Effect of d-cycloserine on fear extinction training in adults with social anxiety disorder

Abstract

Preclinical and clinical data have shown that D-cycloserine (DCS), a partial agonist at the N-methyl-d-aspartate receptor complex, augments the retention of fear extinction in animals and the therapeutic learning from exposure therapy in humans. However, studies with non-clinical human samples in de novo fear conditioning paradigms have demonstrated minimal to no benefit of DCS. The aim of this study was to evaluate the effects of DCS on the retention of extinction learning following de novo fear conditioning in a clinical sample. Eighty-one patients with social anxiety disorder were recruited and underwent a previously validated de novo fear conditioning and extinction paradigm over the course of three days. Of those, only 43 (53%) provided analyzable data. During conditioning on Day 1, participants viewed images of differently colored lamps, two of which were followed by with electric shock (CS+) and a third which was not (CS-). On Day 2, participants were randomly assigned to receive either 50 mg DCS or placebo, administered in a double-blind manner 1 hour prior to extinction training with a single CS+ in a distinct context. Day 3 consisted of tests of extinction recall and renewal. The primary outcome was skin conductance response to conditioned stimuli, and shock expectancy ratings were examined as a secondary outcome. Results showed greater skin conductance and expectancy ratings in response to the CS+ compared to CS- at the end of conditioning. As expected, this difference was no longer present at the end of extinction training, but returned at early recall and renewal phases on Day 3, showing evidence of return of fear. In contrast to hypotheses, DCS had no moderating influence on skin conductance response or expectancy of shock during recall or renewal phases. We did not find evidence of an effect of DCS on the retention of extinction learning in humans in this fear conditioning and extinction paradigm.

Trial registration: ClinicalTrials.gov NCT02066792.

Conflict of interest statement

The authors have read the journal's policy and the authors have the following competing interests: SGH receives financial support from the Alexander von Humboldt Foundation and compensation for his work as editor from SpringerNature and the Association for Psychological Science. He also receives compensation for this role as an advisor from the Palo Alto Health Sciences and for his work as a Subject Matter Expert from John Wiley & Sons, Inc. and SilverCloud Health, Inc. MWO receives financial support for his role as chair on the scientific advisory board for Big Health. Ltd. MP receives financial support for Consultation and his role on the advisory boards for the following Almatica Pharma, Aptinyx, Brackett Global, Brainsway, EMA Wellness, Seelos Therapeutics, Sophren Therapeutics; Research Grants: NIH, Janssen; Equity: Argus, Doyen Medical, Medavante, Mensante Corporation, Mindsite, Targia Pharmaceuticals; Royalty/patent: SIGH-A, SAFER interviews. JAJS receives compensation for his role as a consultant to Big Health, Ltd. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Schematic of experimental paradigm.

In the habituation phase on Day 1, stimuli (i.e., lamp “turning on” to show one of three colors) were presented across the two contexts (A). In the conditioning phase on Day 1 (B), the color of the lamp light served as a conditioned Stimulus. Three lights were presented randomized and counterbalanced across participants. Two lights were paired with shock at a 62.5% reinforcement rate and served as the conditioned stimuli that either underwent extinction on Day 2 (CS+E) or remained unextinguished until Day 3 (CS+U). A third color, never paired with shock, provided a reference for differential conditioning (CS-). In the extinction phase on Day 2 (C), the CS+E and CS- were presented without shock in a different (safe) context. One hour prior to extinction, participants took either DCS or PBO. In the recall (D) and renewal (E) phases on Day 3, all three stimuli were presented without shock to test between-session extinction retention and generalization of extinction to the threat context, respectively.

Fig 2. Conditioned skin conductance responses (SCR) across all phases of the experiment.

Note. DCS was administered 1 hour prior to extinction. PBO = placebo group, DCS = d-cycloserine, SCR = skin conductance response, SE = 1 standard error, CS- = stimulus that was not paired with shock, CS+E = stimulus that was paired with shock during conditioning and presented in the extinction phase, CS+U = stimulus that was paired with shock during conditioning but not presented in the extinction phase.

Fig 3. Expectancy of shock (US expectancy) following first and last presentation of different conditioned stimuli, across experimental phases.

Note. Ratings were made retrospectively (i.e. after phase concluded). PBO = placebo group, DCS = d-cycloserine, SCR = skin conductance response, SE = 1 standard error, CS- = stimulus that was not paired with shock, CS+E = stimulus that was paired with shock during conditioning and presented in the extinction phase, CS+U = stimulus that was paired with shock during conditioning but not presented in the extinction phase.