Identifying Physiological and Cognitive Indicators of Subthreshold Depression and Major Depressive Disorder Progression Risk

Ayaka Shimizu,1 Satoshi Yokoyama,2 Alan SR Fermin,1 Yuki Mitsuyama,1 Keisuke Mizoi,1 Junichiro Yoshimoto,3,4 Toshi A Furukawa,5 Koki Takagaki,6 Yuri Okamoto,6 Yasumasa Okamoto,1 Go Okada1 1Department of Psychiatry and Neurosciences, Hiroshima University, Hiroshima, Japan; 2Faculty of Humanities, Niigata University, Niigata, Japan; 3Department of Biomedical Data Science, School of Medicine, Fujita Health University, Aichi, Japan; 4Division of Computational Science, International Center for Brain Science, Fujita Health University, Aichi, Japan; 5Office of Institutional Advancement and Communications, Kyoto University, Kyoto, Japan; 6Health Service Center, Hiroshima University, Hiroshima, JapanCorrespondence: Go Okada, Department of Psychiatry and Neuroscience, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan, Tel +81 82 257 5208, Fax +81 82 257 5209, Email [email protected]: Subthreshold depression (StD), depressive symptoms below the diagnostic threshold for major depressive disorder (MDD), is associated with functional impairment and increased risk of MDD onset, but its physiological and cognitive characteristics remain unclear. This study aimed to identify objective markers of StD and validate predictive factors for MDD onset.Patients and Methods: Among 168 university students, participants were classified into a StD group (n=87) and a healthy control group (n=81) using the Beck Depression Inventory-II (BDI-II). The StD group was further subdivided into “low depression” (BDI-II < 10, n = 21) and “maintained depression” (BDI-II ≥ 10, n = 66) based on their BDI-II scores at baseline. Assessments included voice characteristics, heart rate variability (HRV), peripheral body temperature, emotion recognition, and neurocognitive tasks. Between-group differences were tested using ANOVA and MANOVA, and participants were followed for MDD onset at 3-month intervals until March 2024.Results: Compared to controls, the StD group showed increased vocal arousal (p = 0.007), elevated peripheral body temperature (p < 0.001), and reduced low-frequency HRV (p = 0.018). Sustained attention and executive function were impaired (p < 0.05). Accuracy in emotion recognition was lower for happy and surprised expressions (p = 0.030; p = 0.038). Subgroup analysis revealed more pronounced impairments in HRV, executive function, and emotion recognition in the maintained depression subgroup, which also had a higher MDD incidence (7 cases). In contrast, the low depression group showed selective attentional deficits and impaired emotion recognition, but no MDD onset.Conclusion: StD correlates with physiological and cognitive abnormalities reflecting MDD, and persistent symptoms suggest increased progression risk. These findings present candidate markers (voice arousal, HRV, body temperature, emotion recognition) for early identification and risk stratification; however, conclusions should be interpreted cautiously given the exploratory design.Keywords: subthreshold depression, major depressive disorder, heart rate variability, cognitive function, voice analysis, emotion recognition