Transcriptional profiles of antidepressant resistance across the corticolimbic pathway of chronically stressed mice.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology June 1, 2026 Trevonn M Gyles, Eric M Parise, Molly Estill et al.
Treatment-resistant depression (TRD) affects about one-third of people with major depressive disorder, but its molecular basis is unclear. In a mouse model, chronic social defeat stress was followed by sequential treatment with fluoxetine and ketamine, allowing classification into antidepressant-responsive and non-responsive animals. RNA sequencing of the nucleus accumbens and prefrontal cortex revealed distinct transcriptional signatures. Prior fluoxetine exposure primed some mice for molecular and behavioral response to ketamine, but this priming was absent in non-responders, indicating that resistance stems not from treatment failure alone but from a lack of adaptive molecular priming. Gene co-expression network analysis identified modules linked to stress susceptibility and antidepressant resistance, offering insight into gene networks underlying TRD.