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Cited by 142Anxiety, Depression, Psychometrics, Treatment, Cognitive ProcessesMemory and Neural MechanismsPosttraumatic Stress Disorder Research

D-cycloserine enhancement of fear extinction is specific to successful exposure sessions: evidence from the treatment of height phobia

Open access
Smits, Jasper A.J., Rosenfield, David, Otto, Michael W., Powers, Mark B., Hofmann, Stefan G., Telch, Michael J., Pollack, Mark H., Tart, Candyce D.·2013·Biological Psychiatry
DOI 10.1016/j.biopsych.2012.12.009PMC PMC3636175
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Abstract

Background Whereas some studies have shown clear evidence for an augmentation effect of d-cycloserine (DCS) on exposure therapy for anxiety disorders, other studies have shown weak effects or no effect at all. Some preclinical data suggest that the DCS augmentation effect is moderated by the success of the extinction trials. Therefore, we conducted a re-analysis of existing data to examine whether the effects of DCS on clinical outcome would vary as a function of response to the exposure session (i.e. exposure success). Methods In a clinical trial, patients with height phobia received two sessions involving 30 minutes of virtual reality exposure therapy and were randomly assigned to a pill placebo (N=14) or 50 mg of DCS (N=15) immediately after each session. Results Mixed-effects regression analysis showed that the effects of DCS administration on clinical improvement was moderated by the level of fear experienced just prior to concluding exposure sessions. Patients receiving DCS exhibited significantly greater improvement in symptoms relative to patients who received placebo when subjective fear was low at the end of the exposure. In contrast, when end fear was still elevated, patients receiving DCS improved less compared to those receiving placebo. Conclusions DCS appears to enhance the benefits of exposure treatment when applied after a successful session, but it seems to have detrimental effects when administered after inadequate/unsuccessful exposures. Trial Registry The Trial is registered at ClinicalTrials.gov (NCT01102803).

AI snapshot

Written from the paper’s full text.

TL;DR

In a re-analysis of a null trial of post-session D-cycloserine (DCS) for height phobia, DCS augmentation of exposure therapy depended on how much fear remained at the end of the exposure session. DCS improved outcome when end fear was low but worsened outcome relative to placebo when end fear remained elevated.

Key findings

  • The effect of DCS vs. placebo on next-session CGI-I was moderated by prior-session end fear: interaction β = −.05, t(50) = 2.84, p = .007.
  • At end fear = 0 (“no fear”), DCS-treated patients were rated almost 1 full point more improved on CGI-I than placebo-treated patients: β = .99, t(44) = 2.10, p = .04.
  • At end fear = 36 (mean + 1 SD), DCS-treated patients were rated .84 points less improved on CGI-I than placebo-treated patients: β = −.84, t(48) = 2.75, p = .025.
  • Among DCS-treated patients, higher prior-session end fear predicted worse current CGI-I: β = .03, t(48) = 2.43, p = .019; this relation was not significant for placebo (p = .12).

Methods

  • Re-analysis of a clinical trial in which 29 medication-free adults with DSM-IV-TR acrophobia (mean age = 33.38; 76% female) received two sessions of 30 minutes of virtual reality exposure therapy and were randomized to placebo (N = 14) or 50 mg DCS (N = 15) immediately after each session.
  • End fear was the subjective units of distress rating just before concluding each exposure session; clinical improvement was indexed by the clinician-rated CGI-I at the beginning of the next session/posttreatment.
  • Mixed-effects regression predicted CGI-I from drug condition, prior-session end fear, and their interaction, controlling for baseline CGI-S, beginning fear, and number of virtual floors passed; models used full information maximum likelihood, Satterthwaite correction, and an unstructured covariance matrix.

Limitations

  • The paper states the sample was relatively small, only post-session 50 mg DCS was examined, dose-response and timing cannot be inferred, and the analysis was post-hoc proof-of-concept requiring replication in larger and more diverse samples with other anxiety disorders.
  • The paper also notes uncertainty about whether end fear or within-session fear reduction is the critical moderator, and that pre-session dosing may still offer more powerful DCS augmentation than post-session dosing.
  • Evident from the text: all dropouts were in the placebo condition, and the sample was restricted to adults with height phobia.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.biopsych.2012.12.009

Cites

24 of 24 references verified0 citation errors · 0 not checkable

Statistics

4 tests recomputed · 0 with the reported and recomputed p on opposite sides of .05

Claims the paper makes

0 of 25 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    For participants in the placebo condition, the relation between end fear at the previous session and CGI-I at the current session was not significant.

    “we found that the relation between end fear at the previous session and CGI-I at the current session was not significant for participants in the Placebo condition [p=.12].”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The fear rating provided just prior to concluding an exposure session is a valid index of exposure success (fear extinction), with lower ratings indicating greater success.
  • Findingown data

    The effect of DCS administration on clinical improvement was moderated by the level of fear experienced just prior to concluding exposure sessions.

    “Mixed-effects regression analysis showed that the effects of DCS administration on clinical improvement was moderated by the level of fear experienced just prior to concluding exposure sessions.”
    • Also stated in: § Results · plain
      “As hypothesized, the effect of pill administration (DCS vs. Placebo) on CGI-I at the beginning of the next session was moderated by the session end fear level [β= −.05, t (50) = 2.84, p = .007 for the interaction between condition and end fear level].”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The fear rating provided just prior to concluding an exposure session is a valid index of exposure success (fear extinction), with lower ratings indicating greater success.
  • Findingown data

    When end fear was elevated (36, 1 SD above the sample mean), patients receiving DCS improved less compared to those receiving placebo.

    “In contrast, when end fear was still elevated, patients receiving DCS improved less compared to those receiving placebo.”
    • Also stated in: § Results · plain
      “For participants who reported end fear at 1 SD above the mean of the sample (end fear = 36), those receiving DCS were rated .84 points less improved on the CGI-I than those receiving placebo [β = −.84, t(48) = 2.75, p = .025].”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The fear rating provided just prior to concluding an exposure session is a valid index of exposure success (fear extinction), with lower ratings indicating greater success.
  • Findingown data

    When end fear was low (0), patients receiving DCS exhibited significantly greater improvement in symptoms relative to patients receiving placebo.

    “Patients receiving DCS exhibited significantly greater improvement in symptoms relative to patients who received placebo when subjective fear was low at the end of the exposure.”
    • Also stated in: § Results · plain
      “For patients reporting an end fear of 0 [“no fear”], those receiving DCS were rated almost 1 full point more improved on the CGI-I than those receiving placebo [β = .99, t (44) = 2.10, p = .04].”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The fear rating provided just prior to concluding an exposure session is a valid index of exposure success (fear extinction), with lower ratings indicating greater success.
  • Findingown data

    For participants receiving DCS, higher end fear at the previous session was associated with worse CGI-I at the next session.

    “However, for those receiving DCS, the relation between prior session end fear and current session CGI-I was significant [β = .03, t(48)= 2.43, p = .019], with higher end fear being associated with higher (worse) CGI-I at the next session.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The fear rating provided just prior to concluding an exposure session is a valid index of exposure success (fear extinction), with lower ratings indicating greater success.
  • Classified as probably not a substantial claim. 15
  • May combine two claims. 13

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    There was considerable variability in end fear ratings and CGI-I scores.

    “We observed considerable variability in end fear ratings (M=21.84; SD=14.54; range: 0-62) and CGI-I scores (M=2.57; SD=0.98; range: 1-4)”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The fear rating provided just prior to concluding an exposure session is a valid index of exposure success (fear extinction), with lower ratings indicating greater success.

  • May combine two claims.

    Findingown data

    On average, patients showed reasonable fear extinction and improvement in clinical status, with no evidence of worsening in clinical status.

    “but the mean scores indicated that, on average, patients showed reasonable fear extinction and improvement in clinical status, with no evidence of worsening in clinical status (i.e., no participant was rated higher than “4” on the CGI-I).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The fear rating provided just prior to concluding an exposure session is a valid index of exposure success (fear extinction), with lower ratings indicating greater success.

  • Classified as probably not a substantial claim.

    Premisecitation

    Preclinical data suggest that the DCS augmentation effect is moderated by the success of the extinction trials.

    “Some preclinical data suggest that the DCS augmentation effect is moderated by the success of the extinction trials.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [4] Weber, 2007, Effects of D-cycloserine on extinction of learned fear to an olfactory cue, Neurobiol Learn Mem source

      Not checked in the free run.

    • cites [8] Bouton, 2008, D-cycloserine facilitates context-specific fear extinction learning, Neurobiol Learn Mem source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    When extinction trials are limited, DCS can augment fear reconsolidation, leading to increased fear at a subsequent test.

    “Importantly, Lee and colleagues (9) also found evidence for DCS augmentation of fear reconsolidation when extinction trials were limited; subjects that had received only limited cue exposure showed an increase in fear during a subsequent test.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Lee, 2006, Reconsolidation and extinction of conditioned fear: Inhibition and potentiation, J Neurosci source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The CGI-S and CGI-I are widely used measures of global psychopathology severity and improvement initially developed for the study of psychotropic drugs.

    “The CGI-S and CGI-I are widely used measures of global psychopathology severity and improvement initially developed for the study of psychotropic drugs (16).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Guy, 1976

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Participants were randomly assigned to one of two blinded arms: placebo or 50 mg DCS after each session.

    “Eligible participants received two sessions involving 30 minutes of virtual reality exposure therapy and were randomly assigned to one of two blinded arms: (1) administration of pill placebo immediately after each session (N=14) or (2) administration of 50 mg of DCS after each session (N=15).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Preclinical research indicates that the effect of DCS is to enhance whatever emotional learning has occurred; without sufficient extinction learning on drug, there is no or little beneficial outcome to enhance.

    “Preclinical research indicates that the effect of DCS is to enhance whatever emotional learning has occurred; without sufficient extinction learning on drug, there is no or little beneficial outcome to enhance (8).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Bouton, 2008, D-cycloserine facilitates context-specific fear extinction learning, Neurobiol Learn Mem source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The Clinical Global Impressions Improvement scale is an established clinician-rated measure for measuring improvement in clinical trials.

    “We used the Clinical Global Impressions Improvement scale, an established clinician-rated measure for measuring improvement in clinical trials (16), to index improvement in height phobia severity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Guy, 1976

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The observed effects were clinically meaningful, with CGI-I differences between DCS and placebo estimated to be 1 point for very low fear and .84 points in the opposite direction for fear at 1 SD above the sample mean.

    “The observed effects were clinically meaningful, with CGI-I scale score differences between DCS and placebo estimated to be 1 point for those reporting very low fear (i.e., “0”) at the end of the previous session, and .84 points in the opposite direction for patients reporting fear at 1 SD above the sample mean (i.e., “36”) at the end of the previous session.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The fear rating provided just prior to concluding an exposure session is a valid index of exposure success (fear extinction), with lower ratings indicating greater success.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Virtual reality exposure therapy was manualized, administered by advanced doctoral students, and supervised by the first and last authors.

    “VRE was manualized, administered by advanced doctoral students, and supervised by the first and last authors (JAJS and CDT).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    If replicated and extended using data from studies validating the efficacy of pre-session DCS dosing, the results provide the basis for developing an algorithm for the application of DCS in conjunction with exposure therapy for anxiety disorders.

    “If replicated and extended using data from studies validating the efficacy of pre-session DCS dosing, the results of the present study provide the basis for developing an algorithm for the application of DCS in conjunction with exposure therapy for the anxiety disorders.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The fear rating provided just prior to concluding an exposure session is a valid index of exposure success (fear extinction), with lower ratings indicating greater success.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductreasoning

    The study was a post-hoc analysis that at best provides proof-of-concept evidence for post-session dosing of DCS combined with judicious selection of which sessions should be followed by DCS administration.

    “Finally, our study represents a post-hoc analysis that, at best, provides proof-of-concept evidence for post-session dosing of DCS as combined with judicious selection of which sessions should be followed by DCS administration.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    There were no between-group differences on any demographic variables or baseline clinical severity indices.

    “There were no between-group (DCS vs. Placebo) differences on any of the demographic variables or any of the indices of clinical severity assessed at baseline (see Table 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    DCS appears to enhance the benefits of exposure treatment when applied after a successful session, but seems to have detrimental effects when administered after inadequate or unsuccessful exposures.

    “DCS appears to enhance the benefits of exposure treatment when applied after a successful session, but it seems to have detrimental effects when administered after inadequate/unsuccessful exposures.”
    • Also stated in: § Discussion · hedged
      “Consistent with prediction, our results indicated that, when end fear was low (i.e., high extinction learning), patients who received DCS exhibited significantly greater improvement in symptoms relative to patients who received placebo. Conversely, when end fear was higher (i.e., lower extinction learning), patients receiving DCS showed significantly less subsequent improvement in symptom severity”
    • Also stated in: § d-cycloserine Enhancement of Fear Extinction is Specific to Successful Exposure Sessions: Evidence from the Treatment of Height Phobia · plain
      “D-cycloserine enhancement of fear extinction is specific to successful exposure sessions: evidence from the treatment of height phobia”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The fear rating provided just prior to concluding an exposure session is a valid index of exposure success (fear extinction), with lower ratings indicating greater success.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    In the re-analysis, 2 patients contributed one data point, 26 contributed two, and one contributed no data due to dropout.

    “2 patients only had one data point because they dropped out of the study before they could be assessed on CGI-I after the second exposure session, 26 patients had two data points, and one patient dropped out between the first exposure and the follow-up session, thereby contributing no data to the analysis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    All dropouts were in the placebo condition.

    “All dropouts were in the placebo condition.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The sample size was relatively small.

    “First, the sample size was relatively small.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The study only examined post-administration of 50 mg DCS, so it cannot make inferences about dose-response or timing of administration effects.

    “Second, we only examined post-administration of 50 mg of DCS, and therefore cannot make inferences with respect to dose-response or timing of administration effects.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The mixed-effects regression model used full information maximum likelihood estimation and the Satterthwaite correction for calculating degrees of freedom.

    “Finally, the MRM model used full information maximum likelihood estimation and the Satterthwaite correction for calculating degrees of freedom (resulting in different degrees of freedom for the tests of the significance of each regression coefficient).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    All capsules were identical in appearance to maintain the blind.

    “All capsules were identical in appearance to maintain the blind.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Insufficient exposure may set the stage for reconsolidation of active fear memories, and DCS may enhance these adverse reconsolidation effects, leading to poorer outcome relative to placebo.

    “Moreover, insufficient exposure may also set the stage for reconsolidation of active fear memories (23), and there is evidence that DCS may be able to enhance these adverse reconsolidation effects as well, leading to poorer outcome relative to placebo administration, as potentially observed in this and other studies (9, 24).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [23] Eisenberg, 2003, Stability of retrieved memory: Inverse correlation with trace dominance, Science source

      Not checked in the free run.

    • cites [9] Lee, 2006, Reconsolidation and extinction of conditioned fear: Inhibition and potentiation, J Neurosci source

      Not checked in the free run.

    • cites [24] Lee, 2009, D-cycloserine potentiates the reconsolidation of cocaine-associated memories, Learn Mem source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The analyses controlled for fear at the beginning of the session, number of floors successfully passed during exposure, and baseline clinical severity.

    “We also included the following control variables: baseline severity (CGI-S, assessed the week before the first exposure session), fear level at the beginning of the previous exposure session, and number of virtual floors successfully “passed” during the previous session.”
    • Also stated in: § Discussion · hedged
      “Third, our analyses indicated that the fear level reported just prior to concluding exposure interacted with DCS to predict clinical improvement, while controlling for fear at the beginning of the session, number of floors successfully passed during exposure and baseline clinical severity.”
    Quote in the paperSubstantial claim
22 of 22

  • The paper relies on this without support.

    The fear rating provided just prior to concluding an exposure session is a valid index of exposure success (fear extinction), with lower ratings indicating greater success.

    “we used the fear rating patients provided just prior to concluding the exposure exercises as an index of exposure success, with lower end fear ratings indexing evidence of fear extinction and higher end fear ratings indexing relatively unsuccessful fear extinction.”
    “The fear rating provided just prior to concluding the exposure exercises was used as an index for exposure success (i.e., fear extinction), with lower ratings indicating higher success, and higher ratings indicating lower success.”

  • The paper relies on this without support.

    Findings from animal studies on the moderation of DCS augmentation by extinction success generalize to human exposure therapy for anxiety disorders.

    “These findings have direct application to the understanding of the differential effects of DCS augmentation observed in clinical studies with humans.”
    “We used studies reporting the re-analyses of null results with animals (4, 8) as a model for a re-analysis of a null trial of DCS augmentation in humans (15).”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Statistics that don’t add up

Each reported p-value recomputed from its test statistic and degrees of freedom.

  • Inconsistent p-value: t(48) = 2.75, p = .025

    Minor

    The paper reports p = .025 here; recomputing from the test statistic and its degrees of freedom gives p = .008 (two-tailed). The check cannot tell whether the statistic or the p-value is the misprint.

    Reported p = .025 · recomputed p = .008

1 of 1

Statistics recomputed

Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.

  • Doesn’t add upt(48) = 2.75reported p = .025 · recomputed p = .008

    “t(48) = 2.75, p = .025”

  • Consistentt(50) = 2.84reported p = .007 · recomputed p = .007

    “t (50) = 2.84, p = .007”

  • Consistentt(44) = 2.1reported p = .04 · recomputed p = .041

    “t (44) = 2.10, p = .04”

  • Consistentt(48) = 2.43reported p = .019 · recomputed p = .019

    “t(48)= 2.43, p = .019”

4 of 4

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Self-check results appear here once an independent check has confirmed them.

Cites

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Related

Authors
Smits, J. A. J., Rosenfield, D., Otto, M. W., Powers, M. B., Hofmann, S. G., Telch, M. J., Pollack, M. H., & Tart, C. D.
Affiliations
  • Southern Methodist University (US)
  • Boston University (US)
  • The University of Texas at Austin (US)
  • Rush University Medical Center (US)
  • Raymond G. Murphy VA Medical Center (US)
Corresponding author
Smits, Jasper A.J.
ORCID
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2013-06
Volume
73
Issue
11
Pages
1054-1058
ISSN
0006-3223 (ISSN-L)
DOI
10.1016/j.biopsych.2012.12.009
PMC
PMC3636175
OpenAlex
W2072549054
Semantic Scholar
7ae003f1050ed9b66eb493693ded742d52930519
Cited by
142
References
24
Citations by year
2026: 1 · 2024: 1 · 2023: 4 · 2022: 7 · 2021: 3 · 2020: 6 · 2019: 9 · 2018: 22 · 2017: 22 · 2016: 13 · 2015: 19 · 2014: 24 · 2013: 11
FWCI
30.25
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Biological Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of Mental Health (R01MH075889)
Topics
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
Keywords
D-cycloserine, fear extinction, exposure therapy, virtual reality exposure therapy, treatment response, anxiety disorders
MeSH terms
Adult, Cycloserine, Double-Blind Method, Extinction, Psychological, Fear, Female, Follow-Up Studies, Humans, Male, Phobic Disorders, Regression Analysis, Severity of Illness Index, Virtual Reality Exposure Therapy

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