Amygdala Subregions Tied to SSRI and Placebo Response in Patients with Social Anxiety Disorder

Abstract

The amygdala is a key structure in the pathophysiology of anxiety disorders, and a putative target for anxiolytic treatments. Selective serotonin reuptake inhibitors (SSRIs) and placebo seem to induce anxiolytic effects by attenuating amygdala responsiveness. However, conflicting amygdala findings have also been reported. Moreover, the neural profile of responders and nonresponders is insufficiently characterized and it remains unknown whether SSRIs and placebo engage common or distinct amygdala subregions or different modulatory cortical areas. We examined similarities and differences in the neural response to SSRIs and placebo in patients with social anxiety disorder (SAD). Positron emission tomography (PET) with oxygen-15-labeled water was used to assess regional cerebral blood flow (rCBF) in 72 patients with SAD during an anxiogenic public speaking task, before and after 6-8 weeks of treatment under doubleblind conditions. Response rate was determined by the Clinical Global Impression-Improvement scale. Conjunction analysis revealed a common rCBF-attenuation from pre-to post-treatment in responders to SSRIs and placebo in the left basomedial/basolateral and right ventrolateral amygdala. This rCBF pattern correlated with behavioral measures of reduced anxiety and differentiated responders from nonresponders. However, nonanxiolytic treatment effects were also observed in the amygdala. All subgroups, including nonresponders, showed deactivation of the left lateral part of the amygdala. No rCBF differences were found between SSRI responders and placebo responders. This study provides new insights into the brain dynamics underlying anxiety relief by demonstrating common amygdala targets for pharmacologically and psychologically induced anxiety reduction, and by showing that the amygdala is functionally heterogeneous in anxiolysis.

Reduced Anterior Temporal and Hippocampal Functional Connectivity During Face Processing Discriminates Individuals with Social Anxiety Disorder from Healthy Controls and Panic Disorder, and Increases Following Treatment

“…In a recent PET study in which SAD subjects responded to either placebo or SSRI treatment, reduction in (amygdala) brain activity was similar in both groups (Faria et al, 2012). Hence, we cannot rule out that left hippocampus-left temporal pole FC would increase in response to any treatment.…”

Placebo Effects: From the Neurobiological Paradigm to Translational Implications

“…This pattern correlates with behavioral measures of reduced anxiety and differentiates responders from nonresponders, with no differences between SSRI responders and placebo responders. Therefore, this pattern is capable of differentiating responders from nonresponders to both SSRI and placebos, which indicates that drugs and placebos act on common amygdala targets and amygdala-frontal connections (Faria et al, 2012(Faria et al, , 2014.…”

“…In social anxiety disorder, positron emission tomography has been used to assess regional cerebral blood flow during an anxiogenic public speaking task, before and after 6-8 weeks of treatment with selective serotonin reuptake inhibitors (SSRI) under double-blind conditions (Faria et al, 2012(Faria et al, , 2014. Conjunction analysis reveals a common attenuation of regional cerebral blood flow from pre-to posttreatment in responders to SSRI and placebo in the left basomedial/basolateral and right ventrolateral amygdala, including amygdala-frontal projections to dorsolateral prefrontal cortex and rostral anterior cingulate cortices ( Figure 1G).…”

Targeting the Modulation of Neural Circuitry for the Treatment of Anxiety Disorders

“…For example, when PET techniques were used to assess the effects of SSRI treatment in patients with SAD, the SSRI-treated subjects showed a selective deactivation of the left lateral amygdala not associated with a reduction in anxiety status. By contrast, the left basomedial/basolateral and right ventrolateral regions of the amygdala were deactivated in both SSRI-treated and placebo patients who showed improvement in anxiety symptoms (Faria et al, 2012) (Fig. 1).…”

“…Red indicates the site of reduced activation irrespective of treatment (placebo versus SSRI) seen in responders; blue indicates a purely pharmacodynamic nonaxiolytic effect on rCBF that was seen in both responders and nonresponders treated with an SSRI; and yellow indicates an effect related to repeated testing. Reprinted with permission from Faria et al (2012). L, left; R, right.…”