Decreased Hippocampal Volume is Related to White Matter Abnormalities in Treatment-Resistant Depression

Despite considerable research on the pathophysiology of unipolar depression, relationships between gray and white matter brain changes associated with treatment-resistant depression (TRD) have been sparsely investigated. Here, we used voxel-based morphometry and tract-based spatial statistics to examine differences in fronto-limbic gray matter volume and their connecting white matter tracts, respectively. We compared a well-characterized group of medication-free TRD patients (n = 22), who had homogenous treatment backgrounds consisting of standardized psychotherapeutic treatment and a combination of antidepressants and mood stabilizers, to matched healthy controls (n = 21). In comparison to healthy controls, TRD patients showed reduced gray matter volume in the left medial orbitofrontal cortex and bilateral hippocampus. Increased fractional anisotropy (FA) in the left angular bundle, and increased FA and mode of anisotropy (MO) in the right uncinate fasciculus were also found amongst TRD patients. Critically, left hippocampus volume was negatively correlated with FA values in the nearby left angular bundle in the TRD group only. Therefore, TRD was associated with concurrent reduced gray matter volume and aberrant white matter structure, and with, abnormalities in the left hippocampus and its related projections in particular. Development of treatments targeting this region may be fruitful for depression in general, and for this group of patients who are especially difficult to treat.