Transcriptional Profiles in Nucleus Accumbens of Antidepressant Resistance in Chronically Stressed Mice.

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.

Study at a glance

Abstract

Unsuccessful response to several courses of antidepressants is a core feature of treatment-resistant depression (TRD), a severe condition that affects a third of patients with depression treated with conventional pharmacotherapy. However, the molecular mechanisms underlying TRD remain poorly understood. Here, we assessed the successful vs. unsuccessful response to ketamine (KET) in chronically stressed mice that failed to respond to initial treatment with fluoxetine (FLX) as a rodent model of TRD and characterized the associated transcriptional profiles in the nucleus accumbens (NAc) using RNA-sequencing. We observed that failed treatment with FLX exerts a priming effect that promotes behavioral and transcriptional responses to subsequent ketamine treatment. We also identified specific gene networks that are linked to both susceptibility to stress and resistance to antidepressant response. Collectively, these findings offer valuable insights into the molecular mechanisms underlying antidepressant resistance and help address a critical gap in preclinical models of TRD.