d-Cycloserine (DCS) is a partial NMDA receptor agonist that has been shown to enhance therapeutic response to exposure-based treatments for anxiety disorders, but has not been tested in the treatment of combat-related posttraumatic stress disorder (PTSD). The aim of this randomized, double-blind, placebo-controlled trial was to determine whether DCS augments exposure therapy for PTSD in veterans returning from Iraq and Afghanistan and to test whether a brief six-session course of exposure therapy could effectively reduce PTSD symptoms in returning veterans. In contrast to previous trials using DCS to enhance exposure therapy, results indicated that veterans in the exposure therapy plus DCS condition experienced significantly less symptom reduction than those in the exposure therapy plus placebo condition over the course of the treatment. Possible reasons for why DCS was associated with poorer outcome are discussed.
Extinction involves enhanced neural plasticity in the basolateral nucleus of the amygdala, which is reliant on N-methyl-d-aspartate (NMDA) receptors ( Royer and Pare, 2002), and NMDA agonists have been shown to enhance extinction learning. Specifically, d-cycloserine (DCS), a partial NMDA receptor agonist, enhances extinction of conditioned fear in infrahumans (e.g., Davis et al., 2006 and Yamamoto et al., 2008). Because exposure-based treatments involve extinction learning ( Milad et al., 2006), acute DCS administration may stimulate NMDA-glutamate synapses involved in emotional learning, thereby strengthening extinction learning and treatment effects ( Ledgerwood et al., 2004 and Rothbaum, 2008).
Small doses of DCS have been shown to enhance response to exposure-based therapy of specific phobia (Ressler et al., 2004), social anxiety disorder (Guastella et al., 2008 and Hofmann et al., 2006), panic disorder (Otto et al., 2010), and obsessive-compulsive disorder (Kushner et al., 2007 and Wilhelm et al., 2008), with medium to large effects (Norberg et al., 2008). Patients have required fewer sessions to achieve gains, had higher remission rates, and lower relapse rates (Hofmann, 2007 and Kushner et al., 2007).
Because PTSD entails strong conditioning to a specific context (Milad et al., 2006), higher-order conditioning (Foa et al., 1989), and is associated with impaired extinction learning and retention (Blechert et al., 2007, Guthrie and Bryant, 2006, Milad et al., 2008 and Milad et al., 2009), it is an ideal context to study the impact of DCS. Due to the very slight side-effect profile and low cost (see Hofmann, 2007), DCS may allow exposure therapy of PTSD to be delivered in fewer sessions to achieve more rapid and sustained change. If care can be delivered more efficiently, more resources will be available to meet the considerable demands for PTSD treatment, especially in the military and VA contexts. Only one study has been published testing DCS in PTSD patients (De Kleine et al., 2012). It found that DCS did not enhance overall treatment effects in a sample of civilian mixed trauma survivors, although DCS did increase the likelihood of treatment response in a subgroup of participants with severe symptoms who had completed all treatment sessions.
The primary aim of this randomized, double-blind, placebo-controlled trial funded by the VA as part of a joint VA/NIMH solicitation, was to determine whether DCS augments exposure therapy for PTSD in returning veterans. We hypothesized that DCS combined with brief exposure therapy would lead to more rapid and greater PTSD and depression symptom reduction relative to exposure plus placebo.
A secondary exploratory aim was to examine whether a brief exposure therapy could promote symptom relief among veterans with PTSD. New veterans are reluctant to engage in a lengthy therapy (e.g., Seal et al., 2010), and they have considerable stigma about mental health care and competing occupational demands and other logistical barriers to care (e.g., Hoge et al., 2004). As a result, we shortened the intervention for the veterans in this trial to six sessions.
