Development of Pregnenolone as a Treatment for Depression

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).