Cytokine alterations and cognitive impairment in major depressive disorder: From putative mechanisms to novel treatment targets

Overwhelming evidence indicates the involvement of immune-inflammatory processes in the pathophysiology of major depressive disorder (MDD). Peripheral cytokine alterations serve as one of most consistently reported indices of subthreshold inflammatory state observed in MDD. Although cytokines cannot pass directly through the blood-brain barrier, a number of transport mechanisms have been reported. In addition, peripheral cytokines may impact central nervous system via downstream effectors of their biological activity. Animal model studies have provided evidence that cytokines might impact cognitive performance through direct and indirect effects on long-term potentiation, neurogenesis and synaptic plasticity. Therefore, it has been hypothesized that cytokine alterations might contribute to cognitive impairment that is widely observed in MDD and persists beyond episodes of acute relapse in the majority of patients. Although several studies have provided that peripheral cytokine alterations might be related to cognitive deficits in patients with MDD, the quality of evidence still leaves much to be desired due to methodological heterogeneity and limitations. In this article, we provide an overview of studies investigating the association between peripheral cytokine alterations and cognitive performance in MDD, discuss underlying mechanisms and neural substrates. Finally, we propose possible treatment targets related to cytokine alterations taking into account existing evidence for antidepressant efficacy of anti-inflammatory pharmacological treatment modalities.