D-Cycloserine vs Placebo as Adjunct to Cognitive Behavioral Therapy for Obsessive-Compulsive Disorder and Interaction With Antidepressants: A Randomized Clinical Trial

JAMA Psychiatry. 2015 Jul;72(7):659-67. doi: 10.1001/jamapsychiatry.2015.0546.


Importance: It is unclear whether d-cycloserine (DCS), a partial N-methyl-d-aspartate agonist that enhances fear extinction, can augment the effects of exposure-based cognitive behavioral therapy (CBT) for obsessive-compulsive disorder (OCD).

Objectives: To examine whether DCS augments the effects of CBT for OCD and to explore (post hoc) whether concomitant antidepressant medication moderates the effects of DCS.

Design, setting, and participants: A 12-week, double-blind randomized clinical trial with 3-month follow-up conducted at an academic medical center between September 4, 2012, and September 26, 2013. Participants included 128 adult outpatients with a primary diagnosis of OCD and a Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score of 16 or higher. Concurrent antidepressant medication was permitted if the dose had been stable for at least 2 months prior to enrollment and remained unchanged during the trial. The main analysis was by intention-to-treat population.

Interventions: All participants received a previously validated Internet-based CBT protocol over 12 weeks and were randomized to receive either 50 mg of DCS or placebo, administered 1 hour before each of 5 exposure and response prevention tasks.

Main outcomes and measures: Clinician-administered Y-BOCS score at week 12 and at 3-month follow-up. Remission was defined as a score of 12 or lower on the Y-BOCS.

Results: In the primary intention-to-treat analyses, DCS did not augment the effects of CBT compared with placebo (mean [SD] clinician-rated Y-BOCS score, DCS: 13.86 [6.50] at week 12 and 12.35 [7.75] at 3-month follow-up; placebo: 11.77 [5.95] at week 12 and 12.37 [6.68] at 3-month follow-up) but showed a significant interaction with antidepressants (clinician-rated Y-BOCS, B = -1.08; Z = -2.79; P = .005). Post hoc analyses revealed that antidepressants significantly impaired treatment response in the DCS group but not the placebo group, at both posttreatment and follow-up (clinician-rated Y-BOCS: t62 = -3.00; P = .004; and t61 = -3.49; P < .001, respectively). In the DCS group, a significantly greater proportion of antidepressant-free patients achieved remission status at follow-up (60% [95% CI, 45%-74%]) than antidepressant-medicated patients (24% [95% CI, 9%-48%]) (P = .008). Antidepressants had no effect in the placebo group (50% [95% CI, 36%-64%] remission rate in both groups).

Conclusions and relevance: The findings suggest that antidepressants may interact with DCS to block its facilitating effect on fear extinction. Use of DCS may be a promising CBT augmentation strategy but only in antidepressant-free patients with OCD.

Trial registration: clinicaltrials.gov Identifier: NCT01649895.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antidepressive Agents / therapeutic use*
  • Cognitive Behavioral Therapy / methods*
  • Combined Modality Therapy
  • Cycloserine / therapeutic use*
  • Double-Blind Method
  • Female
  • Humans
  • Internet
  • Male
  • Middle Aged
  • Obsessive-Compulsive Disorder / therapy*
  • Receptors, N-Methyl-D-Aspartate / agonists
  • Therapy, Computer-Assisted / methods
  • Treatment Outcome
  • Young Adult


  • Antidepressive Agents
  • Receptors, N-Methyl-D-Aspartate
  • Cycloserine

Associated data

  • ClinicalTrials.gov/NCT01649895