Dose Timing of D-Cycloserine to Augment CBT for Social Anxiety Disorder

The purpose of this study is to examine the efficacy of 50 mg of d-cycloserine in comparison to placebo (a pill containing no medication) for improving the effectiveness of cognitive-behavioral therapy (CBT) in reducing symptoms associated with social anxiety disorder. In addition, the study will examine whether the effectiveness of d-cycloserine depends on the timing of the pill administration (i.e., 1- hour before the session or immediately after the session) as well as the success of the CBT therapy sessions. The investigators hypothesize that the tailored post-session DCS administration condition will outperform the other conditions (pre-session DCS, placebo, and non-tailored post-session DCS). This will be evidenced by short- and long-term improvements in social anxiety severity.

Study Overview

• Status: Completed
• Conditions: Social Anxiety Disorder
• Intervention / Treatment: Drug: Placebo; Drug: D-Cycloserine; Behavioral: Cognitive Behavioral Therapy

• Study Type: Interventional
• Enrollment (Actual): 152
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Boston University
  • Texas
    • Austin, Texas, United States, 78712
      • University of Texas at Austin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 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 (designated by the patient as the most important source of current distress) of social anxiety disorder as defined by DSM-5 criteria.
• A total score > 60 on the LSAS.
• Physical examination and laboratory findings without clinically significant abnormalities.
• Willingness and ability to participate in the informed consent process and comply with the requirements of the study protocol.

Exclusion Criteria:

• A lifetime history of bipolar disorder, schizophrenia, psychosis, delusional disorders or obsessive-compulsive disorder; an eating disorder in the past 6 months; organic brain syndrome, mental retardation or other cognitive dysfunction that could interfere with capacity to engage in therapy; a history of substance or alcohol abuse or dependence (other than nicotine) in the last 6 months or otherwise unable to commit to refraining from alcohol use during the acute period of study participation.
• PTSD within the past 6 months. Entry of patients with other mood or anxiety disorders will be permitted if the SAD is judged to be the predominant disorder, in order to increase accrual of a clinically relevant sample. Patients with significant suicidal ideation (MADRS item 10 score > 3) or who have enacted suicidal behaviors within 6 months prior to intake will be excluded from study participation and referred for appropriate clinical intervention.
• Patients must be off concurrent psychotropic medication (e.g., antidepressants, anxiolytics, beta blockers) for at least 2 weeks prior to initiation of randomized treatment.
• 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.
• Pregnant women, lactating women, and women of childbearing potential who are not using medically accepted forms of contraception (e.g., IUD, oral contraceptives, barrier devices, condoms and foam, or implanted progesterone rods stabilized for at least 3 months).
• Any concurrent psychotherapy initiated within 3 months of baseline, or ongoing psychotherapy of any duration directed specifically toward treatment of the SAD is excluded. Prohibited psychotherapy includes CBT or psychodynamic therapy focusing on exploring specific, dynamic causes of the phobic symptomatology and providing management skills. General supportive therapy initiated > 3 months prior is acceptable.
• Prior non-response to adequately-delivered exposure (i.e., as defined by the patient's report of receiving specific and regular exposure assignments as part of a previous treatment).
• Patients with a history of head trauma causing loss of consciousness, seizure or ongoing cognitive impairment. Current use of isoniazid or ethionamide compounds
• Insufficient command of the English language

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tailored Post-Session DCS; Individuals in this condition will receive 5 weeks of CBT for social anxiety disorder and two pills (i.e. one placebo before and one dcs/placebo after the session). The type of pill (i.e. dcs vs. placebo) will be determined after the session.	Drug: Placebo; Sugar pill; Drug: D-Cycloserine; D-cycloserine is a medication thought to be associated with fear extinction.; Other Names: D-cycloserine, DCS; Behavioral: Cognitive Behavioral Therapy; This will be a 5-session version of a group CBT protocol with 4-6 patients and 2 therapists per group emphasizing repeated exposure practices. Session 1 involves an introduction and orientation to the CBT model. Sessions 2-5 emphasize repeated exposure tasks, which consist of role-play activities to confront fearful situations in a group setting while disputing cognitive distortions (coupled with the fading of safety behaviors). At the conclusion of each exposure session, patients will be encouraged to continue to apply home-practice strategies (such as giving speeches in front of a mirror). Continued practice of the interventions will be considered part of treatment, and patients will be asked to refrain from alternative treatment for four weeks following completion of the last treatment session.; Other Names: CBT
Active Comparator: Pre-Session DCS; Individuals in this condition will receive 5 weeks of CBT for social anxiety disorder and two pills (i.e. one dcs before and one placebo after the session).	Drug: Placebo; Sugar pill; Drug: D-Cycloserine; D-cycloserine is a medication thought to be associated with fear extinction.; Other Names: D-cycloserine, DCS; Behavioral: Cognitive Behavioral Therapy; This will be a 5-session version of a group CBT protocol with 4-6 patients and 2 therapists per group emphasizing repeated exposure practices. Session 1 involves an introduction and orientation to the CBT model. Sessions 2-5 emphasize repeated exposure tasks, which consist of role-play activities to confront fearful situations in a group setting while disputing cognitive distortions (coupled with the fading of safety behaviors). At the conclusion of each exposure session, patients will be encouraged to continue to apply home-practice strategies (such as giving speeches in front of a mirror). Continued practice of the interventions will be considered part of treatment, and patients will be asked to refrain from alternative treatment for four weeks following completion of the last treatment session.; Other Names: CBT
Placebo Comparator: Placebo; Individuals in this condition will receive 5 weeks of CBT for social anxiety disorder and two pills (i.e. one placebo before and one placebo after the session).	Drug: Placebo; Sugar pill; Behavioral: Cognitive Behavioral Therapy; This will be a 5-session version of a group CBT protocol with 4-6 patients and 2 therapists per group emphasizing repeated exposure practices. Session 1 involves an introduction and orientation to the CBT model. Sessions 2-5 emphasize repeated exposure tasks, which consist of role-play activities to confront fearful situations in a group setting while disputing cognitive distortions (coupled with the fading of safety behaviors). At the conclusion of each exposure session, patients will be encouraged to continue to apply home-practice strategies (such as giving speeches in front of a mirror). Continued practice of the interventions will be considered part of treatment, and patients will be asked to refrain from alternative treatment for four weeks following completion of the last treatment session.; Other Names: CBT
Active Comparator: Non-Tailored Post-Session DCS; Individuals in this condition will receive 5 weeks of CBT for social anxiety disorder and two pills (i.e. one placebo before and one dcs after the session).	Drug: Placebo; Sugar pill; Drug: D-Cycloserine; D-cycloserine is a medication thought to be associated with fear extinction.; Other Names: D-cycloserine, DCS; Behavioral: Cognitive Behavioral Therapy; This will be a 5-session version of a group CBT protocol with 4-6 patients and 2 therapists per group emphasizing repeated exposure practices. Session 1 involves an introduction and orientation to the CBT model. Sessions 2-5 emphasize repeated exposure tasks, which consist of role-play activities to confront fearful situations in a group setting while disputing cognitive distortions (coupled with the fading of safety behaviors). At the conclusion of each exposure session, patients will be encouraged to continue to apply home-practice strategies (such as giving speeches in front of a mirror). Continued practice of the interventions will be considered part of treatment, and patients will be asked to refrain from alternative treatment for four weeks following completion of the last treatment session.; Other Names: CBT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Social Anxiety Symptom Severity	The main outcome was a composite Z-score from the Liebowitz Social Anxiety Scale (LSAS) and the Social Phobic Disorders Severity and Change Form (SPD-SC Form). "The Composite Z-score of the LSAS and SPD-SC Form indicates the number of standard deviations away from the mean. A Z-score of 0 is equal to the mean of a reference population. Negative numbers indicate values lower symptom severity and positive numbers indicate higher symptom severity. The LSAS is a 24-item scale that measures fear and avoidance in social and performance situations within the last week, using 0 (no fear/never avoids) to 3 (severe fear/usually avoids) scale. LSAS scores range from 0-144 with higher scores indicated worse outcomes. The SPD-S is the Clinical Global Impression Scale27 adapted for SAD, which instructs evaluators to use a 7-point scale (1=normal, not at all ill; 7=among the most extremely ill patients) to index the severity of social anxiety.	Assessments took place at multiple time points from baseline to 3-month follow-up. The three-month is reported

Collaborators and Investigators

• Sponsor: University of Texas at Austin
• Collaborators: Boston University; Rush University Medical Center; Southern Methodist University
• Investigators: Principal Investigator: Jasper A Smits, Ph.D., University of Texas at Austin; Principal Investigator: Mark Pollack, M.D., Rush University Medical Center; Principal Investigator: Stefan Hofmann, Ph.D., Boston University

Publications and helpful links

General Publications

• Dutcher CD, Dowd SM, Zalta AK, Taylor DJ, Rosenfield D, Perrone A, Otto MW, Pollack MH, Hofmann SG, Smits JAJ. Sleep quality and outcome of exposure therapy in adults with social anxiety disorder. Depress Anxiety. 2021 Nov;38(11):1182-1190. doi: 10.1002/da.23167. Epub 2021 May 19.
• Smits JAJ, Pollack MH, Rosenfield D, Otto MW, Dowd S, Carpenter J, Dutcher CD, Lewis EM, Witcraft SM, Papini S, Curtiss J, Andrews L, Kind S, Conroy K, Hofmann SG. Dose Timing of D-Cycloserine to Augment Exposure Therapy for Social Anxiety Disorder: A Randomized Clinical Trial. JAMA Netw Open. 2020 Jun 1;3(6):e206777. doi: 10.1001/jamanetworkopen.2020.6777.
• Hofmann SG, Papini S, Carpenter JK, Otto MW, Rosenfield D, Dutcher CD, Dowd S, Lewis M, Witcraft S, Pollack MH, Smits JAJ. Effect of d-cycloserine on fear extinction training in adults with social anxiety disorder. PLoS One. 2019 Oct 17;14(10):e0223729. doi: 10.1371/journal.pone.0223729. eCollection 2019.
• Hofmann SG, Carpenter JK, Otto MW, Rosenfield D, Smits JA, Pollack MH. Dose timing of D-cycloserine to augment cognitive behavioral therapy for social anxiety: Study design and rationale. Contemp Clin Trials. 2015 Jul;43:223-30. doi: 10.1016/j.cct.2015.06.015. Epub 2015 Jun 23.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2014
• Primary Completion (Actual): July 1, 2018
• Study Completion (Actual): July 1, 2018

Study Registration Dates

• First Submitted: February 17, 2014
• First Submitted That Met QC Criteria: February 19, 2014
• First Posted (Estimate): February 20, 2014

Study Record Updates

• Last Update Posted (Actual): June 9, 2020
• Last Update Submitted That Met QC Criteria: May 26, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Keywords: Social Phobia
• Additional Relevant MeSH Terms: Mental Disorders; Phobic Disorders; Anxiety Disorders; Phobia, Social; 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: R34MH099318 (U.S. NIH Grant/Contract)