Approximately half of patients with social anxiety disorder (SAD) do not achieve remission from cognitive behavioral therapy, which relies on direct extinction of social fears. Direct extinction can be inefficient and costly; social learning theories propose that social fears may be extinguished vicariously through others’ safety experiences. Potentiating vicarious extinction through pharmacologic agents such as oxytocin, an endogenous neuromodulator involved in social affiliation and fear regulation, may offer a novel strategy for augmenting extinction in SAD.
We hypothesized that vicarious extinction would reduce conditioned threat responses in SAD, oxytocin would potentiate the effects of vicarious extinction, and oxytocin’s effects would be moderated by gender. In this randomized, double-blind, placebo-controlled study, participants (n = 104; n = 51 SAD, n = 53 healthy controls) first completed an acquisition procedure outside of the scanner, and received 24 IU intranasal oxytocin or matching placebo prior to completing a vicarious extinction and reinstatement test while undergoing fMRI and recording skin conductance responses (SCR). During acquisition, there was a significant main effect of stimulus type, as all participants displayed greater SCR in CS+s compared to CS-, suggesting that the task was effective in evoking conditioned threat.
SCR findings partially supported a pattern of attenuated conditioned threat responses to the vicariously extinguished cue (CS + S) compared to the unextinguished cue (CS + R), but there remained a significant difference between the CS + S and CS-, and this was evident across all participants, not just in SAD. fMRI results did not reveal benefits of vicarious extinction in SAD. Contrary to hypotheses, there were no effects of diagnostic group or drug condition or their interaction; oxytocin showed no effects on SCRs or brain responses to CS + R versus CS + S cues. However, as expected, oxytocin demonstrated gender-dependent effects, as fMRI results showed significant drug by gender interactions in the amygdala, insula, hippocampus, and ventromedial prefrontal cortex, with oxytocin increasing threat responding to vicariously non-extinguished CS+ in men compared to women.
Findings underscore effects of oxytocin that vary by gender in fear regulation-related neural circuitry. The authors thank Tonix Pharmaceuticals, Inc., for providing study drug (TNX-1900 and placebo) as part of a drug donation agreement with the University of Washington. TNX-1900 is a proprietary formulation of intranasal oxytocin, an investigational new drug that has not been approved for any indication.
The authors also thank Mark Pettet for assistance in writing custom scripts for analysis of psychophysiological data. This work was funded by the Brain and Behavior Research Foundation Young Investigator Grant (AF), University of Washington Royalty Research Fund (AF), and NEI EY07031 (GG). Department of Psychology, University of Washington, Seattle, WA, USA Gillian Grennan, Xiaoqian Xiao, Margaret A.
Iannazzi, Yuchen Zhao, Kavin Srinakarin & Angela Fang Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA Department of Psychology, Stockholm University, Stockholm, Sweden Department of Clinical Neuroscience, Division of Psychology, Karolinska Institutet, Stockholm, Sweden Correspondence to Gillian Grennan or Angela Fang. The authors have no competing interests to disclose. The study was approved by the University of Washington Human Subjects Division Institutional Review Board Committee J (IRB#00005647).
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