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. 2025 Jan 1:368:493-502.
doi: 10.1016/j.jad.2024.09.112. Epub 2024 Sep 17.

White matter microstructural and inflammation-based subgroups in bipolar disorder II depression differentiate in depressive and psychotic symptoms

Yuan Cao  1 , Paulo Lizano  2 , Meng Li  3 , Tara Chand  4 , Huan Sun  5 , Xiaoqin Zhou  6 , Gaoju Deng  7 , Xipeng Long  8 , Jinshi Mu  9 , Qiyong Gong  10 , Martin Walter  11 , Changjian Qiu  12 , Zhiyun Jia  13
Affiliations

White matter microstructural and inflammation-based subgroups in bipolar disorder II depression differentiate in depressive and psychotic symptoms

Yuan Cao et al. J Affect Disord. .

Abstract

Background: Elevated inflammation and impaired white matter (WM) microstructure have been observed in bipolar disorder (BD). The link between inflammation, WM integrity, and psychiatric symptoms in BD-II depression (BDII-D) remains unknown. We aimed to define BDII-D subgroups through the interplay of inflammation and WM microstructure, and to explore differences in psychiatric symptoms between subgroups, thus offering insight into elucidating the explanatory measures linked to BDII-D.

Methods: WM differences were compared between 146 BDII-D individuals and 151 health controls (HCs) by Tract-Based Spatial Statistics. Partial correlation with multiple comparison corrections was used to explore associations between WM, inflammation, and psychiatric symptoms. The canonical correlation analysis metrics of WM and inflammation followed by k-means clustering were used to define WM microstructural-inflammation subgroups of BDII-D. The differences in clinical profiles were compared between the subgroups.

Results: Compared with HCs, BDII-D showed significant WM alterations in the anterior thalamic radiation (ATR), cingulum, forceps, and inferior fronto-occipital fasciculus. In BDII-D, lower fraction anisotropy (FA) within the right ATR and cingulum were significantly associated with higher interleukin-6, while lower FA in the cingulum and lower axial diffusivity in the forceps major exhibited significant links with higher C-reactive protein. Among the subgroups identified, subgroup II characterized by elevated inflammation and impaired WM integrity displayed greater psychiatric symptoms.

Conclusions: WM alterations are concentrated in emotional neurocircuits and are linked to inflammation in BDII-D. WM-inflammation subgroups exhibit distinct variations in psychiatric symptoms. Thus, WM alterations and inflammation might be an explanatory process in the pathophysiology of BDII-D.

Keywords: Bipolar II depression; Canonical correlation analysis; Inflammatory cytokines; K-means clustering; Subgroup; White matter.

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Conflict of interest statement

Declaration of competing interest MW is a member of the advisory boards and gave presentations for the following companies: Boehringer Ingelheim, Germany; Bayer AG, Germany; and Biologische Heilmittel Heel GmbH, Germany. MW has further conducted studies with institutional research support from HEEL and from Janssen Pharmaceutical Research for a clinical trial (IIT) on ketamine in patients with major depression unrelated to this investigation. All other authors report no conflict of interest.