Extinction of fear is thought to use similar learning mechanisms as learning or conditioning of fear, and both are blocked by antagonists at the glutamatergic N-methyl-D-aspartate (NMDA) receptor. Futhermore, agonists at this site appear to augment some forms of learning in animal and human trials. The process of extinction of conditioned fear has recently been shown to be facilitated by D-Cycloserine (DCS), an NMDA agonist, given in individual doses prior to extinction training in an animal model. We have preliminary evidence that a similar effect is found in human subjects undergoing controlled exposure therapy for specific phobia. This translational research application represents a blinded, randomized, placebo-controlled efficacy study with the goal of determining whether a drug that acutely enhances learning in animal models will facilitate the extinction of fear that occurs with behavioral exposure therapy and whether a drug that has been shown to interfere with the extinction of fear will decrease the efficacy of exposure therapy. Specifically, it is proposed that a single dose of DCS, given shortly before each of 2 individual virtual reality exposure (VRE) therapy sessions, will significantly enhance the rate of response and possibly the efficacy of treatment, and that a single dose of alprazolam, a benzodiazepine, given shortly before each of 2 VRE therapy sessions, will significantly retard the long term efficacy of treatment. To this end, we propose to enroll 176 participants with the fear of public speaking to achieve 132 completers, or approximately 44 per group. Participants will be randomly assigned to receive VRE in combination with 50 mg DCS, placebo, or .5mg Alprazolam. Comprehensive multi-modal outcomes will be assessed by independent assessors blind to subject condition on interviews, self-report measures, psychophysiological measures, and a behavioral avoidance test consisting of an actual speech in front of a live audience. Participants will be assessed pre- and post-treatment and at follow-ups of 3 and 12 months to assess long-term effects. This type of combined treatment - specific pharmacotherapeutic augmentation of psychotherapy - would be novel and would potentially be generalizable to many different forms of psychotherapy for a wide range of disorders. If this translational research is successful, the ability of a relatively benign agent administered acutely before a psychotherapy session to facilitate the psychotherapeutic process could have important clinical, humanitarian, and economic advantages.
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