Nepicastat for Posttraumatic Stress Disorder (PTSD) in OIF/OEF Veterans

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.