Amygdala activity after subchronic escitalopram administration in healthy volunteers: A pharmaco-functional magnetic resonance imaging study

Abstract

Background: Selective serotonin reuptake inhibitors (SSRIs) are used for the treatment of several conditions including anxiety disorders, but the basic neurobiology of serotonin function remains unclear. The amygdala and prefrontal cortex are strongly innervated by serotonergic projections and have been suggested to play an important role in anxiety expression. However, serotonergic function in behaviour and SSRI-mediated neurobiological changes remain incompletely understood.

Aims: To investigate the neural correlates of subchronic antidepressant administration.

Methods: We investigated whether the 2- to 3-week administration of a highly selective SSRI (escitalopram) would alter brain activation on a task robustly shown to recruit the bilateral amygdala and frontal cortices in a large healthy volunteer sample. Participants performed the task during a functional magnetic resonance imaging acquisition before (n = 96) and after subchronic escitalopram (n = 46, days of administration mean (SD) = 15.7 (2.70)) or placebo (n = 40 days of administration mean (SD) = 16.2 (2.90)) self-administration.

Results: Compared to placebo, we found an elevation in right amygdala activation to the task after escitalopram administration without significant changes in mood. This effect was not seen in the left amygdala, the dorsomedial region of interest, the subgenual anterior cingulate cortex or the right fusiform area. There were no significant changes in connectivity between the dorsomedial cortex and amygdala or the subgenual anterior cingulate cortex after escitalopram administration.

Conclusions: To date, this most highly powered study of subchronic SSRI administration indicates that, contrary to effects often seen in patients with anxiety disorders, subchronic SSRI treatment may increase amygdala activation in healthy controls. This finding highlights important gaps in our understanding of the functional role of serotonin.

Keywords: Functional magnetic resonance imaging; antidepressants; anxiety; emotion; escitalopram.

Figure 1.

Schematic of the emotional face processing task. Participants viewed blocks of happy, fearful and neutral faces, separated by a fixation cross. There were 12 blocks of stimuli in total, and four of each emotion. Participants were instructed to label the gender of the faces displayed via button press.

Figure 2.

Activation changes during emotional face processing (faces vs fixation cross: red-yellow colour indicates increases, blue decreases) were seen within the (a) bilateral amygdala, (b) dorsal ROI and (c) sgACC. These baseline changes were recapitulated in the betas extracted from (d) the right amygdala, (e) the left amygdala, (f) dorsal ROI and (g) the sgACC. Significantly increased activation of the task was seen (h) in the right amygdala after subchronic escitalopram administration, but not within the (i) left amygdala, (j) dorsal ROI (although there was a trend level increase) and (k) sgACC. Significant results were considered at pSVC < 0.05 (small volume-corrected analyses) and p < 0.05 (average parameter analyses).

Figure 3.

Significant connectivity (gPPI β value) during emotional face processing (faces vs fixation cross) between the dorsal ROI and (a) the right amygdala (but not (b) the left amygdala) and (c) the sgACC. No significant changes in connectivity between the dorsal ROI and the (d) right amygdala, (e) left amygdala or (f) sgACC were seen following subchronic escitalopram administration. (g) The dorsal ROI mask was used for these analyses. Significant results were considered at pSVC < 0.05 (small volume-corrected analyses) and p < 0.05 (average parameter analyses).