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Cited by 288Anxiety, Depression, Psychometrics, Treatment, Cognitive ProcessesPosttraumatic Stress Disorder ResearchPsychotherapy Techniques and Applications

D-Cycloserine Augmentation of Exposure-Based Cognitive Behavior Therapy for Anxiety, Obsessive-Compulsive, and Posttraumatic Stress Disorders: A Systematic Review and Meta-analysis of Individual Participant Data

Open access
Mataix-Cols, David, Fernández de la Cruz, Lorena, Monzani, Benedetta, Rosenfield, David, Andersson, Erik, Pérez-Vigil, Ana, Frumento, Paolo, de Kleine, Rianne A. +49 more·2017·JAMA Psychiatry
DOI 10.1001/jamapsychiatry.2016.3955
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Abstract

Importance: Whether and under which conditions D-cycloserine (DCS) augments the effects of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders is unclear. Objective: To clarify whether DCS is superior to placebo in augmenting the effects of cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders and to evaluate whether antidepressants interact with DCS and the effect of potential moderating variables. Data Sources: PubMed, EMBASE, and PsycINFO were searched from inception to February 10, 2016. Reference lists of previous reviews and meta-analyses and reports of randomized clinical trials were also checked. Study Selection: Studies were eligible for inclusion if they were (1) double-blind randomized clinical trials of DCS as an augmentation strategy for exposure-based cognitive behavior therapy and (2) conducted in humans diagnosed as having specific phobia, social anxiety disorder, panic disorder with or without agoraphobia, obsessive-compulsive disorder, or posttraumatic stress disorder. Data Extraction and Synthesis: Raw data were obtained from the authors and quality controlled. Data were ranked to ensure a consistent metric across studies (score range, 0-100). We used a 3-level multilevel model nesting repeated measures of outcomes within participants, who were nested within studies. Results: Individual participant data were obtained for 21 of 22 eligible trials, representing 1047 of 1073 eligible participants. When controlling for antidepressant use, participants receiving DCS showed greater improvement from pretreatment to posttreatment (mean difference, -3.62; 95% CI, -0.81 to -6.43; P = .01; d = -0.25) but not from pretreatment to midtreatment (mean difference, -1.66; 95% CI, -4.92 to 1.60; P = .32; d = -0.14) or from pretreatment to follow-up (mean difference, -2.98, 95% CI, -5.99 to 0.03; P = .05; d = -0.19). Additional analyses showed that participants assigned to DCS were associated with lower symptom severity than those assigned to placebo at posttreatment and at follow-up. Antidepressants did not moderate the effects of DCS. None of the prespecified patient-level or study-level moderators was associated with outcomes. Conclusions and Relevance: 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.

AI snapshot

Written from the paper’s full text.

TL;DR

In this individual participant data meta-analysis, D-cycloserine (DCS) produced a small short-term augmentation effect on exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders. The effect was not moderated by antidepressant use, and only publication year emerged as a significant moderator.

Key findings

  • Controlling for antidepressant use, DCS was superior to placebo from pretreatment to posttreatment (mean difference, −3.62; 95% CI, −0.81 to −6.43; P = .01; d = −0.25), but not from pretreatment to midtreatment (mean difference, −1.66; 95% CI, −4.92 to 1.60; P = .32; d = −0.14) or follow-up (mean difference, −2.98; 95% CI, −5.99 to 0.03; P = .05; d = −0.19).
  • DCS recipients had lower symptom severity than placebo recipients at posttreatment (difference, −3.19; 95% CI, −0.95 to −5.43; P = .006; d = −0.21) and follow-up (difference, −2.54; 95% CI, −0.04 to −5.04; P = .05; d = −0.16).
  • Antidepressants did not moderate DCS effects, but regardless of randomized treatment, participants taking antidepressants improved more from pretreatment to follow-up (difference, −4.32; 95% CI, −0.64 to −8.01; P = .02; d = −0.28).
  • Only publication year was a significant moderator: more recent studies showed smaller DCS–placebo differences at follow-up (b = 4.02; 95% CI, 0.59–7.45; P = .02; d = 0.26). Subgroup analyses found DCS advantage only for social anxiety disorder, and antidepressant moderation only for panic disorder with or without agoraphobia (n = 77; 2 studies).

Methods

  • One-stage individual participant data meta-analysis of double-blind randomized placebo-controlled trials of DCS augmentation for exposure-based CBT/behavior therapy in specific phobia, social anxiety disorder, panic disorder with or without agoraphobia, obsessive-compulsive disorder, or posttraumatic stress disorder; PubMed, EMBASE, and PsycINFO were searched from inception to February 10, 2016.
  • IPD were obtained for 21 of 22 eligible trials, representing 1047 of 1073 eligible participants (523 DCS, 521 placebo; 3 missing group allocation); mean (SD) age was 32.1 (13.5) years, 516 (49.4%) were women, 275 (26.9%) were receiving antidepressants, and mean (SD) treatment sessions were 7.6 (4.5).
  • Outcomes were harmonized to ranked scores (range 0–100) and analyzed with a 3-level multilevel model nesting repeated measures within participants within studies, using intent-to-treat analyses and testing prespecified and post hoc moderators.

Limitations

  • The paper states less power to detect study-level moderators/predictors and for subgroup analyses; only 4 pediatric studies, limiting generalizability to younger populations; different outcome measures required transformation to ranked scores; and in-session experiences could not be examined as moderators.
  • Evident from the text: one eligible trial (26 participants) could not be included because the local ethics committee did not allow data sharing, leaving 97.6% of available data; discrepancies between provided IPD and original reports were found in 16 of 21 studies (29 mismatches, mostly antidepressant medication counts); and DCS dose was highly skewed (428/523 [81.8%] received 50 mg), with most trials administering the drug about 1 hour before exposure, limiting variability for dose and timing analyses.

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

Integrity signals

Registry

Crossref · 10.1001/jamapsychiatry.2016.3955

Cites

66 of 66 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 20 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    When controlling for antidepressant use, participants receiving DCS did not show greater improvement from pretreatment to follow-up than those receiving placebo (mean difference, -2.98; 95% CI, -5.99 to 0.03; P = .05; d = -0.19).

    “or from pretreatment to follow-up (mean difference, -2.98, 95% CI, -5.99 to 0.03; P = .05;d = -0.19)”
    • Also stated in: § Results of Syntheses (Primary Aim) · plain
      “or from pretreatment to follow-up (difference, -2.98; 95% CI, -5.99 to 0.03; P = .05;d = -0.19)”
    Quote in the paperSubstantial claim
  • Findingown data

    Regardless of randomized treatment condition, participants taking antidepressants improved more from pretreatment to follow-up than those not taking antidepressants (difference, -4.32; 95% CI, -0.64 to -8.01; P = .02; d = -0.28).

    “However, we did find that regardless of randomized treatment condition, participants taking antidepressants improved more from pretreatment to follow-up than those not taking antidepressants (difference, -4.32; 95% CI, -0.64 to -8.01; P = .02,d = -0.28)”
    Quote in the paperNot a substantial claim
  • Findingown data

    Antidepressant use did not moderate any of the effects of DCS on outcome.

    “Antidepressants did not moderate the effects of DCS.”
    • Also stated in: § Results of Syntheses (Primary Aim) · plain
      “Results showed that antidepressant use did not moderate any of the effects of DCS on outcome (Table 1).”
    Quote in the paperSubstantial claim
  • Findingown data

    Participants assigned to DCS had lower symptom severity than those assigned to placebo at follow-up (difference, -2.54; 95% CI, -0.04 to -5.04; P = .05; d = -0.16).

    “and at follow-up (difference, -2.54; 95% CI, -0.04 to -5.04; P = .05;d = -0.16).”
    Quote in the paperSubstantial claim
  • Findingown data

    The overall risk-of-bias score was not a significant moderator of any of the DCS effects.

    “Additional post hoc analyses showed that the overall score in the Cochrane Collaboration Tool for Assessing Risk of Bias for each individual study (eResults and eTables 5 and 6 in the Supplement) was not a significant moderator of any of the DCS effects (Table 2).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 24
  • Classified as probably not a substantial claim. 22
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingown data

    Only 1 significant moderator emerged: year of publication; more recent studies showed a smaller difference between DCS and placebo for pretreatment to follow-up improvement (b = 4.02; 95% CI, 0.59-7.45; P = .02; d = 0.26).

    “Only 1 significant moderator emerged: year of publication.Specifically, the more recent the study, the smaller the difference between DCS and placebo for pretreatment to follow-up improvement (b = 4.02; 95% CI, 0.59-7.45;P = .02,d= 0.26).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Individual participant data were obtained for 21 of 22 eligible trials, representing 1047 of 1073 eligible participants.

    “Individual participant data were obtained for 21 of 22 eligible trials, representing 1047 of 1073 eligible participants.”
    • Also stated in: § Study Selection and IPD Obtained · plain
      “We were able to obtain IPD from 21 of these 22 studies.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Findingown data

    The different outcome measures had different ranges and distributions.

    “As expected, the different outcome measures had different ranges and dis- tributions (eFigure in the Supplement), and therefore, the data were transformed to ensure a common measurement across studies (eMethods 2 in the Supplement).”
    Quote in the paperSubstantial claim

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

    Findingnone given

    This meta-analysis includes 97.6% of all eligible data.

    “To our knowledge, this meta-analysis includes 97.6% of all eligible data.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Antidepressants significantly moderated DCS effects only for participants with panic disorder with or without agoraphobia, the smallest diagnosis sample (n = 77) and only 2 studies.

    “Antidepressants signifi- cantly moderated DCS effects only for participants with panic disorder with or without agoraphobia, which made up the smallest diagnosis sample in our meta-analysis (n = 77) and included only 2 studies (eTable 1 in the Supplement).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    428 of 523 participants (81.8%) received 50 mg of DCS.

    “While 428 of 523 participants (81.8%) received 50 mg of DCS, some received 250 mg or even 500 mg.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    In sensitivity analysis excluding single-session studies, participants receiving DCS did not show greater improvement from pretreatment to posttreatment (difference, -2.85; 95% CI, -5.91 to 0.21; P = .06; d = -0.21).

    “In the analysis controlling for antidepressant use as a moderator of the DCS effects (primary aim 1), participants receiving DCS did not show greater improvement from pretreatment to posttreatment (difference, -2.85; 95% CI, -5.91 to 0.21; P = .06;d = -0.21)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Random effects for improvement from pretreatment to midtreatment, pretreatment to posttreatment, and pretreatment to follow-up were significant, indicating significant variability between studies and suggesting possible moderators.

    “The random effects for the improvement from pretreatment to midtreatment (χ 2 10 = 144.02;P < .001),pretreatment to posttreat-ment (χ 2 10 = 150.83;P < .001),and pretreatment to follow-up (χ 2 10 = 1102.70;P < .001)were significant, indicating significant variability in the amount of improvement between studies, hence suggesting the existence of possible moderators.”
    Quote in the paperSubstantial claim

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

    Findingown data

    Eleven different primary outcome measures were identified in the included studies.

    “We identified 11 different primary outcomes measures in the included studies (eTable 1 in the Supplement).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The group by time interaction from pretreatment to posttreatment was significant, with a coefficient of -3.62 (SE 1.44, P = .01), indicating greater improvement for DCS than placebo at posttreatment.

    “Group × time pretreatment | -3.62 (1.44) | .01 b”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Data were obtained for all participants who were initially randomized in each of the studies for which IPD were available.

    “Data were obtained for all participants who were initially randomized in each of the studies for which IPD were available.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    The multilevel model analyses were coded to perform the equivalent of a repeated-measures analysis of covariance, retaining all participants even if they missed assessments or dropped out (intent-to-treat analyses).

    “Our MLM analyses, performed using Hierarchical Linear and Nonlinear Modeling version 7.01 (Scientific Software International Inc), were coded to perform the MLM equivalent of a repeated-measures analysis of covariance, allowing slopes and intercepts to vary between studies and retaining all participants even if they missed assessments or dropped out (ie, intent-to-treat analyses).”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    The authors established whether any randomized participant data were not included and requested all data on randomized patients in order to perform intent-to-treat analyses.

    “We established whether any randomized participant data were not included in the data sets (eg, if authors conducted analyses based on completers only, we requested all data on randomized patients in order to perform intent-to-treat analyses).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Fear at the end of an exposure therapy session has emerged as a possible important variable because it has been shown to moderate DCS efficacy in 2 studies and the efficacy of yohimbine and methylene blue.

    “For example, fear at the end of an exposure therapy session has emerged as 1 possible important variable 57 because it has been shown to moderate DCS efficacy in 2 studies 58,61 as well as the efficacy of 2 other pharmacological enhancement strategies (yohimbine 62 and methylene blue 63 ).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [57]

      Not checked in the free run.

    • cites [58]

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    • cites [61]

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    • cites [62]

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

    Study design and conductown data

    One data set included 2 nonrandomized participants who were excluded prior to analysis.

    “Additionally, one of the data sets included 2 nonrandomized participants who were excluded prior to analysis.”
    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

    Authors of 5 included studies were contacted to request missing data; all missing data were provided except for the age variable in one study.

    “Authors of 5 of the included studies were contacted to request missing data.All missing data were provided except for the age variable in one of the studies.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The Cochrane Collaboration Tool for Assessing Risk of Bias was used post hoc to explore possible bias in the individual studies.

    “The Cochrane Collaboration Tool for Assessing Risk of Bias 33,34 was used (post hoc) to explore possible bias in the individual studies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    There have only been 4 studies using pediatric samples, which limits the generalizability of the results to younger populations.

    “Similarly, there have only been 4 studies using pediatric samples, which limits the generalizability of our results to younger populations.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Trial details, such as randomization methods and intervention details, were crosschecked against the original publications.

    “Trial details, such as randomization methods and intervention details, were crosschecked against the original publications.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    The original data were transformed into ranked data to ensure a common metric across studies (score range, 0-100).

    “Specifically, we transformed the original data into ranked data to ensure a common metric across studies (score range, 0-100).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The data were checked with respect to range, missing or extreme values, errors, and consistency with the published data.

    “The data were checked with respect to range, missing or extreme values, errors, and consistency with the published data.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    The authors checked for unusual allocation patterns or distributions of participant characteristics and checked whether there were trials with inappropriate allocation.

    “We checked for unusual allocation patterns or distributions of participant characteristics and checked whether there were trials with inappropriate allocation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    Different studies used different outcome measures, and these had to be transformed into ranked scores to ensure a single metric across studies.

    “Another limitation is that different studies used different outcome measures, and for this reason, these had to be transformed into ranked scores to ensure a single metric across studies.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    All discrepancies except one were successfully resolved by correspondence with the authors.

    “All discrepancies, except for a mismatch on the medication breakdown in one study (where we assumed that the actual data set was correct) were successfully resolved by correspondence with the authors.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Discrepancies between the provided IPD and the original reports were found in 16 of 21 studies; 29 mismatches were found, most related to different numbers of patients receiving antidepressant medication reported in the publication versus the data set.

    “Discrepancies between the provided IPD and the original reports were found in 16 of 21 studies.Twenty-nine mismatches were found, most of which were related to different numbers of patients receiving antidepressant medication reported in the publication vs the data set.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Corresponding authors of 6 eligible studies were contacted to request data on all randomized participants because initially only information on completers had been provided; data were received for 31 noncompleters who had originally been omitted.

    “Corresponding authors of 6 of the eligible studies were contacted to request data on all randomized participants because initially only information on completers had been provided.Data were received for 31 noncompleters who had originally been omitted from the data sets.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    Two authors independently assessed IPD data sets, with queries resolved by a third author.

    “Two authors (B.M. and L.F.C.) independently assessed IPD data sets, with queries resolved by a third author (D.M.-C.).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Because there were only 21 studies, power to detect even a large effect size (d = 0.80) for study-level moderators/predictors was only approximately 0.70 for single predictors and about 0.40 for diagnosis.

    “On the other hand, because there were only 21 studies, the power to detect even a large effect size (d = 0.80) for the study-level moderators/predictors (eg, sample size and diagnosis) was only approximately 0.70 for single predictors (eg, sample size) and only about 0.40 for diagnosis, which was comprised of 4 dummy variables.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The authors excluded any nonrandomized participants from the data sets.

    “We excluded any nonrandomized participants from the data sets.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Eligibility criteria were prospectively defined, and all relevant published and unpublished trials were sought to avoid bias.

    “Eligibility criteria were prospectively defined, and all relevant published and unpublished trials were sought to avoid bias.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    The study protocol was registered with PROSPERO (CRD42015025359).

    “The study protocol was registered with PROSPERO (CRD42015025359) and it is accessible from http://www.crd.york.ac.uk/PROSPERO/display _record.asp?ID=CRD42015025359.”
    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

    Each trial was checked individually, and the trial data were sent to the original authors for verification.

    “Each trial was checked individually, and the trial data were sent to the original authors for verification.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Despite several initial trials showing promising results in humans with anxiety disorders, larger trials conducted within the past 5 years have produced mixed results.

    “Despite several initial trials showing promising results in humans with anxiety disorders, [18][19][20] larger trials conducted within the past 5 years 21,22 have produced mixed results.[23][24][25][26]”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [18][19][20]

      Not checked in the free run.

    • cites [21]

      Not checked in the free run.

    • cites [22]

      Not checked in the free run.

    • cites [23][24][25][26]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A large trial in obsessive-compulsive disorder found a significant interaction effect between DCS and antidepressant medication in a post hoc analysis; concomitant antidepressants impaired treatment response in patients randomized to DCS but not in patients randomized to placebo.

    “Further, a large trial in obsessive-compulsive disorder 22 found a significant interaction effect between DCS and antidepressant medication in a post hoc analysis; concomitant antidepressants impaired treatment response in patients randomized to DCS but not in patients randomized to placebo.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Individual participant data meta-analyses are considered the gold standard of meta-analysis and offer advantages over traditional meta-analyses that rely on summary statistics, including better control of patient-level and study-level confounders and increased power for detecting interaction effects and subgroup analyses.

    “Individualparticipant data meta-analyses are considered the gold standard of meta-analysis and offer a number of important advantages over traditional meta-analyses that rely on summary statistics, including the better control of patient-level and study-level confounders and increased power for detecting interaction effects and subgroup analyses.31,32”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [31]

      Not checked in the free run.

    • cites [32]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DCS is a partial N-methyl-D-aspartate agonist that facilitates fear extinction in animals and reduces return of fear when given before or shortly after extinction training.

    “One promising strategy is the administration of Dcycloserine (DCS), a partial N-methyl-D-aspartate agonist that facilitates fear extinction in animals and reduces return of fear when given before or shortly after extinction training.16”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The combination of CBT and selective serotonin reuptake inhibitors is not superior to CBT alone in the long run and may have deleterious effects and result in increased relapse rates after discontinuation of medication.

    “In general, the combination of these treatment modalities is not superior to CBT alone in the long run [11][12][13] and may in fact have deleterious effects and result in increased relapse rates after discontinuation of medication.14,15”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [11][12][13]

      Not checked in the free run.

    • cites [14]

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    • cites [15]

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    These results suggest that DCS may only be indicated in patients who are not receiving antidepressants, but these results require replication.

    “These results, which are consistent with the animal literature, [28][29][30] suggest that DCS may only be indicated in patients who are not receiving antidepressants, but these results require replication.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28][29][30]

      Not checked in the free run.

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

    Premisecitation

    Variables such as the number of CBT sessions, the dose and number of DCS administrations, the timing of drug administration, the success of the exposure sessions, or compliance with between-session homework assignments may contribute to the conflicting results obtained to date.

    “Variables, such as the number of CBT sessions, the dose and number of DCS administrations, the timing of drug administration, the success of the exposure sessions, or compliance with between-session homework assignments, may also contribute to the conflicting results obtained to date.26”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26]

      Not checked in the free run.

39 of 39

  • The paper relies on this without support.

    A substantial proportion of patients with anxiety, obsessive-compulsive, or posttraumatic stress disorders do not achieve sufficient symptom relief with first-line CBT or selective serotonin reuptake inhibitors and require additional long-term care.

    “While there is ample support for the efficacy of CBT and selective serotonin reuptake inhibitors, a substantial proportion of patients do not achieve sufficient symptom relief and require additional long-term care.”

  • The authors state this as an assumption.

    In one study with a mismatch on the medication breakdown, the actual data set was correct.

    “where we assumed that the actual data set was correct”
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?

Self-check

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

Each contradiction between two passages listed here was confirmed by an independent check.

  • Midtreatment confidence interval is not centered on its estimate

    Minor

    The reported 95% CI has a midpoint of -3.20, not the reported difference of -1.69. The other reported confidence intervals for these differences are centered on their estimates.

    Reported -1.69 · recomputed -3.2

  • Number of studies screened differs between text and flowchart

    Minor

    The results say 377 studies were analyzed for eligibility, while the flowchart says 376 studies were screened for eligibility.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Higgins JPT, Altman DG; Cochrane Statistical Methods Group and the Cochrane Bias Methods Group. Assessing risk of bias in included studies. In: Higgins J, Green S, eds. Cochrane Handbook of Systematic Reviews of Interventions. West Sussex, United Kingdom: The Cochrane Collaboration and John Wiley & Sons Ltd; 2008.

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Authors
Mataix-Cols, D., Fernández de la Cruz, L., Monzani, B., Rosenfield, D., Andersson, E., Pérez-Vigil, A., Frumento, P., de Kleine, R. A., Difede, J., Dunlop, B. W., Farrell, L. J., Geller, D., Gerardi, M., Guastella, A. J., Hofmann, S. G., Hendriks, G.-J., Kushner, M. G., Lee, F. S., Lenze, E. J., Levinson, C. A., McConnell, H., Otto, M. W., Plag, J., Pollack, M. H., Ressler, K. J., Rodebaugh, T. L., Rothbaum, B. O., Scheeringa, M. S., Siewert-Siegmund, A., Smits, J. A. J., Storch, E. A., Ströhle, A., Tart, C. D., Tolin, D. F., van Minnen, A., Waters, A. M., Weems, C. F., Wilhelm, S., Wyka, K., Davis, M., Rück, C., and the DCS Anxiety Consortium, Altemus, M., Anderson, P., Cukor, J., Finck, C., Geffken, G. R., Golfels, F., Goodman, W. K., Gutner, C., Heyman, I., Jovanovic, T., Lewin, A. B., McNamara, J. P., Murphy, T. K., Norrholm, S., & Thuras, P.
Affiliations
  • Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden2Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden
  • Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
  • King's College London (GB)
  • Southern Methodist University (US)
  • Karolinska Institutet (SE)
  • Center for Anxiety Disorders Overwaal, Institution for Integrated Mental Health Care Pro Persona, Nijmegen, the Netherlands7Behavioral Science Institute, NijCare, Radboud University Nijmegen, Nijmegen, the Netherlands
  • Weill Cornell Medicine (US)
  • Emory University (US)
  • Griffith University (AU)
  • Harvard University (US)
  • The University of Sydney (AU)
  • Boston University (US)
  • Radboud University Nijmegen (NL)
  • University of Minnesota (US)
  • Washington University in St. Louis (US)
  • University of Louisville (US)
  • Stiftung Charité (DE)
  • Rush University Medical Center (US)
  • Tulane University (US)
  • The University of Texas at Austin (US)
  • University of South Florida (US)
  • New Mexico VA Health Care System (US)
  • Yale University (US)
  • Iowa State University (US)
  • City University of New York (US)
  • Region Stockholm (SE)
  • Georgia State University (US)
  • University of Florida Health (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • Great Ormond Street Hospital (GB)
  • Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia
  • Minneapolis VA Health Care System (US)
ORCID
Venue
JAMA Psychiatry
Publisher
American Medical Association (AMA)
Published
2017-05-01
Volume
74
Issue
5
Pages
501
ISSN
2168-622X (ISSN-L)
DOI
10.1001/jamapsychiatry.2016.3955
OpenAlex
W2581718547
Semantic Scholar
59b8ce2a096830feb38c552f023b54ab4acb53e9
Cited by
288
References
66
Citations by year
2026: 14 · 2025: 11 · 2024: 27 · 2023: 24 · 2022: 26 · 2021: 39 · 2020: 34 · 2019: 33 · 2018: 61 · 2017: 19
FWCI
51.98
Type
journal article
Language
en
Update notices
correction (2017-05-01)
Open access
Locations
  • JAMA Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • Radboud Repository (Radboud University) (submittedVersion)
  • Digital Commons - University of South Florida (University of South Florida) (submittedVersion)
  • Leiden Repository (Leiden University) (submittedVersion)
  • CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
  • OpenBU (Boston University) (submittedVersion)
  • Griffith Research Online (submittedVersion)
  • Radboud Repository (Radboud University) (submittedVersion, other-oa)
Funders
  • Eli Lilly and Company
  • Pfizer
  • Massachusetts General Hospital
  • University of Oxford
  • National Institutes of Health
  • National Institute on Drug Abuse (T32DA007261)
Topics
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
  • Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
  • Social Sciences › Psychology › Clinical Psychology › Psychotherapy Techniques and Applications
Keywords
D-cycloserine, augmentation therapy, anxiety disorders, obsessive-compulsive disorder, post-traumatic stress disorder, specific phobia, social anxiety disorder, panic disorder, symptom severity, treatment response variability, placebo response, medication adherence, individual differences in treatment response, individual differences
MeSH terms
Antidepressive Agents, Anxiety Disorders, Combined Modality Therapy, Cycloserine, Drug Synergism, Humans, Implosive Therapy, Obsessive-Compulsive Disorder, Stress Disorders, Post-Traumatic, N-Methylaspartate, Outcome Assessment, Health Care, Excitatory Amino Acid Agonists

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