Nepicastat for Posttraumatic Stress Disorder (PTSD) in OIF/OEF Veterans
Condition: Posttraumatic Stress Disorder
MeSH terms: Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic
Intervention: Nepicastat; Placebo
Intervention description: 100-800mg; 100-800mg placebo
Intervention MeSH terms: Dopamine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 100.0
Sex: All
Minimum age: 19 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: PTSD; Veterans; Nepicastat; OIF/OEF

Summary:

      This study proposes a multi-site, randomized, double-blind, placebo-controlled clinical trial
      of the dopamine-ß-hydroxylase (DBH) inhibitor, nepicastat, for the treatment of posttraumatic
      stress disorder (PTSD) in outpatients who have previously served in a combat zone during
      Operation Iraqi Freedom and Operation Enduring Freedom (OIF/OEF)or other Southwest conditions
      since 19800. A DBH inhibitor's mechanism of action is to decrease neuronal noradrenaline (NA)
      release by inhibiting DBH conversion of dopamine (DA) to NA. Animal models of PTSD and human
      studies have found a substantial increase in NA activity for these animal models and for PTSD
      in humans. Furthermore, recent clinical studies have improved PTSD hyper-arousal symptoms by
      reducing the NA over-activity using agents like NA post-synaptic antagonists. Key support for
      the proposed study is based on a similar improvement in PTSD symptoms after treatment with
      the DBH inhibitor, disulfiram.

      In the experience of the clinical investigators, the most common chief complaint of the
      OIF/OEF veterans with PTSD is hyperarousal (DSM-IV criterion D symptom cluster). These
      symptoms significantly interfere with social, occupational, and interpersonal function.
      Standard treatments with antidepressants are not fully effective in treating the symptoms of
      PTSD in veterans; thus, new treatments are needed. An intervention, such as nepicastat, aimed
      at reducing hyperarousal, as well as other PTSD symptoms, would have significant impact of
      restoring overall function and quality of life in OIF/OEF veterans with PTSD. Since
      hyperarousal symptoms responded relatively quickly to medications of this type, our study in
      120 outpatient veterans with PTSD will compare nepicastat 120 mg/day vs. placebo in a 6-week
      double-blind, randomized clinical trial (RCT). The veterans will be followed for an
      additional 8 weeks after the RCT, during which, those who have a priori defined positive
      clinical response to the study medication, nepicastat vs. placebo, will be continued on the
      study medication, in order to assess further improvement and safety. Those patients who do
      not have a positive clinical response during the 6 week RCT will be offered the addition of
      the standard first-line PTSD pharmacotherapy, paroxetine, during the 8 weeks extension phase.
      Thus, weeks 7-14 offer an opportunity to evaluate longer-term nepicastat efficacy and to
      compare the treatment response of nonresponders after augmentation with paroxetine.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Signed informed consent

          -  Patient understands the risks and benefits and agrees to visit frequency and
             procedures

          -  Male or female

          -  Any race or ethnic origin

          -  Served in OIF/OEF or Afghanistan conflicts or other Southwest Asia conditions

          -  Currently Active Duty, National Guard, Reservist, Veteran, and/or Retired Military

          -  Diagnosis of PTSD (by MINI (Mini International Neuropsychiatric Interview) and CAPS-DX
             (Clinician Administered PTSD scale- Diagnostic Form) using Rule of Fours and total
             CAPS-DX score of 45)

          -  No substance use disorders in the previous 2 weeks and no substance dependence
             disorders in the past 4 weeks (except for nicotine and caffeine)

          -  Free of psychotropic medication for 2 weeks prior to randomization

          -  Physical and laboratory panel are within normal limits or not clinically significant

          -  Women of childbearing potential must be using medically-approved methods of birth
             control

          -  ≥19 to 65 years of age

        Exclusion Criteria:

          -  Lifetime history of bipolar I, schizophrenia, schizoaffective or cognitive disorders

          -  Actively considering plans of suicide or homicide

          -  Psychotic symptoms that in the investigator's opinion impair the patient's ability to
             give informed consent or make it unsafe for patient to be maintained without a
             neuroleptic

          -  Unstable general medical conditions or a contraindication to the use of nepicastat

          -  Women planning to become pregnant or breastfeed during the study

          -  Current or pending incarceration

          -  Terminal Illness