American Board of Psychological Specialties

By George D. Zgourides, MD, PsyD

Anxiety disorders, one of the most prevalent psychiatric illnesses in the general population, are estimated to be present in at least 15% to 20% of health clinic patients (American Psychiatric Association, 2000). And while anxiety is readily amenable to cognitive-behavioral therapy in the majority of cases, some anxious individuals—for unknown reasons—either experience a temporary or limited response to treatment, or experience no response at all (Barlow, 2004).
An anti-tuberculosis drug, d-cycloserine (DCS), has recently piqued the interest of behavioral researchers for its apparent anti-anxiety properties. According to meta-analyses (Norberg, Krystal, & Tolin, 2008), DCS is a n-methyl-d-aspartate (NMDA) receptor agonist working at the strychnine-insensitive glycine recognition site that appears to facilitate the extinction of learned fear in humans and animals when used in combination with exposure therapy. DCS at the doses used in anxiety therapy has few if any significant side-effects, and appears generally well-tolerated (Hofmann, Pollack, & Otto, 2006).
Working with animal trials, Walker, Ressler, Lu, and Davis (2002) reported that DCS, when either given systemically or infused into the amygdala of rodents, significantly decreased learned fear responses. The authors concluded DCS likely works, not by weakening previous unconditioned stimuli (US), but by enhancing the learning of an inhibitory association (CS) that competes with, and overcomes, previously learned associations. The implication here is that DCS does not facilitate the “forgetting” of anxiety, but instead facilitates the learning of a competing response, similar to reciprocal inhibition.
Initial studies of DCS in human trials proved disappointing. Heresco-Levy et al. (2002) conducted a double-blind cross-over design study in 11 post-traumatic stress disorder patients and failed to find any positive psychotherapeutic effects of DCS. However, the patients in the Heresco-Levy study did not receive any cognitive or behavioral therapy along with the DCS. Also, the PTSD patients received chronic dosing of DCS. Taken together, these results seem to imply that acute dosing of DCS might be needed to be most effective when used adjunctively with psychotherapy.
In fact, Ressler et al. (2004) recommended that patients receive acute dosing of DCS in the form of a single dose prior to therapy. Specifically, these authors found that a dose of either 50 mg or 500 mg of DCS taken two to four hours prior to each of two virtual reality therapy exposure sessions reduced patients’ acrophobia. In other words, in their double-blind study with a randomized sample of 28 patients, Ressler et al. (2004) noted that DCS combined with exposure therapy provided significantly reduced acrophobia compared to controls, and treatment gains were maintained at three months.
Hofmann, Meuret, and colleagues (2006) reported positive results from their double-blind placebo controlled study with 27 patients into the role of DCS in reducing social phobia, in this case fear of speaking in public. Patients were given a 50 mg dose one hour prior to exposure therapy in which patients faced increasingly challenging public speaking situations. Patients receiving the DCS versus the placebo demonstrated significant treatment gains that were evident during the treatment, immediately post-treatment and at one-month follow-up. Interestingly, treatment gains increased over time, with the greatest differences between groups being seen at the one-month mark. The authors attributed this to new long-term learning requiring a time-dependent consolidation period.
Guastella et al. (2007) reported DCS does not appear to enhance exposure when used in non-clinical or sub-clinical populations. In their two studies, 100 spider-fearful participants were either administered DCS (50 mg or 500 mg) or were given placebo prior to treatment. Subjects were assessed at pre-treatment, immediately post- treatment, and at 3.5 weeks post-treatment. Significant return of fear was noted at follow-up, especially in non-treatment contexts. Both of the authors’ studies failed to demonstrate any cognitive enhancing effects of DCS, suggesting that DCS may be most effective in clinically disordered patients.
Wilhelm et al. (2008) added DCS to 10 behavior therapy sessions with 23 OCD patients. These sessions were conducted twice weekly, and participants received either 100 mg of d-cycloserine or a placebo one hour prior to the treatment. The researchers found OCD symptoms were significantly improved at mid-treatment in the DCS group, and depressive symptoms were significantly improved at post-treatment in the DCS group. Wilhelm et al. (2008) concluded their data supported using DCS to augment behavior therapy for OCD.  

Concluding Comments
Per meta-analysis of anti-anxiety treatment interventions, a number of reports on the efficacy of DCS in human trials are promising, indicating additional controlled double-blind research into this novel agent is needed. In particular, comparative research would be helpful in determining to what degree, if any, DCS can be used reliably to treat specific types of anxiety in specific populations. Also, controlled double-blind research that compares the efficacy of DCS with traditional anti-anxiety medications is essential. What is likely at this point, however, is that DCS is neither a panacea nor solely effective without psychotherapy, especially behavior therapy.
Patients and clinicians benefit when a range of interventions are available for any particular problem. For those seeking relief from an anxiety disorder, DCS in combination with psychotherapy may be an option. Appropriate assessment, clinical judgment, and personal preferences will necessarily guide the specifics and direction of treatment. n

References
American Psychiatric Association (APA). (2000). Diagnostic and Statistical Manual of Mental Disorders 4th Edition Text Revision. Washington, DC: Author.
Barlow, D. H. (2004). Anxiety and its disorders: The nature and treatment of anxiety and panic (2nd ed.). New York: Guilford.
Guastella, A. J., Dadds, M. R., Mitchell, P., & Richardson, G. (2007). A randomized controlled trial of the effect of d-cycloserine on exposure therapy for spider fear. Journal of Psychiatric Research, 41(6), 466-471.    
Heresco-Levy, U., Kremer, I., Javitt, D. C., Goichman, R., Reshef, A., Blanura, M., & Cohen, T. (2002). Pilot-controlled trial of d-cycloserine for the treatment of post-traumatic stress syndrome. International Journal of Neuropsychopharmacology, 5, 301-307.
Hofmann, S. G., Meuret, A. E., Smits, J. A., Simon, N. M., Pollack, M. H., Eisenmenger, K., Shiekh, M., & Otto, M. W. (2006). Augmentation of exposure therapy with d-cycloserine for social anxiety disorder. Archives of General Psychiatry, 63, 298-304.
Hofmann, S. G., Pollack, M. H., & Otto, M. W. (2006). Augmentation treatment of psychotherapy for anxiety disorders with d-cycloserine. CNS Drug Reviews, 12(3-4), 208-217.
Norberg, M. M., Krystal, J. H., & Tolin, D. F. (2008). A meta-analysis of d-cycloserine and the facilitation of fear extinction and exposure therapy. Biological Psychiatry, 63(12), 1118-1126.
Ressler, K. J., Rothbaum, B. O., Tannenbaum, L., Anderson, P., Graap, K., Zimand, E., Hodges, L., & Davis, M. (2004). Cognitive enhancers as adjuncts to psychotherapy. Archives of General Psychiatry, 61, 1136-1144.
Walker, D. L., Ressler, K. J., Lu, K., & Davis, M. (2002). Facilitation of conditioned fear extinction by systemic administration of intra-amygdala infusion of d-cycloserine as assessed with fear-potentiated startle in rats. The Journal of Neuroscience, 22(6), 2343-2351.
Wilhelm, S., Buhlmann, U., Tolin, D. F., Meunier, S. A., Pearlson, G. D., Reese, H. E., Cannistraro, P., Jenike, M. A., & Ruach, S. L. (2008). Augmentation of behavior therapy with D-cycloserine for obsessive-compulsive disorder. American Journal of Psychiatry, 165(3), 335-341.