Intron Retention as a Homeostatic State Variable for Drug Response and Recovery: Lessons from Depression for Broader Applications.
Norihiro Okada, Kenshiro Oshima, Akiko Maruko, Akinori Nishi, Yoshinori Kobayashi
International Journal of Molecular Sciences April 16, 2026 DOI: 10.3390/ijms27083539 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Longitudinal Peer reviewed |
|---|---|
| Interventions | Hangekobokuto (HKT) Ketamine |
| Topics | Depression Ketamine |
| Keywords | Animals Humans Antidepressive agents Homeostasis Introns Biomarkers Inflammation Drug response Mild cognitive impairment Intron retention Pharmacodynamic biomarker |
| Key findings | Argues that intron retention (IR) can act as a homeostatic state variable and sensitive biomarker of stress adaptation and recovery, often preceding or outperforming differential gene expression readouts. The authors contend IR signatures could serve as pharmacodynamic metrics for blood-based monitoring of drug response, citing IR normalization with hangekobokuto (HKT) and links between pre-treatment IR patterns and innate-immune activity in ketamine non-responders. |
Abstract
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 beyond depression, using early cognitive decline (mild cognitive impairment, MCI) as a stringent, biologically distal test case for blood-based IR/DI readouts and motivating independent cohort replication and longitudinal validation.
Comparable studies
Other narrative reviews on ketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation Adults with treatment-resistant depression | 2021 | Review | |
| Ketamine: a paradigm shift for depression research and treatment | 2019 | Review | |
| Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective | 2019 | Review | |
| Ketamine: A tale of two enantiomers | 2020 | Review | |
| Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor | 2021 | Review |