Neuroactive Steroids and Traumatic Brain Injury (TBI) in OEF/OIF Veterans
Condition: Brain Injuries, Traumatic
MeSH terms: Brain Injuries; Brain Injuries, Traumatic
Intervention: Pregnenolone; Placebo
Intervention description: Pregnenolone 50 mg BID x 14 DAYS, followed by Pregnenolone 150 mg BID x 14 DAYS, followed by Pregnenolone 250 mg BID x thereafter for the remainder of the 8-week trial; Same as active comparator, except placebo dispensed.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 53.0
Sex: All
Minimum age: 21 Years
Maximum age: 55 Years
Healthy volunteers: No
Keywords: brain injuries, traumatic; pregnenolone; Veteran; OEF/OIF; neurosteroid; allopregnanolone

Summary:

      Purpose: Mild traumatic brain injury (TBI) is extremely common among Operation Enduring
      Freedom/Operation Iraqi Freedom (OEF/OIF) 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 randomized controlled
      trial (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.

      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.
    

Eligibility criteria:

        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].