  By focusing on melancholic features with biological homogeneity, this study
aimed to identify a small number of critical functional connections (FCs) that
were specific only to the melancholic type of MDD. On the resting-state fMRI
data, classifiers were developed to differentiate MDD patients from healthy
controls (HCs). The classification accuracy was improved from 50 % (93 MDD and
93 HCs) to 70% (66 melancholic MDD and 66 HCs), when we specifically focused on
the melancholic MDD with moderate or severer level of depressive symptoms. It
showed 65% accuracy for the independent validation cohort. The biomarker score
distribution showed improvements with escitalopram treatments, and also showed
significant correlations with depression symptom scores. This classifier was
specific to melancholic MDD, and it did not generalize in other mental
disorders including autism spectrum disorder (ASD, 54% accuracy) and
schizophrenia spectrum disorder (SSD, 45% accuracy). Among the identified 12
FCs from 9,316 FCs between whole brain anatomical node pairs, the left DLPFC /
IFG region, which has most commonly been targeted for depression treatments,
and its functional connections between Precuneus / PCC, and between right DLPFC
/ SMA areas had the highest contributions. Given the heterogeneity of the MDD,
focusing on the melancholic features is the key to achieve high classification
accuracy. The identified FCs specifically predicted the melancholic MDD and
associated with subjective depressive symptoms. These results suggested key FCs
of melancholic depression, and open doors to novel treatments targeting these
regions in the future.
