Efficacy of D-Cycloserine for Enhancing Response to Cognitive-Behavior Therapy for Panic Disorder

doi:10.1016/j.biopsych.2009.07.036

Biological Psychiatry

Volume 67, Issue 4, 15 February 2010, Pages 365-370

https://doi.org/10.1016/j.biopsych.2009.07.036 Get rights and content

Background

Traditional combination strategies of cognitive-behavior therapy plus pharmacotherapy have met with disappointing results for anxiety disorders. Enhancement of cognitive-behavior therapy with d-cycloserine (DCS) pharmacotherapy represents a novel strategy for improving therapeutic learning from cognitive-behavior therapy that remains untested in panic disorder.

Method

This is a randomized, double-blind, placebo-controlled augmentation trial examining the addition of isolated doses of 50 mg d-cycloserine or pill placebo to brief exposure-based cognitive-behavior therapy. Randomized participants were 31 outpatients meeting DSM-IV criteria for panic disorder with or without agoraphobia, who were offered five sessions of manualized cognitive-behavior therapy emphasizing exposure to feared internal sensations (interoceptive exposure) but also including informational, cognitive, and situational exposure interventions. Doses of study drug were administered 1 hour before cognitive-behavior therapy sessions 3 to 5. The primary outcome measures were the Panic Disorder Severity Scale (PDSS) and Clinicians' Global Impressions of Severity.

Results

Results indicated large effect sizes for the additive benefit of d-cycloserine augmentation of cognitive-behavior therapy for panic disorder. At posttreatment and 1 month follow-up, participants who received d-cycloserine versus placebo had better outcomes on the PDSS and global severity of disorder and were significantly more likely to have achieved clinically significant change status (77% vs. 33%). There were no significant adverse effects associated with DCS administration.

Conclusions

This pilot study extends support for the role of d-cycloserine in enhancing therapeutic learning from exposure-based cognitive-behavior therapy and is the first to do so in a protocol emphasizing exposure to feared internal sensations of anxiety in panic disorder.

Section snippets

Participant Selection

Identical study protocols were approved by the Institutional Review Board at each of three study sites. Participants were first screened by phone, followed by in-person diagnostic and severity evaluations with masters or doctoral level clinicians. After a complete description of the study, participants provided written informed consent. Participants then underwent diagnostic evaluation using the Structured Clinical Interview for DSM-IV (SCID-IV) (21) and severity rating using the Clinician

PDSS

The multivariate ANCOVA of PDSS scores at posttreatment and follow-up, controlling for pretreatment PDSS scores (mean 13.8 ± 3.3), yielded a significant main effect of group in favor of DCS, with a large effect size [F(1,24) = 7.34, p = .012, η²_p = .234, d = 1.11]. There was no significant main effect of time [F(1,24) = .02, p = .901, η²_p = .001], nor was there a significant group by time interaction [F(1,24) = .093, p = .763, η²_p = .004], indicating that the stronger response for DCS did not

Discussion

We found that administration of single doses of DCS, 1 hour before each of three exposure sessions within a five-session protocol, significantly enhanced the efficacy of brief CBT for panic disorder. In addition to significant differences in continuous outcome measures, at posttreatment, 77% of patients who had received DCS, compared with only 33% of patients who had received placebo augmentation, met criteria for clinically significant change. The treatment gains of the DCS group were

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NMDA receptor-mediated processing in inferior frontal gyrus facilitates acquisition and extinction learning and strengthens renewal
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Citation Excerpt :
In particular the partial NMDAR agonist d-cycloserine (DCS) showed enhancing effects in fear extinction,(e.g. Ledgerwood et al., 2003). This finding led to DCS now being widely used in psychotherapy of phobias, social anxiety and panic disorder, in combination with exposure treatments (Otto et al., 2010; Ressler et al., 2004; Smits et al., 2013). Also in our previous studies with healthy human participants in a non-fear-related predictive learning task, NMDAR modulation before extinction learning was shown to influence extinction learning while concurrently altering BOLD activation in hippocampal and prefrontal regions.
While the renewal effect of extinction is considered to be invoked by attention to context during the extinction phase, there is also evidence that processing during initial learning (acquisition) may be important for later renewal. A noradrenergic agonist and a dopaminergic antagonist, administered before acquisition, did not affect renewal, however, the effects of NMDAergic neurotransmission in this regard are as yet unknown.
In a previous study, administration of a single dose of the NMDA agonist d-cycloserine (DCS) before extinction learning facilitated extinction in the context of acquisition (AAA), but had no effect upon renewal. In the present fMRI study, DCS was administered prior to the initial acquisition of a predictive learning task, in order to investigate whether NMDA receptor (NMDAR) stimulation at this timepoint will modulate overall learning as well as the level of renewal, while increasing activation in the extinction- and renewal-relevant brain regions of inferior frontal gyrus (iFG) and hippocampus (HC).
DCS facilitated acquisition, as well as extinction learning in the context of acquisition (AAA), and raised the level of ABA renewal. While BOLD activation during acquisition did not differ between treatment groups, activation in bilateral iFG showed a double dissociation during processing of AAA extinction trials, with DCS-mediated higher activation in right iFG and deactivation in left iFG. In contrast, placebo showed higher activation in left iFG and deactivation in right iFG. During the test (recall) phase, left iFG and right anterior hippocampus activation was increased in DCS participants who showed renewal, with activation in this region correlating with the ABA renewal level.
The results demonstrate that NMDA receptor stimulation can facilitate both initial learning and extinction of associations, and in this way has an impact upon the resultant level of renewal. In particular NMDAergic processing in iFG appears relevant for the facilitation of AAA extinction and ABA recall in the test phase.
Maximizing the non-specific factors in brief cognitive behavioral therapy for panic disorder and agoraphobia: A multiple baseline case series documenting feasibility and initial efficacy
2022, Asian Journal of Psychiatry
There is evidence for non-specific factors impacting treatment outcomes, with pragmatic concerns regarding the need to popularize briefer formats of cognitive behavioral therapy (CBT). The need to have more culturally suitable and acceptable forms of CBT is also indicated. We evaluated the feasibility and efficacy of a brief 5 session CBT (bCBT) in participants (N = 4) with panic disorder (PD) and agoraphobia, using a non-concurrent multiple baseline design. In this case series, efforts were made to maximize non-specific factors of psychotherapy in bringing about treatment outcomes. Reliable and significant treatment effects were observed at post-intervention and follow-up assessments. The present study offers preliminary evidence of a bCBT protocol that comprises the efforts to maximize the non-specific factors in psychotherapy such as credibility, expectancy, and the therapeutic alliance in bringing treatment outcomes; however, further controlled evaluation is warranted. We also discuss the mechanisms contributing to these treatment outcomes in the present protocol.
D-cycloserine as adjunct to brief computerised CBT for spider fear: Effects on fear, behaviour, and cognitive biases
2020, Journal of Behavior Therapy and Experimental Psychiatry
In anxiety disorders, cognitive behavioural therapy (CBT) improves information-processing biases such as implicit fear evaluations and avoidance tendencies, which predicts treatment response. Thus, these cognitive biases might constitute important treatment targets. This study investigated (i) whether information-processing biases could be changed following single-session computerised CBT for spider fear, and (ii) whether this effect could be augmented by administration of D-cycloserine (DCS).
Spider-fearful individuals were randomized to receiving either 250 mg of DCS (n = 21) or placebo (n = 17). Three hours after drug administration, they received single-session computerized CBT, characterized by psychoeducation and exposure elements. Spider fear was assessed using self-report, behavioural, and information processing (Extrinsic Affective Simon Task & Approach Avoidance Task) measures at baseline (before drug administration), post-treatment, 1-day, and 1-month follow-up.
Linear mixed-effects analyses indicated significant improvements on self-report and behavioural spider fear indices following CBT, but not on cognitive bias measures. There was no evidence of an augmentation effect of DCS on any outcome. Cognitive bias measures at 1-day were not predictive of 1-month follow-up spider fear in adjusted linear regression analyses.
Results might be biased by limited representativeness of the sample (high education and intelligence, largely Caucasian ethnicity, young age). The study was also only powered for detection of medium-sized DCS effects.
These findings do not provide evidence for information-processing biases relating to treatment outcome following computerised CBT for spider fear or augmentation with DCS.
Facilitative effects of environmental enrichment for cocaine relapse prevention are dependent on extinction training context and involve increased TrkB signaling in dorsal hippocampus and ventromedial prefrontal cortex
2020, Behavioural Brain Research
Cocaine-cue extinction training combined with brief interventions of environmental enrichment (EE) was shown previously to facilitate extinction and attenuate reacquisition of cocaine self-administration in rats. It is unknown whether or not the usefulness of this approach would be undermined if extinction training took place in a novel rather than familiar context. Drawing on previous studies involving pharmacological interventions, we hypothesized that the facilitative effects of EE for cocaine relapse prevention would be independent of the context used for extinction training. Rats trained to self-administer cocaine underwent cocaine-cue extinction training in either the familiar self-administration context or a novel context, with or without EE. Rats then were tested for reacquisition of cocaine self-administration in the familiar context. Target brain regions were lysed and probed for memory-related changes in receptors for glutamate and BDNF by western blotting. Contrary to our hypothesis, the facilitative effects of EE for cocaine relapse prevention were dependent on the context used for extinction training. While EE facilitated extinction regardless of context used, it inhibited cocaine relapse only after extinction training in the familiar context. EE was associated with increased GluA2 in nucleus accumbens, TrkB in dorsal hippocampus and activated TrkB in ventromedial prefrontal cortex. Of these, the changes in dorsal hippocampus and ventromedial prefrontal cortex mirrored outcomes of the cocaine relapse tests in that these changes were specific to rats receiving EE plus extinction training in the familiar context. These findings support a role for hippocampal-prefrontal BDNF-TrkB signaling in extinction-based relapse prevention strategies involving EE.
D-Cycloserine and estradiol enhance fear extinction in nulliparous but not primiparous female rats
2019, Neurobiology of Learning and Memory
Female reproductive experience has been shown to alter the hormonal, neurobiological and behavioural features of fear extinction, which is the laboratory basis of exposure therapy. This raises uncertainties as to whether pharmacological agents that enhance fear extinction in reproductively inexperienced females are equally effective in reproductively experienced females. The aim of the current study was therefore to compare the effects of two pharmacological enhancers of fear extinction, d-cycloserine (DCS) and estradiol, between nulliparous (virgin) and primiparous (reproductively experienced) female rats. In Experiment 1, nulliparous and primiparous females received systemic administration of either DCS or saline immediately after extinction training, and were tested for extinction recall the following day. DCS enhanced extinction recall in nulliparous females that showed low levels of freezing at the end of extinction training, but not among those that showed high levels of freezing at the end of extinction training. DCS did not enhance fear extinction in primiparous females, regardless of their level of freezing at the end of extinction training. In Experiment 2, nulliparous and primiparous female rats received systemic administration of either estradiol or vehicle prior to extinction training. Estradiol enhanced extinction recall among nulliparous females, but not primiparous females. Increasing the dose of estradiol administered prior to extinction training did not alter the outcomes in primiparous females (Experiment 3). Together, these findings suggest that reproductive status may be an important individual difference factor associated with the response to pharmacological modulators of extinction in rats. The implications of these findings for the pharmacological augmentation of exposure therapy in clinical populations are discussed.
Neuromodulatory treatments for post-traumatic stress disorder (PTSD)
2019, Progress in Neuro-Psychopharmacology and Biological Psychiatry
Electroconvulsive therapy has been used successfully in some individuals with posttraumatic stress disorder (PTSD) whose symptoms have not improved with other treatments. But there are only a few reports. Meanwhile, an array of new neuromodulation strategies, including repetitive transcranial magnetic stimulation, transcranial direct current stimulation, vagus nerve stimulation, trigeminal nerve stimulation, and deep brain stimulation have been developed and applied experimentally in the treatment of other psychiatric disorders. This article will review the clinical evidence and mechanistic basis for their use in PTSD.

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Archival ReportEfficacy of D-Cycloserine for Enhancing Response to Cognitive-Behavior Therapy for Panic Disorder

Background

Method

Results

Conclusions

Section snippets

Participant Selection

PDSS

Discussion

Clin Psychol Rev

Biol Psychiatry

Biol Psychiatry

Biol Psychiatry

Biol Psychiatry

J Psychiatr Res

Behav Res Ther

Behav Res Ther

Biol Psychiatry

Addict Behav

J Anxiety Disord

Schizophr Res

Cognitive-behavioral therapy, imipramine, or their combination for panic disorder: A randomized controlled trial

JAMA

A comparison of cognitive therapy, applied relaxation and imipramine in the treatment of panic disorder

Br J Psychiatry

Psychotherapy plus antidepressant for panic disorder with or without agoraphobia: Systematic review

Br J Psychiatry

Combined psychotherapy and pharmacotherapy for mood and anxiety disorders in adults: Review and analysis

Clin Psychol

Cost-efficacy of individual and combined treatments for panic disorder

J Clin Psychiatry

Facilitation of extinction of conditioned fear by d-cycloserine

Curr Dir Psychol Sci

Facilitation of fear extinction by D-cycloserine: Theoretical and clinical implications

Learn Mem

Archival Report
Efficacy of D-Cycloserine for Enhancing Response to Cognitive-Behavior Therapy for Panic Disorder