Functional effects of chronic paroxetine versus placebo on the fear, stress and anxiety brain circuit in Social Anxiety Disorder: initial validation of an imaging protocol for drug discovery.

Recent studies suggest that pharmacologic effects of anxiolytic agents can be mapped as functional changes in the fear, stress and anxiety brain circuit. In this work we investigated the effects of a standard treatment, paroxetine (20mg/day), in subjects with Social Anxiety Disorder (SAD) versus placebo using different fMRI paradigms. The fMRI sessions, performed before and after the treatment, consisted of a public exposition of recorded performance task (PERPT), an emotional face processing task (EFPT) and a 6-min resting state followed by an off-scanner public speaking test. Paroxetine significantly improved the clinical conditions of SAD patients (n=17) vs. placebo (n=16) as measured with Clinical Global Inventory - Improvement (CGI-I) while no change was seen when using Liebowitz Social Anxiety Scale, as expected given the small size of the study population. Paroxetine reduced the activation of insula, thalamus and subgenual/anterior cingulate cortex (ACC) in PERPT. Resting-state fMRI assessment using Independent Component Analysis indicated that paroxetine reduced functional connectivity in insula, thalamus and ACC when compared with placebo. Both paradigms showed significant correlation with CGI-I in rostral prefrontal cortex. Conversely, paroxetine compared to placebo produced activation of right amygdala and bilateral insula and no effects in ACC when tested with EFPT. No treatment effects on distress scores were observed in the off-scanner Public Speaking Test. Overall this study supports the use of fMRI as sensitive approach to explore the neurobiological substrate of the effects of pharmacologic treatments and, in particular, of resting state fMRI given its simplicity and task independence.