Elevated tumor necrosis factor-alpha receptor subtype 1 and the association with abnormal brain function in treatment-resistant depression

Background: Major depressive disorder (MDD) patients have shown elevated plasma levels of pro-inflammatory biomarkers compared to healthy controls. We hypothesized increased serum tumor necrosis factor-alpha receptor subtype 1 (TNF-α R1) is more associated with impaired brain function in patients with treatment-resistant depression (TRD) than those without TRD. Methods: 34 MDD patients and 34 healthy subjects were recruited and we separated MDD patients to TRD group (n = 20) and non-TRD (n = 14) group. Pro-inflammatory cytokines were assessed by enzyme-linked immunosorbent assays. A standardized uptake values (SUV) of glucose metabolism measured by ¹⁸F-FDG positron-emission-tomography (PET) was applied to all subjects for subsequent region-of- interest analyses and whole-brain voxel-wise analyses. ¹⁸F-FDG-PET measures glucose uptake into astrocytes in response to glutamate release from neuronal cells, and was thus used as a proxy measure to quantify glutamatergic neurotransmission in the human brain. Results: Post-hoc analysis revealed that TRD group had higher serum concentrations of TNF-α R1 compared to healthy control or non-TRD group. In the MDD group, higher serum concentrations of TNF-α R1 significantly correlated with decreased SUV in anterior cingulate cortex (ACC) and bilateral caudate nucleus. The ROI analysis further supported the negative correlations of plasma TNF-α R1 and SUV in the ACC and caudate nucleus. Such correlation is more consistent in TRD group than in non-TRD and HC groups. Limitation: Glutamate neurotransmission and the effect of chronic stress on glutamate release in the brain were not measured directly. Conclusions: Increased TNF-α R1 was associated with impaired glutamatergic neurotransmission of caudate nucleus and ACC in MDD patients, particularly in the TRD.