Neurosteroids in PTSD - Biomarkers to Therapeutics

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.

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.