A Meta-Analysis of D-Cycloserine and the Facilitation of Fear Extinction and Exposure Therapy

doi:10.1016/j.biopsych.2008.01.012

Biological Psychiatry

Volume 63, Issue 12, 15 June 2008, Pages 1118-1126

https://doi.org/10.1016/j.biopsych.2008.01.012 Get rights and content

Background

Translational research suggests that D-cycloserine (DCS), a partial N-methyl-D-aspartate (NMDA) receptor agonist, might facilitate fear extinction and exposure therapy by either enhancing NMDA receptor function during extinction or by reducing NMDA receptor function during fear memory consolidation. This article provides a quantitative review of DCS-augmented fear extinction and exposure therapy literature.

Methods

English-language journal articles that examined DCS augmented with fear extinction or exposure therapy were identified through public databases from June 1998 through September 2007, through references of originally identified articles and contact with DCS investigators. Data were extracted for study author, title, and year; trial design; type of subject (animal vs. human; clinical vs. nonclinical); sample size, DCS dose, and timing in relation to extinction/exposure procedures; dependent variable; group means and SDs at post-extinction/exposure; and follow-up outcome.

Results

D-cycloserine enhances fear extinction/exposure therapy in both animals and anxiety-disordered humans. Gains generally were maintained at follow-up, although some lessening of efficacy was noted. D-cycloserine was more effective when administered a limited number of times and when given immediately before or after extinction training/exposure therapy.

Conclusions

This meta-analysis suggests that DCS is a useful target for translational research on augmenting exposure-based treatment via compounds that impact neuroplasticity. D-cycloserine 's major contribution to exposure-based therapy might be to increase its speed or efficiency, because the effects of DCS seem to decrease over repeated sessions. This information might guide translational researchers in discovering more selective and/or effective agents that effectively enhance (or reduce) NMDA receptor function.

Section snippets

Data Sources

Journal articles were identified through searches of the Medline and PsychINFO electronic databases from June 1998 through September 2007 with the search terms [(DCS or D-Cycloserine) and (extinction or exposure therapy)] and restricting to the English language. Relevant studies also were identified through references of originally identified articles and contact with DCS investigators. This literature search identified 44 articles, which then were examined for inclusion.

Study Selection

Randomized,

Results

Effect sizes (Cohen's d) for all studies and specific subgroups are shown in Table 2. At post-treatment (Table 2), human studies were compared with studies of animals. This comparison yielded a significant difference (Q_between = 10.18), with greater effects seen in animal studies. Both animal and human studies nevertheless were associated with significant effect sizes, with a large and robust effect in animal studies (d = 1.19) and a small (but not robust) effect in human studies (d = .42).

Discussion

The results of the present meta-analysis suggest that DCS augments the effects of fear extinction/exposure therapy in both animals and humans. Across all samples, the effect size was large, indicating a substantial increase in efficacy. Although there is ample evidence that exposure-based treatment is effective for the treatment of anxiety disorders, many patients fail to respond adequately to treatment—for example, in studies of panic disorder, only one-half of treated patients met criteria

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ReviewA Meta-Analysis of D-Cycloserine and the Facilitation of Fear Extinction and Exposure Therapy

Background

Methods

Results

Conclusions

Section snippets

Data Sources

Study Selection

Results

Discussion

Neuroscience

Neuron

Neuron

Neuropharmacology

Neurosci Lett

Brain Res

Biol Psychiatry

Biol Psychiatry

Biol Psychiatry

Behav Res Ther

Physiol Behav

Pharmacol Biochem Behav

Behav Brain Res

Behav Brain Res

Neuroscience

Behav Brain Res

Behav Res Ther

Neuroscience

J Psychiatr Res

Neurobiol Learn Mem

Behav Res Ther

Biol Psychiatry

Neurobiol Learn Mem

Schizophr Res

Schizophr Res

Brain Res

Biol Psychiatry

Behav Res Ther

The NMDA antagonist MK-801 blocks the extinction of Pavlovian fear conditioning

Behav Neurosci

The NMDA receptor antagonist MK-801 blocks acquisition and extinction of conditioned hypoalgesic responses in the rat

Q J Exp Psychol B

Long-term potentiation as a substrate for memory: Evidence from studies of amygdaloid plasticity and Pavlovian fear conditioning

Hippocampus

Fear conditioning induces associative long-term potentiation in the amygdala

Nature

Role of NMDA receptors and MAP kinase in the amygdala in extinction of fear: Clinical implications for exposure therapy

Eur J Neurosci

Glycine site agonists of the NMDA receptor: A review

CNS Drug Reviews

Facilitation of conditioned fear extinction by systemic administration or intra-amygdala infusions of D-cycloserine as assessed with fear-potentiated startle in rats

J Neurosci

Effects of D-cycloserine on extinction of conditioned freezing

Behav Neurosci

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

Arch Gen Psychiatry

Augmentation of exposure therapy with D-cycloserine for social anxiety disorder

Arch Gen Psychiatry

Facilitation of extinction of conditioned fear by d-cycloserine

Curr Dir Psychol Sci

Neural systems involved in fear and anxiety measured with fear-potentiated startle

Am Psychol

Pharmacotherapy for performance anxiety disorders: Occasionally useful but typically contraindicated

J Clin Psychol

Review
A Meta-Analysis of D-Cycloserine and the Facilitation of Fear Extinction and Exposure Therapy