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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Major Depressive Disorder, Anxiety Depression, HIV

Intervention / Treatment
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* Drug: Placebo
* Drug: Pregnenolone


Participation Criteria
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Eligibility Criteria
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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 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 exogenous sex steroids hormones such as preparations containing estrogen or testosterone 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) <75% adherence to study drug prior to baseline MRI 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.)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be randomized to receive oral pregnenolone or placebo.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Placebo<br>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<br>* (4-week ramp, 4-week steady dosing)<br>|
| Experimental: Pregnenolone<br>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<br>* (4-week ramp, 4-week steady dosing)<br>* Other names: Neuroactive steroid;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, Depression, Neuroactive Steroid, Pregnenolone