Neurosteroids in PTSD - Biomarkers to Therapeutics

The purpose of this research is to determine if a study medication called Dehydroepiandrosterone (DHEA) helps to reduce PTSD symptoms in OEF/OIF/OND Veterans. In addition to finding out if DHEA is effective for treating PTSD symptoms, this research seeks to determine if DHEA is effective in treating other symptoms, such as depression and anxiety. Depression and anxiety are symptoms that are frequently present in Veterans who are experiencing PTSD. Another purpose of this research is to takes pictures of the brain using magnetic resonance imaging (MRI) and blood levels of various small molecules including neurosteroids and also proteins, which may be affected by the study drug and/or related to symptoms in Veterans with PTSD. This study seeks to determine if DHEA is changed to other compounds after it is taken by mouth and the safety and effectiveness of DHEA in Veterans with PTSD. This is an "add-on" study and Veterans enrolled in the study will continue to take all of their current medications without any changes (also called "usual care"), and DHEA or a sugar pill (also called a "placebo") will then be added to their current medication regimen.

Study Overview

Status

Terminated

Intervention / Treatment

Detailed Description

This is a parallel-group, double-blind, placebo (PBO)-controlled, randomized Phase 2 pilot study using adjunctive dehydroxyepiandrosterone [DHEA (400 mg)] to establish Proof of Concept (POC) for use of this agent in Veterans with PTSD.

The investigators' first objective is POC target engagement to evaluate a one-time adjunctive oral dose of DHEA (400 mg) relative to PBO on the neuronal circuity of fear-anxiety-emotion connectivity. This will be achieved by comparing pre- to post-treatment changes in amygdala-hippocampal functional connectivity to DHEA and PBO during fMRI activation. The investigators hypothesize that compared with PBO, DHEA will increase task-associated fMRI functional connectivity between the amygdala and hippocampus (primary outcome).

The second objective is to determine if an 8-week treatment with adjunctive DHEA is superior to PBO in reducing symptoms of PTSD (CAPS-5) and depression (BDI) in OEF/OIF/OND Veterans, and enhancing resilience (CD-RISC). The investigators hypothesize that 400mg DHEA will result in reduced PTSD and depression symptom severity relative to PBO, as determined by a pre- to post-treatment decrease in CAPS-5 and BDI scores, respectively, with enhancement in resilience scores using the CD-RISC at 6-weeks.

The third objective is to evaluate the impact of DHEA relative to PBO on serum neurosteroid levels in OEF/OIF/OND Veterans with PTSD. The investigators hypothesize that DHEA will result in a statistically-significant increase in serum neurosteroid levels (DHEA, DHEAS, androsterone) relative to PBO, as determined by pre- to post-treatment reductions in PTSD symptoms severity. This association will be evaluated by correlating neurosteroid levels with PTSD, depression, and resilience scores over 6 weeks of treatment.

The exploratory objective is to determine preliminary evidence for an association of fMRI and myelin integrity measures of fear-anxiety-emotion circuits with serum neurosteroid levels and treatment response to DHEA. Changes in myelin integrity following DHEA treatment will be evaluated using novel susceptibility diffusion imaging [STI]), as DHEA impacts myelination in preclinical rodent models. The investigators will also determine if serum neurosteroid levels are correlated with myelin integrity on STI. The investigators hypothesize that fMRI and myelin integrity of fear-anxiety circuits will correlate with serum neurosteroids and treatment response.

Study Type

Interventional

Enrollment (Actual)

5

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • North Carolina
      • Durham, North Carolina, United States, 27705
        • Durham VA Medical Center, Durham, NC

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • OEF/OIF/OND era Veterans
  • PTSD diagnosis (CAPS-5 score 33).
  • Negative pregnancy test if female.

    • Sexually active subjects are required to use a medically acceptable form of birth control if they are of childbearing potential and could become pregnant during the study.
    • A medically acceptable form of birth control includes non-hormonal intrauterine devices, surgical sterilization, or double barrier methods (e.g., diaphragm with contraceptive jelly, condom with contraceptive foam, cervical caps with contraceptive jelly).
    • Sexual abstinence with agreement to continue abstinence or to use a medically acceptable method of contraception should sexual activity occur is permissible.
  • Female participants must have had a normal mammogram within the last year (if older than 40)
  • Female participants must have had a normal pelvic exam within the last year
  • No change in medications less than 4 weeks before baseline assessment
  • No anticipated need to alter medications for PTSD for the 6-week study duration (as determined by study physician's review of records and/or discussion with prescribing physician).
  • Ability to fully participate in the informed consent process

Exclusion Criteria:

  • Unstable medical or neurological illness, including seizures, renal impairment or CVA and inability to participate in neuroimaging (fMRI).
  • Use of oral contraceptives or other hormonal supplements, as it is unclear if DHEA metabolism to other neurosteroids such as estradiol may potentially impact contraceptive efficacy.
  • Significant suicidal or homicidal ideation.
  • Current DSM-5 diagnosis of bipolar disorder, schizophrenia, or other psychotic disorder (including major depression with psychotic features), or cognitive disorder due to a general medical condition.
  • Female patients who are pregnant or breast-feeding.
  • Known allergy to study medication.
  • History of moderate or severe TBI.
  • Substance dependence within past three months, per DSM-5 criteria (excluding caffeine and nicotine).
  • Abnormal prostate specific antigen (PSA; >2.5ng/ml in males age 49 or less; >4ng/ml in males age 50 or greater) or history of prostate cancer, breast cancer, or uterine cancer.
  • A family history of prostate, breast or endometrial cancer in a first-degree relative.
  • Presence of any factors/conditions, medical or non-medical, that may interfere with conduction of study assessments in the judgment of the study team.
  • Serious or unstable cardiovascular, hepatic, renal, metabolic, respiratory, or hematologic illness, symptomatic peripheral vascular disease, or other medical condition or psychiatric conditions or behaviors that would compromise participation and/or likely to lead to worsening of symptoms during the course of the study in the opinion of study physician and research team.
  • Are non-ambulatory or require the use of crutches or a walker.
  • Taking Narcotic medications or benzodiazepines for any reason.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
No Intervention: Placebo
Subjects will receive a one-time oral dose of PBO prior to initial brain imaging followed by sustained administration of PBO for 6 weeks.
Placebo Comparator: DHEA
Subjects will receive a one-time oral dose of DHEA prior to initial brain imaging followed by sustained administration of DHEA for 6 weeks.
Subjects will be randomized to receive a one-time oral dose of DHEA (400mg) or PBO and sustained administration of the study drug for 6 weeks. There will be a 2 week placebo lead-in period [all participants], followed by subjects continuing in the randomization block of DHEA or placebo for 6 weeks following acute administration).

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Functional Connectivity Between Amygdala-hippocampus Assessed Using fMRI Based Shifted-attention Emotion Appraisal (SEAT) Paradigm.
Time Frame: 6 weeks
The Shifted-Attention Emotion Appraisal (SEAT) Paradigm will present compound stimuli that include both emotional faces (e.g. sad, happy, angry) and neutral scenes. In three different conditions, participants are asked to respond to three different questions: (1) 'Gender'; (2) 'Inside/Outside'; or (3) 'Like/Dislike'. This allows multiple components of cognition to be probed including (1) implicit emotional processing, (2) attentional modulation, and (3) cognitive modulation of emotion. Item-specific memory will be tested first using yes/no recognition judgments. The conjunctive memory test will require participants to make "match" (previously viewed faces and buildings presented in a combinations seen during encoding) or "mismatch" (items in combinations not previously seen together) judgments. Change in SEAT paradigm (Z score) from baseline to 6 weeks
6 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Clinician-Administered PTSD Scale for DSM-5 (CAPS-5)
Time Frame: Baseline and 6 weeks
The CAPS is the gold standard in PTSD assessment. The CAPS-5 is a 30-item structured interview that can be used to make a diagnosis of PTSD and assess PTSD symptoms. It assesses the intensity and frequency of PTSD symptoms. Change in total CAPS-5 score from baseline to 6 weeks. Scores range from 0-80; higher score indicates greater severity.
Baseline and 6 weeks
Beck-Depression Inventory-II (BDI-II)
Time Frame: Baseline and 6 weeks
The BDI-II is a 21-item self-report inventory of depression symptoms. The minimum and maximum values for the BDI-II are (0-63). Change in total BDI-II score from baseline to 6 weeks. Higher score indicates greater severity.
Baseline and 6 weeks
Hamilton Anxiety Rating Scale (HAM-A)
Time Frame: Baseline and 6 weeks
The HAM-A is clinician-rated interview that measures presence of anxiety-related symptoms in 14 areas. Total score ranges from 0 to 56. Higher score indicates greater anxiety. Change in total HAM-A score from baseline to 6 weeks
Baseline and 6 weeks
Symptom Checklist-90-Revised (SCL-90-R)
Time Frame: Baseline and 6 weeks
Change in total SCL-90-R score (range: 90 to 450; higher score indicates greater severity) from baseline to 6 weeks. This scale assesses somatization, obsessive-compulsive, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism.
Baseline and 6 weeks
Patient-Reported Outcomes Measurement Information System (PROMIS) - Pain Intensity Scale
Time Frame: Baseline and 6 weeks
PROMIS Pain Intensity is a three item scale measuring the severity of pain using a five-point Likert-type scale (i.e., no pain=1, mild=2, moderate=3, severe=4, very severe=5).Change in total PROMIS Pain Intensity Scale score (range: 3 to 15) from baseline to 6 weeks. Higher score indicates greater severity.
Baseline and 6 weeks
Patient-Reported Outcomes Measurement Information System (PROMIS) - Sleep Disturbance Scale
Time Frame: Baseline and 6 weeks
The 8-item PROMIS Sleep Disturbance measures sleep disturbance with each item on the measure rated on a 5-point scale (1=never; 2=rarely; 3=sometimes; 4=often; and 5=always) with a range in score from 8-40. Change in total PROMIS-Sleep Disturbance score from baseline to 6 weeks. Higher score indicates greater severity.
Baseline and 6 weeks
PROMIS-Anger Scale
Time Frame: Baseline and 6 weeks
The PROMIS-Anger Scale is an 8-item scale that assesses anger. Scores range from 5 to 25, with higher scores indicating greater anger severity. Change in total PROMIS-Anger score from baseline to 6 weeks.
Baseline and 6 weeks
Barrat Impulsivity Scale (BIS-11)
Time Frame: Baseline and 6 weeks
The BIS-11 is a 30 item questionnaire to measure impulsiveness. Items are answered on a 4-point scale. Total scores range from 30-120 with a higher summed score indicating higher impulsivity. Change in total BIS-11 score from baseline to 6 weeks.
Baseline and 6 weeks
Connor-Davidson Resilience Scale (CD-RISC)
Time Frame: Baseline and 6 weeks
The CD-RISC scale assesses resiliency in individuals. There are 25 items in the survey, each item is scored from 0-4, and the total ranges from 0-100. Higher scores indicate greater resilience. Change in total CD-RISC score from baseline to 6 weeks.
Baseline and 6 weeks
Hamilton Depression Ratings Scale (HAM-D)
Time Frame: Baseline and 6 weeks
The HAM-D is a standardized, clinician-administered rating scale; assesses 17 items characteristically associated with major depression. Total scores range from 0-50. Higher score indicates greater severity. Change in total HAM-D score from baseline to 6 weeks.
Baseline and 6 weeks
Patient-Reported Outcomes Measurement Information System (PROMIS) - Depression Scale
Time Frame: Baseline and 6 weeks
PROMIS-Depression Scale is a self-reported scale of depressive symptoms Each item is scored 1-5 (1 = Never; 5 = Always). Total ranges are 8 to 40. Higher score indicates greater severity. Change in total PROMIS Depression score from baseline to 6 weeks.
Baseline and 6 weeks
Patient-Reported Outcomes Measurement Information System (PROMIS) - Anxiety Scale
Time Frame: Baseline and 6 weeks
The PROMIS-Anxiety Scale is a self-report of anxiety symptoms. Each item is scored 1-5 (1 = Never; 5 = Always). Total score ranges from 8 to 40. Higher score indicates greater severity. Change in total PROMIS Anxiety score from baseline to 6 weeks.
Baseline and 6 weeks
Clinician Global Impression Scale (CGI)
Time Frame: Baseline and 6 weeks
The CGI scale will be used to rate improvement in the subject's condition. Total score range of 0-30. Higher scores indicates greater severity. Change in total CGI score from baseline to 6 weeks.
Baseline and 6 weeks
Brief Pain Inventory (BPI)
Time Frame: Baseline and 6 weeks
The Brief Pain Inventory (BPI) assesses the severity of pain and its impact on functioning. Total range of 0-110. Higher score indicates greater severity. Change in total BPI score from baseline to 6 weeks.
Baseline and 6 weeks

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Serum DHEA
Time Frame: 6 weeks
Change in serum levels of DHEA from baseline to 6 weeks
6 weeks
Myelin Integrity Susceptibility Tensor Imaging (STI)
Time Frame: 6 weeks
Change in STI (Z score) from baseline to 6 weeks
6 weeks
Serum DHEAS
Time Frame: 6 weeks
Change in serum DHEAS levels from baseline to 6 weeks
6 weeks
Serum Androsterone
Time Frame: 6 weeks
Change in serum androsterone levels from baseline to 6 weeks
6 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Steven Szabo, MD PhD, Durham VA Medical Center, Durham, NC

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 8, 2019

Primary Completion (Actual)

November 16, 2020

Study Completion (Actual)

November 16, 2020

Study Registration Dates

First Submitted

March 30, 2018

First Submitted That Met QC Criteria

March 30, 2018

First Posted (Actual)

April 6, 2018

Study Record Updates

Last Update Posted (Estimate)

May 5, 2023

Last Update Submitted That Met QC Criteria

May 3, 2023

Last Verified

May 1, 2023

More Information

Terms related to this study

Keywords

Other Study ID Numbers

  • MHBB-021-17S
  • 1IK2CX001397-01A2 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Posttraumatic Stress Disorder

Clinical Trials on DHEA

3
Subscribe