Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear

Arch Gen Psychiatry. 2004 Nov;61(11):1136-44. doi: 10.1001/archpsyc.61.11.1136.


Background: Traditional pharmacological approaches to treating psychiatric disorders focus on correcting presumed biochemical abnormalities. However, some disorders, particularly the anxiety-related disorders exemplified by specific phobia, have an emotional learning component to them that can be facilitated with psychotherapy.

Objective: To determine whether D-cycloserine (DCS), a partial agonist at the N-methyl-d-aspartate receptor that has previously been shown to improve extinction of fear in rodents, will also improve extinction of fear in human phobic patients undergoing behavioral exposure therapy.

Design: Randomized, double-blind, placebo-controlled trial examining DCS vs placebo treatment in combination with a precisely controlled exposure paradigm.

Setting: Participants were recruited from the general community to a research clinic.

Participants: Twenty-eight subjects with acrophobia diagnosed by the Structured Clinical Interview for DSM-IV were enrolled.

Interventions: After we obtained pretreatment measures of fear, subjects were treated with 2 sessions of behavioral exposure therapy using virtual reality exposure to heights within a virtual glass elevator. Single doses of placebo or DCS were taken prior to each of the 2 sessions of virtual reality exposure therapy. Subjects, therapists, and assessors were blind to the treatment condition. Subjects returned at 1 week and 3 months posttreatment for measures to determine the presence and severity of acrophobia symptoms.

Main outcome measures: Included were measures of acrophobia within the virtual environment, measures of acrophobia in the real world, and general measures of overall improvement. An objective measure of fear, electrodermal skin fluctuation, was also included during the virtual exposure to heights. Symptoms were assessed by self-report and by independent assessors at approximately 1 week and 3 months posttreatment.

Results: Exposure therapy combined with DCS resulted in significantly larger reductions of acrophobia symptoms on all main outcome measures. Subjects receiving DCS had significantly more improvement compared with subjects receiving placebo within the virtual environment (1 week after treatment, P</=.001; 3 months later, P</=.05). Subjects receiving DCS also showed significantly greater decreases in posttreatment skin conductance fluctuations during the virtual exposure (P</=.05). Additionally, subjects receiving DCS had significantly greater improvement compared with subjects receiving placebo on general measures of real-world acrophobia symptoms (acrophobia avoidance [P</=.02], acrophobia anxiety [P</=.01], attitudes toward heights [P</=.04], clinical global improvement [P</=.01], and number of self-exposures to real-world heights [P</=.01]); the improvement was evident early in treatment and was maintained at 3 months.

Conclusion: These pilot data provide initial support for the use of acute dosing of DCS as an adjunct to exposure-based psychotherapy to accelerate the associative learning processes that contribute to correcting psychopathology.

Publication types

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

MeSH terms

  • Adult
  • Combined Modality Therapy
  • Cycloserine / administration & dosage
  • Cycloserine / pharmacology
  • Cycloserine / therapeutic use*
  • Desensitization, Psychologic / methods*
  • Double-Blind Method
  • Extinction, Psychological / drug effects
  • Fear / drug effects
  • Fear / psychology
  • Female
  • Humans
  • Male
  • Middle Aged
  • Phobic Disorders / diagnosis
  • Phobic Disorders / drug therapy
  • Phobic Disorders / therapy*
  • Pilot Projects
  • Placebos
  • Psychiatric Status Rating Scales
  • Receptors, N-Methyl-D-Aspartate / agonists
  • Treatment Outcome


  • Placebos
  • Receptors, N-Methyl-D-Aspartate
  • Cycloserine