New meta-analysis in JAMA Psychiatry: Does d-cycoserine add to CBT?

D-cycloserine (DCS) is a partial NMDA agonist that facilitates fear extinction in animals and reduces return of fear when given before  extinction training. Despite several initial trials showing promising results in humans with anxiety disorders larger trials conducted within the past 5 years have produced mixed results. Our large trial in obsessive-compulsive disorder22 found no general effect of DCS but a significant interaction effect between DCS and antidepressant medication in a post hoc analysis;  antidepressants impaired treatment response in patients randomized to DCS but not in patients randomized to placebo.

We collected Individual participant data for 21 of 22 DCS trials, representing 1047 of 1073 eligible participants. When controlling for antidepressant use, participants receiving DCS showed greater improvement from pretreatment to posttreatment (mean difference, −3.62; 95% CI, −0.81 to −6.43; P = .01; d = −0.25) but not from pretreatment to midtreatment (mean difference, −1.66; 95% CI, −1.60 to 4.92; P = .32; d = −0.14) or from pretreatment to follow-up (mean difference, −2.98, 95% CI, −0.03 to 5.99; P = .05; d = −0.19). Only 1 significant moderator emerged: year of publication. Specifically, the more recent the study, the smaller the difference between DCS and placebo for pretreatment to follow-up improvement (b = 4.02; 95% CI, 0.59-7.45; P = .02, d = 0.26).

Conclusion: D-cycloserine is associated with a small augmentation effect on exposure-based therapy. The small size of the effect makes the clinical usefulness of DCS doubtful.


Mataix-Cols D, Fernández de la Cruz L, Monzani B, Rosenfield D, Andersson E, Pérez-Vigil A, Frumento P, de Kleine RA, Difede J, Dunlop BW, Farrell LJ, Geller D, Gerardi M, Guastella AJ, Hofmann SG, Hendriks G, Kushner MG, Lee FS, Lenze EJ, Levinson CA, McConnell H, Otto MW, Plag J, Pollack MH, Ressler KJ, Rodebaugh TL, Rothbaum BO, Scheeringa MS, Siewert-Siegmund A, Smits JAJ, Storch EA, Ströhle A, Tart CD, Tolin DF, van Minnen A, Waters AM, Weems CF, Wilhelm S, Wyka K, Davis M, Rück C, for the DCS Anxiety Consortium. D-Cycloserine Augmentation of Exposure-Based Cognitive Behavior Therapy for Anxiety, Obsessive-Compulsive, and Posttraumatic Stress DisordersA Systematic Review and Meta-analysisJAMA Psychiatry. Published online January 25, 2017. doi:10.1001/jamapsychiatry.2016.3955