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

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.

Study Overview

• Status: Completed
• Conditions: Panic Disorder
• Intervention / Treatment: Drug: d-cycloserine; Drug: placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 180
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • Hartford, Connecticut, United States, 06106
      • Institute of Living
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02215
      • Boston University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: D-cycloserine; DCS-augmented CBT	Drug: d-cycloserine; 50mg; Other Names: DCS
Placebo Comparator: Placebo; placebo-augmented CBT	Drug: placebo; 50mg

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Boston University Charles River Campus
• Collaborators: National Institute on Drug Abuse (NIDA); National Institute of Mental Health (NIMH)
• Investigators: Study Chair: Michael W Otto, PhD, Boston University; Principal Investigator: David F Tolin, PhD, Institute of Living; Principal Investigator: Mark H Pollack, MD, Rush University Medical Center

Publications and helpful links

General Publications

• Otto MW, Pollack MH, Dowd SM, Hofmann SG, Pearlson G, Szuhany KL, Gueorguieva R, Krystal JH, Simon NM, Tolin DF. RANDOMIZED TRIAL OF D-CYCLOSERINE ENHANCEMENT OF COGNITIVE-BEHAVIORAL THERAPY FOR PANIC DISORDER. Depress Anxiety. 2016 Aug;33(8):737-45. doi: 10.1002/da.22531. Epub 2016 Jun 17.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2008
• Primary Completion (Actual): August 1, 2014
• Study Completion (Actual): August 1, 2014

Study Registration Dates

• First Submitted: November 13, 2008
• First Submitted That Met QC Criteria: November 13, 2008
• First Posted (Estimate): November 14, 2008

Study Record Updates

• Last Update Posted (Actual): March 7, 2018
• Last Update Submitted That Met QC Criteria: February 5, 2018
• Last Verified: February 1, 2018

More Information

Terms related to this study

• Keywords: Anxiety; Panic Disorder; CBT; Cognitive Behavioral Therapy; D-cycloserine; DCS
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Anxiety Disorders; Disease; Panic Disorder; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antimetabolites; Anti-Bacterial Agents; Antitubercular Agents; Antibiotics, Antitubercular; Anti-Infective Agents, Urinary; Renal Agents; Cycloserine
• Other Study ID Numbers: R01MH081116 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes