In mice with depression-like symptoms from chronic social defeat stress, (R)-ketamine produced more potent and longer-lasting antidepressant effects than (S)-ketamine. RNA sequencing of the prefrontal cortex showed that transforming growth factor (TGF)-β signaling may explain these differences. (R)-ketamine, but not (S)-ketamine, reversed reduced expression of Tgfb1 and its receptors in the prefrontal cortex and hippocampus. Blocking TGF-β1 with inhibitors or a neutralizing antibody prevented (R)-ketamine's antidepressant effects. Depleting microglia also blocked these effects. Recombinant TGF-β1 itself produced rapid and lasting antidepressant effects in mice, suggesting a microglial TGF-β1-dependent mechanism and potential for new human antidepressants.
Treatment-resistant depression (TRD) affects about one-third of people with major depression, leading to higher suicide rates and impaired functioning. Originally defined as nonresponse to tricyclic antidepressants, TRD now includes inadequate response to multiple antidepressant classes, psychotherapy, and neuromodulation. Inconsistent criteria complicate prevalence estimates and diagnosis, with many presumed TRD cases actually involving bipolar depression or other disorders. Neurobiological research identifies glutamatergic dysregulation, default-mode network hyperactivity, impaired neuroplasticity, chronic inflammation, and epigenetic changes as markers. Clinically, patients experience persistent anhedonia, cognitive deficits, and sleep disturbances. Subtypes with distinct treatment responses have been identified, and biomarker-driven categories guide personalized care. Future work must standardize definitions and integrate multimodal biomarkers.