Role of Cytokines in Treatment-Resistant Depression
The exact pathophysiology of major depressive disorder (MDD) has yet to be fully elucidated. The belief that depression is strictly a disorder of monoaminergic consequences is undergoing great reconsideration due to the lack of efficacy of the current pharmacotherapeutics. There is compelling clinical literature implicating a role for cytokines in the pathophysiology of MDD. IL-6 and IL-1β are pleiotropic inflammatory cytokines that have been reported to be elevated in patients with MDD. The present studies were undertaken to investigate the relationship between IL-6 and IL-1β in animal models of depressive-like behavior. In rats subjected to learned helplessness or a submissive behavior paradigm, analysis of brain tissue homogenates revealed elevated levels of IL-6 protein in the absence of elevations in IL-1β. Central administration of recombinant mouse IL-6 produced depressive-like phenotypes in mice in the absence of IL-1β induced increases in brain tissue or IL-1β related sickness behavior typical of a general CNS inflammatory response. These data therefore suggest that IL-6 and IL-1β have distinct roles in mediating depressive-like and sickness behaviors, respectively. Administration of the SSRI fluoxetine in the presence of centrally administered IL-6 failed to produce the expected antidepressant-like response in mice. Further, administration of fluoxetine to mice with endogenous overexpression of brain IL-6 (MRL/MpJ-Faslpr/lpr (LPR mice)) failed to produce the expected antidepressant-like effect relative to fluoxetine-treated WT control mice (MRL/MpJ+/+). Interestingly, blockade of IL-6 trans-signaling by co-administration of a gp130/Fc monomer or an anti-mouse IL-6 antibody with IL-6 prevented the IL-6-induced depressive-like behavior as well as attenuated IL-6-induced increases in brain protein levels. Taken together these data indicate that depressive-like behavior may be related to elevated levels of IL-6 in the brain and suggest that modulation of the IL-6 signaling pathway by way of preventing de novo IL-6 production may have therapeutic potential for treatment-resistant depression.