# A Neurosteroid Intervention for Menopausal and Perimenopausal Depression

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $709,593

## Abstract

Abstract
 Major depressive disorder (MDD) is a major cause of disability worldwide and is twice as common in
women as in men. Women are at heightened risk for depression onset during the menopausal transition, which
includes both perimenopause and early postmenopause. Menopausal Major Depressive Disorder (mMDD) is
usually accompanied by comorbid conditions that interfere with functioning and wellbeing, including hot
flashes, cognitive complaints, anxiety, fatigue and sleep dysregulation. Despite the elevated risk of depression
in this population, there have been few placebo-controlled trials to treat mMDD. Many women prefer
alternatives to the typical treatment options for mMDD of antidepressants or estrogen replacement therapy.
Importantly, menopausal women often seek integrative treatments, such as nutritional supplements, despite a
paucity of data thus far to support the efficacy or safety of such compounds.
 Pregnenolone is an endogenous neurosteroid that is made from cholesterol in the brain and adrenals
that is sold as an over-the-counter supplement in the United States. Preclinical literature suggests that a
pregnenolone analogue is effective in animal models of depression. Low cerebrospinal fluid levels of
pregnenolone are reported in humans with depression, low serum levels in anxiety and low parietal cortex
levels in people who commit suicide. We conducted two placebo-controlled pilot studies of exogenous
pregnenolone administration in depressed patients. The first study showed a greater reduction in depressive
symptoms with pregnenolone in a mixed sample of patients with bipolar depression and MDD. A second study
focused on bipolar depression and again found a greater improvement in depressive symptoms with
pregnenolone than placebo. Pregnenolone was well tolerated in both studies. Women showed a more robust
response than men in both pilot studies and women over age 40 years showed a stronger response than did
younger women. In addition, improvement in cognition (e.g. memory) was observed with pregnenolone in
women and reduction in depressive symptoms strongly correlated with increases in blood pregnenolone levels.
Given the wide availability of pregnenolone and the promising preclinical and clinical data, particularly in
women, we propose a trial of this supplement in women in the menopausal transition with MDD (mMDD).
 A two-site (Dallas and Boston), randomized, double-blind, placebo-controlled trial of 16 weeks of
pregnenolone is proposed in 144 women over age 40 with mMDD using an innovative sequential parallel
comparison clinical trial design. Depressive symptoms, anxiety symptoms, hot flashes, sleep, quality of life and
cognition will be assessed. Serum neurosteroid levels will be obtained at baseline and exit. An experienced
research team will conduct the clinical trial. The principal investigators each have over 18 years of experience
conducting clinical trials in patients with mood disorders. The co-investigators also have ext...

## Key facts

- **NIH application ID:** 9852937
- **Project number:** 5R01AG056426-03
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** E SHERWOOD BROWN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $709,593
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852937

## Citation

> US National Institutes of Health, RePORTER application 9852937, A Neurosteroid Intervention for Menopausal and Perimenopausal Depression (5R01AG056426-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9852937. Licensed CC0.

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