Volumes of hippocampal subfields suggest a continuum between schizophrenia, major depressive disorder and bipolar disorder

Abstract

Objective: There is considerable debate as to whether the continuum of major psychiatric disorders exists and to what extent the boundaries extend. Converging evidence suggests that alterations in hippocampal volume are a common sign in psychiatric disorders; however, there is still no consensus on the nature and extent of hippocampal atrophy in schizophrenia (SZ), major depressive disorder (MDD) and bipolar disorder (BD). The aim of this study was to verify the continuum of SZ - BD - MDD at the level of hippocampal subfield volume and to compare the volume differences in hippocampal subfields in the continuum.

Methods: A total of 412 participants (204 SZ, 98 MDD, and 110 BD) underwent 3 T MRI scans, structured clinical interviews, and clinical scales. We segmented the hippocampal subfields with FreeSurfer 7.1.1 and compared subfields volumes across the three diagnostic groups by controlling for age, gender, education, and intracranial volumes.

Results: The results showed a gradual increase in hippocampal subfield volumes from SZ to MDD to BD. Significant volume differences in the total hippocampus and 13 of 26 hippocampal subfields, including CA1, CA3, CA4, GC-ML-DG, molecular layer and the whole hippocampus, bilaterally, and parasubiculum in the right hemisphere, were observed among diagnostic groups. Medication treatment had the most effect on subfields of MDD compared to SZ and BD. Subfield volumes were negatively correlated with illness duration of MDD. Positive correlations were found between subfield volumes and drug dose in SZ and MDD. There was no significant difference in laterality between diagnostic groups.

Conclusion: The pattern of hippocampal volume reduction in SZ, MDD and BD suggests that there may be a continuum of the three disorders at the hippocampal level. The hippocampus represents a phenotype that is distinct from traditional diagnostic strategies. Combined with illness duration and drug intervention, it may better reflect shared pathophysiology and mechanisms across psychiatric disorders.

Keywords: MRI; bipolar disorder; hippocampal subfields; major depressive disorder; psychosis continuum; schizophrenia.

Figure 1

Coronal, sagittal and axial views of 12 hippocampal subfields. The hippocampal subfield volumes were overlaid on whole-brain T1-weighted images in a specific participant in this study. These images were displayed using FreeView. R, right; L, left; (S), superior; I, inferior; (A), anterior; (P), posterior; CA, cornu ammonis; GC-ML-DG, granule cells in the molecular layer of the dentate gyrus; HATA, hippocampal-amygdaloid-transition-area.

Figure 2

Pairwise comparisons of hippocampal subfield volumes across SZ, MDD, and BD. Each violin plot shows the volume distribution of each hippocampal subfield, in which a solid line and two dotted lines indicate the median and quartiles, respectively. Pairwise volume differences were significant at the 0.05 (∗) level after false discovery rate correction at the subfield level. SZ, patients with schizophrenia; MDD, patients with major depression disorder; BD, patients with bipolar disorder; CA, cornu ammonis; GC-ML-DG, granule cells in the molecular layer of the dentate gyrus; HATA, hippocampal-amygdaloid-transition-area.

Figure 3

Relationships between illness duration and hippocampal volumes in each diagnostic group. Non-parametric correlations were statistically significant for bilateral parasubiculum (right, p = 2.52 × 10⁻²; left, p = 1.35 × 10⁻²) in SZ group. SZ, patients with schizophrenia; MDD, patients with major depression disorder; BD, patients with bipolar disorder.