Development of Pregnenolone as a Treatment for Depression

NCCIH Development of Pregnenolone as a Treatment for Depression R61 Phase

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.

Study Overview

• Status: Completed
• Conditions: Major Depressive Disorder
• Intervention / Treatment: Drug: Pregnenolone 500 mg; Drug: Pregnenolone 800 mg; Drug: Placebo

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 Type: Interventional
• Enrollment (Actual): 34
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 61 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pregnenolone 500 > Pregnenolone 800 > Placebo; 3 exposures in order: Pregnenolone 500 mg capsule by mouth, daily for 7 days followed by 14 day washout.; Pregnenolone 800 mg capsule by mouth, daily for 7 days followed by 14 day washout.; Matching placebo capsule by mouth, daily for 7 days.	Drug: Pregnenolone 500 mg; Pregnenolone 500 mg capsule.; Other Names: Neurosteroid; Drug: Pregnenolone 800 mg; Pregnenolone 800 mg capsule.; Other Names: Neurosteroid; Drug: Placebo; Placebo capsule manufactured to mimic pregnenolone capsule.
Experimental: Pregnenolone 500 > Placebo > Pregnenolone 800; 3 exposures in order: Pregnenolone 500 mg capsule by mouth, daily for 7 days followed by 14 day washout.; Matching placebo capsule by mouth, daily for 7 days followed by 14 day washout.; Pregnenolone 800 mg capsule by mouth, daily for 7 days.	Drug: Pregnenolone 500 mg; Pregnenolone 500 mg capsule.; Other Names: Neurosteroid; Drug: Pregnenolone 800 mg; Pregnenolone 800 mg capsule.; Other Names: Neurosteroid; Drug: Placebo; Placebo capsule manufactured to mimic pregnenolone capsule.
Experimental: Pregnenolone 800 > Pregnenolone 500 > Placebo; 3 exposures in order: Pregnenolone 800 mg capsule by mouth, daily for 7 days followed by 14 day washout.; Pregnenolone 500 mg capsule by mouth, daily for 7 days followed by 14 day washout.; Matching placebo capsule by mouth, daily for 7 days.	Drug: Pregnenolone 500 mg; Pregnenolone 500 mg capsule.; Other Names: Neurosteroid; Drug: Pregnenolone 800 mg; Pregnenolone 800 mg capsule.; Other Names: Neurosteroid; Drug: Placebo; Placebo capsule manufactured to mimic pregnenolone capsule.
Experimental: Pregnenolone 800 > Placebo > Pregnenolone 500; 3 exposures in order: Pregnenolone 800 mg capsule by mouth, daily for 7 days followed by 14 day washout.; Matching placebo capsule by mouth, daily for 7 days followed by 14 day washout.; Pregnenolone 500 mg capsule by mouth, daily for 7 days.	Drug: Pregnenolone 500 mg; Pregnenolone 500 mg capsule.; Other Names: Neurosteroid; Drug: Pregnenolone 800 mg; Pregnenolone 800 mg capsule.; Other Names: Neurosteroid; Drug: Placebo; Placebo capsule manufactured to mimic pregnenolone capsule.
Experimental: Placebo > Pregnenolone 500 > Pregnenolone 800; 3 exposures in order: Matching placebo capsule by mouth, daily for 7 days followed by 14 day washout.; Pregnenolone 500 mg capsule by mouth, daily for 7 days followed by 14 day washout.; Pregnenolone 800 mg capsule by mouth, daily for 7 days.	Drug: Pregnenolone 500 mg; Pregnenolone 500 mg capsule.; Other Names: Neurosteroid; Drug: Pregnenolone 800 mg; Pregnenolone 800 mg capsule.; Other Names: Neurosteroid; Drug: Placebo; Placebo capsule manufactured to mimic pregnenolone capsule.
Experimental: Placebo > Pregnenolone 800 > Pregnenolone 500; 3 exposures in order: Matching placebo capsule by mouth, daily for 7 days followed by 14 day washout.; Pregnenolone 800 mg capsule by mouth, daily for 7 days followed by 14 day washout.; Pregnenolone 500 mg capsule by mouth, daily for 7 days.	Drug: Pregnenolone 500 mg; Pregnenolone 500 mg capsule.; Other Names: Neurosteroid; Drug: Pregnenolone 800 mg; Pregnenolone 800 mg capsule.; Other Names: Neurosteroid; Drug: Placebo; Placebo capsule manufactured to mimic pregnenolone capsule.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Amygdala-PCC Functional Connectivity	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).	7 days
dlPFC-Insula Functional Connectivity	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).	7 days
GABA Concentration.	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.	7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pregnenolone Level	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.	7 days
Allopregnanolone Level	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.	7 days
Systematic Assessment for Treatment Emergent Events (SAFTEE)	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.	7 days
Pregnenolone Dose	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.	7 days

Collaborators and Investigators

• Sponsor: University of Texas Southwestern Medical Center
• Collaborators: National Center for Complementary and Integrative Health (NCCIH)
• Investigators: Principal Investigator: Sherwood Brown, MD, PhD, UT Southwestern Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2019
• Primary Completion (Actual): May 31, 2022
• Study Completion (Actual): May 31, 2022

Study Registration Dates

• First Submitted: August 22, 2018
• First Submitted That Met QC Criteria: August 22, 2018
• First Posted (Actual): August 24, 2018

Study Record Updates

• Last Update Posted (Actual): May 1, 2024
• Last Update Submitted That Met QC Criteria: April 25, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Depression; Women; Pregnenolone
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Mood Disorders; Depression; Depressive Disorder; Depressive Disorder, Major; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Neurosteroids
• Other Study ID Numbers: STU 052018-030; 1R61AT009625-01A1 (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