Exposure, D-Cycloserine Enhancement, and Genetic Modulators in Panic Disorder

Study Overview
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Brief Summary
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This is a 5-year double blind, randomized, controlled, trial conducted at three treatment sites, aimed at showing the acute and longer-term effects of DCS augmentation of exposure-based CBT for panic disorder relative to placebo augmentation. By demonstrating that DCS can enhance the results of even a brief treatment strategy, the investigators are seeking to validate an approach that fits well with the practice limitations and applications of CBT in effectiveness studies.

Detailed Description
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In this application, the investigators propose to further validate and expand upon one of the apparent striking successes of translational research. Specifically, basic research on the neural circuitry underlying fear extinction led to the examination of d-cycloserine (DCS), a partial agonist of the NMDA receptor in the amygdala, as an agent capable of enhancing extinction learning (Davis et al., 2006; Davis et al., in press). Following successful validation of this strategy in the animal laboratory (see Ledgerwood et al., 2005; Richardson et al., 2004), Ressler et al. (2004) showed that single doses of d-cycloserine (DCS) could enhance extinction in a human exposure paradigm for height phobic adults. This exciting initial finding was replicated by this research team for the treatment of social anxiety disorder (Hofmann et al., 2006), as well as an initial pilot study of the treatment of panic disorder (Tolin et al., 2006). As discussed by Anderson and Insel (2006), these findings have the potential to foster significant advances in the treatment of anxiety disorders. The present study represents the further application of DCS for augmenting the effects of exposure-based cognitive-behavior therapy (CBT), now applied to the treatment of panic disorder with or without agoraphobia. In the current application, the investigators propose a five-year study to show the acute and longer-term effects of DCS augmentation of exposure-based CBT relative to placebo augmentation. This study is noteworthy for the use of a brief treatment strategy that has been shown to be successful in previous trials (e.g., Clark et al., 1999; Roy-Byrne et al., 2005) and has served as the basis for the DCS augmentation effect seen in a pilot study for this application. By demonstrating that DCS can enhance the results of even a brief treatment strategy, the investigators are seeking to validate an approach that fits well with the practice limitations and applications of CBT in effectiveness studies (e.g., Katon et al., 2006; Roy-Byrne et al. 2005). Furthermore, by studying the genetic predictors of the overall response to CBT, and DCS augmentation in particular, the investigators hope to further elucidate the nature of DCS augmentation and the selection of particularly responsive subgroups of patients in need. This agenda is in accords with the ultimate goal of personalized therapy: identifying individual patterns of pathophysiology that indicate which pharmacological or behavioral treatment will be most useful for any individual patient (Anderson & Insel, 2006, p. 320). The study design is a double blind, randomized, controlled, trial conducted at three treatment sites. Patient with panic disorder will randomly receive DCS or placebo 1 hour prior to sessions 3-5 of a 5-session CBT protocol that includes 2 additional booster sessions over the course of follow-up. Patients will be enrolled over 5 years with the identical treatment protocol followed at each of the sites. Sites will nonetheless differ with respect to study management and analysis procedures.

Official Title
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Exposure, D-Cycloserine Enhancement, and Genetic Modulators in Panic Disorder

Conditions
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Panic Disorder

Intervention / Treatment
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* Drug: d-cycloserine
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female outpatients > 18 years of age with a primary psychiatric diagnosis of panic disorder with or without agoraphobia CGI-severity score of 4 or higher Physical examination and laboratory findings without clinically significant abnormalities Off concurrent psychotropic medication for at least 2 weeks prior to initiation of randomized treatment, OR stable on current medication for a minimum of 6 weeks and willing to maintain a stable dose Willingness and ability to comply with the requirements of the study protocol Exclusion Criteria: Agoraphobia sufficiently severe as to limit patient's ability to travel to and participate in weekly sessions Posttraumatic stress disorder, substance use disorder, eating disorder, or organic mental disorder within the past 6 months Lifetime history of psychotic disorder, bipolar disorder, or developmental disorder Significant suicidal ideation or suicidal behaviors within the past 6 months Significant personality dysfunction likely to interfere with study participation Serious medical illness or instability for which hospitalization may be likely within the next year Patients with a current or past history of seizures (other than febrile seizures in childhood) Pregnant women, lactating women, and women of childbearing potential who are not using medically accepted forms of contraception Concurrent psychotherapy initiated within 3 months of baseline, or ongoing psychotherapy of any duration directed specifically toward treatment of the panic disorder other than general supportive therapy initiated at least 3 months prior to study Prior adequate trial of CBT for panic disorder

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: D-cycloserine<br>DCS-augmented CBT | Drug: d-cycloserine<br>* 50mg<br>* Other names: DCS;|
| Placebo Comparator: Placebo<br>placebo-augmented CBT | Drug: placebo<br>* 50mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Panic Disorder Severity Scale (PDSS) | The percent change in PDSS score from baseline to the relevant assessment points is the continuous primary outcome measure. The PDSS consists of seven items, each rated on a 0 to 4 scale (0 denoting none, and higher ratings reflecting greater degrees of symptom severity; for a possible range in scores from 0 to 28). In the tabular data below we present the total scores (sum of items). | baseline, mid-TX, post-TX, follow-up visits 1-4 | 
| Remission Status | Remission status will be used as the primary categorical outcome variable. The CGI-S was used in determining whether patients met the CGI-S of 1 or 2 component of the remission status criteria (i.e., zero panic attacks and CGI-S of 1 or 2 at endpoint). No values are missing because remission must be confirmed; missing status is assigned to disorder status. Hence results are for the full randomized sample. | Pre-treatment, Post-Treatment, and each follow-up sessions | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Depression Severity | Depression severity was assessed with the MADRS, with scores ranging from 0 to 60. Higher scores indicate greater depression. | Baseline, Tx Endpoint, Each of 4 follow-up assessments | 
| Quality of Life Ratings | Quality of life as assessed by the Q-LES-Q. Scores range from 14-70 for total raw score, higher scores indicate higher quality of life ratings. | Baseline, Tx Endpoint, Each of 4 follow-up assessments | 
| Role Functioning | LIFE-RIFT. For this clinician-rated measure, total scores range from 0 to 20, with higher scores indicating greater impairment | Baseline, Tx Endpoint, Each of 4 follow-up assessments | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anxiety, Panic Disorder, D-cycloserine, DCS, Cognitive Behavioral Therapy, CBT