with a prominent clinical cognitive signature (C+) and relative absence of the signature (C-). We will enrich for C+, the signature of interest, at a 2:1 ratio. Participants will be randomly assigned to receive guanfacine (shown to ameliorate cognitive control deficits in our preliminary data) plus sertraline or placebo plus sertraline.	Drug: Guanfacine; Guanfacine immediate release is an established and safe FDA-approved treatment that acts directly by stimulating α2A adrenoceptors.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Remission of depressive symptoms	A score of <=5 on the PHQ-9	8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in disability	Score on the Sheehan Disability Scale which ranges from 0 to 30	8 weeks
Change in quality of Life	Score on the Short Form 8 Health Survey (SF-8) which ranges from 0 to 100	8 weeks

Collaborators and Investigators

• Sponsor: Stanford University
• Investigators: Principal Investigator: Leanne Williams, PhD, Stanford University

Study record dates

Study Major Dates

• Study Start (Actual): March 3, 2026
• Primary Completion (Estimated): October 1, 2028
• Study Completion (Estimated): February 1, 2029

Study Registration Dates

• First Submitted: May 6, 2024
• First Submitted That Met QC Criteria: May 8, 2024
• First Posted (Actual): May 10, 2024

Study Record Updates

• Last Update Posted (Actual): March 5, 2026
• Last Update Submitted That Met QC Criteria: March 3, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Depression; Cognitive Symptoms; Precision Psychiatry
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Behavioral Symptoms; Pathological Conditions, Signs and Symptoms; Behavior; Signs and Symptoms; Depression; Neurobehavioral Manifestations; Organic Chemicals; Hydrocarbons; Hydrocarbons, Cyclic; Carboxylic Acids; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Amines; Guanidines; Amidines; Acids, Carbocyclic; Phenylacetates; 1-Naphthylamine; Sertraline; Guanfacine
• Other Study ID Numbers: 2025-1145

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