Dose Timing of D-Cycloserine to Augment Exposure Therapy for Social Anxiety Disorder: A Randomized Clinical Trial

Abstract

Importance: Findings suggest that the efficacy of D-cycloserine (DCS) for enhancing exposure therapy may be strongest when administered after sessions marked by low fear at the conclusion of exposure practice. These findings have prompted investigation of DCS dosing tailored to results of exposure sessions.

Objective: To compare tailored postsession DCS administration with presession DCS administration, postsession DCS administration, and placebo augmentation of exposure therapy for social anxiety disorder.

Design, setting, and participants: This double-blind randomized clinical trial involved adults with social anxiety disorder enrolled at 3 US university centers. Symptom severity was assessed at baseline, weekly during treatment, and at 1-week and 3-month follow-up. Data analysis was performed from September 2019 to March 2020.

Interventions: Participants completed a 5-session treatment and received pills commensurate with their condition assignment at sessions 2 through 5, which emphasized exposure practice.

Main outcomes and measures: Symptom severity was evaluated by the Liebowitz Social Anxiety Scale and Social Phobic Disorders-Severity Form as administered by independent evaluators.

Results: A total of 152 participants were enrolled (mean [SD] age, 29.24 [10.16] years; 84 men [55.26%]). Compared with placebo, presession and postsession conditions showed greater symptom improvement (b = -0.25; 95% CI, -0.37 to -0.13; P < .001; d = 1.07; and b = -0.20; 95% CI, -0.32 to -0.07; P = .002; d = 0.85) and lower symptom severity (b = -0.51; 95% CI, -0.81 to -0.21; P < .001; d = 0.76; and b = -0.49; 95% CI, -0.80 to -0.18; P = .002; d = 0.72) at 3-month follow-up. No differences were found between presession and postsession conditions. The tailored condition showed no advantage over placebo. Compared with the tailored condition, presession and postsession conditions evidenced greater decreases (b = -0.22; 95% CI, -0.34 to -0.10; P < .001; d = 0.94; and b = -0.17, 95% CI, -0.29 to -0.04; P = .008; d = 0.72) and lower symptom severity (b = -0.44, 95% CI, -0.73 to -0.14; P = .004; d = 0.64; and b = -0.41, 95% CI, -0.72 to -0.11; P = .008; d = 0.61) at 3-month follow-up.

Conclusions and relevance: Administration of DCS enhanced exposure therapy for social anxiety disorder when given before or after the exposure session. However, the study failed to achieve the aim to develop a tailored clinical application.

Trial registration: ClinicalTrials.gov Identifier: NCT02066792.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Smits reported receiving grants from the National Institute of Mental Health (NIMH), National Institute on Drug Abuse, and the Cancer Prevention and Research Institute of Texas during the conduct of the study; and personal fees from Big Health, Aptinyx, Elsevier, American Psychological Association, and Oxford University Press outside the submitted work. Dr Pollack reported receiving grants from NIMH and Janssen Pharmaceutical during the conduct of the study; personal fees from Almatica, Aptinyx, Brackett, Brainsway, EMA Wellness, Seelos, and Sophren Therapeutics; and speaking fees from Argus, Doyen, Mensante, Mindsite, and Targia outside the submitted work. Dr Otto reported receiving personal fees from Big Health outside the submitted work. Dr Dowd reported receiving grants from NIMH and Janssen Pharmaceutical and personal fees from Wellness Network outside the submitted work. Mr Carpenter reported receiving grants from NIMH during the conduct of the study. Ms Witcraft reported receiving grants from NIMH during the conduct of the study. Mr Papini reported receiving support from the NIMH and the Donald D. Harrington Foundation during the conduct of the study. Dr Andrews reported receiving grants from Boston University during the conduct of the study. Ms Conroy reported receiving grants from NIMH during the conduct of the study. Dr Hofmann reported receiving grants from NIMH and the James McDonnell Foundation, an Alexander von Humboldt Research Award, and personal fees from Springer/Nature, Association for Psychological Science, John Wiley & Son, Palo Alto Health Science, and SilverCloud Health outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. CONSORT Flow Diagram

EOT indicates end of treatment (1-week follow-up).

Figure 2.. Multivariate Outcome by Treatment Condition at Each Assessment Point

LSAS indicates Liebowitz Social Anxiety Scale; and SPD-S, Social Phobic Disorders-Severity Form (SPD-S).