Development of Pregnenolone as a Treatment for Depression R61

Study Overview
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Brief Summary
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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
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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.

Official Title
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Development of Pregnenolone as a Treatment for Depression R61

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Drug: Pregnenolone 500 mg
* Drug: Pregnenolone 800 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Female

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: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pregnenolone 500 > Pregnenolone 800 > Placebo<br>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<br>* Pregnenolone 500 mg capsule.<br>Drug: Pregnenolone 800 mg<br>* Pregnenolone 800 mg capsule.<br>Drug: Placebo<br>* Placebo capsule manufactured to mimic pregnenolone capsule.<br>|
| Experimental: Pregnenolone 500 > Placebo > Pregnenolone 800<br>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<br>* Pregnenolone 500 mg capsule.<br>Drug: Pregnenolone 800 mg<br>* Pregnenolone 800 mg capsule.<br>Drug: Placebo<br>* Placebo capsule manufactured to mimic pregnenolone capsule.<br>|
| Experimental: Pregnenolone 800 > Pregnenolone 500 > Placebo<br>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<br>* Pregnenolone 500 mg capsule.<br>Drug: Pregnenolone 800 mg<br>* Pregnenolone 800 mg capsule.<br>Drug: Placebo<br>* Placebo capsule manufactured to mimic pregnenolone capsule.<br>|
| Experimental: Pregnenolone 800 > Placebo > Pregnenolone 500<br>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<br>* Pregnenolone 500 mg capsule.<br>Drug: Pregnenolone 800 mg<br>* Pregnenolone 800 mg capsule.<br>Drug: Placebo<br>* Placebo capsule manufactured to mimic pregnenolone capsule.<br>|
| Experimental: Placebo > Pregnenolone 500 > Pregnenolone 800<br>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<br>* Pregnenolone 500 mg capsule.<br>Drug: Pregnenolone 800 mg<br>* Pregnenolone 800 mg capsule.<br>Drug: Placebo<br>* Placebo capsule manufactured to mimic pregnenolone capsule.<br>|
| Experimental: Placebo > Pregnenolone 800 > Pregnenolone 500<br>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<br>* Pregnenolone 500 mg capsule.<br>Drug: Pregnenolone 800 mg<br>* Pregnenolone 800 mg capsule.<br>Drug: Placebo<br>* Placebo capsule manufactured to mimic pregnenolone capsule.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Functional connectivity. | Amygdala-PCC or dlPFC-insula functional connectivity using structural neuroimaging. | 7 days | 
| GABA concentration. | Occipital GABA concentration using spectroscopy. | 7 days | 
| Systematic Assessment for Treatment Emergent Events (SAFTEE). | 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). The higher total score (all items summed together) indicates a higher level of side effect burden. | 7 days | 
| Serum pregnenolone level. | Measure blood serum pregnenolone and allopregnanolone levels. | 7 days | 
| Pregnenolone dose. | Identify a dose of pregnenolone that demonstrates bioavailabilit and tolerability. | 7 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pregnenolone, Women, Depression