The limited efficacy of available antidepressant therapies may be due to how they affect the underlying brain network. The purpose of this study was to develop a melancholic MDD biomarker to identify critically important functional connections (FCs), and explore their association to treatments. Resting state fMRI data of 130 individuals (65 melancholic major depressive disorder (MDD) patients, 65 healthy controls) were included to build a melancholic MDD classifier, and 10 FCs were selected by our sparse machine learning algorithm. This biomarker generalized to a drug-free independent cohort of melancholic MDD, and did not generalize to other MDD subtypes or other psychiatric disorders. Moreover, we found that antidepressants had a heterogeneous effect on the identified FCs of 25 melancholic MDDs. In particular, it did impact the FC between left dorsolateral prefrontal cortex (DLPFC)/inferior frontal gyrus (IFG) and posterior cingulate cortex (PCC)/precuneus, ranked as the second 'most important' FC based on the biomarker weights, whilst other eight FCs were normalized. Given that left DLPFC has been proposed as an explicit target of depression treatments, this suggest that the limited efficacy of antidepressants might be compensated by combining therapies with targeted treatment as an optimized approach in the future.

It is well known that depressive disorder is heterogeneous, yet little is known about its neurophysiological subtypes. In the present study, we identified neurophysiological subtypes of depression related to specific neural substrates. We performed cluster analysis for 134 subjects (67 depressive subjects and 67 controls) using a high-dimensional dataset consisting of resting state functional connectivity measured by functional MRI, clinical questionnaire scores, and various biomarkers. Applying a newly developed, multiple co-clustering method to this dataset, we identified three subtypes of depression that are characterized by functional connectivity between the right Angular Gyrus (AG) and other brain areas in default mode networks, and Child Abuse Trauma Scale (CATS) scores. These subtypes are also related to Selective Serotonin-Reuptake Inhibitor (SSRI) treatment outcomes, which implies that we may be able to predict effectiveness of treatment based on AG-related functional connectivity and CATS.

Complex relationships between depression and chronic pain have been reported in previous studies. However, only a few neuroimaging studies have investigated similarities and differences in neural systems underlying them. We examined the brain functions in the resting state of 43 patients with depression, 41 patients with chronic pain (somatoform pain disorder) and 41 healthy controls, by using regional homogeneity (ReHo) and functional connectivity analysis. Depressive symptoms were assessed by using the Beck Depression Inventory-Second Edition (BDI-II). ReHo values for the dorsolateral prefrontal cortex (DLPFC) significantly decreased for chronic pain patients, and functional connectivity between the DLPFC and thalamus decreased only for these patients. These findings are indicative of distinct brain functions related to depression and chronic pain. Understanding these differences would further elucidate the pathophysiology of these conditions.

Since optimal treatment at an early stage leads to remission of symptoms and recovery of function, putative biomarkers leading to early diagnosis and prediction of therapeutic responses are desired. The current study aimed to use a metabolomic approach to extract metabolites involved in both the diagnosis of major depressive disorder (MDD) and the prediction of therapeutic response for escitalopram. We compared plasma metabolites of MDD patients (n = 88) with those in healthy participants (n = 88) and found significant differences in the concentrations of 20 metabolites. We measured the Hamilton Rating Scale for Depression (HRSD) on 62 patients who completed approximately six-week treatment with escitalopram before and after treatment and found that kynurenic acid and kynurenine were significantly and negatively associated with HRSD reduction. Only one metabolite, kynurenic acid, was detected among 73 metabolites for overlapped biomarkers. Kynurenic acid was lower in MDD, and lower levels showed a better therapeutic response to escitalopram. Kynurenic acid is a metabolite in the kynurenine pathway that has been widely accepted as being a major mechanism in MDD. Overlapping biomarkers that facilitate diagnosis and prediction of the treatment response may help to improve disease classification and reduce the exposure of patients to less effective treatments in MDD.