Cited by 498Memory and Neural MechanismsAnxiety, Depression, Psychometrics, Treatment, Cognitive ProcessesPosttraumatic Stress Disorder Research

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Effects of D-Cycloserine on Extinction: Translation From Preclinical to Clinical Work

Davis, Michael, Ressler, Kerry, Rothbaum, Barbara O., Richardson, Rick·2006·Biological Psychiatry

DOI 10.1016/j.biopsych.2006.03.084

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Abstract

Administration of benzodiazepines or serotonin reuptake inhibitors in combination with behavior therapy for the treatment of many anxiety disorders has generally lead to only modest gains. In this article we suggest that pharmacotherapy aimed not at treating the symptoms of anxiety but instead aimed at improving the learning that takes place in exposure therapy might actually improve the effectiveness of exposure therapy. This idea was based on animal work showing that the partial N-methyl-D-aspartate (NMDA) agonist D-cycloserine (DCS) facilitated extinction of fear when given either before or shortly after exposure to fearful cues, reduced return of fear that is normally seen when extinction training is followed by stress, and led to generalized extinction, where DCS given in combination with exposure to one fearful cue led to extinction to another cue previously paired with the same aversive event. These finding suggested that DCS might facilitate exposure-based psychotherapy, which was verified in a small clinical study showing that DCS facilitated exposure therapy for fear of heights in a well-controlled virtual reality environment.

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BackgroundSelf-citation
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Background
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Background
D-Cycloserine Facilitation of Fear Extinction and Exposure-Based Therapy Might Rely on Lower-Level, Automatic Mechanisms
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Background
Learning and memory in conditioned fear extinction: Effects of d-cycloserine
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Background
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BackgroundInfluential
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BackgroundMethod
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Background
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“In response to this issue, Davis et al. (2006) have reasoned that under fear conditioning experiences, the NMDA receptors may already be saturated, and that because DCS is a partial agonist, it may have relative inhibitory effects at times of fear.”
Background
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Self-citation
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BackgroundResult
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“Preclinical research has demonstrated that DCS facilitates extinction learning and memory in rodents [9], which provides the rationale”
BackgroundSelf-citation
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Background
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“As enhancer of NMDA receptor function and thus a facilitator of certain forms of synaptic plasticity and learning, DCS is used in combination with cue exposure therapy (CET) to facilitate extinction of conditioned fear responses in various anxiety disorders including phobias and post-traumatic stress disorder [16,80,8…”
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Treatment of avoidance behavior as an adjunct to exposure therapy: Insights from modern learning theory
Treanor, M., & Barry, T. J. (2017) · Behaviour Research and Therapy · doi:10.1016/j.brat.2017.04.009 · Cited by 65
Serotonin 1B Autoreceptors Originating in the Caudal Dorsal Raphe Nucleus Reduce Expression of Fear and Depression-Like Behavior
McDevitt, R. A., Hiroi, R., Mackenzie, S. M., Robin, N. C., Cohn, A., Kim, J. J., & Neumaier, J. F. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2010.12.029 · Cited by 60
Psychopharmacological Issues in the Treatment of TBI and PTSD
McAllister, T. W. (2009) · The Clinical Neuropsychologist · doi:10.1080/13854040903277289 · Cited by 62
“Preclinical work (Yamamoto et al, 2008 ), as well as some human studies in various anxiety disorders (Davis, Ressler, Rothbaum, & Richardson, 2006 ; Norberg, Krystal, & Tolin, 2008 ) have suggested a role for this compound as an adjunct to cognitive behavioral therapy.”
Background
Bringing the bedside to the bench, and then to the community: a prospectus for intervention research in late‐life anxiety disorders
Lenze, E. J., & Wetherell, J. L. (2009) · International Journal of Geriatric Psychiatry · doi:10.1002/gps.2074 · Cited by 57
“A significant recent success combining neurobiology with basic behavioral theory in anxiety is d-cycloserine augmentation of exposure therapy (Davis et al., 2006), lending support for research merging fMRI paradigms related to the ‘cognitive control of affect’ circuit of frontal-limbic interactions…”
Background
Cognitive enhancers for facilitating drug cue extinction: Insights from animal models
Dhonnchadha, B. Á. N., & Kantak, K. M. (2011) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2011.01.018 · Cited by 57
“…literature, DCS has been shown to improve learning and memory in rats (Land and Riccio, 1999; Pussinen and Sirvio, 1999; Lelong et al., 2001) and monkeys (Matsuoka and Aigner, 1996; Schneider et al., 2000), as well as facilitating fear extinction learning (Davis et al., 2006; Vervliet, 2008).”
d-Cycloserine Facilitates Extinction of Conditioned Alcohol-Seeking Behaviour in Rats
Vengeliene, V., Kiefer, F., & Spanagel, R. (2008) · Alcohol and Alcoholism · doi:10.1093/alcalc/agn067 · Cited by 57
Dexamethasone facilitates fear extinction and safety discrimination in PTSD: A placebo-controlled, double-blind study
Michopoulos, V., Norrholm, S. D., Stevens, J. S., Glover, E. M., Rothbaum, B. O., Gillespie, C. F., Schwartz, A. C., Ressler, K. J., & Jovanović, T. (2017) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2017.05.023 · Cited by 57
“…to have similar effects as PTSD on cortisol suppression following dexamethasone administration in combat veterans compared to non-traumatized controls (de Kloet et al., 2007), suggesting that our research cohort may have a ‘ceiling effect’ in this phenotype due to level of total trauma exposure.”
BackgroundSelf-citation
d-Cycloserine Facilitation of Exposure Therapy Improves Weight Regain in Patients With Anorexia Nervosa: A Pilot Randomized Controlled Trial
Levinson, C. A., Rodebaugh, T. L., Fewell, L., Kass, A. E., Riley, E. N., Stark, L., McCallum, K., & Lenze, E. J. (2015) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.14m09299 · Cited by 56
Neuroimaging Studies of Psychological Interventions for Mood and Anxiety Disorders: Empirical and Methodological Review
Frewen, P., Dozois, D. J. A., & Lanius, R. A. (2010) · FOCUS The Journal of Lifelong Learning in Psychiatry · doi:10.1176/foc.8.1.foc92 · Cited by 56
Glutamate Mechanisms Underlying Opiate MemoriesPreprint
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“D-cycloserine, a partial NMDA-R agonist acting at the glycine-binding site, has been used to facilitate extinction memory formation (Davis et al. 2006).”
Method
Pharmacological enhancement of fear reduction: preclinical models
Graham, B. M., Langton, J. M., & Richardson, R. (2010) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2010.01175.x · Cited by 57
“Finally, a fundamental perspective underlying recent research on the pharmacological enhancement of extinction/exposure therapy is that it is critical to focus on the processes underlying the inhibition of the fear rather than the reduction in anxiety per se (Davis et al., 2006).”
BackgroundSelf-citation
Function and mechanisms of memory destabilization and reconsolidation after retrieval
Kida, S. (2020) · Proceedings of the Japan Academy Series B · doi:10.2183/pjab.96.008 · Cited by 57
Effect of d-cycloserine and valproic acid on the extinction of reinstated fear-conditioned responses and habituation of fear conditioning in healthy humans: a randomized controlled trial
Kuriyama, K., Honma, M., Soshi, T., Fujii, T., & Kim, Y. (2011) · Psychopharmacology · doi:10.1007/s00213-011-2353-x · Cited by 54
“When Woods and Bouton (2006) examined the effects of DCS on the facilitation of both the acquisition and extinction of fear conditioning in rats, they did not observe either of them, which they explained by a “renewal effect.” Davis et al. (2006) also observed that DCS suppresses acquired CRs in rats and suggested tha…”
Background
The association between fear extinction, the ability to accomplish exposure and exposure therapy outcome in specific phobia
Raeder, F., Merz, C. J., Margraf, J., & Zlomuzica, A. (2020) · Scientific Reports · doi:10.1038/s41598-020-61004-3 · Cited by 53
Glycine transporter 1 as a potential therapeutic target for schizophrenia-related symptoms: Evidence from genetically modified mouse models and pharmacological inhibition
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Early stress exposure impairs synaptic potentiation in the rat medial prefrontal cortex underlying contextual fear extinction
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Augmentation of Fear Extinction by D-Cycloserine is Blocked by Proteasome Inhibitors
Mao, S.-C., Lin, H., & Gean, P. (2008) · Neuropsychopharmacology · doi:10.1038/npp.2008.30 · Cited by 51
Changes in Dosing and Dose Timing of D-Cycloserine Explain Its Apparent Declining Efficacy for Augmenting Exposure Therapy for Anxiety-related Disorders: An Individual Participant-data Meta-analysis
Rosenfield, D., Smits, J. A. J., Hofmann, S. G., Mataix‐Cols, D., de la Cruz, L. F., Andersson, E., Rück, C., Monzani, B. A., Pérez-Vigil, A., Frumento, P., et al. (2019) · Journal of Anxiety Disorders · doi:10.1016/j.janxdis.2019.102149 · Cited by 52
Self-citation
The anaphase promoting complex is required for memory function in micePreprint
Kuczera, T., Stilling, R. M., Hsia, H., Bahari‐Javan, S., Irniger, S., Nasmyth, K., Sananbenesi, F., & Fischer, A. (2010) · Learning & Memory · doi:10.1101/lm.1998411 · Cited by 51
“(DCS) facilitates fear extinction in rodents and also exhibits beneficial effects in patients suffering from phobia (Ressler et al. 2004; Davis et al. 2006) the effect of DCS injection was blocked when”
Background
Effects of d ‐Cycloserine on Extinction and Reconditioning of Ethanol‐Seeking Behavior in Mice
Groblewski, P. A., Lattal, K. M., & Cunningham, C. L. (2009) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2009.00895.x · Cited by 52
D-Cycloserine into the BLA reverses the impairing effects of exposure to stress on the extinction of contextual fear, but not conditioned taste aversionPreprint
Akirav, I., Segev, A., Motanis, H., & Maroun, M. (2009) · Learning & Memory · doi:10.1101/lm.1565109 · Cited by 51
“One interpretation for the generalization effect is that DCS facilitated fear extinction by affecting the devaluation of the representation of the aversive events associated with conditioned cues (Davis et al. 2006).”
Background
Cognitive-behavioral therapy for social anxiety disorder: the state of the science
Gordon, D., Wong, J., & Heimberg, R. G. (2014) · The Wiley Blackwell Handbook of Social Anxiety Disorder · doi:10.1002/9781118653920.ch22 · Cited by 50
Glutamatergic Systems and Memory Mechanisms Underlying Opioid AddictionPreprint
Heinsbroek, J. A., Vries, T. J. D., & Peters, J. (2020) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a039602 · Cited by 50
“D-cycloserine (DCS) is a partial NMDAR agonist that acts on the glycine-binding site, and shows promise as a facilitator of extinction learning (Davis et al. 2006; Peters and De Vries, 2013).”
Background
Vagus nerve stimulation as a tool for enhancing extinction in exposure-based therapies
Noble, L. J., de Souza, R. R., & McIntyre, C. K. (2018) · Psychopharmacology · doi:10.1007/s00213-018-4994-5 · Cited by 48
“A variety of adjunctive therapies have been examined, including glutamatergic drugs like D-cycloserine (DCS) and ketamine (Ledgerwood 2003; Davis et al. 2006a; b; Feder et al. 2014), noradrenergic drugs (Davis and Myers 2002; Fitzgerald et al. 2015), cannabinoid receptor agonists (Chhatwal et al.…”
Influential
Glutamatergic Targets for Enhancing Extinction Learning in Drug Addiction
Cleva, R. M., Gass, J. T., Widholm, J. J., & Olive, M. F. (2010) · Current Neuropharmacology · doi:10.2174/157015910793358169 · Cited by 51
“Numerous studies have shown that DCS facilitates the extinction of conditioned fear responses in animals and humans (see [125, 126] for reviews), and several recent animal studies have shown that DCS also facilitates the extinction of drug-seeking behavior.”
Background
Understanding the Relationship between Trauma Exposure and Depression among Adolescents after Earthquake: The Roles of Fear and Resilience
Zhou, X., Wu, X., & An, Y. (2016) · Frontiers in Psychology · doi:10.3389/fpsyg.2016.02044 · Cited by 51
“Then, repeatedly exposing a client for prolonged periods to a feared object or traumatic clues in the company of a supportive therapist (e.g., Davis et al., 2006), which can make adolescents habituate to these cues, and thus reduce the fear response (e.g., Hofmann, 2008), which in turn can lead to…”
Background
D-cycloserine facilitates socially reinforced learning in an animal model relevant to autism spectrum disorders
Modi, M. E., & Young, L. J. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.01.026 · Cited by 47
Pharmacological Enhancement of Behavioral Therapy: Focus on Posttraumatic Stress Disorder
Choi, D. C., ROTHBAUM, B. O., Gerardi, M. A., & Ressler, K. J. (2009) · Current topics in behavioral neurosciences · doi:10.1007/7854_2009_10 · Cited by 47
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Multistage drug effects of ketamine in the treatment of major depression
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“learning in humans and animals [111], and in the following, its efficacy in augmenting psychotherapy in anxiety disorders was shown repeatedly [112].”
Background
Does d-Cycloserine Augmentation of CBT Improve Therapeutic Homework Compliance for Pediatric Obsessive–Compulsive Disorder?
Park, J. M., Small, B. J., GELLER, D. A., Murphy, T. K., Lewin, A. B., & Storch, E. A. (2013) · Journal of Child and Family Studies · doi:10.1007/s10826-013-9742-1 · Cited by 49
Phosphorylation of Cofilin Regulates Extinction of Conditioned Aversive Memory via AMPAR Trafficking
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“Many mental disorders, such as posttraumatic stress disorder (PTSD), are conditions characterized by increased anxiety, as well as a reduced ability to memory extinction (Myers and Davis, 2002; Davis et al., 2006).”
Background
Stress modulation of cognitive and affective processes
Campeau, S., Liberzon, I., Morilak, D. A., & Ressler, K. J. (2011) · Stress · doi:10.3109/10253890.2011.596864 · Cited by 50
“These animal studies are serving as the basis for a treatment approach in which exposure therapy, a method of choice clinically employed to reduce or minimize fear reactions to specific situations, could be augmented by adjunct pharmacotherapy (D-cycloserine) during exposure to the fear-eliciting situations under cont…”
BackgroundSelf-citation
D-cycloserine augmentation of cognitive behavioral group therapy of social anxiety disorder: Prognostic and prescriptive variables.
Smits, J. A. J., Hofmann, S. G., Rosenfield, D., Hopkins, L. B., Costa, P. T., Simon, N. M., O’Cleirigh, C. M., Meuret, A. E., Marques, L. M., Otto, M. W., et al. (2013) · Journal of Consulting and Clinical Psychology · doi:10.1037/a0034120 · Cited by 46
“Following preclinical research demonstrating that DCS can facilitate extinction learning in rodents by enhancing NMDA receptor function (Davis et al., 2006), initial studies of DCS for augmenting exposure therapy for the anxiety disorders have yielded promising results (Bontempo, Panza, & Bloch, 2012).”
Background
Randomized controlled experimental study of hydrocortisone and D-cycloserine effects on fear extinction in PTSD
Inslicht, S. S., Niles, A. N., Metzler, T. J., Lipshitz, S. L., Otte, C., Milad, M. R., Orr, S. P., Marmar, C. R., & Neylan, T. C. (2022) · Neuropsychopharmacology · doi:10.1038/s41386-021-01222-z · Cited by 44
Effects of systemic administration of oxytocin on contextual fear extinction in a rat model of post-traumatic stress disorder.
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Affective lability and difficulties with regulation are differentially associated with amygdala and prefrontal response in women with Borderline Personality Disorder
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“Translational approaches have been successfully used with other clinical phenomena – for example, translating basic fear extinction models to anxiety disorders and vice versa (Davis et al., 2006; Hofmann, 2008) – but are less common in BPD.”
Method
Effects of D-Cycloserine on Extinction: Consequences of Prior Exposure to Imipramine
Werner-Seidler, A., & Richardson, R. (2007) · Biological Psychiatry · doi:10.1016/j.biopsych.2007.04.010 · Cited by 43
Self-citation
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Authors: Davis, M., Ressler, K., Rothbaum, B. O., & Richardson, R.
Affiliations: Emory University (US)
UNSW Sydney (AU)
Corresponding author: Davis, Michael
ORCID: Ressler, Kerry
Rothbaum, Barbara O.
Richardson, Rick
Venue: Biological Psychiatry
Publisher: Elsevier BV
Published: 2006-08
Volume: 60
Issue: 4
Pages: 369-375
ISSN: 0006-3223 (ISSN-L)
DOI: 10.1016/j.biopsych.2006.03.084
OpenAlex: W2162692973
Semantic Scholar: 4b2fc25139b7de7848a13aa43da593a50f3d77c0
Cited by: 498
References: 43
Citations by year: 2026: 6 · 2025: 3 · 2024: 6 · 2023: 9 · 2022: 13 · 2021: 13 · 2020: 10 · 2019: 22 · 2018: 19 · 2017: 25 · 2016: 14 · 2015: 36 · 2014: 32 · 2013: 38 · 2012: 48
FWCI: 2.94
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Biological Psychiatry (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (5r21mh055555-02)
National Institute of Mental Health (MH55555, MH-047840, MH069884, K01MH069884)
Topics: Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
Keywords: D-cycloserine, fear extinction, NMDA receptor agonist, exposure therapy, anxiety disorders, fear of heights, virtual reality exposure, return of fear, phobia treatment
MeSH terms: Animals, Antimetabolites, Conditioning, Classical, Cycloserine, Extinction, Psychological, Fear, Humans, Phobic Disorders, Cognitive Behavioral Therapy, Receptors, N-Methyl-D-Aspartate

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Effects of D-Cycloserine on Extinction: Translation From Preclinical to Clinical Work

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