Antidepressants normalize elevated Toll-like receptor profile in major depressive disorder

Abnormalities in Toll-like receptor (TLR) expression in depression have been inferred in part from observed increases in TLR4 levels in peripheral blood mononuclear cells (PBMCs) and postmortem brains of depressed and suicidal patients. Our previous study found differences in the TLR expression in PBMCs between healthy controls and patients with major depressive disorder. Normalization of increased TLR4 in PBMCs by cognitive behavior psychotherapy has been reported. However, the effects of antidepressants remain unknown. Changes in TLR1-9 expression levels of PBMCs were examined in 56 patients with MDD. The 17-item Hamilton Depression Rating Scale (HAMD-17) and mRNA expression levels of TLRs were assessed in parallel with a housekeeping gene using qRT-PCR before and after treatment with antidepressants. TLR3, TLR4, TLR5, TLR7, TLR8, and TLR9 were expressed at elevated levels in patients with MDD and were significantly decreased by treatment with antidepressants for 4 weeks. Antidepressant treatment completely normalized TLR3, TLR5, TLR7, TLR8, and TLR9 levels, whereas TLR1, TLR2, TLR4, and TLR6 were decreased to below normal levels. A subgroup analysis found that only TLR3 was significantly higher at baseline in the nonremission group. In addition, a multiple linear regression analysis revealed that only low TLR3 before treatment predicted improvement in HAMD-17 scores. These findings suggest that antidepressant treatment exerts anti-inflammatory effects in patients with MDD and identify TLR profiles as a predictor of response to antidepressant therapy. Further studies investigating the effects of manipulating individual TLRs on depression are needed to fully elucidate the underlying mechanism.