Brain activation and connectivity after 2–3 weeks of escitalopram administration in anxiety disorders: A randomised trial

Despite the extensive use of selective serotonin reuptake inhibitors (SSRIs) for anxiety treatment worldwide, their neural mechanism of action remains poorly understood. Based on a systematic line of experimental medicine studies from our laboratory, we posited that SSRI-mediated anxiolysis may be driven by a sustained reduction in positive coupling between the dorsomedial cortex and amygdala in anxious individuals. We conducted a randomised, double-blind, placebo-controlled study investigating amygdala-dorsomedial cortex activation and connectivity during emotion processing after 2–3-week SSRI administration in anxious individuals (ANX) compared to healthy controls (HC). The baseline analysis included 96 HC and 45 ANX participants. The follow-up analysis included 86 HC (placebo n = 40, 73 % female, SSRI n = 46, 74 % female) and 42 ANX participants (placebo n = 22, 86 % female, SSRI n = 20, 80 % female). Consistent with predictions, 2–3 weeks of escitalopram administration altered bilateral amygdala connectivity with the dorsomedial cortex during emotional face processing in people with anxiety disorders compared to healthy controls. However, the effect was in the opposite direction to predicted – positive coupling increased following SSRI in the patient group (right amygdala: ANX-SSRI vs HC-SSRI t = 2.4, p = 0.02; left amygdala: ANX-SSRI vs HC-SSRI t = 2.6, p = 0.01). A follow-up sensitivity analysis confirmed this to be a bilateral effect. These findings suggest that our simple hypothesis of SSRIs inducing a reduction in amygdala-dorsomedial cortex connectivity is incorrect, and the associated brain connectivity may instead increase in the initial weeks of drug administration. The study is registered as a clinical trial at https://www.clinicaltrials.gov . Its clinical trial name is: ‘The Effect of SSRIs on Threat of Shock Potentiated Neural Circuitry’, number: NCT07074652 , URL: https://www.clinicaltrials.gov/study/NCT07074652 . • Selective serotonin reuptake inhibitors are commonly used for anxiety treatment. • However, their neural mechanism of action remains poorly understood. • We investigated brain function after 2–3-week escitalopram administration. • Amygdalocortical connectivity increased in anxious compared to healthy individuals. • Escitalopram-induced changes in brain function may be time- or context-dependent.