Development of Pregnenolone as a Treatment for Depression

Phase 1

Completed

• Conditions: Major Depressive Disorder
• Interventions: Drug: Pregnenolone 500 mg; Drug: Pregnenolone 800 mg; Drug: Placebo

• Registration Number: NCT03645096
• Lead Sponsor: University of Texas Southwestern Medical Center

Brief Summary

Pregnenolone, an over-the-counter supplement, is a naturally occurring neurosteroid made in the adrenal glands and brain. Preclinical research suggests pregnenolone has antidepressant, cognitive enhancing, and neuroprotective properties, particularly in women. The following hypothesis will be tested in this trial: pregnenolone is associated with improvement in depressive symptom severity in women that is associated with changes in the resting state functional connectivity (rsFC) and GABA.

Detailed Description

In this study, 26 adult women meeting criteria for Major Depressive Disorder (MDD) as defined in DSM 5, will be randomized to a double-blind, placebo-controlled, crossover phase I clinical trial of pregnenolone (i.e. each participant receives 500 mg/d, 800 mg/d pregnenolone and placebo in random order). The study will consist of three 7-day treatment exposures to each pregnenolone dose with a 14-day washout between each exposure. Baseline evaluation will include medical and psychiatric history, psychiatric interview, standard laboratory analyses (i.e., blood draw, ECG), and a brief cognitive battery. Neuroimaging will be collected after each study drug or placebo administration. Study drug tolerability and participant safety will be assessed throughout the study (6 in-clinic visits + a safety visit) using structured clinical interviews, self-report questionnaires, and standard laboratory analyses.

Study Timeline

• Study First Submitted: 2018-08-22
• Study First Submitted QC: 2018-08-22
• Study First Posted: 2018-08-24
• Study Start: 2019-09-01
• Primary Completion: 2022-05-31
• Study Completion: 2022-05-31
• Results First Submitted: 2023-08-24
• Status Verified: 2024-04
• Results First Submitted QC: 2024-04-25
• Last Update Submitted: 2024-04-25
• Results First Posted: 2024-05-01
• Last Update Posted: 2024-05-01

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 34

Inclusion Criteria

• Women, ages 18-65 years, with current MDD (mild or moderate severity per DSM-5) based on SCID-CV.
• No psychotropic medications, other than PRN (as needed) hypnotics, within 28 days of randomization (medication free).
• PRN hypnotics allowed up to 3 days prior to study drug administrations but not while receiving study drug.

Read More

Exclusion Criteria

• Severe MDD based on DSM-5 severity criteria and/or a baseline HRSD score > 27 (consistent with severe depressive symptom severity).
• High risk for suicide (active SI with plan/intent or > 2 lifetime attempts in lifetime or any in the past 6 months).
• Treatment resistant depression (fail two adequate antidepressant trials or ECT during current episode).
• Vulnerable populations (e.g. pregnant/nursing, severe cognitive or intellectual impairment, incarcerated).
• Coronary artery disease, atrial fibrillation, stroke, deep vein thrombosis, pulmonary embolism or blood clotting disorder, or any severe, life threatening or unstable, medical condition.
• History of allergic reaction or side effects with prior pregnenolone use.
• Current substance use disorder defined as meeting criteria for a use disorder based on the SCID interview and self-reported use within the past 3 months, or a positive baseline urine drug screen.
• Current psychotic features (hallucinations, delusions, disorganized thought processes) or eating disorders.
• Anxiety disorders of sufficient severity to be the primary focus of clinical attention (e.g. severe obsessive compulsive or post-traumatic stress disorders).
• Hormone-sensitive conditions (i.e. breast cancer; uterine/ovarian cancer, endometriosis, uterine fibroids).
• Clinically significant laboratory, physical examination, or electrocardiogram (ECG) findings.
• Currently using oral contraceptives containing progestin (barrier methods allowed).

Read More

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Pregnenolone 500 > Pregnenolone 800 > Placebo	Placebo	3 exposures in order: 1. Pregnenolone 500 mg capsule by mouth, daily for 7 days followed by 14 day washout. 2. Pregnenolone 800 mg capsule by mouth, daily for 7 days followed by 14 day washout. 3. Matching placebo capsule by mouth, daily for 7 days.
Pregnenolone 500 > Placebo > Pregnenolone 800	Pregnenolone 500 mg	3 exposures in order: 1. Pregnenolone 500 mg capsule by mouth, daily for 7 days followed by 14 day washout. 2. Matching placebo capsule by mouth, daily for 7 days followed by 14 day washout. 3. Pregnenolone 800 mg capsule by mouth, daily for 7 days.
Pregnenolone 500 > Placebo > Pregnenolone 800	Placebo	3 exposures in order: 1. Pregnenolone 500 mg capsule by mouth, daily for 7 days followed by 14 day washout. 2. Matching placebo capsule by mouth, daily for 7 days followed by 14 day washout. 3. Pregnenolone 800 mg capsule by mouth, daily for 7 days.
Pregnenolone 800 > Pregnenolone 500 > Placebo	Placebo	3 exposures in order: 1. Pregnenolone 800 mg capsule by mouth, daily for 7 days followed by 14 day washout. 2. Pregnenolone 500 mg capsule by mouth, daily for 7 days followed by 14 day washout. 3. Matching placebo capsule by mouth, daily for 7 days.
Pregnenolone 800 > Placebo > Pregnenolone 500	Pregnenolone 500 mg	3 exposures in order: 1. Pregnenolone 800 mg capsule by mouth, daily for 7 days followed by 14 day washout. 2. Matching placebo capsule by mouth, daily for 7 days followed by 14 day washout. 3. Pregnenolone 500 mg capsule by mouth, daily for 7 days.
Pregnenolone 800 > Placebo > Pregnenolone 500	Pregnenolone 800 mg	3 exposures in order: 1. Pregnenolone 800 mg capsule by mouth, daily for 7 days followed by 14 day washout. 2. Matching placebo capsule by mouth, daily for 7 days followed by 14 day washout. 3. Pregnenolone 500 mg capsule by mouth, daily for 7 days.
Pregnenolone 800 > Placebo > Pregnenolone 500	Placebo	3 exposures in order: 1. Pregnenolone 800 mg capsule by mouth, daily for 7 days followed by 14 day washout. 2. Matching placebo capsule by mouth, daily for 7 days followed by 14 day washout. 3. Pregnenolone 500 mg capsule by mouth, daily for 7 days.
Placebo > Pregnenolone 500 > Pregnenolone 800	Pregnenolone 800 mg	3 exposures in order: 1. Matching placebo capsule by mouth, daily for 7 days followed by 14 day washout. 2. Pregnenolone 500 mg capsule by mouth, daily for 7 days followed by 14 day washout. 3. Pregnenolone 800 mg capsule by mouth, daily for 7 days.
Placebo > Pregnenolone 500 > Pregnenolone 800	Placebo	3 exposures in order: 1. Matching placebo capsule by mouth, daily for 7 days followed by 14 day washout. 2. Pregnenolone 500 mg capsule by mouth, daily for 7 days followed by 14 day washout. 3. Pregnenolone 800 mg capsule by mouth, daily for 7 days.
Placebo > Pregnenolone 800 > Pregnenolone 500	Pregnenolone 500 mg	3 exposures in order: 1. Matching placebo capsule by mouth, daily for 7 days followed by 14 day washout. 2. Pregnenolone 800 mg capsule by mouth, daily for 7 days followed by 14 day washout. 3. Pregnenolone 500 mg capsule by mouth, daily for 7 days.
Placebo > Pregnenolone 800 > Pregnenolone 500	Placebo	3 exposures in order: 1. Matching placebo capsule by mouth, daily for 7 days followed by 14 day washout. 2. Pregnenolone 800 mg capsule by mouth, daily for 7 days followed by 14 day washout. 3. Pregnenolone 500 mg capsule by mouth, daily for 7 days.
Pregnenolone 500 > Pregnenolone 800 > Placebo	Pregnenolone 800 mg	3 exposures in order: 1. Pregnenolone 500 mg capsule by mouth, daily for 7 days followed by 14 day washout. 2. Pregnenolone 800 mg capsule by mouth, daily for 7 days followed by 14 day washout. 3. Matching placebo capsule by mouth, daily for 7 days.
Pregnenolone 800 > Pregnenolone 500 > Placebo	Pregnenolone 500 mg	3 exposures in order: 1. Pregnenolone 800 mg capsule by mouth, daily for 7 days followed by 14 day washout. 2. Pregnenolone 500 mg capsule by mouth, daily for 7 days followed by 14 day washout. 3. Matching placebo capsule by mouth, daily for 7 days.
Pregnenolone 500 > Pregnenolone 800 > Placebo	Pregnenolone 500 mg	3 exposures in order: 1. Pregnenolone 500 mg capsule by mouth, daily for 7 days followed by 14 day washout. 2. Pregnenolone 800 mg capsule by mouth, daily for 7 days followed by 14 day washout. 3. Matching placebo capsule by mouth, daily for 7 days.
Pregnenolone 500 > Placebo > Pregnenolone 800	Pregnenolone 800 mg	3 exposures in order: 1. Pregnenolone 500 mg capsule by mouth, daily for 7 days followed by 14 day washout. 2. Matching placebo capsule by mouth, daily for 7 days followed by 14 day washout. 3. Pregnenolone 800 mg capsule by mouth, daily for 7 days.
Pregnenolone 800 > Pregnenolone 500 > Placebo	Pregnenolone 800 mg	3 exposures in order: 1. Pregnenolone 800 mg capsule by mouth, daily for 7 days followed by 14 day washout. 2. Pregnenolone 500 mg capsule by mouth, daily for 7 days followed by 14 day washout. 3. Matching placebo capsule by mouth, daily for 7 days.
Placebo > Pregnenolone 500 > Pregnenolone 800	Pregnenolone 500 mg	3 exposures in order: 1. Matching placebo capsule by mouth, daily for 7 days followed by 14 day washout. 2. Pregnenolone 500 mg capsule by mouth, daily for 7 days followed by 14 day washout. 3. Pregnenolone 800 mg capsule by mouth, daily for 7 days.
Placebo > Pregnenolone 800 > Pregnenolone 500	Pregnenolone 800 mg	3 exposures in order: 1. Matching placebo capsule by mouth, daily for 7 days followed by 14 day washout. 2. Pregnenolone 800 mg capsule by mouth, daily for 7 days followed by 14 day washout. 3. Pregnenolone 500 mg capsule by mouth, daily for 7 days.

Primary Outcome Measures

Name	Time	Method
Amygdala-PCC Functional Connectivity	7 days	Determine if an increase in Amygdala-PCC functional connectivity is observed with pregnenolone as compared to placebo.; Amygdala-PCC functional connectivity was measured using resting state fMRI blood-oxygen-level dependent (BOLD) response and transformed to standardized z-scores (with μ=0 and σ=1) for analysis. Functional connectivity was measured three times corresponding to three treatments (500 mg pregnenolone, 800 mg pregnenolone, and placebo). Better outcomes are represented by greater functional connectivity, and are indicated by a higher z-score at 500 mg or 800 mg, relative to that at placebo (i.e., there is no absolute threshold).
dlPFC-Insula Functional Connectivity	7 days	Determine if an increase in dlPFC-Insula functional connectivity is observed with pregnenolone as compared to placebo.; dlPFC-Insula functional connectivity was measured using resting state fMRI blood-oxygen-level dependent (BOLD) response and transformed to standardized z-scores (with μ=0 and σ=1) for analysis. Functional connectivity was measured three times corresponding to three treatments (500 mg pregnenolone, 800 mg pregnenolone, and placebo). Better outcomes are represented by greater functional connectivity, and are indicated by a higher z-score at 500 mg or 800 mg, relative to that at placebo (i.e., there is no absolute threshold).
GABA Concentration.	7 days	Determine if an increase in occipital GABA concentration is observed with pregnenolone, as compared to placebo.; Occipital GABA concentration using spectroscopy with tCr reference. Higher concentration values are representative of a greater anti-depressant effect.

Secondary Outcome Measures

Name	Time	Method
Pregnenolone Level	7 days	Assess bioavailability of pregnenolone by demonstrating increases in serum pregnenolone and allopregnanolone with pregnenolone administration. Change (increases) in blood serum pregnenolone levels are indicative of bioavailability.
Allopregnanolone Level	7 days	Assess bioavailability of pregnenolone by demonstrating increases in serum pregnenolone and allopregnanolone with pregnenolone administration. Change (increases) in blood serum allopregnanolone levels are indicative of bioavailability.
Systematic Assessment for Treatment Emergent Events (SAFTEE)	7 days	Assess safety and tolerability of pregnenolone at the doses tested.; SAFTEE is a side effect self-report assessment scale that consists of 56 potential side effects. Participants rate how bothersome each side effect is on a scale of "none" (0), "mild" (1), "moderate" (2), "severe" (3). Total scores range from 0 to 168. A higher total score (sum of all items) indicates a higher level of side effect burden.
Pregnenolone Dose	7 days	Identify a dose of pregnenolone that demonstrates bioavailability (see "Pregnenolone Level" and "Allopregnanolone Level" outcome measures), tolerability (see "SAFTEE" outcome measure); and is associated with a significant change in a biosignature.

Trial Locations

Locations (1)

UT Southwestern Medical Center; 🇺🇸 Dallas, Texas, United States