Intron Retention as a Homeostatic State Variable for Drug Response and Recovery: Lessons from Depression for Broader Applications

Clinically robust molecular biomarkers for depression have remained elusive, despite extensive transcriptomic research. This gap is consequential: depression is prevalent and heterogeneous, yet objective measures to quantify burden, stratify patients, and track recovery remain limited. Here we review evidence that intron retention (IR) can serve as a homeostatic state variable—and therefore a sensitive biomarker—reporting stress adaptation and recovery at an upstream regulatory layer, often preceding or outperforming differential gene expression (DEG) readouts. Mechanistically, IR enables bidirectional fine-tuning of effective gene output: increased IR (IncIR) can throttle output under overload, whereas decreased IR (DecIR) releases this brake to restore gene output. Because these shifts are reversible and treatment-responsive, IR signatures can function not only as disease markers but also as pharmacodynamic metrics for blood-based monitoring of drug response and recovery. To evaluate the clinical utility of IR, we use depression as a proof-of-concept and focus on two interventions: (i) the Kampo formula hangekobokuto (HKT), which is associated with IR normalization consistent with reduced peripheral inflammatory load. and (ii) ketamine, where IR patterns measured before ketamine treatment in non-responders are linked to stronger innate-immune/antiviral activity, suggesting a higher inflammatory load that may limit treatment benefit. Finally, we discuss transdiagnostic extensions using early cognitive decline as a concrete example. Although peripheral blood may only indirectly reflect the primary drivers of MCI-stage dementia risk—potentially yielding smaller IR/DI effect sizes than in depression—consistent group-level shifts can still emerge in adequately powered cohorts, supporting IR as a practical blood-based readout even when causal pathology lies outside the blood.