Acute 5-HT reuptake blockade potentiates human amygdala reactivity

Abstract

Variability in serotonin (5-HT) function is associated with individual differences in normal mood and temperament, as well as psychiatric illnesses, all of which are influenced by amygdala function. This study evaluated the acute effects of 5-HT reuptake blockade on amygdala function using pharmacological functional MRI. Eight healthy men completed a double-blind balanced crossover study with the selective 5-HT reuptake inhibitor, citalopram (20 mg infused over 30 min), and normal saline. Amygdala reactivity in response to novel facial expressions was assessed on three successive scans, once before drug/placebo infusion, once early in the infusion, and once at the end of infusion. Acute citalopram administration resulted in concentration-dependent increases in human amygdala reactivity to salient stimuli. The current pattern of 5-HT-mediated amygdala reactivity may represent an important pathway through which SSRIs achieve an antidepressant effect. Intriguingly, our data may also reveal a mechanism contributing to clinical observations of extreme agitation, restlessness, and suicidal ideation in some individuals during acute SSRI treatment. Developing a comprehensive model of how 5-HT modulates human amygdala reactivity supporting behavioral and physiological arousal will be instrumental for our understanding of basic neurobehavioral processes, their dysfunction in psychiatric illnesses, and their contribution to mechanism of treatment response.

Figure 1

(a) Amygdala clusters exhibiting greater activation as a function of acute citalopram, Left amygdala (−24, −6, −22) cluster size = 115 voxels, T = 6.05, p < 0.001; right amygdala (22, 4, −16) cluster size = 56 voxels, T = 3.39, p = 0.006. Individual fMRI responses at baseline and at end of citalopram infusion for left amygdala (b) and right amygdala (c).

Figure 2

Change in left amygdala reactivity (−26, −6, −26) between baseline and late infusion during citalopram and placebo. Paired t-test (t = 5.35, df = 7, p = 0.001).

Figure 3

Amygdala reactivity correlates with citalopram concentration. Scans are color coded (time 2 is shaded, time 3 is solid). Citalopram concentrations could not be estimated for one subject due to missing plasma samples (n = 7 for this analysis only).