Enhancing Prolonged Exposure Therapy for Posttraumatic Stress Disorder with D-Cycloserine: Further Support for Treatments That Promote Experience-Dependent Neuroplasticity

Abstract

t n i r P osttraumatic stress disorder (PTSD) is a common, distressing, and debilitating consequence of the experience of extremely stressful life events, exemplified by combat, sexual assault, torture, or natural disasters. Although the majority of people exposed to these extreme events recover within days to months, long-term follow-up of Vietnam Veterans and survivors of the Nazi Death Camps indicate that for many traumatized people, symptoms persist for decades, perhaps for the rest of their lives (1,2). The very persistence of the impact of what can be a single life experience suggests that traumatization profoundly engages neuroplasticity mechanisms. In addition, compromised neuroplasticity may be a factor preventing individuals with PTSD from benefiting from available social supports and from psychotherapies and pharmacotherapies for PTSD. In this issue of Biological Psychiatry, de Kleine et al. (3) present the first test of the hypothesis that enhancing N-methyl-D-aspartate (NMDA) glutamate receptor function could increase the efficacy of prolonged exposure (PE) therapy, an evidence-based behavioral therapy for PTSD. In this case, NMDA receptor function was enhanced by administration of the partial agonist of the glycineB site of the NMDA receptor, D-cycloserine, a drug that did not show direct effects on PTSD symptoms outside the context of behavioral therapy (4). In the study by de Kleine et al. (3), 75 patients with PTSD were randomized to receive D-cycloserine 50 mg or placebo 1 hour prior to PE sessions. Eight patients dropped out before taking a dose of research medication. The study was designed to deliver 10 PE sessions, but 19 of the 67 patients (28.5%) who took at least one dose of randomized medication and who met remission criteria on a self-rated PTSD scale were permitted to terminate treatment early. In the intent-to-treat analysis, there were no significant treatment effects on the clinician-rated (Clinician Administered PTSD Scale) and self-rated PTSD symptom measures. However, in the intent-to-treat analysis, D-cycloserine was associated with a 3-fold increase in the likelihood of showing a clinically meaningful improvement of PTSD symptoms (10 point or greater reduction of the total score on the Clinician Administered PTSD Scale). In the group of treatment completers, patients treated with D-cycloserine were more than 4 times as likely to show a clinical response by the end of treatment and more than 9 times as likely to maintain this response at a 3-month posttreatment follow-up evaluation. This paper extends the impact of the work initiated by the group at Emory University (Atlanta, Georgia) that provided evidence in