Single dose of mirtazapine modulates whole-brain functional connectivity during emotional narrative processing

The link between neurotransmitter-level effects of antidepressants and their clinical effect remain poorly understood. A single dose of mirtazapine decreases limbic responses to fearful faces in healthy subjects, but it is unknown whether this effect applies to complex emotional situations and dynamic connectivity between brain regions. Thirty healthy volunteers listened to spoken emotional narratives during functional magnetic resonance imaging (fMRI). In an open-label design, 15 subjects received 15 mg of mirtazapine two hours prior to fMRI while 15 subjects served as a control group. We assessed the effects of mirtazapine on regional neural responses and dynamic functional connectivity associated with valence and arousal. Mirtazapine attenuated responses to unpleasant events in the right fronto-insular cortex, while modulating responses to arousing events in the core limbic regions and the cortical midline structures (CMS). Mirtazapine decreased responses to unpleasant and arousing events in sensorimotor areas and the anterior CMS implicated in self-referential processing and formation of subjective feelings. Mirtazapine increased functional connectivity associated with positive valence in the CMS and limbic regions. Mirtazapine triggers large-scale changes in regional responses and functional connectivity during naturalistic, emotional stimuli. These span limbic, sensorimotor, and midline brain structures, and may be relevant to the clinical effectiveness of mirtazapine.