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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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The Lancet Psychiatry Commission on psychological treatments research in tomorrow's science
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“The efficacy of the NMDA receptor antagonist D-cycloserine in facilitating fear extinction in both the rat fear potentiated startle paradigm and in human acrophobic patients indicate a predictive validity for this approach (Ressler et al., 2004; Ledgerwood et al., 2005; Davis et al., 2006).”
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Reger, G. M., Holloway, K. M., Candy, C., Rothbaum, B. O., Difede, J., Rizzo, A. A., & Gahm, G. A. (2011) · Journal of Traumatic Stress · doi:10.1002/jts.20574 · Cited by 188
Self-citationRabinak, C. A., Angstadt, M., Lyons, M., Mori, S., Milad, M. R., Liberzon, I., & Phan, K. L. (2013) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2013.09.009 · Cited by 148
Sensory Pathways and Emotional Context for Action in Primate Prefrontal Cortex
Barbas, H., Zikopoulos, B., & Timbie, C. M. (2010) · Biological Psychiatry · doi:10.1016/j.biopsych.2010.08.008 · Cited by 152
GOFF, D., CATHER, C., GOTTLIEB, J., EVINS, A., WALSH, J., RAEKE, L., OTTO, M., SCHOENFELD, D., & GREEN, M. (2008) · Schizophrenia Research · doi:10.1016/j.schres.2008.08.012 · Cited by 144
“In anxiety disorders, intermittent treatment with Dcycloserine combined with cognitive behavioral therapy has produced persistent therapeutic effects (Davis et al., 2006).”
A hippocampal Cdk5 pathway regulates extinction of contextual fear
Sananbenesi, F., Fischer, A., Wang, X., Schrick, C., Neve, R. L., Radulović, J., & Tsai, L. (2007) · Nature Neuroscience · doi:10.1038/nn1943 · Cited by 143
Individual differences in recovery from traumatic fear
Holmes, A., & Singewald, N. (2012) · Trends in Neurosciences · doi:10.1016/j.tins.2012.11.003 · Cited by 147
D-Cycloserine in Neuropsychiatric Diseases: A Systematic Review
Schade, S., & Paulus, W. (2016) · International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyv102 · Cited by 135
“The mechanism of action of DCS might change or even reverse under conditions with great stress and might be due to different surrounding neurotransmitter concentrations (Hood et al., 1989; Watson et al., 1990; Sheinin et al., 2001; Davis et al., 2006).”
BackgroundCannabinoid facilitation of fear extinction memory recall in humans
Rabinak, C. A., Angstadt, M., Sripada, C. S., Abelson, J. L., Liberzon, I., Milad, M. R., & Phan, K. L. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.06.063 · Cited by 163
“As mentioned previously, DCS has been shown to enhance extinction learning in rats and humans and facilitate exposure therapy in patients with anxiety (Davis et al., 2006; Hofmann, 2007, 2008; Ledgerwood et al., 2003, 2004, 2005; Norberg et al., 2008; Ressler et al., 2004; Walker et al., 2002).”
A psychobiological rationale for oxytocin in the treatment of posttraumatic stress disorder
Olff, M., Langeland, W., Witteveen, A., & Denys, D. (2010) · CNS Spectrums · doi:10.1017/s109285290000047x · Cited by 135
Different Fear States Engage Distinct Networks within the Intercalated Cell Clusters of the Amygdala
Busti, D., Geracitano, R., Whittle, N., Dalezios, Y., Mańko, M., Kaufmann, W. A., Sätzler, K., Singewald, N., Capogna, M., & Ferraguti, F. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.6100-10.2011 · Cited by 137
“Elucidation of the neural bases of fear inhibition represents, therefore, the best hope for the identification of novel target mechanisms to treat anxiety disorders (Davis et al., 2006; Holmes and Quirk, 2010).”
BackgroundEnhancing exposure-based therapy from a translational research perspective
Hofmann, S. G. (2007) · Behaviour Research and Therapy · doi:10.1016/j.brat.2007.06.006 · Cited by 138
Gass, J. T., & Olive, M. F. (2008) · Biological Psychiatry · doi:10.1016/j.biopsych.2008.11.001 · Cited by 132
Social fearfulness in the human brain
Miskovic, V., & Schmidt, L. A. (2012) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2011.08.002 · Cited by 126
Pharmacotherapy of PTSD: premises, principles, and priorities.
Ravindran, L. N., & Stein, M. B. (2009) · Brain Research · doi:10.1016/j.brainres.2009.03.037 · Cited by 153
“…or early in the development of PTSD. Similarly, investigators have proposed a role for agents that augment glutamate transmission during psychotherapeutic processes targeted towards enhancing extinction of conditioned fears and traumatic memories (Davis et al., 2006; Heresco-Levy et al., 2002).”
BackgroundGlover, E. M., Phifer, J. E., Crain, D. F., Norrholm, S. D., Davis, M., Bradley, B., Ressler, K. J., & Jovanovic, T. (2011) · Depression and Anxiety · doi:10.1002/da.20880 · Cited by 130
Self-citationInduction and Expression of Fear Sensitization Caused by Acute Traumatic Stress
Perusini, J. N., Meyer, E. M., Long, V., Rau, V., Nocera, N. A., Avershal, J., Maksymetz, J., Spigelman, I., & Fanselow, M. S. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2015.224 · Cited by 128
Weisman, J. S., & Rodebaugh, T. L. (2018) · Clinical Psychology Review · doi:10.1016/j.cpr.2017.10.010 · Cited by 143
Exposure therapy in eating disorders revisited
Koskina, A., Campbell, I. C., & Schmidt, U. (2013) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2012.11.010 · Cited by 127
The learning of fear extinction
Furini, C., Myskiw, J., & Izquierdo, I. (2014) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2014.10.016 · Cited by 124
Behavioral tagging of extinction learning
Myskiw, J. D. C., Benetti, F., & Izquierdo, I. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1220875110 · Cited by 126
Powers, M. B., Smits, J. A. J., Otto, M. W., Sanders, C., & Emmelkamp, P. M. G. (2009) · Journal of Anxiety Disorders · doi:10.1016/j.janxdis.2009.01.001 · Cited by 122
NMDA receptors and fear extinction: implications for cognitive behavioral therapy
Davis, M. (2011) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2011.13.4/mdavis · Cited by 120
Self-citationLopresto, D., Schipper, P., & Homberg, J. R. (2015) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2015.10.009 · Cited by 125
Labrie, V., & Roder, J. (2009) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2009.08.002 · Cited by 118
“extinction learning when administered acutely (Parnas et al., 2005; Davis et al., 2006).”
BackgroundResultInfluentialReichel, C. M., Moussawi, K., Do, P. H., Kalivas, P. W., & See, R. E. (2011) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.111.179317 · Cited by 116
“In addition, medicationfacilitated cue-exposure therapies have begun to emerge in several fields of psychiatry, with the most notable success seen in the area of phobia treatment (Ressler et al., 2004; Davis et al., 2006).”
BackgroundSmits, J. A. J., Rosenfield, D., Otto, M. W., Marques, L., Davis, M. L., Meuret, A. E., Simon, N. M., Pollack, M. H., & Hofmann, S. G. (2013) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2013.06.020 · Cited by 114
“…research is the investigation of D-cycloserine (DCS), a partial agonist of the glycine recognition site of the N-Methyl-D-Aspartate receptor (NMDAr), as an augmentation strategy for exposure-based cognitive behavioral therapy for the anxiety disorders (Davis et al., 2006; Hofmann et al., 2011).”
BackgroundInfluentialSelf-citationAlvarez, R. P., Johnson, L., & Grillon, C. (2007) · Learning & Memory · doi:10.1101/lm.493707 · Cited by 110
“treatment of anxiety disorders, there is growing interest in better understanding the mechanisms that underlie extinction (Quirk 2002; Bouton 2004; Davis et al. 2006).”
BackgroundAngiotensin type 1 receptor inhibition enhances the extinction of fear memory
Marvar, P. J., Goodman, J., Fuchs, S., Choi, D. C., Banerjee, S., & Ressler, K. J. (2014) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.08.024 · Cited by 110
Self-citationAndersson, E., Hedman‐Lagerlöf, E., Enander, J., Djurfeldt, D. R., Ljótsson, B., Červenka, S., Isung, J., Svanborg, C., Mataix‐Cols, D., Kaldo, V., et al. (2015) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2015.0546 · Cited by 113
The use of cognitive enhancers in animal models of fear extinction
Kaplan, G. B., & Moore, K. A. (2011) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2011.01.009 · Cited by 113
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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