Gene-set analyses converged on synaptic and glutamatergic signaling, implicating glutamate receptor activity and ionotropic receptor complexes as central pathways, consistent with the functional roles of BDNF, MAPK1, and GSK3B in regulating neuronal excitability and synaptic plasticity that underlie antidepressant response and relapse vulnerability in TRD. Here, BDNF is linked to treatment resistant depression.