Development of Pregnenolone as a Treatment for Depression

The University of Texas System (UT)

Status and phase: Completed; Phase 1

Conditions: Major Depressive Disorder

Treatments: Drug: Placebo; Drug: Pregnenolone 800 mg; Drug: Pregnenolone 500 mg

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT03645096

1R61AT009625-01A1 (U.S. NIH Grant/Contract)

STU 052018-030

Details and patient eligibility

About

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.

Full 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.

Enrollment: 34 patients

Sex: Female

Ages: 18 to 65 years old

Volunteers: No Healthy Volunteers

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).

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Quadruple Blind

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34 participants in 6 patient groups

Pregnenolone 500 > Pregnenolone 800 > Placebo

Experimental group

Description:

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.

Treatment:

Drug: Pregnenolone 500 mg

Drug: Placebo

Drug: Pregnenolone 800 mg

Pregnenolone 500 > Placebo > Pregnenolone 800

Experimental group

Description:

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.

Treatment:

Drug: Pregnenolone 500 mg

Drug: Placebo

Drug: Pregnenolone 800 mg

Pregnenolone 800 > Pregnenolone 500 > Placebo

Experimental group

Description:

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.

Treatment:

Drug: Pregnenolone 500 mg

Drug: Placebo

Drug: Pregnenolone 800 mg

Pregnenolone 800 > Placebo > Pregnenolone 500

Experimental group

Description:

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.

Treatment:

Drug: Pregnenolone 500 mg

Drug: Placebo

Drug: Pregnenolone 800 mg

Placebo > Pregnenolone 500 > Pregnenolone 800

Experimental group

Description:

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.

Treatment:

Drug: Pregnenolone 500 mg

Drug: Placebo

Drug: Pregnenolone 800 mg

Placebo > Pregnenolone 800 > Pregnenolone 500

Experimental group

Description:

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.

Treatment:

Drug: Pregnenolone 500 mg

Drug: Placebo

Drug: Pregnenolone 800 mg