Familial risk for major depression: differential white matter alterations in healthy and depressed participants

Psychol Med. 2023 Aug;53(11):4933-4942. doi: 10.1017/S003329172200188X. Epub 2022 Sep 2.


Background: Major depressive disorder (MDD) has been associated with alterations in brain white matter (WM) microstructure. However, diffusion tensor imaging studies in biological relatives have presented contradicting results on WM alterations and their potential as biomarkers for vulnerability or resilience. To shed more light on associations between WM microstructure and resilience to familial risk, analyses including both healthy and depressed relatives of MDD patients are needed.

Methods: In a 2 (MDD v. healthy controls, HC) × 2 (familial risk yes v. no) design, we investigated fractional anisotropy (FA) via tract-based spatial statistics in a large well-characterised adult sample (N = 528), with additional controls for childhood maltreatment, a potentially confounding proxy for environmental risk.

Results: Analyses revealed a significant main effect of diagnosis on FA in the forceps minor and the left superior longitudinal fasciculus (ptfce-FWE = 0.009). Furthermore, a significant interaction of diagnosis with familial risk emerged (ptfce-FWE = 0.036) Post-hoc pairwise comparisons showed significantly higher FA, mainly in the forceps minor and right inferior fronto-occipital fasciculus, in HC with as compared to HC without familial risk (ptfce-FWE < 0.001), whereas familial risk played no role in MDD patients (ptfce-FWE = 0.797). Adding childhood maltreatment as a covariate, the interaction effect remained stable.

Conclusions: We found widespread increased FA in HC with familial risk for MDD as compared to a HC low-risk sample. The significant effect of risk on FA was present only in HC, but not in the MDD sample. These alterations might reflect compensatory neural mechanisms in healthy adults at risk for MDD potentially associated with resilience.

Keywords: diffusion tensor imaging; familial risk; major depressive disorder; white matter.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anisotropy
  • Brain / diagnostic imaging
  • Depression
  • Depressive Disorder, Major* / diagnostic imaging
  • Diffusion Tensor Imaging / methods
  • Genetic Predisposition to Disease
  • Humans
  • White Matter* / diagnostic imaging