Elsevier

Journal of Affective Disorders

Volume 241, 1 December 2018, Pages 454-460
Journal of Affective Disorders

Research paper
D-Cycloserine augmentation of cognitive behavior therapy for pediatric OCD: Predictors and moderators of outcome

https://doi.org/10.1016/j.jad.2018.07.042Get rights and content

Highlights

  • No baseline variables moderated the effects of DCS augmentation of CBT for OCD.

  • Better insight at pre-treatment was associated with more improvement over treatment.

  • Several baseline variables were associated with a decreased likelihood of remission.

  • Need to adapt existing CBT protocols to personalize treatments.

Abstract

Background

Over half of children receiving cognitive behavioral therapy (CBT) for obsessive compulsive disorder (OCD) do not fully remit. To improve response rates and enhance extinction learning, d-cycloserine (DCS) has been examined as an augmenting agent of CBT. To direct children with OCD towards treatments with the highest likelihood of success, the current study evaluated the conditions under which DCS augmentation works best (i.e., moderators) and the baseline characteristics associated with outcome, irrespective of treatment type (i.e., predictors).

Methods

Data came from a two-site randomized controlled trial (N = 142) in which children received either DCS + CBT (n = 70) or placebo + CBT.

Results

No baseline variables moderated the effects of DCS augmentation on CBT outcome. However, several predictor variables were associated with a decreased likelihood of achieving remission status, including higher family accommodation scores, higher impairment scores, higher depression scores, and higher externalizing scores. Furthermore, better insight at pre-treatment was associated with more improvement longitudinally on a clinician-rated summary measure of illness severity.

Limitations

The current study did not examine all variables that had previously been shown to moderate or predict treatment outcome (e.g., family history of OCD or cognitive profile).

Conclusions

The absence of significant moderators suggests that baseline factors cannot yet be used to determine who benefits most from DCS. To maximize treatment benefits for children presenting with identified predictors of worse treatment outcome, clinicians might need to adapt existing CBT protocols and administer additional interventions that address patients’ specific problem areas.

Introduction

Pediatric obsessive-compulsive disorder (OCD) is a disabling psychiatric illness that affects between 1 to 3% of children and significantly interferes in their academic, social, and familial functioning (Douglass et al., 1995, Zohar, 1999). Fortunately, cognitive behavioral therapy (CBT) is an efficacious treatment for this debilitating condition (Freeman et al., 2014a, Watson and Rees, 2008). Much research has demonstrated that CBT outperforms non-active (e.g., waitlist; Bolton et al., 2011) and active (e.g., treatment-as-usual; relaxation training; Freeman et al., 2014b, Lewin et al., 2014) comparison conditions and the reduction in obsessive-compulsive symptom severity persists for up to seven-years following treatment (O'Leary et al., 2009). However, up to 60% of children receiving CBT for OCD do not fully remit (POTS, 2004).

To improve the response rate and accelerate treatment response, researchers have attempted to augment CBT with cognitive enhancers (Farrell et al., 2013, Storch et al., 2010b, Storch et al., 2016), such as D-cycloserine (DCS), an NMDA partial agonist thought to enhance extinction learning (Ledgerwood et al., 2003, Ressler et al., 2004). Results of the largest trial to date demonstrated that DCS augmentation of CBT for pediatric OCD did not expedite treatment gains, nor was it more effective than CBT monotherapy (Storch et al., 2016). However, as demonstrated in adults with OCD (Andersson et al., 2015, Otto et al., 2016), certain baseline factors may moderate patients’ response to DCS. Given the need to direct children with OCD towards treatments with the highest likelihood of success, the current study aims to identify the conditions under which DCS augmentation works best (i.e., moderators) and the baseline characteristics associated with outcome, irrespective of treatment type (i.e., predictors).

Identifying the baseline factors that moderate DCS augmentation of CBT for pediatric OCD could facilitate the allocation and optimization of treatment to most efficiently meet patients’ needs. Additionally, a more personalized approach to treatment might ultimately lead to better clinical outcomes and can inform future randomized clinical trials (e.g., moderators can be included in stratification algorithms to maximize power). However, given the methodological requirements needed to facilitate a successful examination of the predictors and moderators of DCS augmentation (i.e., large sample size, two or more treatment arms for moderation analyses; Kraemer et al., 2002), little to no research has evaluated this important question in pediatric OCD. Therefore, our research questions were informed by past research on (a) the predictors and moderators of CBT for pediatric OCD and (b) DCS augmentation of CBT in adults. Multiple studies have examined predictors of CBT for pediatric OCD (Turner et al., 2018); however, only OCD symptom severity (Garcia et al., 2010, Ginsburg et al., 2008, Rudy et al., 2014, Torp et al., 2015) and degree of family accommodation (Garcia et al., 2010, Ginsburg et al., 2008, Merlo et al., 2009, Rudy et al., 2014) have been consistently examined. A recent review of the literature (Caporino and Storch, 2016) indicated that symptom severity and family accommodation do not uniformly predict outcome across studies. Other demographic and psychosocial variables have been identified as predictors, such as comorbid internalizing or externalizing disorders (Garcia et al., 2010, Storch et al., 2008, Torp et al., 2015;), age (Torp et al., 2015), functional impairment (Garcia et al., 2010), treatment expectations (Lewin et al., 2011), and gender (Rudy et al., 2014). Like OCD symptom severity and family accommodation, these psychosocial factors have not been consistently supported (Caporino and Storch, 2016, Turner et al., 2018). The conflicting findings may be attributed to variation in CBT approach (i.e., family vs. individual) or frequency of sessions (i.e., weekly vs. daily intensive; Caporino and Storch, 2016, McGuire et al., 2015). Additional research using a large sample size and methodologically rigorous design are needed to clarify discordant findings.

Although only a limited number of pediatric studies have compared CBT to other active treatment conditions, two baseline patient factors have emerged as significant moderators. First, children who have a first-degree relative with OCD do poorly in CBT monotherapy when compared to children with no family history (i.e., sporadic cases; Garcia et al., 2010, Turner et al., 2018). Second, children with a comorbid tic disorder respond more favorably to CBT monotherapy compared to those receiving other active treatments (see meta-analysis for review; McGuire et al., 2015, Turner et al., 2018). Similar to the predictor findings, these two moderators have not been consistently replicated (Caporino and Storch, 2016).

To the authors’ knowledge, there is only one established baseline moderator of DCS augmentation of CBT for OCD in adults – antidepressant use (Andersson et al., 2015). Specifically, DCS emerged as a superior augmentation agent compared to placebo for those who were free of antidepressant medication (Andersson et al., 2015). However, Storch et al. (2016) demonstrated that concomitant antidepressants did not moderate outcomes in DCS augmentation of CBT for pediatric OCD. Moreover, a recent meta-analysis on DCS augmentation of CBT for anxiety, OCD, and posttraumatic stress disorders did not find that antidepressants moderated the effects of DCS. In fact, none of the initially specified moderators were associated with treatment outcomes (Mataix-Cols et al., 2017). Thus, the research results are inconsistent. It remains plausible that the moderating effect of an antidepressant may be better explained by other patient factors that led to initiation of medication treatment, such as degree of psychosocial impairment or comorbid anxiety disorder. Therefore, it is crucial to conduct further research to identify theoretically-grounded baseline patient factors, associated with DCS response in OCD.

The current study examines the moderators of DCS augmentation of CBT for children aged 7–17 years with OCD who were randomized to either DCS + CBT or placebo + CBT (see Storch et al., 2016 for study design). Given the study's methodological rigor, multimodal design, large well-characterized sample, and the fact that all patients received CBT, data will also be used to clarify historically conflicted findings regarding the predictors of CBT for pediatric OCD.

Due to the conflicting findings regarding predictors of CBT for pediatric OCD, we adopted an exploratory approach. Specifically, we examined the degree to which demographics (age, gender, race, ethnicity), OCD-specific features (symptom severity, insight, OCD symptom dimensions, family accommodation, impairment), comorbidity (number of comorbidities, a comorbid anxiety, depression, or tic disorder, anxiety symptom severity, depression symptom severity, and externalizing behavior symptom severity), and treatment-related factors (treatment alliance at randomization) predicted response. Additionally, we examined how theoretically- and empirically-grounded variables interact with DCS augmentation to moderate outcome. As described above, only tics and family history have emerged as moderators in the literature. While we did not collect data on family history in this trial, we examined tics. Given that tic comorbidity has led to promising moderator results in previous studies, we decided to explore other comorbidities as moderators (specifically those that had been associated with positive outcomes as predictors). In addition, we explored age and gender, which emerged as predictors in previous studies. Other variables that were included as predictors in the current trial were not examined as moderators either due to limited power (e.g., in the case of race or ethnicity) or because there was no theoretical or empirical justification for why they would be affected by DCS augmentation/enhanced extinction learning. Previous studies of pediatric OCD treatments predominantly focus on the dimensional outcome of the reduction in OCD symptom severity and are only rarely focused on symptom remission (i.e. when a patient has only minimal symptoms, McGuire et al., 2015). To address this limitation, we also examined moderators and predictors of symptom remission.

Section snippets

Description of the parent study

Data came from a two-site randomized controlled trial of DCS augmentation of CBT for pediatric OCD, described by Storch et al. (2016). Eligible patients were enrolled at Massachusetts General Hospital (MGH) in Boston, MA and University of South Florida (USF) in St. Petersburg, FL. Both sites obtained approval from their respective Institutional Review Boards and parents provided written consent and children provided assent. Inclusion criteria were: (a) current and primary DSM-IV-TR OCD

Sample characteristics

Demographic characteristics by treatment group are shown in Table 1. There were no differences in child's age as a function of treatment group, recruitment site or the group by site interaction. Child gender and race/ethnicity were comparable across treatment groups. There were no group differences in average number of comorbid conditions and the interaction between group and site was not statistically significant. However, there was a main effect of site (F (1, 137) = 6.10, p = .005) with

Discussion

The current study sought to identify both baseline moderators of DCS augmentation of CBT for pediatric OCD, and predictors of response in this large and well-characterized sample. Identifying moderators and predictors of CBT for pediatric OCD could optimize treatment to more efficiently meet patients’ needs, inform stratification algorithms in future randomized clinical trials, and align with the personalization of psychiatric medicine. The clinical characteristics reported by patients in the

Contributors

Dr Wilhelm had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Wilhelm, Berman, Small, Storch, Geller. Acquisition of data: Wilhelm, Berman, Small, Storch, Geller. Statistical analysis: Small. Interpretation of data: Wilhelm Berman, Small, Storch, Porth, Geller. Drafting of the manuscript: Wilhelm Berman, Small, Storch, Porth, Geller. Critical revision of the manuscript for

Funding

This study was supported by NIMH grants (R01MH09338 and R01 MH093402) awarded to Drs. Storch and Geller, respectively. The clinicaltrials.gov Identifier is NCT00864123. The sponsor was not involved in the design, data collection, analysis, writing of the report, or in the decision to submit the paper for publication.

Conflicts of interest

Dr. Wilhelm has received research support in the form of free medication and matching placebo from Forest Laboratories for clinical trials funded by the NIH. Dr. Wilhelm is a presenter for the Massachusetts General Hospital Psychiatry Academy in educational programs supported through independent medical education grants from pharmaceutical companies; she has received royalties from Elsevier Publications, Guilford Publications, New Harbinger Publications, and Oxford University Press. Dr. Wilhelm

Acknowledgments

The following individuals contributed to data collection and/or analysis or provided writing or editing assistance. Study Coordinators or Research Assistants: P. Jane Mutch, PhD, Allison Kennel, ARNP, and Nicole McBride, BS (University of South Florida) and Alyssa Faro, BA, Kesley Ramsay, BA, Ashley Brown, BA, Andrew Mittelman, BA, Abigail Stark, BA, Allison Cooperman, BA, Angelina Gomez, BA, and Rachel Porth, BA (Massachusetts General Hospital). Therapists: Chelsea Ale, PhD, Marni Jacob, PhD,

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      In addition, the role of cognitive enhancers for optimizing ERP outcomes requires further exploration. Although the benefits of d-cycloserine (DCS) enhancement of ERP for youth with OCD remain unclear, perhaps due to variable dosing regimens and study designs (Wilhelm et al., 2018; Olatunji et al., 2015), a recent study demonstrating the moderating effect of cingulate glutamate on ERP response in youth with OCD, suggests that targeted pharmacologic augmentation may enhance ERP outcome in biologically-defined subgroups of youth (O'Neill et al., 2017). Cognitive therapy (CT) for OCD focuses on the intrusive unwanted thoughts and maladaptive appraisals of these thoughts that are defining features of OCD.

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      Many factors influence ERP response rates (e.g., for a mega-analysis, see Steketee, Siev, Yovel, Lit, & Wilhelm, 2019), but comorbid depression is especially problematic since 40–70% of individuals with OCD will meet criteria for depression in their lifetime (Middleton, Wheaton, Kayser, & Simpson, 2019; Motivala et al., 2018; Pinto, Mancebo, Eisen, Pagano, & Rasmussen, 2006; Ruscio, Stein, Chiu, & Kessler, 2010). Although some research suggests that the severity of comorbid depression is inversely associated with ERP responsivity (Keeley, Storch, Merlo, & Geffken, 2008; McKay et al., 2015; Overbeek, Schruers, Vermetten, & Griez, 2002; Steketee et al., 2019; Storch et al., 2008; Wilhelm et al., 2018), this finding is not consistent. Abramowitz, Franklin, Street, Kozak, and Foa (2000) found that depression only interfered in ERP when it was severe, and other research suggests that depression is not associated with OCD treatment outcome (e.g., Maher et al., 2010; Wheaton, Rosenfield, Foa, & Blair Simpson, 2015).

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