# Neurosteroids in PTSD - Biomarkers to Therapeutics

> **NIH VA IK2** · DURHAM VA MEDICAL CENTER · 2021 · —

## Abstract

Posttraumatic stress disorder (PTSD) is extremely common among Operation Enduring Freedom/Operation
Iraqi Freedom/Operation New Dawn (OEF/OIF/OND) Veterans, impacting approximately 20% of
OEF/OIF/OND Veterans enrolled in VA healthcare. Pharmacological management of PTSD is unfortunately
frequently suboptimal, and many OEF/OIF/OND Veterans experience persistent and unalleviated symptoms.
Currently there are only two FDA-approved pharmacological treatments for PTSD (sertraline and paroxetine,
each approved ~15 years ago). There is thus an acute and urgent need for the development of new
pharmacological treatments for PTSD that are effective and well-tolerated. Neurosteroids are
endogenous molecules that are enriched in human brain, and many neurosteroids exhibit anxiolytic-like
actions and modulate the HPA axis. In addition, neurosteroids such as dehydroepiandrosterone (DHEA) are
immediately accessible for translation to clinical trials, as DHEA is available over-the-counter as a dietary
supplements in the U.S. Neurosteroid interventions may represent an important new lead for the
management of PTSD symptoms in OEF/OIF/OND Veterans. Based on our preliminary data in 660
OEF/OIF/OND male Veterans (indicating DHEAS levels as significantly reduced in PTSD) and rodent data
from multiple research groups demonstrating anxiolytic actions of neurosteroids, we proposed the following:
A parallel-group, double-blind, placebo (PBO)-controlled, randomized Phase 2 pilot study using adjunctive
DHEA (400 mg) will be evaluated to establish Proof of Concept (POC) for this agent in Veterans with PTSD.
Our 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. We hypothesize that compared with PBO, DHEA will increase task-associated
fMRI functional connectivity between the amygdala and hippocampus (primary outcome).
Our second objective is to determine if a 6-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). We 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.
Our third objective is to evaluate the impact of DHEA relative to PBO on serum neurosteroid levels in
OEF/OIF/OND Veterans with PTSD. We 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
correlat...

## Key facts

- **NIH application ID:** 10295751
- **Project number:** 5IK2CX001397-04
- **Recipient organization:** DURHAM VA MEDICAL CENTER
- **Principal Investigator:** Steven Szabo
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-07-01 → 2020-11-23

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10295751

## Citation

> US National Institutes of Health, RePORTER application 10295751, Neurosteroids in PTSD - Biomarkers to Therapeutics (5IK2CX001397-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10295751. Licensed CC0.

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