New research suggests intrinsic differences in serotonergic neuron morphology and the resulting circuitry may contribute to selective serotonin reuptake inhibitor (SSRI) resistance in patients with major depressive disorder (MDD).
In a study published in Molecular Psychiatry, 803 MDD patients were taken off all medication and started on an eight-week regimen of citalopram or escitalopram. Depressive behaviours were assessed with the Quick Inventory of Depressive Symptomatology and Hamilton Depression Rating Scale.
Given the substantial heterogeneity within the MDD patient population, patients at extreme ends of the SSRI response spectrum were selected for cellular analyses. Within the entire cohort, three extreme SSRI-remitters (R) and three extreme SSRI-non-remitters (NR) were identified, from whom induced pluripotent stem cells (iPSCs) and serotonergic neurons were generated.
Serotonin (5-HT) biochemistry revealed no significant differences in 5-HT release and re-uptake or in genes related to 5-HT biochemistry.
NR patient-derived serotonergic neurons exhibited altered neurite growth and morphology downstream, with lowered expression of key protocadherin alpha genes (PCDHA6 and PCDHA8) compared with healthy controls and responders. Furthermore, knockdown of protocadherin alpha genes directly regulated iPSC-derived neurite length and morphology.