Development of Pregnenolone as a Treatment for Depression R61

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.

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).