Neuroactive Steroids and Traumatic Brain Injury (TBI) in OEF/OIF Veterans

Purpose: Mild traumatic brain injury (TBI) is extremely common among OEF/OIF (Operation
Enduring Freedom/Operation Iraqi Freedom) era Veterans. Mild TBI is frequently accompanied by
post-traumatic stress disorder (PTSD) and depression symptoms, co-occurring disorders that
contribute to increased disability and decreased quality of life. Neuroactive steroids (NS)
represent promising pharmacological candidates for intervention for these diverse symptom
domains, since a number of these molecules demonstrate pronounced neuroprotective and
neurotrophic properties. The NS pregnenolone (PREG) is a logical therapeutic option, since it
enhances learning and memory and also increases myelination in rodent models. Further,
decreases in PREG have been associated with depressive symptoms, and PREG is also metabolized
to allopregnanolone (ALLO), an anxiolytic downstream NS that is decreased in PTSD. ALLO also
enhances neurogenesis in rodents. The investigators thus propose an RCT in OEF/OIF era
Veterans with mild TBI.

Methodology: The design of this study will be randomized, placebo-controlled, double-blind.
Trial duration will be 10 weeks, consisting of a 2-week placebo lead-in period for all
subjects, followed by 8 weeks of treatment with either pregnenolone or placebo. The primary
cognitive outcome measure will be executive functioning (as assessed by the Tower of London
test), and the primary behavioral outcome measure will be PTSD Cluster D symptoms (as
assessed by the Clinician-Administered PTSD Scale, CAPS). The investigators will also
determine if PREG administration in OEF/OIF Veterans with mild TBI increases downstream ALLO
and/or other GABAergic NS levels, and the investigators will identify the specific metabolism
profile of PREG following eight weeks of treatment with this neurosteroid. A subset of
patients will also receive pre/post neuroimaging (functional magnetic resonance imaging
[fMRI], diffusion tensor imaging [DTI], and quantitative susceptibility
mapping/susceptibility tensor imaging [QSM/STI]).

Anticipated Findings: The investigators hypothesize that treatment with PREG in OEF/OIF era
Veterans with mild TBI will significantly improve executive functioning compared to the
placebo condition. The investigators also predict that treatment with PREG will decrease
Cluster D PTSD symptoms compared to treatment with placebo.

Inclusion Criteria:

- 21-55 years of age, any ethnic group, either sex

- History of mild TBI since 2001

- The investigators will adhere to the operational definition of mild TBI suggested by
the World Health Organization Task Force (Holm et al 2005), with the exception of
Glasgow Coma Scale score criteria (not available for these subjects): a.) One or more
of the following: confusion or disorientation, loss of consciousness for 30 minutes or
less, post-traumatic amnesia for less than 24 hours, and/or other transient
neurological abnormalities such as focal signs, seizure, and intracranial lesion not
requiring surgery; Glasgow Coma Scale (GCS) score of 13-15 after 30 minutes
post-injury or later upon presentation for health care (GCS unavailable). This WHO
diagnostic definition of mild TBI is also consistent with the CDC Report to Congress
on Mild TBI in the United States, September 2003 (specifically, altered consciousness
attributable to the head injury [=transient confusion, disorientation or impaired
consciousness] or self reported loss of consciousness lasting 30 minutes or less).

- Ability to participate fully in the informed consent process.

- No anticipated need to alter psychiatric medications for the 10-week duration of the
study. Since this study is adjunctive to treatment-as-usual, patients will not be
tapered from any psychiatric medications they may be receiving at enrollment.

- No changes in psychotropic or behavioral interventions during the study or in the 4
weeks prior to study enrollment.

Exclusion Criteria:

- For this pilot study, the investigators will diverge slightly from the above WHO
definition of mild TBI and exclude patients who report a history of seizures for this
investigation. Although no seizures have been reported to the FDA in relationship to
pregnenolone use, pregnenolone could theoretically influence seizure threshold if
metabolized to its sulfated derivative, which demonstrates negative modulatory actions
at GABAA receptors. Since the preliminary data suggest that pregnenolone
administration increases the GABAergic neuroactive steroid allopregnanolone five-fold,
however, and since allopregnanolone demonstrates marked anticonvulsant activity in a
number of animal seizure models, this theoretical risk may be small or non-existent.

- Subjects with current suicidal or homicidal ideation necessitating clinical
intervention or representing an imminent concern.

- Concomitant medications for medical conditions will be addressed on a case-by-case
base and determined if exclusionary.

- Current DSM-IV diagnosis of bipolar disorder, schizophrenia or other psychotic
disorder, or cognitive disorder due to a general medical condition other than TBI.

- Female patients who are pregnant or breast-feeding.

- Known allergy to study medication.

- Substance dependence or abuse (other than nicotine dependence), as determined by MINI
assessment.

- Serious unstable medical illness. History of cerebrovascular accident, prostate,
uterine or breast cancer.

- Use of oral contraceptives or other hormonal supplementation such as estrogen
[although early studies suggested no effects on menstrual cycle, alterations in
downstream metabolites of pregnenolone could theoretically impact efficacy of oral
contraceptives and estrogen replacement].