Norepinephrine system dysconnectivity in major depressive disorder: the effect of short term SSRI treatment

Despite the long history of norepinephrine hypothesis in depression, the neuropathology involving norepinephrine remains elusive. This study aims to map the whole-brain functional connectivity (FC) of the major norepinephrine nucleus locus coeruleus (LC) and further investigate the effect of escitalopram, an antidepressant with minimal direct norepinephrine effects, on the LCNE system in patients with major depressive disorder (MDD). Totally 253 MDD patients and 227 healthy controls (HCs) were recruited. The Philips-scanning dataset from Xiangya (52 patients and 88 HCs) served as the discovery sample, while the Siemens-scanning dataset from Xiangya (95 patients and 90 HCs) served as the across-scanner sample and the dataset from Inner Mongolia (88 patients and 53 HCs) as the across-center replication sample. Forty-eight patients entered a naturalistic observational trial of 8-weeks of escitalopram-only treatment. Bilateral LC were selected as regions of interest for FC analysis. Compared to HCs, patients exhibited decreased LCNE system connectivity with the multimodal association (dorsolateral/medial prefrontal) cortices and increased connectivity with the sensory/motor cortex. This imbalanced FC pattern replicated in two independent samples and consistently correlated with depressive symptom severity. The LCNE system dysconnectivity in MDD mapped with a significant overlap on the norepinephrine transporter distribution based on prior PET data. As expected, no significant changes of the LCNE connectivity occurred with 8-weeks of escitalopram treatment. We provide robust evidence for a striking sensory-multimodal imbalance in LCNE system connectivity across three independent samples, with a potential link to NE transporter chemoarchitecture, that is not alleviated by a serotonin selective antidepressant agent.