Forecasting disease trajectory based on baseline characteristics and symptom dynamics of patients with recurrent major depressive disorder

Background

Major depressive disorder (MDD) is highly recurrent, yet predictors of relapse, recurrence, and persistent symptoms remain incompletely understood [1,2]. Identifying patients who are likely to remain well, experience symptom fluctuation, or remain persistently depressed is essential for developing personalized monitoring and prevention strategies. Using monthly follow-up surveys administered to a subsample of the Korean Mood Disorder Genetic Study-Depression (KOMOGEN-D) cohort, we investigated predictors of short-term disease trajectories in female patients with recurrent MDD.

Methods

Participants were recruited from the KOMOGEN-D cohort [3]. Female patients with recurrent MDD completed a comprehensive baseline interview assessing depressive episode history, stressful life events, family history, childhood adversity, neuroticism, parental bonding, and social relationships. Following the baseline interview, participants were sent a link to a monthly web survey for six months (a total of seven time points including the baseline). Monthly follow-up assessed depressive symptom severity using the Patient Health Questionnaire-9 (PHQ-9) and recent stressful life events including interpersonal, occupational, financial, traumatic, and family-related events. Participants with three or more missing monthly follow-ups were excluded, while PHQ-9 scores for those with two or fewer missing assessments were imputed using k-Nearest Neighbors algorithm (k=5). Gaussian mixture modelling was used as an agnostic, data-driven approach to identify subgroups based on PHQ-9 symptom trajectories. Baseline predictors of disease course were examined using multivariable logistic regression.

Results

Of 185 participants, 174 were included in the trajectory analyses. Gaussian mixture modelling identified three distinct symptom trajectory groups: minimal symptoms (Cluster 1, n = 64), moderate-to-severe symptoms with high variability (Cluster 2, n = 90), and severe persistent depression (Cluster 3, n = 20). Higher baseline PHQ-9 scores, higher neuroticism, childhood maltreatment, greater exposure to stressful life events, and longer prior depressive episodes were associated with increased odds of persistent symptoms or relapse/recurrence. In contrast, being married and living with a spouse and having more close relationships were associated with lower risk. Recent stressful life events showed a temporal association with depressive symptom severity, with events occurring within the prior month showing the strongest association with PHQ-9 scores. This relationship was most evident in the minimal-symptom and fluctuating moderate-to-severe symptom groups, but not in the severe persistent depression group. Compared with the other groups, the severe persistent depression group had higher rates of prior suicide attempts and stress-coupled depressive episodes, whereas the minimal-symptom group showed lower neuroticism and greater social connectedness.

Conclusions

This prospective cohort study identified three distinct short-term symptom trajectories in women with recurrent MDD. Nearly half of the participants showed fluctuating symptoms, while the remainder remained relatively well or persistently severely depressed. The severe persistent depression group had higher rates of prior suicide attempts and stress-coupled depressive episodes, whereas the minimal-symptom group showed lower neuroticism and greater social connectedness. Detailed clinical and psychosocial assessment may help identify relapse-prone or persistently depressed individuals and inform personalized prevention strategies.

References

1. Eaton, W.W., Shao, H., Nestadt, G., Lee, H.B., Bienvenu, O.J., Zandi, P., 2008. Population-based study of first onset and chronicity in major depressive disorder. Arch. Gen. Psychiatry 65, 513–520. https://doi.org/10.1001/archpsyc.65.5.513
2. Solomon, D.A., Keller, M.B., Leon, A.C., Mueller, T.I., Lavori, P.W., Shea, M.T., Coryell, W., Warshaw, M., Turvey, C., Maser, J.D., Endicott, J., 2000. Multiple recurrences of major depressive disorder. Am. J. Psychiatry 157, 229–233. https://doi.org/10.1176/appi.ajp.157.2.229
3. Min, S., Rhee, S.J., Song, Y., Ha, K., Ahn, Y.M., Kendler, K.S., Flint, J., KOMOGEN‐D Group, 2026. Deep Phenotyping at Scale: Study Protocol for the Korean Mood Disorder Genetic Study‐Depression ( KOMOGEN ‐D). Am. J. Med. Genet. B Neuropsychiatr. Genet. 201, 105–115. https://doi.org/10.1002/ajmg.b.33056