This application is in response to PAR-12-071: Collaborative R34s for Pilot Studies of Innovative Treatments in Mental Disorders (Collaborative R34). D-cycloserine (DCS) is a partial N-methyl-D-aspartate glutamate agonist that has been shown to enhance exposure therapies for anxiety disorders. This approach is grounded in recent research advances in understanding the neural circuitry underlying fear extinction and is based upon one of the striking successes of translational research. All human clinical studies to date have administered DCS at least 1 hour prior to the exposure sessions. This dose-timing strategy limits the clinical utility of this highly promising augmentation strategy, especially sine accumulating research suggest that the efficacy of DCS for enhancing exposure therapy outcomes may depend on the success of exposure sessions. Pre-clinical and initial clinical data suggest that the DCS exposure-augmentation effect can also be obtained when DCS is administered immediately after an extinction trial when it follows successful exposure sessions. The proposed study builds upon this extant research by testing the efficacy of tailored post-session DCS administration (i.e., only following successful exposure sessions) for augmenting exposure therapy. In order to maintain high internal validity in this R34 study, we will enroll patients with social anxiety disorder (SAD) in a previously validated 5-session CBT protocol and randomize them to: (1) tailored post-session DCS administration; (2) pre-session DCS administration; (3) placebo administration; or (4) non-tailored post-session DCS administration. The primary outcomes will be short- and long-term improvements in social anxiety severity: We expect that the tailored post-session DCS administration condition will outperform the pre-session DCS administration, placebo administration, and non-tailored post-session DCS administration conditions, respectively, at posttreatment, 1-month and 3-month follow-up. In addition, we will explore potential moderators of the efficacy of tailored post-session DCS administration for augmenting exposure therapy. This application is the logical next step in the study of DCS. It provides an important innovative move toward the realization of personalized medicine by providing the first step in the eventual development of an algorithm for administering DCS in CBT with the goal of maximizing the efficacy and cost-effectiveness of therapy for anxiety disorders, which are some of the most prevalent mental conditions, making this a project of potentially high public health significance.

Public Health Relevance

This study addresses an important public health issue by evaluating dose-timing of d-cycloserine (DCS), a cognitive enhancer of exposure therapy for anxiety disorders, including social anxiety disorder. The proposed study is the first human trial evaluating a tailored post-session administration strategy for DCS augmentation of exposure therapy. The proposed study will examine whether clinicians are to only administer the drug after successful exposure sessions and withhold the drug after unsuccessful sessions, and thus not reinforce deleterious learning. The results of this study may help us maximize future DCS augmentation strategies by identifying sessions that should be augmented with DCS. Results of this study are likely to have significant implications for clinical practice and address important issues relevant to the use of DCS across the anxiety disorders.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Planning Grant (R34)
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Special Emphasis Panel (ZMH1)
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Hillefors, MI
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Rush University Medical Center
Schools of Medicine
United States
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Otto, Michael W; Kredlow, M Alexandra; Smits, Jasper A J et al. (2016) Enhancement of Psychosocial Treatment With D-Cycloserine: Models, Moderators, and Future Directions. Biol Psychiatry 80:274-283