Neuroactive Steroid to Treat Depressed Mood: A Trial for People With HIV (SOOTHE)

In Vivo Targeting of Neuroactive Steroid and Immune Networks for Depression in People Living With HIV

This study will determine the effects of pregnenolone on brain function, inflammation and depressive symptoms in people with HIV who have depression. Participants in this study will receive a pill of either pregnenolone or placebo, and can stay on their current antidepression medications. Brain imaging and behavioral assessments will be performed during the study.

Study Overview

• Status: Recruiting
• Conditions: HIV; Major Depressive Disorder; Anxiety Depression
• Intervention / Treatment: Drug: Placebo; Drug: Pregnenolone

Detailed Description

Pregnenolone is a neuroactive steroid that exhibits actions highly relevant to treating depression in people with HIV. The investigators' recent human data suggest that neuroactive steroids are decreased in people with HIV and depression. In addition, multiple groups have reported reductions in neuroactive steroids in people without HIV who have depression. A total of 120 people living with HIV on antiretroviral therapy with depression will be randomized to either pregnenolone or placebo (2 groups/90 participants receiving pregnenolone and 30 participants receiving placebo). Drug dosage will begin at 50 mg daily and incrementally increase to 500 mg daily within the first 4 weeks, with a stable 500 mg/day regimen for the final 4 weeks. Behavioral testing and blood draw will be performed at baseline, 2 weeks, 4 weeks, and 8 weeks, while magnetic resonance spectroscopy (MRS), and task-based functional magnetic resonance imaging (MRI) will be conducted at 2 weeks and 8 weeks.

The investigators hypothesize that pregnenolone will be well-tolerated in people with HIV and depression, and that this intervention may improve brain activity and reduce inflammation.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Hemi Park, MPH; Phone Number: 857-282-3788; Email: MGHSOOTHE@PARTNERS.ORG
• Study Contact Backup: Name: Shibani S. Mukerji, MD, PhD; Phone Number: 857-282-9950; Email: SMUKERJI@MGB.ORG

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Massachusetts General Hospital
      • Principal Investigator: Shibani Mukerji, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 18-85 years
• HIV-1 viral load <200 copies/mL on antiretroviral therapy (ART) at screening visit
• Center for Epidemiological Studies - Depression (CES-D) score ≥ 20

Exclusion Criteria:

• Contraindication to magnetic resonance imaging (MRI) or poor-quality baseline MRI preventing image analyses as determined by radiologist assessment
• Recent severe infections including opportunistic infections, active bacterial, mycobacterial, fungal, or certain viral infections
• Vulnerable populations (e.g., pregnant/nursing, severe cognitive or intellectual impairment, incarcerated)
• Use of cobicistat or ritonavir
• High risk for suicide (active suicidal ideation (SI) with plan/intent as assessed by using the Columbia Suicide Severity Rating (C-SSRS) or > 2 attempts in lifetime or any in the past 6 months) or expresses homicidal ideation necessitating clinical intervention or representing an imminent concern
• Any severe (life-threatening or unstable) medical condition as determined by clinician assessment
• Blood pressure, with the lowest reading taken after three repeat readings during screening visit, ≥ 160 mmHg systolic OR ≥ 95 mmHg diastolic or other life-threatening vital signs as determined by clinician assessment
• Clinically significant abnormalities in physical examination or ECG that would interfere with study participation
• Decompensated cirrhosis, active liver inflammation (alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≥ 5 times the upper limit of normal) or unsuppressed viral hepatitis B or C infection
• Severe renal disease (estimated glomerular filtration rate ≤ 30 mL/min/1.73m2)
• Seizure disorder requiring antiepileptic treatment
• History of allergic reaction or side effects with prior pregnenolone use
• Currently using testosterone enanthate, testosterone cypionate, or estrogen containing preparations that significantly increase systemic estrogen levels, including but not limited to oral and transdermal forms of estrogen. All other forms of exogenous sex steroid hormones will be evaluated at the discretion of the PI and/or clinical delegates.
• Currently using systemic immunosuppressive agents, including corticosteroids, chemotherapy, or specific immunomodulating agents, such as monoclonal antibodies and TNF-inhibitors
• Excessive alcohol or other substances use that would interfere with classification of major depression disorder, study procedures and/or follow-up
• Current diagnosis of bipolar disorder
• Diagnosis of a psychotic disorder (current or lifetime)
• Diagnosis of schizophrenia (current or lifetime)
• <70% adherence to study drug prior to randomization
• Inability to swallow pills/capsules
• Not able to complete neuropsychological testing in English
• Concurrent participation in another interventional trial, except for lifestyle and device studies (For vaccination studies, individuals in the observation period are not exclusionary. Other interventions will be evaluated at the discretion of the PI and/or clinical delegates.)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Placebo; Participants will be on the following dosage schedule: 50 mg daily for 2 weeks, THEN 100 mg daily for 1 week, THEN 250 mg daily for 1 week, THEN 500 mg daily for 4 weeks	Drug: Placebo; (4-week ramp, 4-week steady dosing)
Experimental: Pregnenolone; Participants will be on the following dosage schedule: 50 mg daily for 2 weeks, THEN 100 mg daily for 1 week, THEN 250 mg daily for 1 week, THEN 500 mg daily for 4 weeks	Drug: Pregnenolone; (4-week ramp, 4-week steady dosing); Other Names: Neuroactive steroid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gamma-aminobutyric acid (GABA) Concentration	Comparison between Pregnenolone and Placebo Groups of Left Insular Cortex GABA Concentration, Adjusted for Baseline.	Day 14, Day 56

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Center for Epidemiological Studies-Depression (CES-D; scores range from 0 (no symptoms) to 60 (maximum severity of depressive symptoms))	Comparison of Percentage of Pregnenolone and Placebo Groups Showing Clinical Improvement of Depression at Study End. The revised CES-D is administered, and the total score is calculated by adding the responses to the 20 questions.	Day 0, Day 14, Day 56
CD14+CD16+ Monocytes	Comparison of the Percentage of CD14+CD16+ Monocytes Over Time Adjusted for Baseline Between Pregnenolone and Placebo Groups	Day 0, Day 14, Day 28, Day 56
GABA Concentration in Responders	Comparison of Baseline Left Insular Cortex GABA and Pregnenolone Between Participants in Pregnenolone Group with Clinical Improvement Compared to Clinical Non-Improvers in Pregnenolone Group	Day 0, Day 14, Day 56
Adverse Events	Comparison of the Incidence and Severity of Adverse Events Between Pregnenolone and Placebo Groups	Day 14, Day 56
Dose Modifications	Comparison of Dose Modifications Required Between Pregnenolone and Placebo Groups	Day 14, Day 56

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: National Institute of Mental Health (NIMH); Institute for Medical Research, Inc.
• Investigators: Principal Investigator: Shibani S. Mukerji, MD, PhD, Massachusetts General Hospital

Publications and helpful links

General Publications

• Mukerji SS, Misra V, Lorenz DR, Chettimada S, Keller K, Letendre S, Ellis RJ, Morgello S, Parker RA, Gabuzda D. Low Neuroactive Steroids Identifies a Biological Subtype of Depression in Adults with Human Immunodeficiency Virus on Suppressive Antiretroviral Therapy. J Infect Dis. 2021 May 20;223(9):1601-1611. doi: 10.1093/infdis/jiaa104.

Study record dates

Study Major Dates

• Study Start (Actual): March 3, 2023
• Primary Completion (Estimated): June 30, 2027
• Study Completion (Estimated): January 31, 2028

Study Registration Dates

• First Submitted: October 4, 2022
• First Submitted That Met QC Criteria: October 6, 2022
• First Posted (Actual): October 7, 2022

Study Record Updates

• Last Update Posted (Estimated): September 12, 2025
• Last Update Submitted That Met QC Criteria: September 7, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: Depression; HIV; Pregnenolone; Neuroactive Steroid
• Additional Relevant MeSH Terms: Mental Disorders; Behavioral Symptoms; Mood Disorders; Depressive Disorder; Behavior; Depression; Depressive Disorder, Major; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neurotransmitter Agents; Substandard Drugs; Pharmaceutical Preparations; Pharmacologic Actions; Chemical Actions and Uses; Polycyclic Compounds; Pregnanes; Steroids; Fused-Ring Compounds; Gonadal Steroid Hormones; Gonadal Hormones; Pregnenes; Hydroxycorticosteroids; Adrenal Cortex Hormones; Progesterone Congeners; Neurosteroids; Counterfeit Drugs; Pregnenolone
• Other Study ID Numbers: 2022P001941; 1R01MH131194-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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.: No