Background: Proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), are associated with the pathophysiology of major depressive disorder (MDD). Several studies have reported that increased TNF-α might be associated with tryptophan depletion, which eventually could result in MDD. However, other studies revealed that TNF-α increased serotonin firing in raphe. Therefore, whether TNF-α increases or decreases serotonin activity remains unclear. Here, we aimed to determine the relationship between serum TNF-α level and central serotonergic activity using the loudness dependence of auditory evoked potentials (LDAEP) and standardized low-resolution brain electromagnetic tomography (sLORETA), as well as to evaluate the effects of antidepressants on TNF-α levels.

Methods: LDAEP, serum TNF-α level, and depression severity were measured in 64 MDD outpatients pre and post 3 months of treatment.

Results: Pretreatment TNF-α levels were negatively correlated with the pretreatment N1 sLORETA-LDAEP, P2 sLORETA-LDAEP, and N1/P2 sLORETA-LDAEP (p < 0.05). In multiple regression analysis for N1/P2 sLORETA-LDAEP, lower N1/P2 sLORETA-LDAEP was significantly related to higher TNF-α (CE = -0.047, p = 0.017) when all subjects were dichotomized based on the median TNF-α level (7.16 pg/mL) into pretreatment low- and high-TNF-α groups. In addition, the pretreatment Beck Depression Inventory, P2 LDAEP, and N1/P2 sLORETA-LDAEP were greater in the high-TNF-α groups than in the low-TNF-α groups (p < 0.05). Moreover, the posttreatment TNF-α level was significantly decreased compared to the pretreatment TNF-α level (z = -2.581, p = 0.01). However, the posttreatment TNF-α levels were not associated with posttreatment LDAEP.

Conclusions: Higher TNF-α level is associated with decreased LDAEP, which could indicate compensatory elevation of central serotonin activity in outpatients with MDD, although this effect disappeared and TNF-α level was reduced after three months of antidepressant treatment.