Matt G. Kushner

D-Cycloserine Augmented Exposure Therapy for Obsessive-Compulsive Disorder

BACKGROUND D-cycloserine (DCS), a glutamatergic partial N-methyl-d-aspartate (NMDA) agonist, can facilitate extinction learning related to cued fear in animals and humans. We predicted that DCS would accelerate obsession-related distress reduction in patients with obsessive-compulsive disorder (OCD) undergoing extinction-based exposure therapy. METHODS We administered DCS (125 mg) or placebo in a double-blind fashion to individuals with OCD approximately 2 hours before each exposure session. RESULTS D-cycloserine decreased both the number of exposure sessions required to achieve clinical milestones and the rate of therapy dropout. After four exposure sessions, patients in the DCS group reported significantly greater decreases in obsession-related distress compared with the placebo group; however, after additional sessions, the placebo group tended to catch up. CONCLUSIONS D-cycloserine augmentation has the potential to increase the efficiency, palatability, and overall effectiveness of standard exposure therapy for OCD.

Imipramine Plus Cognitive-Behavioral Therapy in the Treatment of School Refusal

OBJECTIVE To investigate the efficacy of 8 weeks of imipramine versus placebo in combination with cognitive-behavioral therapy (CBT) for the treatment of school-refusing adolescents with comorbid anxiety and major depressive disorders. METHOD This was a randomized, double-blind trial with 63 subjects entering the study and 47 completing. Outcome measures were weekly school attendance rates based on percentage of hours attended and anxiety and depression rating scales. RESULTS Over the course of treatment, school attendance improved significantly for the imipramine group (z = 4.36, p < .001) but not for the placebo group (z = 1.26, not significant). School attendance of the imipramine group improved at a significantly faster rate than did that of the placebo group (z = 2.39, p = .017). Over the 8 weeks of treatment, there was a significant difference between groups on attendance after controlling for baseline attendance; mean attendance rate in the final week was 70.1% +/- 30.6% for the imipramine group and 27.6% +/- 36.1% for the placebo group (p < .001). Defining remission as 75% school attendance, 54.2% of the imipramine group met this criterion after treatment compared with only 16.7% from the placebo group (p = .007). Anxiety and depression rating scales decreased significantly across treatment for both groups, with depression on the Childrens Depression Rating Scale-Revised decreasing at a significantly faster rate in the imipramine group compared with the placebo group (z = 2.08, p = .037). CONCLUSIONS Imipramine plus CBT is significantly more efficacious than placebo plus CBT in improving school attendance and decreasing symptoms of depression in school-refusing adolescents with comorbid anxiety and depression.

Carbon dioxide in the study of panic disorder: issues of definition, methodology, and outcome

The carbon dioxide (CO(2)) challenge paradigm has been useful for modeling panic in the laboratory. While showing promise as a technique able to promote a better understanding of the etiology of panic disorder (PD), this goal has been impeded by the lack of standardization of the challenge methodology and by uncertainty concerning the optimal definition and assessment of laboratory panic. The purpose of this paper is to highlight the impact of method variance on laboratory findings and to present recommendations for future challenge research. We begin by reviewing studies that have employed CO(2) as a stimulus for panic provocation focusing on the status of key methodological parameters between the studies and the relationship of these parameters to findings. We then make pragmatic and theoretically-based recommendations concerning approaches to methodological standardization, the establishment of a valid laboratory panic definition and the desirability of using of additional outcome measures. We conclude that although further work is needed to improve the CO(2) challenge laboratory model of panic, this paradigm can play an important role in understanding the psychopathology of PD.

Introduction to the Special Issue on “Anxiety Sensitivity and Addictive Behaviors”

Anxiety sensitivity (AS) is a cognitive, individual difference variable characterized by a fear of arousal-related bodily sensations due to beliefs that such sensations are signs of impending catastrophic physical, psychological, or social outcomes. AS has been linked to increased risk for the development and maintenance of panic attacks and anxiety disorders, and more recently has been related to risk for other psychopathological conditions including those related to substance misuse. This article introduces a special issue of Addictive Behaviors focusing on cutting edge findings on the relations of AS to substance use and abuse. We set the stage for the following series of eight novel empirical papers by providing a review of background on the ways in which AS has been hypothetically linked to increased risk for the development of substance abuse and addiction. We also consider whether AS might be differentially related to risk for abuse of specific classes of drugs with different pharmacological effects (e.g., depressants vs. stimulants). Finally, we consider how AS might be related to substance use disorder maintenance or relapse risk through its putative effects in increasing drug withdrawal severity and in lowering tolerance for withdrawal symptoms. Our overriding goal in writing this Introduction was to provide an organizational template for integrating the featured studies and to recommend promising directions for future work into the association of AS and substance use-related problems.

The effects of restraint stress on voluntary ethanol consumption in rats.

Sixty Wistar rats (Rattus norvegicus) were assigned to 4 groups of 15 rats each: ethanol stress (ES), ethanol no-stress (EN), isocaloric stress (IS) and isocaloric no-stress (IN). The effect of restraint stress on daily intake of ethanol and a 0.72% solution of glucose was examined in an ABA design (stress-no stress-stress). During the stress phases, 2 groups were subjected to daily 15-min restraint stress, whereas 2 groups were placed in different cages for 15 min as a control. All 4 groups were then given 6-hr access to their assigned liquid alone for 4 days followed by a choice between their assigned liquid and water on the 5th day. The ES group significantly increased their ethanol intake (g/kg) compared to the EN group on choice days but not on forced days. Percentage preference for ethanol was significantly greater and increased at a faster rate over the 75-day testing period compared with the EN group. However, total ethanol consumption (g/kg) and percentage preference did not vary as a function of phase. It is notable that the effects of restraint stress on ethanol self-administration persisted even after the stress schedule was removed.

Predictors of Treatment Response in Anxious-Depressed Adolescents With School Refusal

OBJECTIVE To identify predictors of treatment response to 8 weeks of cognitive-behavioral therapy (CBT) among anxious-depressed adolescents with school refusal, half of whom received imipramine plus CBT and half of whom received placebo plus CBT. METHOD A hierarchical multiple regression analysis was used to evaluate the following variables as potential predictors of treatment response as measured by school attendance at the end of treatment: baseline severity (school attendance at baseline), drug group (imipramine versus placebo), presence of separation anxiety disorder (SAD), and presence of avoidant disorder (AD). RESULTS Baseline attendance, CBT plus imipramine, SAD, and AD were significant predictors of treatment response and accounted for 51% of the variance in outcome. Specifically, a higher rate of attendance at baseline and receiving imipramine predicted a better response to treatment whereas the presence of SAD and AD predicted a poorer response to treatment. The relationship between sociodemographic variables and treatment outcome was also evaluated. Age and socioeconomic status were unrelated to school attendance after treatment. Males had significantly higher rates of attendance after treatment than females. CONCLUSIONS Adolescents with school refusal are a heterogeneous population and require individualized treatment planning. Variables such as diagnosis and severity at the start of treatment should be taken into consideration when planning treatment.

Anxiety mediates the association between anxiety sensitivity and coping-related drinking motives in alcoholism treatment patients

Anxiety sensitivity (AS), the tendency to interpret feelings of anxiety as dangerous, is a core dispositional trait in a well articulated and extensively studied cognitive model of proneness to anxiety disorder. In recent years, there has been an increasing body of findings that also links AS to the tendency to use alcohol in general and the tendency to use alcohol as a means of coping with negative affect in particular. We expand on this empirical base by proposing and testing a theoretical model in which anxiety symptoms mediate the association between AS and alcohol use. That is, we propose that AS promotes anxiety symptoms, which, in turn, promote alcohol use aimed at coping with anxiety and other negative affect states. Over a 1-year data collection period, we assessed 82 alcohol-dependent individuals shortly after they began an intensive alcoholism treatment program. Self-reported anxiety symptoms associated with distinct anxiety syndromes were obtained with reference to the month period preceding their entry into the treatment program. Other information, including the presence of withdrawal symptoms, was obtained via interview. We found that syndrome-related anxiety symptoms and Trait Anxiety, but not State Anxiety or withdrawal symptoms, mediated the significant association between AS and the self-reported tendency to use alcohol as a means of controlling anxiety symptoms. Demonstrating a similar pattern of findings, but much less robustly so, were tests of these mediator models using alcohol use aimed at coping with negative affect (vs. coping with anxiety per se) as an outcome. In discussing these findings, we attempt to further develop a coherent model that incorporates AS, anxiety symptoms, and drinking motives. Our findings suggest that these relationships may differ for negative affect not specifically related to anxiety. We also discuss the possible associations of AS to withdrawal symptoms implied by our findings.

Self-administration of alcohol before and after a public speaking challenge by individuals with social phobia.

: K. Abrams, M. Kushner, K. Medina, and A. Voight (2001) showed that alcohol attenuates social anxiety symptoms in socially phobic individuals. This article examines whether social anxiety symptoms can lead to increased alcohol use in this same population. Forty-four individuals with social phobia attended 2 laboratory sessions, spaced 1 week apart, in groups of approximately 10. Participants underwent a social anxiety challenge during 1 session and a control task during the other. Half of the sample self-administered alcohol immediately before, and half immediately after, these 2 activities. As predicted, participants consumed more alcohol following the anxiety challenge than following the control task; however, the opposite pattern was evidenced for drinking preceding [corrected] the 2 activities. These findings add to an understanding of why social phobia and alcohol problems tend to co-occur.

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.

Meta-analysis of supplemental treatment for depressive and anxiety disorders in patients being treated for alcohol dependence.

Approximately half of those receiving treatment for an alcohol use disorder (AUD) also suffer with an anxiety or depressive (internalizing) disorder. Because all internalizing disorders mark a poor alcohol treatment outcome, it seems reasonable to supplement AUD treatment with a psychiatric intervention when these disorders co-occur with AUD. However, this conclusion may be faulty given that the various possible interrelationships between AUD and internalizing disorders do not uniformly imply a high therapeutic yield from this approach. Unfortunately, the studies conducted to date have been too few and too small to resolve this important clinical issue with confidence. Therefore, we used a meta-analytic method to synthesize the effects from published randomized controlled trials examining the impact of supplementing AUD treatment with a psychiatric treatment for co-occurring internalizing disorder (N = 15). We found a pooled effect size (d) of .32 for internalizing outcomes and .22 for a composite of alcohol outcomes; however, the alcohol outcomes effect sizes were greater than this for some specific outcome domains. Subgroups that differed in terms of internalizing outcomes included treatment type (medication vs. cognitive behavioral therapy) and treatment focus (anxiety vs. depression). There was also a trend for the studies with better internalizing disorder outcomes to have better alcohol outcomes. These results indicate that clinical outcomes (both psychiatric and alcohol-related) could be somewhat improved by supplementing AUD treatment with psychiatric treatment for co-occurring internalizing disorder.