Transcriptional Profiles in Nucleus Accumbens of Antidepressant Resistance in Chronically Stressed Mice.
bioRxiv : the preprint server for biology – March 17, 2025
Source: PubMed
Summary
Brain chemistry reveals why some antidepressants work better after failed treatments. Scientists found that when standard antidepressants don't work initially, they actually "prime" the brain to respond better to ketamine therapy later. Using mouse studies, researchers discovered specific gene patterns in a brain reward center that influence both stress sensitivity and treatment success. This insight could help doctors better predict and personalize depression treatments.
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.