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Cognitive Enhancers as Adjuncts to Psychotherapy: Use of D-Cycloserine in Phobic Individuals to Facilitate Extinctionof Fear
Abstract
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.
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In the citing paper
“DCS is an agonist of the N-methyl-D-aspartate (NMDA) glutamate receptor, and it has been shown to increase the efficacy of exposure therapies for a number of anxiety disorders (Hofmann, Sawyer, and Asnaani, 2012; Ressler, Rothbaum, Tannenbaum, Anderson, et al. 2004).”
From Advancing the treatment of anxiety disorders in transition‐age youth: a review of the therapeutic effects of unconscious exposure. (2025) · cites this paper as Ressler, Rothbaum, Tannenbaum, Anderson, et al. 2004
In the citing paper
“Participants who received the drug (oral administration two to four hours before each session) showed greater improvements than those who received a placebo.”
From Mediators and Mechanisms of Change in Psychotherapy Research (2007) · cites this paper as Ressler et al. 2004
In the citing paper
“The effects were evident one week and three months after treatment.”
From Mediators and Mechanisms of Change in Psychotherapy Research (2007) · cites this paper as Ressler et al. 2004
In the citing paper
“Recently, DCS combined with imaginal or virtual reality exposure (VRE) therapy has been shown to reduce length of treatment for some anxiety disorders, including acrophobia (Ressler et al, 2004), social phobia (Guastella et al, 2008; Hofmann et al, 2006), and panic disorder (Otto et al, 2010), which, like PTSD, include learned avoidance and cued emotional distress as salient symptoms.”
From D-cycloserine augmentation of exposure therapy for post-traumatic stress disorder: a pilot randomized clinical trial (2014) · cites this paper as Ressler et al, 2004
In the citing paper
“The choice of dosing regimen for our studies was based on the Ressler et al (2004) study, which showed that there was no difference in efficacy between the 50 and 500 mg dose of DCS on enhancing exposure therapy outcomes.”
From D-cycloserine augmentation of exposure therapy for post-traumatic stress disorder: a pilot randomized clinical trial (2014) · cites this paper as Ressler et al (2004)
In the citing paper
“We chose weekly dosing, administered 90 min before exposure sessions, as this regimen has been effective in multiple animal and human fear extinction studies (Ledgerwood et al, 2003; Ressler et al, 2004; Walker et al, 2002)”
From D-cycloserine augmentation of exposure therapy for post-traumatic stress disorder: a pilot randomized clinical trial (2014) · cites this paper as Ressler et al, 2004
In the citing paper
“These pilot data add to the literature showing that DCS-enhanced exposure therapy is effective for the treatment of anxiety disorders (Hofmann et al, 2006; Ressler et al, 2004).”
From D-cycloserine augmentation of exposure therapy for post-traumatic stress disorder: a pilot randomized clinical trial (2014) · cites this paper as Ressler et al, 2004
In the citing paper
“Our data, in conjunction with that of Ressler et al (2004), Hofmann et al (2006), and Otto et al (2010), form a compelling pattern of evidence supporting the hypothesis that DCS may facilitate extinction learning.”
From D-cycloserine augmentation of exposure therapy for post-traumatic stress disorder: a pilot randomized clinical trial (2014) · cites this paper as Ressler et al, 2004
In the citing paper
“Shortly thereafter, several groups reported that DCS administration before or after exposure therapy, a form of treatment based on the principles of fear extinction learning, was effective in alleviating the symptoms of acrophobia (67), panic disorder (68), social anxiety disorder (69, 70), and obsessive–compulsive disorder (71–73).”
From Conditioned fear associated phenotypes as robust, translational indices of trauma-, stressor-, and anxiety-related behaviors (2014) · cites this paper as [67]
In the citing paper
“The rationale for selecting 50 mg as the dose was that this dose showed efficacy in previous work examining exposure enhancement with pre-session administration of DCS (10, 11).”
From D-cycloserine enhancement of fear extinction is specific to successful exposure sessions: evidence from the treatment of height phobia (2013) · cites this paper as [10]
In the citing paper
“In humans, DCS administration can likewise facilitate the loss of fear resulting from exposure that causes incomplete fear loss in controls (acrophobia: Ressler, Rothbaum, Tannenbaum, Anderson, Graap, Zimand, Hodges, & Davis, 2004; social phobia: Guastella, Richardson, Lovibond, Rapee, Gaston, Mitchell, & Dadds, 2008; Hofmann, Meuret, Smits, Simon, Pollack, Eisenmenger, Shiekh, & Otto, 2006;”
From D-cycloserine facilitates context-specific fear extinction learning (2008) · cites this paper as Ressler, Rothbaum, Tannenbaum, Anderson, Graap, Zimand, Hodges, & Davis, 2004
In the citing paper
“Indeed, in clinical studies, Ressler et al (2004) and Hofmann et al (2006) have recently reported that DCS facilitates fear extinction in patients with anxiety disorders.”
From Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD (2008) · cites this paper as Ressler et al, 2004
In the citing paper
“This, considered collectively with findings from animal studies, leads to the postulation that DCS administration without extinction training cannot facilitate fear extinction.”
From Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD (2008) · cites this paper as Ressler et al, 2004
In the citing paper
“Heresco-Levy et al (2002) used daily chronic dosing without exposure therapy, while Hofmann et al (2006) and Ressler et al (2004) used acute dosing with exposure therapy.”
From Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD (2008) · cites this paper as Ressler et al (2004)
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Metadata
- Authors
- Ressler, K. J., Rothbaum, B. O., Tannenbaum, L., Anderson, P., Graap, K., Zimand, E., Hodges, L., & Davis, M.
- Affiliations
- Emory University (US)
- Virtually Better (US)
- University of North Carolina at Charlotte (US)
- Venue
- Archives of General Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2004-11-01
- Volume
- 61
- Issue
- 11
- Pages
- 1136
- ISSN
- 0003-990X (ISSN-L)
- OpenAlex
- W2156900283
- Cited by
- 1,063
- References
- 45
- Citations by year
- 2026: 4 · 2025: 13 · 2024: 14 · 2023: 17 · 2022: 54 · 2021: 20 · 2020: 20 · 2019: 31 · 2018: 35 · 2017: 53 · 2016: 30 · 2015: 52 · 2014: 62 · 2013: 74 · 2012: 79
- FWCI
- 82.58
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Archives of General Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (MH-047840, MH069884, K01MH069884)
- Topics
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
- Keywords
- D-cycloserine, acrophobia, specific phobia, NMDA receptor partial agonist, fear extinction, virtual reality exposure therapy, nootropic drugs, adjunctive pharmacotherapy, skin conductance, anxiety disorders, fear learning, avoidance behavior, medication adherence
- MeSH terms
- Adult, Combined Modality Therapy, Cycloserine, Desensitization, Psychologic, Double-Blind Method, Extinction, Psychological, Fear, Female, Humans, Male, Middle Aged, Phobic Disorders, Pilot Projects, Placebos, Psychiatric Status Rating Scales, Receptors, N-Methyl-D-Aspartate, Treatment Outcome
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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