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Effects of D-Cycloserine on Extinction: Translation From Preclinical to Clinical Work
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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“Similar impairments of fear recall and additional enhancements of fear extinction are observed following acute antibiotic exposure in humans and rodents (Bach et al., 2018;Davis et al., 2006;Rodrigues et al., 2014).”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Davis et al., 2006
In the citing paper
“Preclinical research has demonstrated that DCS facilitates extinction learning and memory in rodent models (Davis et al, 2006; Ledgerwood et al, 2003; 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 Davis et al, 2006
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“…inhibit fear, and because interventions that facilitate the ability of patients to inhibit fear offer an effective strategy for the treatment of anxiety (Davis et al., 2006), the findings of Duvarci et al. (2009) might also be important for understanding the origins of anxiety in humans.”
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“The partial NMDA receptor antagonist D-cycloserine has been shown to facilitate extinction of fear in animal models and in phobic human subjects receiving exposure therapy (Davis et al., 2006).”
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“Accumulative evidence indicates that D-cycloserine facilitates both the extinction of fear memory and the extinction of drug-seeking behaviors (Botreau et al. 2006; Davis et al. 2006).”
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“Animal research has shown that DCS facilitates habituation to feared stimuli (see reviews by Barad et al. 2006; Davis et al. 2006; Norberg et al. 2008).”
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“Consistent with the work driving the development of DCS for augmenting fear extinctionbased interventions (Davis et al., 2006; Otto et al., 2016b, 2016c), we found that administering DCS prior to interoceptive exposure sessions sped up the reduction in anxiety sensitivity and thus led to lower levels of anxiety sensit…”
BackgroundPreclinical Perspectives on Posttraumatic Stress Disorder Criteria in DSM-5
Tye, S. J., Voorhees, E. E. V., Hu, C., & Lineberry, T. W. (2015) · Harvard Review of Psychiatry · doi:10.1097/hrp.0000000000000035 · Cited by 6
No harmful effect of propranolol administered prior to fear memory extinction in rats and humans
Luyten, L., Chalkia, A., Schnell, A. E., Özcan, B., Leng, L., Schroyens, N., Oudenhove, L. V., Vanpaemel, W., & Beckers, T. (2024) · Journal of Anxiety Disorders · doi:10.1016/j.janxdis.2024.102870 · Cited by 4
Pareek, T., Overton, J. S., Nguyen, L. T., Rahman, M. T., Sharmin, D., Cook, J. M., & Platt, D. M. (2022) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2022.109735 · Cited by 5
Sepahvand, T., Nazari, N., Qin, T., Rajani, V., & Yuan, Q. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2309986120 · Cited by 7
“NMDAR enhancement has been suggested as a potential therapeutic strategy to relieve maladaptive fear (61, 62), given that DCS facilitates the extinction of threat memory in animals (40, 41, 63).”
BackgroundNeurobiology of Resilience to Cope Against the Life Adversity
Jung, Y., & Chae, J. (2010) · 대한정신약물학회지 · Cited by 5
Animal Models to Investigate Social Support Induced Anxiety Reductions
Majumdar, S., Lungwitz, E. A., Andrews, K. D., Chambers, J. E., & Truitt, W. A. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-813693-5.00012-5 · Cited by 5
Glutamatergic Neuroplasticity in Addiction
Bechard, A. R., & Knackstedt, L. A. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-812202-0.00005-1 · Cited by 5
Weems, C. F., & Neill, E. L. (2020) · Current Treatment Options in Psychiatry · doi:10.1007/s40501-020-00206-y · Cited by 5
Update on the Assessment, Diagnosis, and Treatment of Individuals with Social Anxiety Disorder
Delong, H., & Pollack, M. H. (2008) · FOCUS The Journal of Lifelong Learning in Psychiatry · doi:10.1176/foc.6.4.foc431 · Cited by 5
Emmelkamp, P. M. G., & Powers, M. B. (2009) · Springer eBooks · doi:10.1007/978-0-387-09757-2_26 · Cited by 5
Fischer, A., & Tsai, L. (2009) · Humana Press eBooks · doi:10.1007/978-1-60327-329-9_4 · Cited by 5
Cognitive Enhancers in Exposure Therapy for Anxiety and Related Disorders
Hofmann, S. G., Gutner, C. A., & Asnaani, A. (2012) · Springer eBooks · doi:10.1007/978-1-4614-3342-2_6 · Cited by 3
Extinktion: Neurowissenschaftliche Erkenntnisse zur Frage, wie Menschen sich ändern
Hamm, A. O., Wendt, J., & Volkmann, M. (2017) · Verhaltenstherapie · doi:10.1159/000455659 · Cited by 6
“Die Verbesserung der Extinktion tritt auch dann auf, wenn DCS erst 60 min nach dem Extinktionstraining verabreicht wird, ein Beleg dafür, dass DCS vor allem die Konsolidierung der Extinktion begünstigt [Davis et al., 2006].”
BackgroundBurhans, L. B., Smith‐Bell, C. A., & Schreurs, B. G. (2017) · Behavioural Pharmacology · doi:10.1097/fbp.0000000000000333 · Cited by 4
“…be facilitated by cognitive enhancers that target the glutamatergic system; for example, D-cycloserine, an NMDA agonist, has been well characterized as a drug that can enhance extinction learning both in animal models of anxiety as well as in a clinical setting (for review, see Davis et al., 2006).”
BackgroundGlutamate Function in Anxiety Disorders and OCD: Evidence from Clinical and Translational Studies
Boff, T. C., Soares, S. J. B., Lima, M. D. M., & Ignácio, Z. M. (2022) · Springer eBooks · doi:10.1007/978-3-030-87480-3_19 · Cited by 4
Gautam, M. (2023) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0000000000001716 · Cited by 4
“When applied to the learning of behaviors to overcome fear, NMDAR antagonists block fear extinction in rats, whereas NMDAR agonists enhance fear extinction.(16) Two pharmacological agents that target the NMDAR are analyzed: D-cycloserine (DCS) and memantine.”
BackgroundSewart, A. R., McGlade, A. L., Treanor, M., Fanselow, M. S., & Craske, M. G. (2021) · Biological Psychology · doi:10.1016/j.biopsycho.2021.108167 · Cited by 4
Smits, J. A. J., Reese, H. E., Powers, M. B., & Otto, M. W. (2009) · Springer eBooks · doi:10.1007/978-1-4419-0612-0_5 · Cited by 4
“The results of these studies converge to suggest that DCS facilitates extinction consolidation in animals ( Davis et al., 2006 ).”
Result
Metadata
- Authors
- Davis, M., Ressler, K., Rothbaum, B. O., & Richardson, R.
- Affiliations
- Emory University (US)
- UNSW Sydney (AU)
- Corresponding author
- Davis, Michael
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2006-08
- Volume
- 60
- Issue
- 4
- Pages
- 369-375
- ISSN
- 0006-3223 (ISSN-L)
- 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
- 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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