Major Depressive DisorderPhase 1/2NCT03505905
A Neurosteroid Intervention for Menopausal and Perimenopausal Depression
A Phase 1/2 study testing Pregnenolone in people with Major Depressive Disorder and Menopause, run by University of Texas Southwestern Medical Center at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 40 to 67 years, women only
- Conditions the study is for
- Major Depressive Disorder, Menopause, Perimenopause
- What is being tested?
- Pregnenolone
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 73 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Sep 2018to 3 Dec 2024
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 40 to 67 years
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Show all 11Show fewer
- Greene Climacteric Scale sub-score for vasomotor symptoms >3
- 5 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
Who cannot join
- 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
Show all 30Show fewer
- Positive baseline urine drug screen of an illicit substance (in this study: opioids and cocaine,) with the exception of a medication used with a prescription (use of a detected substance that is used with a prescription, such as an opioid pain medication, is not necessarily exclusionary and will be based upon judgment of the PI, particularly in the cases of chronic opioid use). Participants who screen positive for marijuana will be offered a rescreen for eligibility at a later date.
- 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)
- Active coronary artery disease, atrial fibrillation, stroke, deep vein thrombosis, pulmonary embolism or blood clotting disorder
- Any severe, life threatening or unstable medical condition that, based on clinician-judgment, would make participation in the study unsafe or inappropriate
- Personal or first degree family history of known hormone sensitive tumors
- History of allergic reaction or side effects with prior pregnenolone use
- Clinically significant laboratory or physical examination findings
- Concurrent enrollment in another clinical trial
- Selective estrogen-receptor modulators (SERMs)
- Hormone replacement therapy
- Hormonal contraceptives, excluding Mirena IUD or other IUD with localized progesterone
- Natural menopause or antidepressant supplements
- Episodic sleep medications (chronic, regular, stable-dose benzodiazepines and hypnotics such as zolpidem, Sonata (Zaleplon), and Lunesta (Eszopiclone) OR sleep-sedating antihistamines such as Unisom (Doxylamine succinate) or diphenhydramine allowed)
- Sub-therapeutic dosages of antidepressants used for other indications will be permissible with the exclusion of SSRIs, SNRIs, and Wellbutrin.
- Phytoestrogens
- Soy-based medications or supplements
Trial locations and contacts
1 site in 1 country.
About this study
HYPOTHESIS:
Pregnenolone administration will be associated with greater reduction in depressive symptom severity than placebo in women with current mMDD.
Read more
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:
- Determine if pregnenolone is associated with greater reduction in anxiety symptom severity than placebo in women with mMDD.
- Determine if pregnenolone is associated with greater improvement in cognition than placebo in women with mMDD.
- Determine if pregnenolone is associated with greater improvement in quality of life than placebo in women with mMDD.
- Determine if pregnenolone is associated with greater improvement in vasomotor symptoms of menopause than placebo.
Mechanistic Aims:
- Determine whether changes in neurosteroid levels with pregnenolone mediate clinical response.
- Determine if baseline neurosteroid levels predict pregnenolone response.
- 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.
Read the detailed description
Despite the introduction of new antidepressants, major depressive disorder (MDD) remains challenging to treat. Antidepressant effectiveness trials conducted suggest depression remission rates of only 15%-35%. Therefore, new antidepressants with mechanisms that move beyond norepinephrine and serotonin targets are greatly needed. Importantly, comorbid symptoms including anxiety, cognitive complaints and somatic symptoms often co-occur with depression and further impact functioning and quality of life.
The lifetime prevalence of MDD in women at > 20%, is approximately twice of that of men, with increased risk during the menopausal transition (perimenopause and early postmenopause). Hot flashes and other menopausal symptoms, such as cognitive symptoms and sleep dysregulation, affect up to 80% of women after perimenopause onset. Two large NIH-funded prospective epidemiological studies demonstrated an increased risk of onset of MDD during perimenopause (mMDD), with hormonal variability serving as a biomarker of risk of MDD. Short-term studies have demonstrated an augmentation benefit of estrogen and serotonin reuptake inhibitors can be used to target both mMDD and hot flashes. However, limited data from controlled trials suggest modest benefit for mMDD with standard antidepressants. Furthermore, due to safety concerns, many women prefer options other than estrogen replacement. Therefore, new and more effective treatments are needed for mMDD. Despite the fact that midlife women are the most frequent consumers of complementary and alternative therapies, trials of these approaches for mMDD are lacking. Pregnenolone is a naturally occurring neurosteroid made from cholesterol in the adrenal glands and brain, sold as an over-the-counter supplement, and the use of which at this time is common, unregulated and unstudied in women around the menopausal transition. Pregnenolone is a precursor of hormones known to fluctuate during the menopausal transition, and may decrease this hormonal variability known to increase the risk of MDD.
Preclinical research suggests that pregnenolone has antidepressant and neuroprotective effects, and improves cognition. Lower cerebrospinal fluid levels of pregnenolone are reported in people with bipolar disorder (BPD) or major depressive disorder (MDD) than controls. The investigators conducted two pilot studies of pregnenolone in depressed patients. The first study included patients with bipolar as well as unipolar depression (i.e. MDD). Pregnenolone (100 mg/d) was superior to placebo in improving depressive symptom severity. The second study found that 500 mg/d of pregnenolone was superior to placebo for bipolar depression. Baseline anxiety, fatigue, anhedonia and physical symptoms predicted a favorable depressive symptom response to pregnenolone compared to placebo. Improvement in cognition (e.g. declarative and working memory) was also observed in women given pregnenolone. Additionally, in women, changes in depressive symptoms showed strong inverse correlations with changes in pregnenolone (r=-0.83), and other neurosteroid levels. Furthermore, in both studies women responded better to pregnenolone relative to placebo for depression than men. Therefore, pregnenolone appears to have sex-specific antidepressant effects, or at least demonstrates a substantial sex difference in response. Women over age 40 showed a more robust response than younger women. Pregnenolone was very well tolerated in both studies. Based on these data, a larger, longer and more definitive trial of pregnenolone is now proposed. Unlike the prior pilot studies, this trial will be larger and focus on unipolar rather than bipolar depression, and will be limited to women with mMDD.
Given the widespread availability of pregnenolone, as well as promising preclinical and clinical data, and the extensive use of integrative treatments among midlife women, the investigators propose to examine its efficacy as an antidepressant in mMDD. Pregnenolone has the potential to provide women with an efficacious and appealing treatment option. To achieve this objective, a randomized, placebo-controlled trial of pregnenolone is proposed in 144 women with mMDD. A novel clinical trial design that enhances power to detect between-group differences and that allows for a longer observation period (16 weeks) will be used. Depressive symptoms, anxiety, quality of life, cognition and vasomotor symptoms (e.g. hot flashes) will be assessed. Blood levels of pregnenolone, and other neurosteroids (e.g. allopregnanolone, progesterone) will be obtained, and safety and tolerability data collected. A multiple PI team with extensive experience in mood disorders clinical trials, women's mental health and neurosteroids will conduct the study.
- Conditions
- Major Depressive Disorder, Menopause, Perimenopause
- Being tested
- Pregnenolone, Placebo
- Keywords
- Pregnenolone
- Medical subject headings
- Depressive Disorder, Major
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PregnenoloneDrug
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.
PlaceboDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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. Receives: 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. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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)
The Hamilton Anxiety Rating Scale (HRSA) is a 14-item observer-rated scale that assesses the degree and pathology associated with anxiety such as anxious mood, tension, fear, and insomnia. Items are scored 0 (absent) through 4 (very severe) with the total score ranging from 0 to 56. Higher scores indicate a greater degree of anxiety symptoms.
Measured: Phase 1 timeframe is Baseline to Week 8; Phase 2 timeframe is Week 8 to Week 16
Pittsburgh Sleep Quality Index (PSQI)
The Pittsburgh Sleep Quality Index (PSQI) is a 9-item self-report scale used to assess sleep quality and disturbances during the past week. Total scores range from 0 to 21 with higher scores indicating poorer sleep quality. Total scores are calculated by adding together the scores of the 7 components (e.g., duration of sleep, sleep disturbance, sleep latency) that comprise the PSQI.
Measured: Phase 1 timeframe is Baseline to Week 8; Phase 2 timeframe is Week 8 to Week 16
Menopause Specific Quality of Life (MEN-QOL)
The Menopause Specific Quality of Life (MEN-QOL) is a 29-item measure used to assess the presence and bother associated with 29-different menopausal symptoms. Items are scored 0 (not bothered at all) to 6 (extremely bothered) with total scores ranging from 0 to 174. Higher total scores indicate worse menopausal symptoms.
Measured: Phase 1 timeframe is Baseline to Week 8; Phase 2 timeframe is Week 8 to Week 16
Greene Climacteric Scale (GCS)
The Greene Climacteric Scale (GCS) is a 21-item menopause symptom checklist providing an objective measure of mood disturbance, hot flushes, night sweats, and vaginal dryness. Items are scored from 0 (not at all) to 3 (extremely) with total scores ranging from 0 to 63. Higher total scores indicate worse menopause symptoms. Total scores are calculated by adding together the scores of the 3 subscales (e.g., psychological, vasomotor, physical) that comprise the GCS.
Measured: Phase 1 timeframe is Baseline to Week 8; Phase 2 timeframe is Week 8 to Week 16
Rey Auditory Verbal Learning Test (RAVLT)
The Rey Auditory Verbal Learning Test (RAVLT) is an auditory assessment of verbal learning and memory, in which the participant is asked to recall a list of words first immediately following presentation (immediate recall) and later following a set period of time (delayed recall). Participant age, years of education, and sex are used to calculate t-scores. T-scores represent how an individual score compares to the mean / average score of that participant's demographic group. Higher t-scores indicate a greater recall of the list of words compared to the average score.
Measured: Phase 1 timeframe is Baseline to Week 8; Phase 2 timeframe is Week 8 to Week 16
Trail Making Test (TMT)
The Trail Making Test (TMT) is a diagnostic tool measuring executive functioning and information processing in which the participant is asked to link a set of randomly distributed numbered and lettered points. Participant age, years of education, and sex are used to calculate t-scores. T-scores represent how an individual score compares to the mean / average score of that participant's demographic group. Higher t-scores indicate a faster time in connecting the set of numbers and letters compared to the average score.
Measured: Phase 1 timeframe is Baseline to Week 8; Phase 2 timeframe is Week 8 to Week 16
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Apr 2018
- Study start1 Sep 2018
- Primary completion3 Dec 2024
- Study completion3 Dec 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Major Depressive DisorderStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Model description
- 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.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 73 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Texas Southwestern Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- Massachusetts General Hospital
- Responsible party
- Principal investigator, Sherwood Brown, MD, PhD, University of Texas Southwestern Medical Center
- Investigators
- Sherwood Brown, MD, PhD, Principal investigator, University of Texas Southwestern Medical CenterMarlene Freeman, MD, Principal investigator, Massachusetts General Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03505905
- Sponsor's protocol ID
- 102017-068
- Status last verified
- Jan 2026
- First submitted
- 13 Apr 2018
- Last updated
- 22 Jan 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 22 Jan 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Neurosteroid Intervention for Menopausal and Perimenopausal Depression
- ClinicalTrials.gov ID
- NCT03505905
- Acronym / sponsor ID
- 102017-068
- Conditions
- Major Depressive Disorder, Menopause, Perimenopause
- Keywords
- Pregnenolone
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 73 participants (actual)
- Lead sponsor
- University of Texas Southwestern Medical CenterUniversity, hospital or other
- Collaborators
- Massachusetts General Hospital
- Study start
- 1 Sep 2018 (actual)
- Primary completion
- 3 Dec 2024 (actual)
- Study completion
- 3 Dec 2024 (actual)
- First posted
- 23 Apr 2018 (actual)
- Results
- Posted 22 Jan 2026
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- Determine if pregnenolone is associated with greater reduction in anxiety symptom severity than placebo in women with mMDD.
- Determine if pregnenolone is associated with greater improvement in cognition than placebo in women with mMDD.
- Determine if pregnenolone is associated with greater improvement in quality of life than placebo in women with mMDD.
- Determine if pregnenolone is associated with greater improvement in vasomotor symptoms of menopause than placebo.
Mechanistic Aims:
- Determine whether changes in neurosteroid levels with pregnenolone mediate clinical response.
- Determine if baseline neurosteroid levels predict pregnenolone response.
- 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.
Detailed description
Despite the introduction of new antidepressants, major depressive disorder (MDD) remains challenging to treat. Antidepressant effectiveness trials conducted suggest depression remission rates of only 15%-35%. Therefore, new antidepressants with mechanisms that move beyond norepinephrine and serotonin targets are greatly needed. Importantly, comorbid symptoms including anxiety, cognitive complaints and somatic symptoms often co-occur with depression and further impact functioning and quality of life.
The lifetime prevalence of MDD in women at > 20%, is approximately twice of that of men, with increased risk during the menopausal transition (perimenopause and early postmenopause). Hot flashes and other menopausal symptoms, such as cognitive symptoms and sleep dysregulation, affect up to 80% of women after perimenopause onset. Two large NIH-funded prospective epidemiological studies demonstrated an increased risk of onset of MDD during perimenopause (mMDD), with hormonal variability serving as a biomarker of risk of MDD. Short-term studies have demonstrated an augmentation benefit of estrogen and serotonin reuptake inhibitors can be used to target both mMDD and hot flashes. However, limited data from controlled trials suggest modest benefit for mMDD with standard antidepressants. Furthermore, due to safety concerns, many women prefer options other than estrogen replacement. Therefore, new and more effective treatments are needed for mMDD. Despite the fact that midlife women are the most frequent consumers of complementary and alternative therapies, trials of these approaches for mMDD are lacking. Pregnenolone is a naturally occurring neurosteroid made from cholesterol in the adrenal glands and brain, sold as an over-the-counter supplement, and the use of which at this time is common, unregulated and unstudied in women around the menopausal transition. Pregnenolone is a precursor of hormones known to fluctuate during the menopausal transition, and may decrease this hormonal variability known to increase the risk of MDD.
Preclinical research suggests that pregnenolone has antidepressant and neuroprotective effects, and improves cognition. Lower cerebrospinal fluid levels of pregnenolone are reported in people with bipolar disorder (BPD) or major depressive disorder (MDD) than controls. The investigators conducted two pilot studies of pregnenolone in depressed patients. The first study included patients with bipolar as well as unipolar depression (i.e. MDD). Pregnenolone (100 mg/d) was superior to placebo in improving depressive symptom severity. The second study found that 500 mg/d of pregnenolone was superior to placebo for bipolar depression. Baseline anxiety, fatigue, anhedonia and physical symptoms predicted a favorable depressive symptom response to pregnenolone compared to placebo. Improvement in cognition (e.g. declarative and working memory) was also observed in women given pregnenolone. Additionally, in women, changes in depressive symptoms showed strong inverse correlations with changes in pregnenolone (r=-0.83), and other neurosteroid levels. Furthermore, in both studies women responded better to pregnenolone relative to placebo for depression than men. Therefore, pregnenolone appears to have sex-specific antidepressant effects, or at least demonstrates a substantial sex difference in response. Women over age 40 showed a more robust response than younger women. Pregnenolone was very well tolerated in both studies. Based on these data, a larger, longer and more definitive trial of pregnenolone is now proposed. Unlike the prior pilot studies, this trial will be larger and focus on unipolar rather than bipolar depression, and will be limited to women with mMDD.
Given the widespread availability of pregnenolone, as well as promising preclinical and clinical data, and the extensive use of integrative treatments among midlife women, the investigators propose to examine its efficacy as an antidepressant in mMDD. Pregnenolone has the potential to provide women with an efficacious and appealing treatment option. To achieve this objective, a randomized, placebo-controlled trial of pregnenolone is proposed in 144 women with mMDD. A novel clinical trial design that enhances power to detect between-group differences and that allows for a longer observation period (16 weeks) will be used. Depressive symptoms, anxiety, quality of life, cognition and vasomotor symptoms (e.g. hot flashes) will be assessed. Blood levels of pregnenolone, and other neurosteroids (e.g. allopregnanolone, progesterone) will be obtained, and safety and tolerability data collected. A multiple PI team with extensive experience in mood disorders clinical trials, women's mental health and neurosteroids will conduct the study.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 4
- Model description
- 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.
| Arm | Type | Receives |
|---|---|---|
| Pregnenlone (phase 1 and 2) | Experimental | Drug: PregnenoloneParticipants 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. |
| Placebo rerandom to placebo | Placebo comparator | Drug: PlaceboParticipants 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. |
| Placebo rerandom to pregnenolone | Experimental | Drug: Pregnenolone, Drug: PlaceboParticipants 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. |
| Placebo responsive cont placebo | Placebo comparator | Drug: PlaceboParticipants 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. |
Who may qualify
- Ages
- 40 to 67 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (11 listed)
- 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
Key exclusion criteria (30 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PregnenoloneIn 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. | Drug | Placebo rerandom to pregnenolone, Pregnenlone (phase 1 and 2) |
| PlaceboIn 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. | Drug | Placebo rerandom to placebo, Placebo rerandom to pregnenolone, Placebo responsive cont placebo |
Primary outcome
Montgomery-Asberg Depression Rating Scale (MADRS)
Time frame: Phase 1 timeframe is Baseline to Week 8; Phase 2 timeframe is Week 8 to Week 16
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.
6 secondary outcomes
Hamilton Anxiety Rating Scale (HRSA)
Time frame: Phase 1 timeframe is Baseline to Week 8; Phase 2 timeframe is Week 8 to Week 16
Pittsburgh Sleep Quality Index (PSQI)
Time frame: Phase 1 timeframe is Baseline to Week 8; Phase 2 timeframe is Week 8 to Week 16
Menopause Specific Quality of Life (MEN-QOL)
Time frame: Phase 1 timeframe is Baseline to Week 8; Phase 2 timeframe is Week 8 to Week 16
Greene Climacteric Scale (GCS)
Time frame: Phase 1 timeframe is Baseline to Week 8; Phase 2 timeframe is Week 8 to Week 16
Rey Auditory Verbal Learning Test (RAVLT)
Time frame: Phase 1 timeframe is Baseline to Week 8; Phase 2 timeframe is Week 8 to Week 16
Trail Making Test (TMT)
Time frame: Phase 1 timeframe is Baseline to Week 8; Phase 2 timeframe is Week 8 to Week 16
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Jan 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Sherwood Brown, MD, PhD principal investigator
University of Texas Southwestern Medical Center
Marlene Freeman, MD principal investigator
Massachusetts General Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Pregnenolone in people with Major Depressive Disorder and Menopause, run by University of Texas Southwestern Medical Center at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 30 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 22 Jan 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 22 Jan 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Montgomery-Asberg Depression Rating Scale (MADRS) (time frame: Phase 1 timeframe is Baseline to Week 8; Phase 2 timeframe is Week 8 to Week 16). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Jan 2026; AzTrials last refreshed its copy on 26 Oct 2026.