Changes in Dosing and Dose Timing of D-Cycloserine Explain Its Apparent Declining Efficacy for Augmenting Exposure Therapy for Anxiety-related Disorders: An Individual Participant-data Meta-analysis.

The apparent efficacy of d-cycloserine (DCS) for enhancing exposure treatment for anxiety disorders appears to have declined over the past 14 years. We examined whether variations in how DCS has been administered can account for this "declining effect". We also investigated the association between DCS administration characteristics and treatment outcome to find optimal dosing parameters. We conducted a secondary analysis of individual participant data obtained from 1047 participants in 21 studies testing the efficacy of DCS-augmented exposure treatments. Different outcome measures in different studies were harmonized to a 0-100 scale. Intent-to-treat analyses showed that, in participants randomized to DCS augmentation (n = 523), fewer DCS doses, later timing of DCS dose, and lower baseline severity appear to account for this decline effect. More DCS doses were related to better outcomes, but this advantage leveled-off at nine doses. Administering DCS more than 60 minutes before exposures was also related to better outcomes. These predictors were not significant in the placebo arm (n = 521). Results suggested that optimal DCS administration could increase pre-to-follow-up DCS effect size by 50%. In conclusion, the apparent declining effectiveness of DCS over time may be accounted for by how it has been administered. Optimal DCS administration may substantially improve outcomes. Registration: The analysis plan for this manuscript was registered on Open Science Framework (https://osf.io/c39p8/).

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.

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.

Behavioral versus cognitive treatment of obsessive-compulsive disorder: an examination of outcome and mediators of change.

OBJECTIVE: To examine symptom change over time, the effect of attrition on treatment outcome, and the putative mediators of cognitive therapy (CT) versus behavior therapy (BT) for obsessive-compulsive disorder (OCD) using archival data. METHOD: Sixty-two adults with OCD were randomized to 20 sessions of CT (N = 30) or BT (N = 32) that consisted of 4 weeks of intensive treatment (16 hr total) and 12 weeks of maintenance sessions (4 hr). Independent evaluators assessed OCD severity using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) at baseline and at Weeks 4, 16 (posttreatment), 26, and 52 (follow-up). Behavioral avoidance, depressive symptoms, and dysfunctional beliefs regarding responsibility were also measured at each assessment. Study hypotheses were tested using multilevel modeling. RESULTS: The slope of change in Y-BOCS scores was significantly greater in BT than in CT (d = 0.69), and those receiving BT had lower Y-BOCS scores at the final assessment than those receiving CT (d = 1.17). The greater slope of change in BT versus CT did not differ for dropouts versus completers. Reduction in depressed mood mediated changes in Y-BOCS across the 2 treatments, but a reduction in sense of responsibility and a decrease in avoidance did not. Instead, Y-BOCS improvements appeared to precede a decrease in avoidance. CONCLUSIONS: BT may have some therapeutic advantage over CT in the treatment of OCD, and this advantage does not appear to be due to a differential pattern of responding for treatment dropouts versus completers. Further, inconsistent with hypotheses, improvements in OCD symptoms were mediated by reductions in depressed mood instead of decreases in avoidance and responsibility. Theoretical, methodological, and clinical implications are discussed.

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

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 extinction learning. Therefore, we conducted a reanalysis 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 before concluding exposure sessions. Patients receiving DCS exhibited significantly greater improvement in symptoms relative to patients who received placebo when fear was low at the end of the exposure. In contrast, when end fear was still elevated, patients receiving DCS improved less compared with those receiving placebo. CONCLUSIONS: D-cycloserine 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 exposure sessions.

Augmentation of exposure therapy with post-session administration of D-cycloserine.

BACKGROUND: Pre-session administration of d-cycloserine (DCS) has been found to augment exposure therapy outcomes in a variety of anxiety disorders. To be able to enhance learning only for successful exposure sessions, it would be beneficial to have the option of administering DCS after rather than before the session, a strategy encouraged by pre-clinical work. We believe the present study is the first published report on the efficacy of post-session administration of DCS in humans. METHOD: Adults (N = 29) with a DSM-IV diagnosis of acrophobia were randomized to receive two sessions of virtual reality exposure therapy (VRE) in combination with placebo or 50 mg of DCS. Instead of administering the pill prior to each of the sessions, as has been done in extant work, we administered the pill immediately following each session. Measures of acrophobia severity were collected at baseline, at each treatment session, 1-week post-treatment, and at 1-month follow-up. RESULTS: Mixed-effects repeated-measures ANOVAs and GLMMs revealed significant improvement in all outcome measures over time, but no between-group differences were observed. At post-treatment, 63.5% of patients in the placebo condition vs. 60.0% of those in the DCS condition were in remission. At 1-month follow up, 63.4% of those in the placebo condition vs. 66.6% of those in the DCS condition were in remission. CONCLUSIONS: These findings do not support the application of post-session DCS administration for augmenting the efficacy of exposure-based treatments. Possible reasons for these findings are discussed. TRIAL REGISTRY: The Trial is registered at ClinicalTrials.gov (NCT01102803).

Physical activity as a moderator of the association between anxiety sensitivity and binge eating.

Individuals with elevated anxiety sensitivity (AS; i.e., fear of somatic arousal) may binge eat to reduce emotional distress. Because physical activity reduces stress reactivity, we predicted that: (1) the relation between AS and binge eating would be moderated by physical activity and (2) coping motives for eating would mediate the association between AS and binge eating such that the relation would be stronger for those low in physical activity. Participants (N=167) completed online self-report measures. Regression analyses revealed that moderate-intensity physical activity (MPA) moderated the relation between AS and binge eating such that AS was not related to binge eating among those who frequently engaged in MPA but was related to binge eating among those who did not report engaging in MPA. Vigorous-intensity physical activity (VPA) moderated in the opposite direction such that the relation between AS and binge eating was significant among persons reporting high levels of VPA but less strong among persons reporting low levels of VPA. The mediation model was also significant, but was not moderated by MPA or VPA. Theoretical and clinical implications are discussed.

Evaluation of the glycine transporter inhibitor Org 25935 as augmentation to cognitive-behavioral therapy for panic disorder: a multicenter, randomized, double-blind, placebo-controlled trial.

OBJECTIVE: A growing body of evidence supports the efficacy of D-cycloserine (DCS), a partial agonist at the N-methyl-D-aspartate (NMDA) glutamate receptor, as augmentation to cognitive-behavioral therapy (CBT) in the treatment of anxiety disorders. Org 25935 is a glycine transporter 1 inhibitor that acts to increase synaptic glycine levels and enhance NMDA-mediated glutamatergic activity. The aim of this study was to examine the efficacy of a glutamatergic compound other than DCS in a CBT augmentation paradigm. METHOD: This was a randomized, double-blind, placebo-controlled, parallel-group clinical trial for which participants were recruited from November 2008 through February 2010. Eligible adult patients diagnosed (DSM-IV) with panic disorder with or without agoraphobia (N = 40) were scheduled to receive 5 manualized CBT treatment sessions. Participants were randomly assigned to receive either a dose of Org 25935 (4 mg or 12 mg) or placebo 2 hours prior to the start of CBT sessions 3, 4, and 5. The primary endpoint was symptomatic change as measured by the Panic Disorder Severity Scale (PDSS) 1 week following the last CBT session. RESULTS: Although mean PDSS total scores decreased significantly from baseline to end of treatment in every group, no statistically significant benefit was observed for Org 25935 (4 or 12 mg) over placebo on the primary endpoint or on any secondary efficacy endpoint. Org 25935 showed no safety issues at either dose but was much better tolerated at the 4-mg dose level than at the 12-mg dose level. CONCLUSIONS: Org 25935 demonstrated no benefit over placebo in augmenting CBT for panic disorder. Study limitations and implications are discussed. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00725725.

The interplay between physical activity and anxiety sensitivity in fearful responding to carbon dioxide challenge.

OBJECTIVE: Physical activity may confer protective effects in the development of anxiety and its disorders. These effects may be particularly strong among individuals who have elevated levels of anxiety sensitivity (AS; i.e., the fear of somatic arousal), an established cognitive-based risk factor for anxiety and its disorders. The present study performed a laboratory test of the interplay between physical activity and AS. METHODS: The participants were adults free of Axis I psychopathology (n = 145) who completed measures of physical activity and AS before undergoing a recurrent 20% carbon dioxide-enriched air (CO(2)) challenge. RESULTS: Consistent with the hypothesis, physical activity was significantly related to CO(2) challenge reactivity among persons with elevated levels of AS, at high levels of physical activity (p < .001) but not at low levels of physical activity (p = .90). Also consistent with hypothesis, irrespective of the level of physical activity, physical activity did not relate significantly to CO(2) challenge reactivity among persons with normative levels of AS (p = .28). CONCLUSIONS: These findings provide novel empirical insight into the role that physical activity may play in terms of resiliency for the development of anxiety disorders. Specifically, the protective effects of physical activity may only be evident at higher doses and among persons who are at increased risk of developing anxiety disorders because they have elevated AS.

Specificity of disgust vulnerability in the distinction and treatment of OCD.

A growing body of research has implicated disgust as a potential risk factor for the development and maintenance of obsessive-compulsive disorder (OCD). The first aim of the present study was to determine whether related, yet distinct, disgust vulnerabilities are endorsed more strongly by individuals with OCD than by those with another anxiety disorder. The second aim was to examine the unique contributions of changes in disgust to symptom improvement observed with exposure-based treatment for OCD. In study 1, individuals with OCD, generalized anxiety disorder (GAD), and nonclinical controls (NCCs) completed a measure of disgust propensity and disgust sensitivity. Compared to NCCs and individuals with GAD, those with OCD more strongly endorsed disgust propensity. However, individuals with OCD did not significantly differ from individuals with GAD in disgust sensitivity, although both groups reported significantly higher disgust sensitivity levels compared to NCCs. Study 2 comprised mediation analyses of symptom improvement among individuals with OCD and revealed that decreases in disgust propensity over time mediated improvement in OCD symptoms, even after controlling for improvements in negative affect. The implications of these findings for conceptualizing the role of disgust in the nature and treatment of OCD are discussed.

Anxiety sensitivity as a mediator of the relationship between moderate-intensity exercise and coping-oriented marijuana use motives.

The present study examined the working hypothesis that moderate-intensity exercise is associated with coping-oriented marijuana use motives through its association with the fear of somatic arousal (ie, anxiety sensitivity). Using data from 146 young adult current marijuana users, we found evidence consistent with this hypothesis. Specifically, moderate-intensity exercise was associated with coping-oriented use motives, even after controlling for frequency of current marijuana use and other co-occurring marijuana use motives. This relationship became nonsignificant after entering anxiety sensitivity as an additional predictor variable, denoting a putative mediational role for this cognitive factor. These findings extend previous work and offer support for the potential utility of moderate-intensity aerobic exercise for the treatment of marijuana use problems.

Psychotropic medication use mediates the relationship between mood and anxiety disorders and obesity: findings from a nationally representative sample.

Growing evidence points to a relationship between obesity and both mood and anxiety disorders, but the question of what accounts for this association remains unanswered. The present study examined the use of psychotropic medications as a mediator of the mood/anxiety disorder-obesity relationship. Data came from the public use dataset of the Canadian Community Health Survey Cycle 1.2 (age 15 years and older, N = 36,984). Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition psychiatric diagnoses of 12-month mood disorders (e.g., major depressive disorder, mania) and anxiety disorders (e.g., panic attacks, panic disorder, social phobia, agoraphobia) were examined as was use of psychotropic medications (e.g., antidepressants, antipsychotics, anxiolytics, hypnotics, mood stabilizers) and obesity (defined as body mass index ≥30). A series of multiple logistic regression analyses were completed to test study hypotheses. Covariates in these analyses included sociodemographic factors, physical activity, and physical illness burden. The use of two medication classes, namely antidepressants and antipsychotics, emerged as significant predictors of obesity as well as mediators of the psychiatric diagnosis-obesity relationship after evaluating all psychotropic medication classes simultaneously, while also controlling for other theoretically relevant variables. The use of these two medications accounted for 86% of the relationship between mood disorders and obesity and 32% of the relationship between anxiety disorders and obesity. The study findings guide advances in the theoretical conceptualization of the mechanisms involved in mood/anxiety disorder-obesity relations. Clinical implications are discussed.

Mediation of symptom changes during inpatient treatment for eating disorders: the role of obsessive-compulsive features.

The present study examined the relative contributions of changes in obsessive-compulsive symptoms among eating-disorder patients with (n = 254) and without (n = 254) obsessive-compulsive disorder (OCD) to eating-disorder symptom improvement observed with inpatient treatment. Consistent with hypothesis, multilevel mediation analyses revealed that improvements in OCD symptoms over time accounted for significant variance in the improvements in eating-disorder symptoms over time, with stronger mediation evident among eating-disorder patients with comorbid OCD (percent mediated; P(M) = 22.5%) compared to those without OCD (P(M) = 12.2%). However, decreases in eating-disorder symptoms over time fully mediated improvements in OCD symptoms over time, and this mediated pathway did not vary substantially as a function of comorbid OCD status. The theoretical and treatment implications of these findings for conceptualizing the relationship between eating disorders and OCD are discussed.

Negative affect as a mediator of the relationship between vigorous-intensity exercise and smoking.

The present cross-sectional study evaluated whether people who engage in vigorous-intensity exercise are better able to regulate negative affective states, thereby changing core maintenance factors of smoking. Participants were a community sample of adults (n = 270) who completed self-report measures of physical activity, cigarette smoking, anxiety sensitivity, and negative affect. Consistent with hypothesis, vigorous-intensity exercise was related to lower levels of cigarette smoking, accounting for 10% of the variance in smoking. Additionally, negative affect mediated the relationship between vigorous-intensity physical activity and cigarette smoking, accounting for about 12% of this relation. Furthermore, these relationships were stronger for individuals with high anxiety sensitivity than for those with low anxiety sensitivity; including anxiety sensitivity as a moderator of the mediated relationship increased the amount of variance accounted for by negative affect to 17%. The findings are discussed in relation to developing further scientific insight into the mechanisms and pathways relevant to understanding the association among vigorous-intensity exercise, smoking, and emotional vulnerability.

Identifying potential barriers to physical activity adherence: anxiety sensitivity and body mass as predictors of fear during exercise.

A growing body of work suggests that obese adults are less likely to adhere to exercise than normal-weight adults because they experience greater levels of discomfort and distress during exercise sessions. The present study introduces and provides a preliminary test of the hypothesis that the distress experienced during exercise among persons with elevated body mass index is particularly high among those who fear somatic arousal (i.e. elevated anxiety sensitivity [AS]). Young adults were randomly assigned to complete 20 min of treadmill exercise (at 70% of their age-adjusted predicted maximum heart rate) or 20 min of rest. Body mass, AS, and negative affect were measured at baseline, and fear was measured at 4-min intervals during the experimental phase. Consistent with the authors' hypothesis, there was a significant Exercise x BMI x ASI interaction (sr(2) = .08), suggesting that the greatest fear levels during exercise were observed among participants with high body mass, but only if they also had elevated AS. These findings offer a new approach for identifying specific vulnerable individuals and have clear clinical implications, given that the amplification factor of AS can be modified with clinical intervention.

Children's adjustment problems in families characterized by men's severe violence toward women: does other family violence matter?

OBJECTIVE: This research examined whether additional forms of family violence (partner-child aggression, mother-child aggression, and women's intimate partner violence [IPV]) contribute to children's adjustment problems in families characterized by men's severe violence toward women. METHODS: Participants were 258 children and their mothers recruited from domestic violence shelters. Mothers and children completed measures of men's IPV, women's IPV, partner-child aggression, and mother-child aggression. Mothers provided reports of children's internalizing and externalizing behavior problems; children provided reports of their appraisals of threat in relation to interparent conflict. RESULTS: After controlling for sociodemographics and men's IPV: (1) each of the additional forms of family violence (partner-child aggression, mother-child aggression, and women's IPV) was associated with children's externalizing problems; (2) partner-child aggression was associated with internalizing problems; and (3) partner-child aggression was associated with children's threat appraisals. The relation of mother-child aggression to externalizing problems was stronger for boys than for girls; gender differences were not observed for internalizing problems or threat appraisals. CONCLUSIONS: Men's severe IPV seldom occurs in the absence of other forms of family violence, and these other forms appear to contribute to children's adjustment problems. Parent-child aggression, and partner-child aggression in particular, are especially important. Systematic efforts to identify shelter children who are victims of parental violence seem warranted. PRACTICE IMPLICATIONS: Men's severe IPV seldom occurs in the absence of other forms of family violence (partner-child aggression, mother-child aggression, and women's IPV), and these different forms of family violence all contribute to children's adjustment problems. Treatment programs for children who come to domestic violence shelters should address these different forms of family violence, especially parent-child aggression.

The efficacy of cognitive-behavioral interventions for reducing anxiety sensitivity: a meta-analytic review.

The present study meta-analytically reviewed the efficacy of cognitive-behavioral therapy (CBT) vs. control conditions in the reduction of anxiety sensitivity. A computerized search was conducted to identify CBT outcome studies that included the Anxiety Sensitivity Index as a dependent variable. Of the 989 studies that were identified, 24 randomized-controlled trials with a total of 1851 participants met inclusion criteria and were included in the analysis. Data were extracted separately for treatment-seeking (16 studies) and at-risk (eight studies) samples. Results indicated large effect sizes for treatment-seeking samples, Hedges' g=1.40, SE=0.21, 95% CI: 1.00-1.81, p<0.001, and moderate to large effect sizes for at risk samples Hedges' g=0.74, SE=0.18, 95% CI: 0.39-1.08, p<0.001. Additionally, both the amount of therapist contact and control modality (waitlist vs. psychological control) moderated the effect sizes for treatment-seeking samples. Our review indicates that CBT is efficacious in reducing anxiety sensitivity. However, more research is needed to determine the mechanisms by which CBT exert its effects on anxiety sensitivity.