Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. eric.nestler@mssm.edu.
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.
Treatment-resistant depression (TRD) affects about a third of patients who do not respond to standard antidepressants, yet its molecular basis is poorly understood. In a mouse model of TRD, where chronically stressed mice failed to respond to fluoxetine, subsequent ketamine treatment produced behavioral and transcriptional changes in the nucleus accumbens. Failed fluoxetine treatment primed the mice for a positive response to ketamine, and specific gene networks linked to stress susceptibility and antidepressant resistance were identified. These findings illuminate molecular mechanisms behind antidepressant resistance and address a gap in preclinical TRD models.