Ketamine rapidly and lastingly reduces depression in people with treatment-resistant depression (TRD), but how it works remains unclear. TRD is linked to inflammation, and ketamine may curb inflammatory processes. Whole blood gene expression was compared between 21 healthy controls and 26 TRD patients, and again in TRD patients 24 hours after a single ketamine infusion. Before treatment, TRD patients showed activation of interferon signaling pathways. Among TRD patients, those who later responded to ketamine had higher levels of two glutamate receptor genes (GRM2 and GRIN2D) before the infusion. Ketamine response produced a distinct gene expression signature, but no evidence of anti-inflammatory changes was found. More research is needed on the peripheral immune system's role.
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.