D-Cycloserine Augmentation of Exposure-Based Cognitive Behavior Therapy for Anxiety, Obsessive-Compulsive, and Posttraumatic Stress Disorders

Mataix‐Cols, David; Cruz, Lorena Fernández de la; Monzani, Benedetta; Rosenfield, David; Andersson, Erik; Pérez-Vigil, Ana; Frumento, Paolo; Kleine, Rianne A. de; Difede, JoAnn; Dunlop, Boadie W.; Farrell, Lara J.; Geller, Daniel; Gerardi, Maryrose; Guastella, Adam J.; Hofmann, Stefan G.; Hendriks, Gert-Jan; Kushner, Matt G.; Lee, Francis S.; Lenze, Eric J.; Levinson, Cheri A.; McConnell, Harry; Otto, Michael W.; Plag, Jens; Pollack, Mark H.; Ressler, Kerry J.; Rodebaugh, Thomas L.; Rothbaum, Barbara O.; Scheeringa, Michael S.; Siewert-Siegmund, Anja; Smits, Jasper A. J.; Storch, Eric A.; Ströhle, Andreas; Tart, Candyce D.; Tolin, David F.; Minnen, Agnes van; Waters, Allison M.; Weems, Carl F.; Wilhelm, Sabine; Wyka, Katarzyna; Davis, Margaret B.; Rück, Christian; Altemus, Margaret; Anderson, Page L.; Cukor, Judith; Finck, Claudia; Geffken, Gary R.; Golfels, Fabian; Goodman, Wayne K.; Gutner, Cassidy A.; Heyman, Isobel; Jovanović, Tanja; Lewin, Adam B.; McNamara, Joseph P. H.; Murphy, Tanya K.; Norrholm, Seth D.; Thuras, Paul

doi:10.1001/jamapsychiatry.2016.3955

Cited by 239 publications

(125 citation statements)

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“…It should be noted that the pattern found by [36], as shown in their Fig 1, was rather different (the linear slope was just a bit larger in the DCS group) and in our opinion does not really justify their summary quoted above. Results indicated no substantial effect of DCS at mid-treatment ( g = -0.09; SMCC = -0.05), which is in line with the findings of Mataix-Cols et al [43]. Thus, the present findings question the idea that DCS temporarily accelerates the effect of behavior therapy for anxiety and obsessive-compulsive disorders.…”

Section: Discussionsupporting

confidence: 92%

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D-cycloserine augmentation of behavior therapy for anxiety and obsessive-compulsive disorders: A meta-analysis

Bürkner¹,

Bittner²,

Holling³

et al. 2017

PLoS ONE

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ObjectiveThe present meta-analysis investigates whether the antibiotic D-cycloserine (DCS), a partial agonist at the glutamatergic N-methyl-D-aspartate receptor, can augment the effect of behavior therapy in humans with anxiety and obsessive-compulsive disorders.MethodA keyword-based computer search was conducted using common electronic databases. Only studies investigating the effect of DCS in humans with anxiety and obsessive-compulsive disorders were included, resulting in 23 studies with a combined sample size of 1314 patients. Effect sizes were coded as Hedges’ g and SMCC, the latter also incorporating differences in pre-treatment values. Bayesian multilevel meta-analysis was applied to take dependencies of effect sizes obtained from the same study into account.ResultsWhile previous meta-analyses found small to moderate improvements, the current results including the most recent research indicate that the overall effect of DCS is very small and almost indistinguishable from zero (g = -0.12, CI = [-0.27, 0.02]; SMCC = -0.10, CI = [-0.29, 0.07]). Slightly larger effects were found for social anxious patients. Further, study quality and year of publication were relevant moderators, with higher quality / more recent studies reported smaller effects of DCS.ConclusionsThese findings raise the question of the usefulness of DCS as an augmentation of exposure therapy for anxiety and obsessive-compulsive disorders. At least, it seems to be less promising than initially thought. The fact that study quality was inversely related to the reported effect sizes underlines the importance of high quality primary research in order to avoid over-estimation of treatment effects in clinical psychology.

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Section: Discussionsupporting

confidence: 92%

“…First, there are three new high quality studies [40,44,45] that were not included in the analysis of Mataix-Cols et al [43]. Second, quite a few primary studies used multiple outcomes to assess symptom severity, but meta-analyses appear to have only used one outcome per study.…”

Section: Theoretical Introductionmentioning

confidence: 99%

D-cycloserine augmentation of behavior therapy for anxiety and obsessive-compulsive disorders: A meta-analysis

Bürkner¹,

Bittner²,

Holling³

et al. 2017

PLoS ONE

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“…VNS can enhance memory consolidation in rats and humans and it also facilitates experience-dependent plasticity [23–24; 27; 45–54]. We have observed similarities and differences in plasticity related to VNS-enhanced and Extended Extinction [28, 30].…”

Section: Discussionmentioning

confidence: 99%

“…Encouraging recent findings indicate that some memory consolidation-enhancing methods, such as mild stress or administration of the NMDA partial agonist D-cycloserine (DCS), promote such generalization of extinction [22–23]. However, results of studies of cognitive enhancers as adjuncts are mixed [24]. Some researchers consider the use of pharmacological cognitive enhancers during exposure-based therapy risky due to the potential for reinforcing learned negative associations with reminders of the trauma, or with the therapy itself, when patients experience a severe anxiety response [25].…”

Section: Introductionmentioning

confidence: 99%

Vagus nerve stimulation promotes generalization of conditioned fear extinction and reduces anxiety in rats

et al. 2019

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Background: Exposure-based therapies are used to treat a variety of trauma- and anxiety-related disorders by generating successful extinction following cue exposure during treatment. The development of adjuvant strategies that accelerate extinction learning, improve tolerability, and increase efficiency of treatment could increase the efficacy of exposure-based therapies. Vagus nerve stimulation (VNS) paired with exposure can enhance fear extinction, in rat models of psychiatric disorders, and chronic administration of VNS reduces anxiety in rats and humans. Objective: We tested whether VNS, like other cognitive enhancers, could produce generalization of extinction for stimuli that are not presented during the extinction sessions, but are associated with the fear event. Methods: Male Sprague Dawley rats underwent auditory fear conditioning with two easily discriminable auditory stimuli. Following fear conditioning, extinction training consisted of exposure to only one of the conditioned sounds. Half of the rats received VNS and half received sham stimulation during with sound presentations. VNS effects on anxiety were examined in a separate study where VNS was administered prior to testing on the elevated plus maze. Results: Sham stimulated rats given 20 presentations of a conditioned stimulus (CS) during the extinction session showed performance that was matched to VNS-treated rats given only 4 presentations of the CS. Despite comparable levels of freezing to the presented CS, only the VNS-treated rats showed a significant decrease in freezing to the CS that was not presented. VNS-induced generalization of extinction was observed only when the two sounds were paired with footshock within the same fear conditioning session; VNS did not promote generalization of extinction when the two sounds were conditioned on different days or in different contexts. On the anxiety test, VNS administration significantly increased time spent in the open arms of the elevated plus maze. Conclusion: These results provide evidence that VNS can promote generalization of extinction to other stimuli associated with a specific fear experience. Furthermore, non-contingent VNS appears to reduce anxiety. The ability to generalize extinction and reduce anxiety makes VNS a potential candidate for use as an adjunctive strategy to improve the efficacy and tolerability of exposure-based therapies.

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“…For example, d-cycloserine, a partial agonist at the N -methyl-D-aspartate receptor, has been shown to enhance discrimination learning in rats [53] and improve outcomes from fear extinction treatments (e.g., exposure) in humans [54,55]. That said, there is mixed evidence for the effectiveness of d-cycloserine when used to augment treatment for those with anxiety disorders [56,57], and it has been suggested that the dosage and timing of d-cycloserine should be tailored to the specific type of psychotherapeutic treatment used [54]. An intriguing, (although given current results, speculative) future direction is to investigate how d-cycloserine might be used in conjunction with exposure protocols that incorporate discrimination training to improve treatment for GAD, especially for patients who show minimal gains in response to more traditional exposure interventions.…”

Section: Discussionmentioning

confidence: 99%

Impaired discriminative fear conditioning during later training trials differentiates generalized anxiety disorder, but not panic disorder, from healthy control participants

Cooper

Grillon²,

Lissek

2018

Comprehensive Psychiatry

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Background Fear conditioning is implicated as a central psychopathological mechanism of anxiety disorders. People with anxiety disorders typically demonstrate reduced affective discrimination between conditioned danger and safety cues. Here, affective discrimination refers to the ability to selectively display fear to dangerous but not safe situations. Though both generalized anxiety disorder (GAD) and panic disorder (PD) are linked to impaired affective discrimination, the clinical phenomenology of these disorders suggests that people with GAD versus PD might be less able to overcome such deficits. It is unclear how this potential difference would manifest during lab-based conditioning. Methods We used a classical fear conditioning paradigm over two discrimination training sessions to examine whether those with GAD, but not PD, would display persistent discrimination deficits. Sixty-seven participants (21 GAD, 19 PD, 27 Healthy Controls) completed a task in which conditioned fear was measured psychophysiologically (fear-potentiated startle), behaviorally, and via self-report. Results Although similar levels of impaired discrimination were found for both GAD and PD groups during initial training, such impairments tended to persist across a subsequent training session only for patients with GAD when compared with Controls. Conclusion Our results provide a foundation for additional research of discrimination deficits in specific anxiety disorders, with an ultimate goal of improved customization of psychological treatments.

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D-Cycloserine Augmentation of Exposure-Based Cognitive Behavior Therapy for Anxiety, Obsessive-Compulsive, and Posttraumatic Stress Disorders

Abstract: D-cycloserine is associated with a small augmentation effect on exposure-based therapy. This effect is not moderated by the concurrent use of antidepressants. Further research is needed to identify patient and/or therapy characteristics associated with DCS response.

Cited by 239 publications

References 62 publications

D-cycloserine augmentation of behavior therapy for anxiety and obsessive-compulsive disorders: A meta-analysis

D-cycloserine augmentation of behavior therapy for anxiety and obsessive-compulsive disorders: A meta-analysis

Vagus nerve stimulation promotes generalization of conditioned fear extinction and reduces anxiety in rats

Impaired discriminative fear conditioning during later training trials differentiates generalized anxiety disorder, but not panic disorder, from healthy control participants

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