When it first emerged just over a decade ago, D-cycloserine (DCS) enhanced cognitive behaviour therapy (CBT) for anxiety was hailed as one of the best examples of translational research in psychiatry. But does this apparent wonder drug really enhance the effects of exposure-based CBT? A recently published meta-analysis attempts to answer this question…
DCS is not an anxiolytic medication. In fact, it is not a psychotropic medication at all, but rather a relatively innocuous antibiotic licensed for the treatment of tuberculous. So what has it got to do with treating anxiety? It just so happens that this medication also acts on neural pathways involved in fear extinction learning. (For the neurophysiologists among you, it is a partial agonist of the glutamatergic N-methyl-D-asparate receptors.) Animal studies have shown that DCS facilitates fear extinction learning and reduces the return of fear when administered just before or just after extinction training trials1. This got researchers thinking that perhaps DCS could aid the treatment of anxiety disorders, since exposure-based CBT is broadly centered on the principles of fear extinction learning.
“As a previous DCS trial therapist, I can attest to the enthusiasm that surrounded the notion of DCS being a “cognitive enhancer” for overcoming fears”
Early trials of DCS-augmented CBT for anxiety-related disorders showed promising results 2-4. Giving patients just one DCS pill at their weekly CBT session seemed to lead to better outcomes and/or more rapid therapeutic responses, compared to a placebo pill 5. This led to huge excitement in the field. As a previous DCS trial therapist, I can attest to the enthusiasm that surrounded the notion of DCS being a “cognitive enhancer” for overcoming fears. Our adolescent trial participants often referred to DCS tablets as “magic pills” and “brain vitamins”. Even us reasonably rational clinicians were convinced that we could tell which patients were receiving DCS versus placebo, despite the fact that it was a double-blind trial. (By the way, after blindness was broken we checked our predictions and we were all guessing at chance level!)
However, after the initial high surrounding the early positive findings a number of subsequent trials started to find negative results 6-9. The DCS bubble appeared to be bursting but, as is often the case in science, the story was not clear-cut. It was suggested that various factors may moderate the effect the DCS and explain inconsistent findings across studies, including the timing of DCS administration, the dose or the total number of doses, and the use of concomitant antidepressant medication.
Thus, the DCS waters had become well and truly muddied and there was a need for clarification. Professor David Mataix-Cols and colleagues undertook a study to do exactly this 10. They conducted a meta-analysis, which involved pooling and analyzing individual participant data from 21 of the 22 randomized controlled trials (RCTs) that had been conducted world-wide to assess the effect of DCS on exposure-based CBT for anxiety, obsessive-compulsive disorder and posttraumatic stress disorder. This equated to data on 1047 participants, yielding them greater statistical power than a standard meta-analysis, which pools overall effects sizes per study, as opposed to individual participant data.
What did the study find? The main analyses revealed that participants who received DCS in conjunction with exposure-based CBT showed an equivalent response from pre-treatment to mid-treatment compared to those who received a placebo, but they displayed significantly greater gains by post-treatment. However, while statistically significant, this advantage was small and arguably not clinically meaningful (less that 4 points on a 0-100 scale). Furthermore, by follow-up the effect was lost, and the DCS and placebo groups were back on a par. The study also looked at a range of potential moderators. Age, sex, diagnosis, number of CBT sessions, number of DCS doses and dose timing did not alter the effect of DCS. In fact, the only significant moderator that emerged was the year of publication; more recent studies found significantly smaller differences in improvement between DCS and placebo from pre-treatment to follow-up.
“DCS may have an effect for better and for worse, facilitating recovery after “good” exposure sessions but interfering with recovery after “bad” exposure sessions”
In summary, this study, which is the most comprehensive analysis to date, does not appear to provide convincing evidence for the clinical utility of DCS in treating anxiety-related disorders. However, the authors raise an interesting and important limitation of previous research. They note that, in previous studies, DCS has been given regardless of the “success” of the CBT session (in fact, it is most commonly administered just before the session has even taken place). This is problematic because there is some suggestion that DCS could enhance reconsolidation of fear memories 5. Thus, DCS may have an effect for better and for worse, facilitating recovery after “good” exposure sessions but interfering with recovery after “bad” exposure sessions in which anxiety does not habituate 11. The authors conclude by suggesting that future research should examine the effects of targeted DCS administrations. Thus, the DCS story lives on…
- Davis, M., Ressler, K., Rothbaum, B. O., & Richardson, R. (2006). Effects of D-cycloserine on extinction: translation from preclinical to clinical work. Biological Psychiatry, 60(4), 369-375.
- Ressler, K. J., Rothbaum, B. O., Tannenbaum, L., Anderson, P., Graap, K., Zimand, E., … & Davis, M. (2004). Cognitive enhancers as adjuncts to psychotherapy: Use of D-cycloserine in phobic individuals to facilitate extinctionof fear. Archives of General Psychiatry, 61(11), 1136-1144.
- Hofmann, S. G., Meuret, A. E., Smits, J. A., Simon, N. M., Pollack, M. H., Eisenmenger, K., … & Otto, M. W. (2006). Augmentation of exposure therapy with D-cycloserine for social anxiety disorder. Archives of General Psychiatry, 63(3), 298-304.
- Kushner, M. G., Kim, S. W., Donahue, C., Thuras, P., Adson, D., Kotlyar, M., … & Foa, E. B. (2007). D-cycloserine augmented exposure therapy for obsessive-compulsive disorder. Biological Psychiatry, 62(8), 835-838.
- Hofmann, S. G., Otto, M. W., Pollack, M. H., & Smits, J. A. (2015). D-cycloserine augmentation of cognitive behavioral therapy for anxiety disorders: an update. Current Psychiatry Reports, 17(1), 1-5.
- Hofmann, S. G., Smits, J. A., Rosenfield, D., Simon, N., Otto, M. W., Meuret, A. E., … & Pollack, M. H. (2013). D-Cycloserine as an augmentation strategy with cognitive-behavioral therapy for social anxiety disorder. American Journal of Psychiatry, 170(7), 751-758.
- Storch, E. A., Merlo, L. J., Bengtson, M., Murphy, T. K., Lewis, M. H., Yang, M. C., … & Geffken, G. R. (2007). D-cycloserine does not enhance exposure–response prevention therapy in obsessive–compulsive disorder. International Clinical Psychopharmacology, 22(4), 230-237.
- Litz, B. T., Salters-Pedneault, K., Steenkamp, M. M., Hermos, J. A., Bryant, R. A., Otto, M. W., & Hofmann, S. G. (2012). A randomized placebo-controlled trial of D-cycloserine and exposure therapy for posttraumatic stress disorder. Journal of Psychiatric Research, 46(9), 1184-1190.
- Mataix-Cols, D., Turner, C., Monzani, B., Isomura, K., Murphy, C., Krebs, G., & Heyman, I. (2014). Cognitive-behavioural therapy with post-session D-cycloserine augmentation for paediatric obsessive-compulsive disorder: pilot randomised controlled trial. The British Journal of Psychiatry, 204(1), 77-78.
- Mataix-Cols, D., de la Cruz, L. F., Monzani, B., Rosenfield, D., Andersson, E., Pérez-Vigil, A., … & Farrell, L. J. (in press). D-Cycloserine Augmentation of Exposure-Based Cognitive Behavior Therapy for Anxiety, Obsessive-Compulsive, and Posttraumatic Stress Disorders: A Systematic Review and Meta-analysis of Individual Participant Data. JAMA psychiatry.
- Smits, J. A., Rosenfield, D., Otto, M. W., Marques, L., Davis, M. L., Meuret, A. E., … & Hofmann, S. G. (2013). D-cycloserine enhancement of exposure therapy for social anxiety disorder depends on the success of exposure sessions. Journal of Psychiatric Research, 47(10), 1455-1461.