D-Cycloserine Augmentation of Cognitive-Behavioral Therapy for Anxiety Disorders

➣ By Cristian Sirbu et al.

Exposure-based interventions are the most effective treatments for anxiety disorders; however, their acceptability in the general population is limited. New translational approaches inspired by basic research in the biological mechanisms of animal extinction learning have the potential to increase the efficacy and speed of exposure therapy. One example of a pharmacological agent with great potential is D-Cycloserine (DCS) a partial agonist of the N-Methyl-D-Aspartate (NMDA) receptors with demonstrated enhancement of extinction learning consolidation. In this article, we discuss the relevance of DCS as an enhancer of cognitive-behavioral therapy for anxiety disorders, focusing on: pharmacological characterization of DCS, documented efficacy of DCS for anxiety disorders treatment and a brief description of ongoing DCS studies from our group.

Characterization of D-Cycloserine DCS was approved by the Food and Drug Administration in 1965 as a broad spectrum oral antibiotic for tuberculosis. Standard doses range from 250-500 mg and some patients can reach doses of 1g per day. Adverse side effects have been documented with doses of 1g per day and include headache, psychosis, seizures, or somnolence. The main contraindications are alcohol use, renal failure, epilepsy (increased risk of seizures), or pregnancy. In addition to its use as an antituberculotic agent, DCS has been evaluated as a medication for schizophrenia and Alzheimer’s dementia, but with low efficacy. Pharmacokinetic studies of DCS indicate that after a single oral dose of 50 mg, the peak plasma level measured 1-2 hours after administration is 3.7 +1.2 mg/dl, with an estimated 2.9 + 0.96 mg/dl peak cerebrospinal fluid level (80% of the peak plasma level).

Efficacy of D-Cycloserine augmentation of exposure therapy for anxiety disorders In studies of exposure therapy augmentation, DCS is used at low isolated doses of 50-500mg either before or shortly after the exposure therapy session. In most studies, DCS is used in association with In Vivo Exposure Therapy (IVET); however, few studies explored the use of Virtual Reality Exposure Therapy (VRET) (see below). Virtual Reality Exposure Therapy (VRET) has documented efficacy in the treatment of specific phobias (acrophobia, flying phobia, claustrophobia, driving phobia, arachnophobia), panic disorder with agoraphobia, social anxiety disorder, and posttraumatic stress disorder.

The mechanisms of exposure therapy in IV and VR involve activation of different physiological systems. Thus, IVET produces changes in heart rate and skin conductance (involving both behavioral activation and inhibition systems) while VRET produces changes in skin conductance (involving only the behavioral inhibition system); therefore, an important question is what effect does DCS have on IVET versus VRET? In studies to date, DCS was used exclusively as an enhancer of either IVET or VRET. In studies using IVET protocols, DCS has demonstrated efficacy for social anxiety disorder, but has yielded mixed results for obsessive-compulsive disorder, panic disorder with agoraphobia, and posttraumatic stress disorder.

Surprisingly, the number of studies investigating the association of DCS and VRET are limited. In two published studies, DCS was used in association with VRET for acrophobia. Ressler et al., administered 50 mg DCS, 500 mg DCS, or placebo two to four hours before two sessions of 30-minute VRET, and demonstrated higher reduction in acrophobic symptoms at one week and three months post treatment for DCS conditions compared with placebo. No difference was noted between 50 and 500 mg DCS. In a recent study in acrophobics, Tart et al. used a similar protocol; however, 50 mg DCS was administered immediately after the two 30-minute sessions of VRET. No difference was noted between the DCS and placebo groups; however, a reanalysis of the data indicated that DCS was superior to placebo only for patients who experienced a successful exposure session.

Contributions from our group

In the past few years, our research on DCS has been focused on two main areas: (1) physicochemical characterization of DCS for anxiety disorders, and (2) investigation of DCS efficacy in acrophobia and dental phobia.

1) Physicochemical characterization of
DCS for anxiety disorders

We conducted extensive studies regarding stability and characterization of DCS reformulation. Most studies using DCS for anxiety disorders use 50 mg DCS capsules. Those are reformulated from the 250 mg Seromycin® capsules. Questions regarding stability as well as potential conversion of D-Cycloserine into L-Cycloserine are important when DCS is reformulated. Research in our lab has demonstrated good stability as well as a lack of conversion to L-Cycloserine during the reformulation of the 250 mg DCS capsules to 50 mg strength. Further, we have demonstrated that the DCS undergoes significant degradation at acidic pH. This brings an important question about the amount of DCS reaching the brain, especially at the low doses (50 mg) used in the treatment of anxiety disorders, considering degradation at the acidic pH in the stomach. This issue has stimulated our interest in identifying new delivery methods (transdermal and nasal) for DCS.

2) DCS efficacy in acrophobia and dental
phobia.

In one of our current studies, we are comparing the efficacy of 50 mg DCS to placebo in acrophobics. The drugs are administered 30 minutes before a three-hour, one-session treatment with either IVET or VRET. This design will allow the first comparison of the effect of DCS on IVET versus VRET using self-report, clinical interview, a Behavioral Avoidance Task, and physiological outcomes (heart rate variability and skin conductance). To date, no side effects have been noted in our participants (either placebo or DCS); data collection is ongoing and no comparison is possible yet since the trial is double blinded.

In a second study, we are investigating the efficacy of 50 mg DCS for reducing anxiety during dental visits and dental avoidance in patients with dental phobia. DCS is administered immediately prior to two dental visits. This ongoing study will provide the first demonstration of DCS efficacy in the context of a naturalistic exposure conducted in the dental office by dental professionals (hygienists). Additionally, DNA and RNA analysis of blood cells collected at baseline, after each treatment session, and at one week follow-up will allow investigation of the moderating effects of genetic polymorphism on DCS efficacy, as well as gene expression profiles, associated with this treatment.

In summary, DCS augmentation represents a significant avenue for optimizing the existing exposure therapy protocols for anxiety disorders, reducing the duration as well as the number of sessions. Studies focusing on new clinical conditions (i.e. dental phobia) as well as the combination of VRET and DCS are important and delineation of clinical parameters of DCS use in both IVER and VRET are critical steps in understanding the optimal use of this promising pharmacological agent.

Cristian Sirbu, Ph.D.
Charleston Area Medical Center
Health Education and Research Institute
West Virginia University School of Medicine Charleston Division
Department of Behavioral Medicine and Psychiatry
cristian.sirbu@camc.org

Gagan Kaushal, Ph.D.
University of Charleston

Patrick Kerr, Ph.D.
West Virginia University School of Medicine Charleston Division

Daniel W. McNeil, Ph.D.
West Virginia University

Andrew W. Goddard, M.D.
Indiana University School of Medicine