A Neurosteroid Intervention for Menopausal and Perimenopausal Depression

NCT03505905 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: 102017-068
• Study Type: interventional
• Target: 73
• Locations: 1 country
• Sites: 1

Brief Summary

HYPOTHESIS: Pregnenolone administration will be associated with greater reduction in depressive symptom severity than placebo in women with current mMDD. STUDY AIMS: Primary Aim: Determine if pregnenolone is associated with greater reduction in depressive symptom severity than placebo in women with mMDD, as measured by MADRS. Secondary Aims:

1. 1.Determine if pregnenolone is associated with greater reduction in anxiety symptom severity than placebo in women with mMDD.
2. 2.Determine if pregnenolone is associated with greater improvement in cognition than placebo in women with mMDD.
3. 3.Determine if pregnenolone is associated with greater improvement in quality of life than placebo in women with mMDD.
4. 4.Determine if pregnenolone is associated with greater improvement in vasomotor symptoms of menopause than placebo.
5. 5.Determine whether changes in neurosteroid levels with pregnenolone mediate clinical response.
6. 6.Determine if baseline neurosteroid levels predict pregnenolone response.
7. 7.Determine whether depressive symptoms, anxiety, sleep or vasomotor symptoms improve first. A crossed-lagged panel model will explore serial correlations between changes in outcome measures.

Conditions

Menopause; Perimenopause; Major Depressive Disorder

Keywords

Pregnenolone

Outcome Measures

Primary Outcomes (1)

• Montgomery-Asberg Depression Rating Scale (MADRS)

  The Montgomery-Asberg Depression Rating Scale (MADRS; primary outcome) is an observer-rated 10-item measure of depressive symptomatology designed for use in clinical trials. Each item is rated from 0-6 in order of increasing severity based upon the assessment of symptoms within the past 7 days. The range of total scores is 0-60, with higher score indicative of more severe depressive symptoms.

  Phase 1 timeframe is Baseline to Week 8; Phase 2 timeframe is Week 8 to Week 16

Secondary Outcomes (6)

• Hamilton Anxiety Rating Scale (HRSA)

  Phase 1 timeframe is Baseline to Week 8; Phase 2 timeframe is Week 8 to Week 16

• Pittsburgh Sleep Quality Index (PSQI)

  Phase 1 timeframe is Baseline to Week 8; Phase 2 timeframe is Week 8 to Week 16

• Menopause Specific Quality of Life (MEN-QOL)

  Phase 1 timeframe is Baseline to Week 8; Phase 2 timeframe is Week 8 to Week 16

• Greene Climacteric Scale (GCS)

  Phase 1 timeframe is Baseline to Week 8; Phase 2 timeframe is Week 8 to Week 16

• Rey Auditory Verbal Learning Test (RAVLT)

  Phase 1 timeframe is Baseline to Week 8; Phase 2 timeframe is Week 8 to Week 16

Study Arms (4)

Pregnenlone (phase 1 and 2)

EXPERIMENTAL

Participants will receive pregnenolone at phase 1 (baseline-WK 7) and 2 (WK 8-16). The titration schedule is as follows: at baseline a 50 mg (BID, 7 days). WK 1=150 mg (BID, 7 days); WK 2=250 mg (BID, 14 days) and WK 4=250 mg (BID, 14 days) (BID, 14 days). At phase 2 (WK 8) to maintain the double blind of rerandomization, treatment in all conditions recommence at a dosage frequency similar to phase 1. At WK 8=250 mg (BID, 7 days); at WK 9=250 mg (BID, 7 days); WK 10=250 mg (BID, 14 days) and WK 12=250 mg (BID, 14 days) . During the participants' final WK (16), they will be instructed to titrate down the treatment according to the following schedule: 150 mg (BID, 4 days) and 50 mg (BID, 4 days), discontinue.

Drug: Pregnenolone

Placebo rerandom to placebo

PLACEBO COMPARATOR

Participants will receive placebo at phase 1 (baseline-WK 7) \& treatment response assessed (MADRS score reduced \<50% at WK8). Nonresponders are rerandomized to receive either treatment at phase 2 (WK8-16).The titration schedule is as follows (dosage throughout is BID): at baseline placebo (7 days). At WK 1= placebo (7 days); at WK 2=placebo (14 days) and WK 4=placebo (14 days). Placebo nonresponders rerandomized to placebo: At WK 8=placebo (7 days);WK 9=placebo (7 days);WK 10=placebo (14 days) and WK 12=placebo (14 days). During the participants' final WK (16), they will be instructed to titrate down (done in order to maintain the double blind) the treatment according to the following schedule: placebo (4 days) and placebo (4 days), discontinue.

Drug: Placebo

Placebo rerandom to pregnenolone

EXPERIMENTAL

Participants will receive placebo at phase 1 (baseline-WK 7) \& treatment response assessed (MADRS score reduced \<50% at WK8). Nonresponders are rerandomized to receive either treatment at phase 2 (WK8-16).The titration schedule is as follows (dosage throughout is BID): at baseline placebo (7 days). At WK 1=placebo (7 days); WK 2=placebo (14 days) \& WK 4=placebo (14 days). Placebo nonresponders who are rerandomized to pregnenolone: At WK 8=250 mg (7 days);WK 9=250 mg (7 days);WK 10=250 mg (14 days) \& WK 12=250 mg (14 days). During the participants' final WK (16), they will be instructed to titrate down the treatment according to the following schedule: 150 mg (4 days) and 50 mg (4 days), discontinue.

Drug: Pregnenolone; Drug: Placebo

Placebo responsive cont placebo

PLACEBO COMPARATOR

Participants will placebo throughout phase 1 (baseline- WK 7) \& treatment response assessed (MADRS score reduced \<50% at WK8). Responders continue to receive placebo at phase 2 (WK8-16).The titration schedule is as follows (dosage throughout is BID): at baseline placebo (7 days). At WK 1=placebo (7 days); WK 2=placebo (14 days) \& WK 4=placebo (14 days). Placebo responders remain on placebo: At WK 8, placebo (7 days); WK 9=placebo (7 days); WK 10=placebo (14 days) \& WK 12=placebo (14 days). During the participants' final WK (16), they will be instructed to titrate down (done in order to maintain the double blind) the treatment according to the following schedule: placebo= 4 days) and placebo=4 days, discontinue.

Drug: Placebo

Interventions

Pregnenolone DRUG

In a sequential parallel comparison design, in a double blind placebo controlled study, the efficacy of pregnenlone treatment relative to placebo in improving depression and anxiety symptoms, cognition, sleep, quality of life and vasomotor symptoms in preimenopausal and menopausal women with MDD.

Placebo rerandom to pregnenolone; Pregnenlone (phase 1 and 2)

Placebo DRUG

In a sequential parallel comparison design, in a double blind placebo controlled study, the efficacy of pregnenlone treatment relative to placebo in improving depression and anxiety symptoms, cognition, sleep, quality of life and vasomotor symptoms in preimenopausal and menopausal women with MDD.

Placebo rerandom to placebo; Placebo rerandom to pregnenolone; Placebo responsive cont placebo

Eligibility Criteria

• Age: 40 Years - 67 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• The participants must meet the following criteria:
• Women aged 40-67 years who are perimenopausal or early postmenopausal (within 5 years of the last menstrual period if not surgically postmenopausal), including:
• Women who have experienced changes in menstrual cycle frequency or duration, and/or physical symptoms indicative of menopausal transition, as determined by clinician
• Women who are using hormonal IUDs (i.e. brands Mirena and Skyla), with FSH level \> 20 mIU/m (as menstrual periods are irregular with IUDs that utilize hormones, making irregular/absent periods difficult to assess as related to the menopausal transition).
• Women with significant menopause-related physical symptoms, indicated by any of the following criteria:
• Greene Climacteric Scale total scores \> 20
• Greene Climacteric Scale sub-score for vasomotor symptoms \>3
• or more bothersome hot flashes per week (self-reported)
• Women meeting DSM-5 criteria for current major depressive disorder (assessed by the SCID)
• Baseline HRSD score of ≥ 18
• Subject agrees to abstain from disallowed medications for the duration of the trial

You may not qualify if:

• The participants must not meet any of the following criteria:
• Vulnerable populations (e.g. pregnant/nursing, severe cognitive or intellectual impairment, incarcerated)
• Pregnancy (determined by urine pregnancy test), intending pregnancy or breast feeding
• Psychiatric disorder other than MDD that is acute and the primary focus of symptom burden or treatment.
• History of bipolar disorder or psychotic disorder
• Current substance use disorder
• Current eating disorder
• Treatment resistant depression (failure of 2 adequate antidepressant trials or electroconvulsive therapy (ECT) during current episode; adequate antidepressant trials are defined as within the US FDA approved dosage for the medication and used for at least 6 weeks, with failure described by the patient as \<50% improvement based on her subjective experience).
• High risk for suicidal acts including active suicidal ideation with plan and intent or \> 2 suicide attempts in lifetime or any attempt in the past 6 months
• Use of selective estrogen-receptor modulators (SERMs), hormone replacement therapy, hormonal contraceptives (hormonal IUDs allowed), episodic sleep medications (chronic, regular, stable-dose benzodiazepines and hypnotics such as zolpidem, Sonata (Zaleplon), and Lunesta (Eszopiclone) OR sleep-seating antihistamines such as Unisom (Doxylamine succinate) or diphenhydramine allowed) within 2 weeks of the baseline visit and randomization. Antidepressants will be allowed for those participants who have been taking the antidepressant for 6 weeks with a stable dose for at least 4 weeks.
• Use of natural menopause and depression supplements, phytoestrogens, soy-based medications, steroids within 2 weeks of baseline visit and randomization.
• Use of any disallowed medications (specified in the Excluded Concomitant Medication section below).
• Women who have received a gonadal hormonal intervention within 1 month prior to study entry (stable thyroid medications are allowed).
• Not using a medically approved method of birth control, if sexually active and not 12 or more months since last menstrual period IUDs, condoms, abstinence are acceptable forms of contraception in this study; due to the possible interactions with the study medication, oral contraceptive pills will be prohibited.
• Uncontrolled hypertension (\>160/95mmHg)

Sponsors & Collaborators

• University of Texas Southwestern Medical Center: lead
• Massachusetts General Hospital: collaborator

Study Sites (1)

UT Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

MeSH Terms

Conditions

Depressive Disorder, Major

Interventions

Pregnenolone

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Hydroxycorticosteroids; Adrenal Cortex Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Progesterone Congeners; Gonadal Steroid Hormones; Gonadal Hormones

Results Point of Contact

• Title: Dr. E. Sherwood Brown
• Organization: University of Texas Southwestern Medical Center

sherwood.brown@utsouthwestern.edu

214-645-6950

Study Officials

• Sherwood Brown, MD, PhD

  University of Texas Southwestern Medical Center

  PRINCIPAL INVESTIGATOR

• Marlene Freeman, MD

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Model Details: A double-blind, placebo-controlled, Sequential Parallel Comparison Design (SPCD) trial of pregnenolone. SPCD is a clinical trial design that may reduce the effect of placebo response on signal detection and maximize the ability to assess efficacy by dividing the trial into two phases, and then re-randomizing placebo non-responders.

Study Record Dates

• First Submitted: April 13, 2018
• First Posted: April 23, 2018
• Study Start: September 1, 2018
• Primary Completion: December 3, 2024
• Study Completion: December 3, 2024
• Last Updated: January 22, 2026
• Results First Posted: January 22, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)