This study aims to identify how enhanced allopregnanolone activity (via pregnenolone) affects behavior and neurobiology that may underlie perimenopausal depression.

Midlife women are burdened with depression risk that is at least partly attributed to changing reproductive steroid dynamics across a prolonged reproductive transition. We hypothesize that declining endogenous allopregnanolone (ALLO) levels across the menopause transition underlies perimenopausal depression. This mechanistic trial aims to amplify the contrast between lower endogenous ALLO levels in perimenopausal women and higher levels induced by pregnenolone. This will be achieved by using the over-the-counter dietary supplement, pregnenolone, in a randomized, double-blind, parallel-arm, placebo-controlled trial. By manipulating ALLO levels together with key measurement of depression domains, this study harnesses the endocrine biology of perimenopause to explicate behavioral and neurobiological mechanisms underlying depression in women across the menopause transition.

Inclusion Criteria:

• Healthy women ages 40 to 60 years in the menopause transition
• Depressive symptoms
• Psychotropic medications are allowed if the dose is stable prior to screening and throughout the study
• Able to read Arabic numerals and perform simple arithmetic
• Able to provide written informed consent

Exclusion Criteria:

• Systemic hormone therapy
• Contraindicated medications with pregnenolone
• Systemic corticosteroid
• Other psychiatric illnesses that are considered to be primary
• Current suicidal ideation
• Active substance use disorders
• Unstable medical conditions
• Obstructive sleep apnea or other primary sleep disorders
• Abnormal hepatic and renal function
• Known allergy to progesterone, exogenous allopregnanolone, or pregnenolone
• History of head injury resulting in loss of consciousness > 20 min
• Inability to comply with barrier contraceptive methods
• Known intellectual disability
• Investigator judgement that study participation constitutes substantial risk given medical or psychiatric condition
• Current or recent participation in clinical trial expected to interfere with risk of or interpretation of study data
• Inability to comply with study procedures