Neurosteroids for PTSD in Veterans

BACKGROUND: There is an acute and urgent need to develop new and effective posttraumatic
stress disorder (PTSD) pharmacotherapies, as there are currently only two FDA-approved
medications for the treatment of PTSD (both of which are from the same drug class and have
shown only moderate effect sizes in FDA registration trials). Many Veterans with PTSD thus
remain symptomatic despite the availability of these treatments, increasing the likelihood of
receiving pharmacological treatment interventions for which there is little or no empirical
evidence. Multiple national and VA working groups focusing on PTSD have identified the
critical need to address the paucity of PTSD pharmacotherapies, and have strongly recommended
more randomized clinical trials to evaluate possible effective pharmacological treatments.
Both preclinical and clinical data suggest that reductions in neurosteroids are involved in
the pathophysiology of PTSD, and that ameliorating these deficits could potentially be
clinically therapeutic - the proposed investigation targeting a neurosteroid intervention for
the treatment of PTSD could thus be a promising research avenue. The investigators therefore
propose to conduct a randomized clinical trial (RCT) to determine the efficacy of a
neurosteroid intervention (pregnenolone) for PTSD and commonly co-occurring disorders in
Iraq/Afghanistan-era Veterans, an understudied cohort that may be less treatment-refractory.

METHODS: This study will be a 10-week randomized, placebo-controlled, double-blind clinical
trial of pregnenolone or matching placebo in Veterans with PTSD. The trial will include a
2-week single-blind placebo lead-in phase followed by 8 weeks of study medication (placebo or
pregnenolone). Forty-five subjects meeting DSM-5 criteria for PTSD (as measured by a CAPS-5
score of 30) will be randomized to receive pregnenolone, and 45 subjects meeting DSM-5
criteria for PTSD will be randomized to receive placebo. The primary outcome for this RCT
will be changes in total CAPS-5 score at Visit 6 for this modified intent-to-treat sample.
Secondary clinical outcomes for this RCT include changes in pain intensity and functional
interference, as measured by the Brief Pain Inventory, Short Form (BPI-SF) and depression
symptoms by the Hamilton-Depression Rating Scale (HAM-D). Blood samples will be collected for
serum analysis at all study visits and frozen in a -80 degree freezer. Upon completion of the
study, samples will be thawed and analyzed using Gas Chromatography/Mass Spectrometry for
neurosteroid analyses and inflammatory markers will be quantified. Genetic analyses will be
conducted to determine therapeutic response.

PREDICTED RESULTS: The investigators hypothesize that treatment with pregnenolone will be
efficacious in Iraq/Afghanistan-era Veterans with PTSD, and will significantly reduce PTSD
symptoms as assessed by the CAPS-5 (primary endpoint) compared to placebo. Secondary
endpoints will include the assessment of conditions that frequently co-occur with PTSD;
specifically, the investigators hypothesize that pregnenolone will also demonstrate efficacy
for co-occurring chronic pain symptoms and depression symptoms. The investigators hypothesize
that increases in pregnenolone and other neurosteroids (and decreases in inflammatory
markers) will predict improvements in PTSD, depression, and chronic pain symptoms. The
investigators also hypothesize that neurosteroids are dysregulated in PTSD, and that specific
SNPs of genes coding for neurosteroidogenic enzymes will be associated with therapeutic
response.

Inclusion Criteria:

- DSM-5 diagnosis of PTSD with CAPS-5 Total Score 3

- Females 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

Exclusion Criteria:

- History of allergy to pregnenolone

- Medical disorders that may preclude safe administration of pregnenolone or exacerbate
PTSD symptoms

- Current suicidal or homicidal ideation necessitating clinical intervention or
representing an imminent concern

- Prior suicide attempt history 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)

- Medical conditions not well controlled will be excluded, at the discretion of the PI
and Medical Team

- Standard pharmacological interventions for PTSD will not be exclusionary, including,
but not limited to:

- antidepressant medications such as SSRIs, SNRIs, tricyclics, bupropion,
mirtazapine, venlafaxine, and nefazodone

- mood stabilizers such as carbamazepine, divalproex, lamotrigine, topiramate

- atypical antipsychotics, and other agents including prazosin

- However, there may be no changes in psychotropic medications for PTSD 4 weeks
prior to study randomization

- Benzodiazepine 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

- Participants on hormonal therapies such as finasteride or hormonal birth control

- Female participants who are pregnant or breast-feeding

- As indicated by the DSM-5, moderate or severe Substance Use Disorders (excluding
caffeine and tobacco) within 1 month of study entry

- Mild Alcohol Use Disorder is not exclusionary, at the judgment of the PI and her
medical team