Anxiety and DepressionPhase 2NCT06188923
A New Intervention to Improve Function in Veterans With Anxiety and Depression
A Phase 2 study testing Pregnenolone in people with Anxiety and Depression, run by VA Office of Research and Development at 1 site in United States.
Trial summary
Anxiety and depression symptoms occur at high rates in Veteran populations and can significantly impact function, compromising the ability to work and to successfully form and maintain valued relationships. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Anxiety and Depression
- What is being tested?
- Pregnenolone
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 84 participants
- Where
- 1 siteUnited States
- Study dates
- 14 Aug 2025to 30 Sep 2028
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
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 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Veterans enrolled for care at the Durham Veterans Affairs Health Care System (VAHCS)
- Veterans who score a minimum score of 20 or higher (moderate symptoms) on the PHQ-ADS (Kroenke et al 2017)
- Oral pregnenolone could reduce the effectiveness of oral contraceptives, thus women will be required to use a medically and study-approved contraceptive or otherwise not be of child-bearing potential. Birth control methods must be non-hormonal.
- No anticipated need to alter psychiatric medications for duration of study involvement
- Ability to participate fully in the informed consent process
Who cannot join
- History of allergy to pregnenolone (PREG)
- Medical disorders that may preclude safe administration of PREG or exacerbate mental or physical health symptoms
- Post-traumatic stress disorder (PTSD) diagnosis, as per the PCL-5 with LEC-5, scores of 38 or higher
- Current suicidal or homicidal ideation necessitating clinical intervention or representing an imminent concern. Prior attempts or suicidal ideation that does not require clinical intervention or represent an imminent concern is permitted
- Serious unstable medical illness, such as history of cerebrovascular accident, prostate, uterine or breast cancer, others (at the discretion of the PI and medical oversight team)
- Standard pharmacological interventions for mental health disorders will not be exclusionary; however, there may be no changes in psychotropic medications for mental or physical health conditions 4 weeks prior to study randomization
Show all 11Show fewer
- Benzodiazepine or opioid use
- Current diagnosis of bipolar disorder, schizophrenia or other psychotic disorder, or cognitive disorder due to a general medical condition other than mild TBI (assessed at screening)
- Initiation or change in psychotherapy within 3 months of randomization (i.e., psychotherapy must be stable for 3 months prior to study start
- Due to lack of safety data in pregnant and breast-feeding women, female participants who are pregnant or breast-feeding will be excluded
- As indicated by the DSM-5, moderate or severe Substance Use Disorders (excluding caffeine and tobacco) within 1 month of study entry
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
Durham VA Medical Center, Durham, NC
Durham, North Carolina, 27705-3875
Jennifer C Naylor, PhD, (919) 286-0411 ext. 7722, jennifer.naylor2@va.gov
Christine E. Marx, MD MA
About this study
Anxiety and depression symptoms occur at high rates in Veteran populations and can significantly impact function, compromising the ability to work and to successfully form and maintain valued relationships. Several other symptoms commonly occur with anxiety and depression, including poor sleep quality and chronic pain. Since all these symptoms frequently occur together, they may have a common underlying biological basis. A single medication that could effectively treat all these symptoms would be ideal. Converging data suggest that pregnenolone is a promising pharmacological agent for treating multiple psychiatric symptoms and functional impairment. The investigators thus propose to conduct a clinical trial of pregnenolone in Veterans with anxiety and depression symptoms. Pregnenolone has minimal side effects, and the prior research demonstrates that pregnenolone is well-tolerated by Veterans. Treatment with pregnenolone could thus be an efficacious new therapeutic for Veterans experiencing depression, anxiety, poor sleep quality and chronic pain conditions.
Read the detailed description
Background: Anxiety and depression disorders can be very debilitating and result in substantial disability. These disorders are extremely common, occurring at rates that exceed other common medical illnesses such as hypertension, diabetes or asthma. Further, anxiety and depression disorders often co-occur (more the rule than the exception) and having one diagnosis substantially increases the risk for having the other. The clinical benefits of an intervention that ameliorates both anxiety and depression-related disability and clinical symptoms could be critically important, as odds of Veteran suicide completion significantly increase when depression co-occurs with anxiety disorders. Extensive preclinical and clinical data (from the investigators' group and others) support a novel neurosteroid intervention (pregnenolone/PREG) as a promising new treatment for anxiety and depression disorders. Furthermore, extensive evidence in rodent models and clinical biomarker candidate studies suggests substantial analgesic, anxiolytic, sleep and anti-inflammatory actions. PREG also significantly reduced low back pain in a randomized controlled trial of 94 OEF/OIF/OND-era Veterans compared to placebo, and allopregnanolone (ALLO) levels are inversely correlated with several commonly co-occurring symptoms, including sleep disturbance and pain disorders. Restoration of ALLO levels via a precursor loading strategy with PREG could thus ameliorate ALLO deficits and alleviate multiple functionally impairing and health-related symptoms. Additionally, PREG has been very well-tolerated in multiple clinical trials and exhibits a very favorable side effect profile - potentially supporting a superior safety and side effect profile advantage compared to existing pharmacological interventions. The investigators thus propose to conduct a 10-week double-blind, randomized, placebo-controlled trial of PREG versus placebo in Veterans with anxiety and depression.
Methods: The primary goal of this proposed project is to conduct a 10-week adaptive, randomized, double-blind, placebo-controlled trial to evaluate flexibly dosed pregnenolone to improve functional impairment and disability associated with anxiety and depression. Following a 2-week placebo-only lead-in period, 84 subjects will be enrolled and randomly assigned to receive PREG or placebo for 8 weeks (flexible dosing strategy). The investigators hypothesize that treatment with PREG will significantly reduce functional impairment and disability associated with anxiety and depression symptoms. Secondary outcomes include diagnostic improvements in anxiety and depression, pain symptoms and sleep quality. The investigators hypothesize that PREG will improve symptoms of anxiety and depression, pain and sleep quality. Finally, the investigators will quantify serum neurosteroid levels at baseline and post-treatment by highly sensitive and specific mass spectrometry-based techniques to determine if PREG and downstream neurosteroid metabolites such as ALLO are predictors of functional/therapeutic response. The investigators will also examine proinflammatory markers. The investigators hypothesize that changes in PREG and other neurosteroids (as well as proinflammatory markers) will predict improvements in mental health and functional outcomes.
Conclusion: Results from the proposed trial could provide rigorous scientific rationale for future pivotal Phase 3 trials to test PREG for the treatment of anxiety and depression disorders (improving functional outcomes and mitigation of pain and sleep disturbance). PREG has been very well-tolerated in multiple Veteran cohorts and could thus be a safe, inexpensive and efficacious new intervention to improve function and multiple behavioral symptoms.
- Conditions
- Anxiety and Depression
- Being tested
- Pregnenolone, Placebo
- Keywords
- pregnenolone, anxiety, depression, pain, sleep
- Medical subject headings
- Anxiety Disorders, Depression, Pain
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PregnenoloneDrug
Pregnenolone 250 milligrams (mg) BID x 14 DAYS, followed by Pregnenolone 500 milligrams (mg) BID x 14 DAYS, followed by Pregnenolone 1000 milligrams (mg) BID x thereafter for the remainder of the 8-week trial.
PlaceboDrug
Same as active comparator, except placebo dispensed
| Study group | Role | What they receive |
|---|---|---|
| Pregnenolone | Active comparator | Pregnenolone 50 milligrams (mg) BID x 14 DAYS, followed by Pregnenolone 150 milligrams (mg) BID x 14 DAYS, followed by Pregnenolone 250 milligrams (mg) BID x thereafter for the remainder of the 8-week trial. Receives: Drug: Pregnenolone |
| Placebo | Placebo comparator | Same as active comparator, except placebo dispensed Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
The World Health Organization disability assessment schedule II (WHODAS-2)
The WHODAS-II is an instrument developed by the World Health Organization to assess behavioral limitations and restrictions regarding participation in specific activity domains experienced by an individual independent of their medical diagnosis. The conceptual frame of reference of this instrument is the International Classification of Functioning, Disability, and Health (ICF). Specifically, the instrument is a 36-item, generic, multidimensional questionnaire designed to evaluate the functioning of the individual in six activity domains (i.e., understanding and communicating, getting around, self-care, getting along with people, life activities, and participation in society). The 12-item WHODAS 2.0 score range from 12 to 60, where higher scores indicate higher disability or loss of function.
Measured: Change from baseline at 10 weeks
Secondary outcomes (3)
Patient Health Questionnaire Anxiety and Depression Scale (PHQ-ADS)
The PHQ-ADS is a 16-item self-reported instrument that combines the nine-item Patient Health Questionnaire depression scale and seven-item Generalized Anxiety Disorder scale-as a composite measure of depression and anxiety. Respondents are asked how much each symptom has bothered them over the past 2 weeks, with response options of "not at all", "several days", "more than half the days", and "nearly every day", scored as 0, 1, 2, and 3. The scale can range from 0 to 48, with higher scores indicating higher levels of depression and anxiety symptomatology.
Measured: Change from baseline at 10 weeks
Brief Pain Inventory, Second Edition (BPI-II)
The Brief Pain Inventory (BPI) is a self-reported scale that measures the severity of pain and the interference of pain on function. The scores range from 0 (no pain) to 10 (pain as severe as you can imagine). There are 4 questions assessing worst pain, least pain, average pain in the past 24 hours, and the pain right now. The Interference scores range from 0 (does not interfere) to 10 (completely interferes). There are 7 questions assessing the interference of pain in the past 24 hours for general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life. Higher scores indicate greater pain and interference.
Measured: Change from baseline at 10 weeks
Pittsburgh Sleep Quality Index (PSQI)
Measured by a single item score, sleep quality is the measurement of how restful and restorative the sleep of an individual is. Pittsburgh Sleep Quality Index: Well- known questionnaire used to measure sleep quality in various patient groups. For overall sleep quality, the minimum score= 0 (better) and the maximum score=3 (worse).
Measured: Change from baseline at 10 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Jan 2024
- Study start14 Aug 2025
- Primary completion30 Jun 2028 (estimated)
- Study completion30 Sep 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Anxiety and DepressionStudies of the same condition, open and under way.
- More trials run by VA Office of Research and DevelopmentThe sponsor's other registered studies.
- 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 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Participants will be randomized to receive the active study medication (pregnenolone) or placebo.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 84 participants (estimated)
Sponsor and investigators
- Lead sponsor
- VA Office of Research and Development
- Sponsor type
- US federal agency
- Responsible party
- Sponsor
- Investigators
- Jennifer C Naylor, PhD, Principal investigator, Durham VA Medical Center, Durham, NCChristine E. Marx, MD MA, Principal investigator, Durham VA Medical Center, Durham, NC
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06188923
- Sponsor's protocol ID
- D4287-R
- Other IDs
- 5I01RX004287-03
- Status last verified
- Oct 2026
- First submitted
- 18 Dec 2023
- Last updated
- 14 Oct 2026
- Results posted
- No
- Data monitoring committee
- No
- 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 14 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A New Intervention to Improve Function in Veterans With Anxiety and Depression
- ClinicalTrials.gov ID
- NCT06188923
- Acronym / sponsor ID
- D4287-R
- Conditions
- Anxiety and Depression
- Keywords
- pregnenolone, anxiety, depression, pain, sleep
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 84 participants (estimated)
- Lead sponsor
- VA Office of Research and DevelopmentUS federal agency
- Study start
- 14 Aug 2025 (actual)
- Primary completion
- 30 Jun 2028 (estimated)
- Study completion
- 30 Sep 2028 (estimated)
- First posted
- 3 Jan 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Anxiety and depression symptoms occur at high rates in Veteran populations and can significantly impact function, compromising the ability to work and to successfully form and maintain valued relationships. Several other symptoms commonly occur with anxiety and depression, including poor sleep quality and chronic pain. Since all these symptoms frequently occur together, they may have a common underlying biological basis. A single medication that could effectively treat all these symptoms would be ideal. Converging data suggest that pregnenolone is a promising pharmacological agent for treating multiple psychiatric symptoms and functional impairment. The investigators thus propose to conduct a clinical trial of pregnenolone in Veterans with anxiety and depression symptoms. Pregnenolone has minimal side effects, and the prior research demonstrates that pregnenolone is well-tolerated by Veterans. Treatment with pregnenolone could thus be an efficacious new therapeutic for Veterans experiencing depression, anxiety, poor sleep quality and chronic pain conditions.
Detailed description
Background: Anxiety and depression disorders can be very debilitating and result in substantial disability. These disorders are extremely common, occurring at rates that exceed other common medical illnesses such as hypertension, diabetes or asthma. Further, anxiety and depression disorders often co-occur (more the rule than the exception) and having one diagnosis substantially increases the risk for having the other. The clinical benefits of an intervention that ameliorates both anxiety and depression-related disability and clinical symptoms could be critically important, as odds of Veteran suicide completion significantly increase when depression co-occurs with anxiety disorders. Extensive preclinical and clinical data (from the investigators' group and others) support a novel neurosteroid intervention (pregnenolone/PREG) as a promising new treatment for anxiety and depression disorders. Furthermore, extensive evidence in rodent models and clinical biomarker candidate studies suggests substantial analgesic, anxiolytic, sleep and anti-inflammatory actions. PREG also significantly reduced low back pain in a randomized controlled trial of 94 OEF/OIF/OND-era Veterans compared to placebo, and allopregnanolone (ALLO) levels are inversely correlated with several commonly co-occurring symptoms, including sleep disturbance and pain disorders. Restoration of ALLO levels via a precursor loading strategy with PREG could thus ameliorate ALLO deficits and alleviate multiple functionally impairing and health-related symptoms. Additionally, PREG has been very well-tolerated in multiple clinical trials and exhibits a very favorable side effect profile - potentially supporting a superior safety and side effect profile advantage compared to existing pharmacological interventions. The investigators thus propose to conduct a 10-week double-blind, randomized, placebo-controlled trial of PREG versus placebo in Veterans with anxiety and depression.
Methods: The primary goal of this proposed project is to conduct a 10-week adaptive, randomized, double-blind, placebo-controlled trial to evaluate flexibly dosed pregnenolone to improve functional impairment and disability associated with anxiety and depression. Following a 2-week placebo-only lead-in period, 84 subjects will be enrolled and randomly assigned to receive PREG or placebo for 8 weeks (flexible dosing strategy). The investigators hypothesize that treatment with PREG will significantly reduce functional impairment and disability associated with anxiety and depression symptoms. Secondary outcomes include diagnostic improvements in anxiety and depression, pain symptoms and sleep quality. The investigators hypothesize that PREG will improve symptoms of anxiety and depression, pain and sleep quality. Finally, the investigators will quantify serum neurosteroid levels at baseline and post-treatment by highly sensitive and specific mass spectrometry-based techniques to determine if PREG and downstream neurosteroid metabolites such as ALLO are predictors of functional/therapeutic response. The investigators will also examine proinflammatory markers. The investigators hypothesize that changes in PREG and other neurosteroids (as well as proinflammatory markers) will predict improvements in mental health and functional outcomes.
Conclusion: Results from the proposed trial could provide rigorous scientific rationale for future pivotal Phase 3 trials to test PREG for the treatment of anxiety and depression disorders (improving functional outcomes and mitigation of pain and sleep disturbance). PREG has been very well-tolerated in multiple Veteran cohorts and could thus be a safe, inexpensive and efficacious new intervention to improve function and multiple behavioral symptoms.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- Participants will be randomized to receive the active study medication (pregnenolone) or placebo.
| Arm | Type | Receives |
|---|---|---|
| Pregnenolone | Active comparator | Drug: PregnenolonePregnenolone 50 milligrams (mg) BID x 14 DAYS, followed by Pregnenolone 150 milligrams (mg) BID x 14 DAYS, followed by Pregnenolone 250 milligrams (mg) BID x thereafter for the remainder of the 8-week trial. |
| Placebo | Placebo comparator | Drug: PlaceboSame as active comparator, except placebo dispensed |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- Veterans enrolled for care at the Durham Veterans Affairs Health Care System (VAHCS)
- Veterans who score a minimum score of 20 or higher (moderate symptoms) on the PHQ-ADS (Kroenke et al 2017)
- Oral pregnenolone could reduce the effectiveness of oral contraceptives, thus women will be required to use a medically and study-approved contraceptive or otherwise not be of child-bearing potential. Birth control methods must be non-hormonal.
- No anticipated need to alter psychiatric medications for duration of study involvement
- Ability to participate fully in the informed consent process
Key exclusion criteria (11 listed)
- History of allergy to pregnenolone (PREG)
- Medical disorders that may preclude safe administration of PREG or exacerbate mental or physical health symptoms
- Post-traumatic stress disorder (PTSD) diagnosis, as per the PCL-5 with LEC-5, scores of 38 or higher
- Current suicidal or homicidal ideation necessitating clinical intervention or representing an imminent concern. Prior attempts or suicidal ideation that does not require clinical intervention or represent an imminent concern is permitted
- Serious unstable medical illness, such as history of cerebrovascular accident, prostate, uterine or breast cancer, others (at the discretion of the PI and medical oversight team)
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 |
|---|---|---|
| PregnenolonePregnenolone 250 milligrams (mg) BID x 14 DAYS, followed by Pregnenolone 500 milligrams (mg) BID x 14 DAYS, followed by Pregnenolone 1000 milligrams (mg) BID x thereafter for the remainder of the 8-week trial. | Drug | Pregnenolone |
| PlaceboSame as active comparator, except placebo dispensed | Drug | Placebo |
Primary outcome
The World Health Organization disability assessment schedule II (WHODAS-2)
Time frame: Change from baseline at 10 weeks
The WHODAS-II is an instrument developed by the World Health Organization to assess behavioral limitations and restrictions regarding participation in specific activity domains experienced by an individual independent of their medical diagnosis. The conceptual frame of reference of this instrument is the International Classification of Functioning, Disability, and Health (ICF). Specifically, the instrument is a 36-item, generic, multidimensional questionnaire designed to evaluate the functioning of the individual in six activity domains (i.e., understanding and communicating, getting around, self-care, getting along with people, life activities, and participation in society). The 12-item WHODAS 2.0 score range from 12 to 60, where higher scores indicate higher disability or loss of function.
3 secondary outcomes
Patient Health Questionnaire Anxiety and Depression Scale (PHQ-ADS)
Time frame: Change from baseline at 10 weeks
Brief Pain Inventory, Second Edition (BPI-II)
Time frame: Change from baseline at 10 weeks
Pittsburgh Sleep Quality Index (PSQI)
Time frame: Change from baseline at 10 weeks
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Oct 2026.
- Individual participant dataSharing planned: No
Related trials for Anxiety and Depression
Recruiting
Virtual Reality Intervention to Improve Psychological Symptom Burden for Cancer Patients Undergoing Treatment
Adjustment Disorder, Anxiety Disorder
Active, not recruiting
Preventing Anxiety and Depression in Older Hispanics
Depression, Anxiety
RecruitingPhase 1
Effects of Intranasal Oxytocin in Patients With Arginine-vasopressin Deficiency
Vasopressin Deficiency
RecruitingObservational study
Evolution of Insomnia During the First Year in Patients Newly Diagnosed With Cancer
Cancer, Insomnia
Recruiting
Neural Mechanisms of Real-world Emotions and Internalizing
Major Depression, Generalized Anxiety
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.
Jennifer C Naylor, PhD principal investigator
Durham VA Medical Center, Durham, NC
Christine E. Marx, MD MA principal investigator
Durham VA Medical Center, Durham, NC
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Pregnenolone in people with Anxiety and Depression, run by VA Office of Research and Development 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 5 inclusion and 11 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: looking for participants now, as of the sponsor's last update on 14 Oct 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 phase mean?
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?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Jennifer C Naylor, PhD ((919) 286-0411 ext. 7722, jennifer.naylor2@va.gov), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The World Health Organization disability assessment schedule II (WHODAS-2) (time frame: Change from baseline at 10 weeks). 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 14 Oct 2026.