Astrocyte-mediated neuroimmune signaling and extracellular matrix regulation in depression and antidepressant response

Major depressive disorder (MDD) is a debilitating condition that imposes a significant burden on global health, with many patients developing treatment-resistant depression (TRD) despite available interventions. Personalized medicine, which tailors treatment based on individual molecular profiles, offers a promising strategy to address this challenge. The primary objective of this study was to elucidate astrocyte-specific mechanisms underlying differential responses to selective serotonin reuptake inhibitors (SSRIs) in MDD and to identify potential therapeutic targets for overcoming treatment resistance. Astrocytes, key regulators of neurotransmitter metabolism, synaptic activity, and neuroimmune responses, have increasingly been implicated in the pathophysiology of depression. To investigate these processes, we employed human-induced pluripotent stem cell (hiPSC) technology to generate astrocytes from SSRI-responsive patients, SSRI-nonresponsive patients, and healthy controls, thereby capturing patient-specific genetic and epigenetic variations in an in vitro platform. Comprehensive transcriptomic profiling, differential gene expression, and coexpression network analyses revealed distinct patterns in immune signaling, extracellular matrix remodeling, and cell cycle regulation between responders and nonresponders, while transcription factor assessments further indicated altered unfolded protein response signaling in nonresponders. Complementary LINCS-based computational screening identified FDA-approved antidepressants and novel repurposing candidates that counteract the pathological astrocyte states observed in nonresponders. Collectively, these results lay the groundwork for leveraging patient-specific astrocyte models to develop innovative, astrocyte-focused interventions for TRD, although further in vivo validation and larger-scale studies are warranted.