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Molecular Biomarkers in Mood Disorders

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Dear Colleagues,

The implementation of molecular biomarkers for psychiatric illnesses still lags behind other biomedical disciplines, despite their widely recognized utility. This is particularly true for mood disorders, such as major depression and bipolar disorder, which are defined by multifactorial gene–environment etiopathogenesis, high heterogeneity, disability, vulnerability to mental/somatic comorbidities, at-risk behaviors, and relapses. While knowledge on the molecular neurobiology of mood disorders is progressing, revealing alterations in circadian and stress–response aspects and changes in neurotransmitter/neuropeptide metabolism and proinflammatory factors in patients, much remains to be clarified about the biochemical networks involved in the various disease stages.

The aim of this Special Issue is therefore to collect research articles, reviews, meta-analyses, and other works focusing on biomarker measurements in blood cells, plasma/serum, saliva, and urine from patients with mood disorders. Investigations of genetic and epigenetic patterns, exploration of coding and non-coding RNA transcripts, and determinations of molecular phenotypes for patient stratification will be considered, possibly following an integrated molecular biology and biochemistry perspective. Articles should report single or multiparametric analytical approaches, using targeted and/or untargeted technologies, also encompassing proteomics and metabolomics. Such an effort may effectively provide fertile platforms for achieving more personalized therapies with individual and societal impact.

Dr. Lionella Palego
Dr. Valerio Dell’Oste
Guest Editors

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18 pages, 1321 KB

Open AccessReview

The IR-Homeostat Hypothesis: Intron Retention as an Evolutionarily Conserved Fine-Tuning Layer and a Reversible Blood Biomarker of Homeostatic Dysregulation in Mood Disorders

by Norihiro Okada, Akiko Maruko, Kenshiro Oshima, Akinori Nishi and Yoshinori Kobayashi

Int. J. Mol. Sci. 2026, 27(7), 3119; https://doi.org/10.3390/ijms27073119 - 30 Mar 2026

Viewed by 338

Abstract

Major depressive disorder (MDD) lacks reliable laboratory tests for diagnosis and treatment monitoring, underscoring the need for robust molecular readouts in blood. Beyond symptom-based classification, MDD can also be viewed as a condition involving impaired homeostatic regulation across stress-responsive, immune, metabolic, and neural systems. Consistent with this perspective, altered intron retention (IR) patterns have been observed in peripheral blood in depression-related and treatment-response contexts, supporting the translational relevance of this RNA-processing layer to mood disorders. A key observation underpinning this review is that IR can function as a reversible, intervention-responsive readout of physiological state. In a pre-symptomatic stress-like state in klotho mutant mice (a premature-aging model), widespread IR increases revert toward a healthy pattern upon treatment, suggesting that IR is embedded in a controllable homeostatic layer. Against the backdrop of limited cross-cohort transferability of differential gene expression (DGE) signatures, we propose that IR provides a mechanistically grounded biomarker layer because it reports regulated RNA processing states rather than context-fragile abundance endpoints. We operationalize IR as a post-transcriptional “throttle” on effective gene output, with increased IR/detained intron (DI) states acting as a reversible brake and decreased IR acting as an accelerator that increases translation-competent mRNA supply. Mechanistic exemplars across immune, metabolic, and neuronal systems (e.g., IFNG, OGT, MAT2A, neuronal activity-triggered intron excision, and intron detention-mediated stemness/differentiation switching in adult neural stem cells) show that defined inputs can switch IR/DI states to tune output kinetics. Integrating these findings, we propose an “Intron Retention Homeostat” (IR-Homeostat) model in which cells sense deviations from physiological set points and implement feedback control of gene output through switchable IR/DI regulation. This framework positions IR not only as a robust state readout for stratification, treatment response prediction, and pharmacodynamic profiling, but also as a tractable entry point to identify the molecular sensors and mediators that couple homeostatic signals to RNA processing control. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Mood Disorders)

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