Major Depressive Disorder
Conditions
Keywords
Depression, Pregnenolone, Women
Brief summary
Pregnenolone, an over-the-counter supplement, is a naturally occurring neurosteroid made in the adrenal glands and brain. Preclinical research suggests pregnenolone has antidepressant, cognitive enhancing, and neuroprotective properties, particularly in women. The following hypothesis will be tested in this trial: pregnenolone is associated with improvement in depressive symptom severity in women that is associated with changes in the resting state functional connectivity (rsFC) and GABA.
Detailed description
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.
Interventions
Pregnenolone 500 mg capsule.
DRUGPregnenolone 800 mg
Pregnenolone 800 mg capsule.
DRUGPlacebo
Placebo capsule manufactured to mimic pregnenolone capsule.
Sponsors
National Center for Complementary and Integrative Health (NCCIH)
University of Texas Southwestern Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Adult women with mild to moderate major depressive disorder (MDD) will receive pregnenolone (500 mg/d, 800 mg/d and placebo) in a randomized, double-blind, crossover design.
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 65 Years
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Amygdala-PCC Functional Connectivity | 7 days | Determine if an increase in Amygdala-PCC functional connectivity is observed with pregnenolone as compared to placebo. Amygdala-PCC functional connectivity was measured using resting state fMRI blood-oxygen-level dependent (BOLD) response and transformed to standardized z-scores (with μ=0 and σ=1) for analysis. Functional connectivity was measured three times corresponding to three treatments (500 mg pregnenolone, 800 mg pregnenolone, and placebo). Better outcomes are represented by greater functional connectivity, and are indicated by a higher z-score at 500 mg or 800 mg, relative to that at placebo (i.e., there is no absolute threshold). |
| dlPFC-Insula Functional Connectivity | 7 days | Determine if an increase in dlPFC-Insula functional connectivity is observed with pregnenolone as compared to placebo. dlPFC-Insula functional connectivity was measured using resting state fMRI blood-oxygen-level dependent (BOLD) response and transformed to standardized z-scores (with μ=0 and σ=1) for analysis. Functional connectivity was measured three times corresponding to three treatments (500 mg pregnenolone, 800 mg pregnenolone, and placebo). Better outcomes are represented by greater functional connectivity, and are indicated by a higher z-score at 500 mg or 800 mg, relative to that at placebo (i.e., there is no absolute threshold). |
| GABA Concentration. | 7 days | Determine if an increase in occipital GABA concentration is observed with pregnenolone, as compared to placebo. Occipital GABA concentration using spectroscopy with tCr reference. Higher concentration values are representative of a greater anti-depressant effect. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pregnenolone Level | 7 days | Assess bioavailability of pregnenolone by demonstrating increases in serum pregnenolone and allopregnanolone with pregnenolone administration. Change (increases) in blood serum pregnenolone levels are indicative of bioavailability. |
| Pregnenolone Dose | 7 days | Identify a dose of pregnenolone that demonstrates bioavailability (see Pregnenolone Level and Allopregnanolone Level outcome measures), tolerability (see SAFTEE outcome measure); and is associated with a significant change in a biosignature. |
| Allopregnanolone Level | 7 days | Assess bioavailability of pregnenolone by demonstrating increases in serum pregnenolone and allopregnanolone with pregnenolone administration. Change (increases) in blood serum allopregnanolone levels are indicative of bioavailability. |
| Systematic Assessment for Treatment Emergent Events (SAFTEE) | 7 days | Assess safety and tolerability of pregnenolone at the doses tested. SAFTEE is a side effect self-report assessment scale that consists of 56 potential side effects. Participants rate how bothersome each side effect is on a scale of none (0), mild (1), moderate (2), severe (3). Total scores range from 0 to 168. A higher total score (sum of all items) indicates a higher level of side effect burden. |
Countries
United States
Participant flow
Recruitment details
Subjects were screened for eligibility from September 2019 through November 2021 at UT Southwestern in Dallas, TX. 34 Subjects were consented by a research study coordinator in a private office within Dr. Brown's PNE Lab.
Pre-assignment details
29 of 34 participants were randomized. It was determined that 5 subjects were not eligible for the study and were not randomized.
Participants by arm
| Arm | Count |
|---|---|
| Pregnenolone 500 > Pregnenolone 800 > Placebo 3 exposures in order:
1. Pregnenolone 500 mg capsule by mouth, daily for 7 days followed by 14 day washout.
2. Pregnenolone 800 mg capsule by mouth, daily for 7 days followed by 14 day washout.
3. Matching placebo capsule by mouth, daily for 7 days.
Pregnenolone 500 mg: Pregnenolone 500 mg capsule.
Pregnenolone 800 mg: Pregnenolone 800 mg capsule.
Placebo: Placebo capsule manufactured to mimic pregnenolone capsule. | 4 |
| Pregnenolone 500 > Placebo > Pregnenolone 800 3 exposures in order:
1. Pregnenolone 500 mg capsule by mouth, daily for 7 days followed by 14 day washout.
2. Matching placebo capsule by mouth, daily for 7 days followed by 14 day washout.
3. Pregnenolone 800 mg capsule by mouth, daily for 7 days.
Pregnenolone 500 mg: Pregnenolone 500 mg capsule.
Pregnenolone 800 mg: Pregnenolone 800 mg capsule.
Placebo: Placebo capsule manufactured to mimic pregnenolone capsule. | 4 |
| Pregnenolone 800 > Pregnenolone 500 > Placebo 3 exposures in order:
1. Pregnenolone 800 mg capsule by mouth, daily for 7 days followed by 14 day washout.
2. Pregnenolone 500 mg capsule by mouth, daily for 7 days followed by 14 day washout.
3. Matching placebo capsule by mouth, daily for 7 days.
Pregnenolone 500 mg: Pregnenolone 500 mg capsule.
Pregnenolone 800 mg: Pregnenolone 800 mg capsule.
Placebo: Placebo capsule manufactured to mimic pregnenolone capsule. | 7 |
| Pregnenolone 800 > Placebo > Pregnenolone 500 3 exposures in order:
1. Pregnenolone 800 mg capsule by mouth, daily for 7 days followed by 14 day washout.
2. Matching placebo capsule by mouth, daily for 7 days followed by 14 day washout.
3. Pregnenolone 500 mg capsule by mouth, daily for 7 days.
Pregnenolone 500 mg: Pregnenolone 500 mg capsule.
Pregnenolone 800 mg: Pregnenolone 800 mg capsule.
Placebo: Placebo capsule manufactured to mimic pregnenolone capsule. | 7 |
| Placebo > Pregnenolone 500 > Pregnenolone 800 3 exposures in order:
1. Matching placebo capsule by mouth, daily for 7 days followed by 14 day washout.
2. Pregnenolone 500 mg capsule by mouth, daily for 7 days followed by 14 day washout.
3. Pregnenolone 800 mg capsule by mouth, daily for 7 days.
Pregnenolone 500 mg: Pregnenolone 500 mg capsule.
Pregnenolone 800 mg: Pregnenolone 800 mg capsule.
Placebo: Placebo capsule manufactured to mimic pregnenolone capsule. | 5 |
| Placebo > Pregnenolone 800 > Pregnenolone 500 3 exposures in order:
1. Matching placebo capsule by mouth, daily for 7 days followed by 14 day washout.
2. Pregnenolone 800 mg capsule by mouth, daily for 7 days followed by 14 day washout.
3. Pregnenolone 500 mg capsule by mouth, daily for 7 days.
Pregnenolone 500 mg: Pregnenolone 500 mg capsule.
Pregnenolone 800 mg: Pregnenolone 800 mg capsule.
Placebo: Placebo capsule manufactured to mimic pregnenolone capsule. | 2 |
| Total | 29 |
Baseline characteristics
| Characteristic | Pregnenolone 500 > Pregnenolone 800 > Placebo | Pregnenolone 500 > Placebo > Pregnenolone 800 | Pregnenolone 800 > Pregnenolone 500 > Placebo | Pregnenolone 800 > Placebo > Pregnenolone 500 | Placebo > Pregnenolone 500 > Pregnenolone 800 | Placebo > Pregnenolone 800 > Pregnenolone 500 | Total |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 4 Participants | 7 Participants | 7 Participants | 5 Participants | 2 Participants | 29 Participants |
| Age, Continuous | 50.50 years STANDARD_DEVIATION 7.19 | 43.25 years STANDARD_DEVIATION 16.86 | 44.29 years STANDARD_DEVIATION 10.94 | 43.71 years STANDARD_DEVIATION 11.22 | 46.00 years STANDARD_DEVIATION 8.4 | 51.00 years STANDARD_DEVIATION 1.41 | 45.62 years STANDARD_DEVIATION 10.31 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 2 Participants | 1 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 3 Participants | 6 Participants | 6 Participants | 3 Participants | 1 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| HAM-D | 14.75 units on a scale STANDARD_DEVIATION 2.5 | 12.75 units on a scale STANDARD_DEVIATION 4.92 | 13.00 units on a scale STANDARD_DEVIATION 4.28 | 14.14 units on a scale STANDARD_DEVIATION 5.34 | 16.00 units on a scale STANDARD_DEVIATION 3.81 | 11.50 units on a scale STANDARD_DEVIATION 7.78 | 13.90 units on a scale STANDARD_DEVIATION 4.39 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants | 3 Participants | 1 Participants | 1 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 3 Participants | 5 Participants | 4 Participants | 4 Participants | 1 Participants | 20 Participants |
| Region of Enrollment United States | 4 participants | 4 participants | 7 participants | 7 participants | 5 participants | 2 participants | 29 participants |
| Sex: Female, Male Female | 4 Participants | 4 Participants | 7 Participants | 7 Participants | 5 Participants | 2 Participants | 29 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 29 | 0 / 29 | 0 / 29 |
| other Total, other adverse events | 0 / 29 | 0 / 29 | 0 / 29 |
| serious Total, serious adverse events | 0 / 29 | 0 / 29 | 0 / 29 |
Outcome results
Primary
Amygdala-PCC Functional Connectivity
Determine if an increase in Amygdala-PCC functional connectivity is observed with pregnenolone as compared to placebo. Amygdala-PCC functional connectivity was measured using resting state fMRI blood-oxygen-level dependent (BOLD) response and transformed to standardized z-scores (with μ=0 and σ=1) for analysis. Functional connectivity was measured three times corresponding to three treatments (500 mg pregnenolone, 800 mg pregnenolone, and placebo). Better outcomes are represented by greater functional connectivity, and are indicated by a higher z-score at 500 mg or 800 mg, relative to that at placebo (i.e., there is no absolute threshold).
Time frame: 7 days
Population: Some fMRI data may have been unusable due to motion in the scanner.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pregnenolone (500 mg) | Amygdala-PCC Functional Connectivity | -0.0815 z-score | Standard Deviation 0.168 |
| Pregnenolone (800 mg) | Amygdala-PCC Functional Connectivity | -0.0530 z-score | Standard Deviation 0.1715 |
| Placebo | Amygdala-PCC Functional Connectivity | -0.0456 z-score | Standard Deviation 0.1736 |
Comparison: Null Hypothesis: Amygdala-PCC functional connectivity (z-score) at 500 mg will be less than or equal to that at placebo.~Alternative Hypothesis: Amygdala-PCC functional connectivity (z-score) at 500 mg will be greater than that at placebo.p-value: 0.19595% CI: [-0.0703, 0.1689]t-test, 1 sided
Comparison: Null Hypothesis: Amygdala-PCC functional connectivity (z-score) at 800 mg will be less than or equal to that at placebo.~Alternative Hypothesis: Amygdala-PCC functional connectivity (z-score) at 800 mg will be greater than that at placebo.p-value: 0.32595% CI: [-0.0943, 0.1467]t-test, 1 sided
Primary
dlPFC-Insula Functional Connectivity
Determine if an increase in dlPFC-Insula functional connectivity is observed with pregnenolone as compared to placebo. dlPFC-Insula functional connectivity was measured using resting state fMRI blood-oxygen-level dependent (BOLD) response and transformed to standardized z-scores (with μ=0 and σ=1) for analysis. Functional connectivity was measured three times corresponding to three treatments (500 mg pregnenolone, 800 mg pregnenolone, and placebo). Better outcomes are represented by greater functional connectivity, and are indicated by a higher z-score at 500 mg or 800 mg, relative to that at placebo (i.e., there is no absolute threshold).
Time frame: 7 days
Population: Some fMRI data may have been unusable due to motion in the scanner.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pregnenolone (500 mg) | dlPFC-Insula Functional Connectivity | 0.0495 z-score | Standard Deviation 0.2524 |
| Pregnenolone (800 mg) | dlPFC-Insula Functional Connectivity | 0.1413 z-score | Standard Deviation 0.3036 |
| Placebo | dlPFC-Insula Functional Connectivity | 0.0855 z-score | Standard Deviation 0.2941 |
Comparison: Null Hypothesis: dlPFC-Insula functional connectivity (z-score) at 500 mg will be less than or equal to that at placebo.~Alternative Hypothesis: dlPFC-Insula functional connectivity (z-score) at 500 mg will be greater than that at placebo.p-value: 0.46895% CI: [-0.1969, 0.1827]t-test, 1 sided
Comparison: Null Hypothesis: dlPFC-Insula functional connectivity (z-score) at 800 mg will be less than or equal to that at placebo.~Alternative Hypothesis: dlPFC-Insula functional connectivity (z-score) at 800 mg will be greater than that at placebo.p-value: 0.45895% CI: [-0.1803, 0.1996]t-test, 1 sided
Primary
GABA Concentration.
Determine if an increase in occipital GABA concentration is observed with pregnenolone, as compared to placebo. Occipital GABA concentration using spectroscopy with tCr reference. Higher concentration values are representative of a greater anti-depressant effect.
Time frame: 7 days
Population: All participants with available data for each treatment condition.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pregnenolone (500 mg) | GABA Concentration. | 0.0947 millimolars (mM) | Standard Deviation 0.0294 |
| Pregnenolone (800 mg) | GABA Concentration. | 0.0861 millimolars (mM) | Standard Deviation 0.0264 |
| Placebo | GABA Concentration. | 0.0974 millimolars (mM) | Standard Deviation 0.0262 |
Comparison: Null Hypothesis: GABA concentration (mM) at 500 mg will be less than or equal to that at placebo.~Alternative Hypothesis: GABA concentration (mM) at 500 mg will be greater than that at placebo.p-value: 0.31695% CI: [-0.0132, 0.0209]t-test, 1 sided
Comparison: Null Hypothesis: GABA concentration (mM) at 500 mg will be less than or equal to that at placebo.~Alternative Hypothesis: GABA concentration (mM) at 500 mg will be greater than that at placebo.p-value: 0.07195% CI: [-0.005, 0.0312]t-test, 1 sided
Secondary
Allopregnanolone Level
Assess bioavailability of pregnenolone by demonstrating increases in serum pregnenolone and allopregnanolone with pregnenolone administration. Change (increases) in blood serum allopregnanolone levels are indicative of bioavailability.
Time frame: 7 days
Population: All participants with available data for each treatment condition.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pregnenolone (500 mg) | Allopregnanolone Level | 2478.39 pg/mL | Standard Deviation 1801.67 |
| Pregnenolone (800 mg) | Allopregnanolone Level | 2489.08 pg/mL | Standard Deviation 2180.59 |
| Placebo | Allopregnanolone Level | 124.22 pg/mL | Standard Deviation 224.62 |
Comparison: Null Hypothesis: Allopregnanolone level (pg/mL) at 500 mg will be less than or equal to that at placebo.~Alternative Hypothesis: Allopregnanolone level (pg/mL) at 500 mg will be greater than that at placebo.p-value: 0.00195% CI: [-3724.93, -1322.22]t-test, 1 sided
Comparison: Null Hypothesis: Allopregnanolone level (pg/mL) at 800 mg will be less than or equal to that at placebo.~Alternative Hypothesis: Allopregnanolone level (pg/mL) at 800 mg will be greater than that at placebo.p-value: 0.00195% CI: [-3739.32, -1221.93]t-test, 1 sided
Secondary
Pregnenolone Dose
Identify a dose of pregnenolone that demonstrates bioavailability (see Pregnenolone Level and Allopregnanolone Level outcome measures), tolerability (see SAFTEE outcome measure); and is associated with a significant change in a biosignature.
Time frame: 7 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pregnenolone (500 mg) | Pregnenolone Dose | 500 mg |
Secondary
Pregnenolone Level
Assess bioavailability of pregnenolone by demonstrating increases in serum pregnenolone and allopregnanolone with pregnenolone administration. Change (increases) in blood serum pregnenolone levels are indicative of bioavailability.
Time frame: 7 days
Population: All participants with available data for each treatment condition.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pregnenolone (500 mg) | Pregnenolone Level | 10902.60 pg/mL | Standard Deviation 11849.18 |
| Pregnenolone (800 mg) | Pregnenolone Level | 11484.75 pg/mL | Standard Deviation 13038.5 |
| Placebo | Pregnenolone Level | 769.63 pg/mL | Standard Deviation 554.5 |
Comparison: Null Hypothesis: Pregnenolone level (pg/mL) at 500 mg will be less than or equal to that at placebo.~Alternative Hypothesis: Pregnenolone level (pg/mL) at 500 mg will be greater than that at placebo.p-value: 0.00695% CI: [-19577.27, -3067.62]t-test, 1 sided
Comparison: Null Hypothesis: Pregnenolone level (pg/mL) at 800 mg will be less than or equal to that at placebo.~Alternative Hypothesis: Pregnenolone level (pg/mL) at 800 mg will be greater than that at placebo.p-value: 0.00395% CI: [-19650.24, -4007.33]t-test, 1 sided
Secondary
Systematic Assessment for Treatment Emergent Events (SAFTEE)
Assess safety and tolerability of pregnenolone at the doses tested. SAFTEE is a side effect self-report assessment scale that consists of 56 potential side effects. Participants rate how bothersome each side effect is on a scale of none (0), mild (1), moderate (2), severe (3). Total scores range from 0 to 168. A higher total score (sum of all items) indicates a higher level of side effect burden.
Time frame: 7 days
Population: All participants with available data for each treatment condition.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pregnenolone (500 mg) | Systematic Assessment for Treatment Emergent Events (SAFTEE) | 16.15 units on a scale | Standard Deviation 12.42 |
| Pregnenolone (800 mg) | Systematic Assessment for Treatment Emergent Events (SAFTEE) | 19.14 units on a scale | Standard Deviation 12.41 |
| Placebo | Systematic Assessment for Treatment Emergent Events (SAFTEE) | 17.60 units on a scale | Standard Deviation 9.65 |
Comparison: Null Hypothesis: SAFTEE (total) scores at 500 mg will be greater than or equal to that at placebo.~Alternative Hypothesis: SAFTEE (total) scores at 500 mg will be less than that at placebo.p-value: 0.33695% CI: [-2.7659, 4.1777]t-test, 1 sided
Comparison: Null Hypothesis: SAFTEE (total) scores at 800 mg will be greater than or equal to that at placebo.~Alternative Hypothesis: SAFTEE (total) scores at 800 mg will be less than that at placebo.p-value: 0.2495% CI: [-9.8131, 4.8131]t-test, 1 sided