Multidimensional biomarker panels suggest a complex pathological basis for post-stroke depression in the DRN-mPFC circuitNew framework identifies biological markers for depression after a stroke

Post-stroke depression (PSD) severely impedes neurological recovery and remains difficult to manage using a serotonin-centered treatment paradigm alone. This review summarizes evidence suggesting that PSD arises not from a single neurotransmitter deficiency, but from coupled dysregulation across multiple biological dimensions—including monoamines, neuropeptides, neurotrophic factors, and immune-inflammatory mediators—within and beyond the dorsal raphe nucleus–medial prefrontal cortex (DRN–mPFC) circuit. On this basis, we outline a provisional biomarker-informed phenotypic framework for PSD, including the “low-monoamine phenotype,” “high inflammatory burden phenotype”, and “neuropeptide-dominant phenotype.” We further discuss the potential therapeutic implications of this framework and the possible value of multimodal biomarkers for risk stratification and mechanism-guided management. However, these phenotype-treatment links remain preliminary and should be interpreted according to the strength of available evidence, with PSD-specific clinical evidence prioritized over indirect evidence from major depressive disorder and animal/mechanistic studies. This review therefore provides an evidence-informed conceptual framework for future biomarker-guided research in PSD rather than formal treatment recommendations.