Relation Between Brain Morphological Features and Psychiatric Hospitalization Risk in Major Depressive and Bipolar Disorders

Abstract

Introduction: Patients with mood disorders, especially, major depressive disorder (MDD) and bipolar disorder (BD), are at heightened risk of relapse and psychiatric rehospitalizations. Therefore, there is an urgent need to identify modifiable biomarkers to inform personalized and intensified prevention strategies for those at the greatest risk of relapse and hospital readmissions. Brain structural measures subserving cognitive function hold particular promise among potential predictive biomarkers.

Methods: In the present study, structural magnetic resonance imaging scans were obtained from 319 patients with BD (n = 241) or MDD (n = 78). [Correction added on 7 March 2025, after first online publication: In the preceding sentence, 'MDD (n=241) or BD (n=78)' has been changed to 'BD (n=241) or MDD (n=78)'.] Longitudinal data on psychiatric hospitalization for up to 10 years were available from the Danish National population-based registers. Interhemispheric hippocampal asymmetry, a putative marker of cognitive function and brain reserve, was calculated for each patient. The association between hippocampal asymmetry and future psychiatric hospitalization was assessed using a cause-specific Cox regression model. Exploratory analyses, also using a cause-specific Cox model, assessed the association of prefrontal and hippocampal gray matter volume and whole-brain white matter volume with hospitalizations.

Results: The results indicated a negative association between rightward hippocampal asymmetry (i.e., left<right) and risk of future hospitalizations (HR = 0.90, corresponding to a 10-year risk reduction of 0.018 for a 1% increase in asymmetry, p = 0.040). Exploratory analysis indicated that a larger right hippocampus volume was associated with a reduced risk of hospitalization (HR = 0.18, p = 0.004) while a larger bilateral dorsolateral prefrontal volume (HR = 1.06, p = 0.01) was associated with an increased risk of hospitalization.

Conclusion: The findings suggest a role for hippocampal and, additionally, prefrontal morphological features in the risk of future psychiatric hospitalizations in mood disorders.

Keywords: bipolar disorder; hippocampus; hospitalization; magnetic resonance imaging; registry data.

FIGURE 1

Sample selection flowchart. Figure 1 provides details of the seven clinical studies from which demographic, clinical, and MRI data from patients with major depressive disorder and bipolar disorder were used for this study. All studies except one (BIO) were intervention trials; however, only pretreatment demographic, clinical, and MRI data were used in the estimation of risk of future psychiatric hospitalizations.

FIGURE 2

Bilateral hippocampus, dorsolateral prefrontal cortex, and anterior cingulate cortex regions of interest. Cortical regions are based on the Desikan–Killiany Atlas and the hippocampus region on the Harvard–Oxford Subcortical Structural Atlas.

FIGURE 3

Aalen–Johansen survival estimates of the probability of being hospitalized in individuals with rightward (R>L) and leftward (L>R) hippocampal asymmetry. The plot illustrates the probability of getting hospitalized in patients with bipolar disorder or major depressive disorder in individuals with L>R hippocampal asymmetry and in those with R>L hippocampal asymmetry. Asymmetry was categorized as L>R and R>L only for visualization purposes, while in the Cox model, hippocampal asymmetry was included as a continuous variable. The risk was estimated using the Aalen–Johansen estimator. The y‐axis represents the cumulative risk of hospitalization, and the x‐axis represents time in years.