**4. Neuroinflammation in Mood Disorders**

There is growing comprehension of the role of the immune system, in general, and neuroinflammation, in particular, in the pathophysiology of mood disorders. Intriguingly, a comprehensive review and meta-analysis reported that despite a high level of heterogeneity, both monotherapy and add-on anti-inflammatory treatment result in a beneficial effect on depressive symptoms. Nonsteroidal anti-inflammatory drugs (NSAIDs) had a better antidepressant effect [51]. According to Yang et al. [52] neuroinflammation and mitochondrial dysfunction are among the characteristics of psychiatric disorders. Both can lead to increased oxidative stress by excessive release of harmful ROS and reactive nitrogen species (RNS), which further promote neuronal damage and subsequent inflammation.

The following sections review findings of high cytokine levels as well as possible causes for neuroinflammation in psychiatric disorders.

#### *4.1. High Proinflammatory Cytokine Levels*

Cumulative data detailed below support the hypothesis that at least in a sub-population of patients afflicted with unipolar depression, the pathophysiology and neurobiological mechanisms underlying resistance to conventional antidepressants stem from high cytokine levels. It also suggests that specific cytokines and their activators and regulators play a role in depression. Indeed, major depression disorder (MDD) and depressed mood are linked with pro-inflammatory cytokines released during periods of disturbance [18]. As nicely elaborated by Jeon and Kim [53], the cytokine hypothesis of depression suggests that cytokine production is initially activated by stress and sympathetic nerve system activation. In turn, cytokines play an important role by acting via neurotransmitter depletion pathways, neuroendocrine pathways, and neural plasticity pathways. There are multiple interactions between these pathways, suggesting existence of a complex model for pathogenesis of depression.

In mouse models of depressive-like behavior, several groups reported hallmark features of neuroinflammation, i.e., microglia and astrocyte reactive morphology, microglial proliferation, increased levels of proinflammatory cytokines, and upregulation of translocator protein (TSPO, a clinical biomarker widely accepted as a surrogate of neuroinflammation that involves an activated state of brain microglia) [54–56]. In humans, positron emission tomography (PET) studies [57,58] enhanced TSPO uptake in several brain regions indicated neuroinflammation in depressed patients.

IL-1β was found to be present in abnormally high levels in plasma, CSF, and postmortem brain tissue of individuals with mood disorders and its levels correlated positively with the severity of depression [59,60]. Accordingly, mRNA levels of proinflammatory cytokines and other related innate immune system proteins were found to be elevated in peripheral blood cells in mood disorder patients [61–66], and their plasma and CSF levels were found to be higher during acute depressive episodes, suggesting the pathogenic function of cytokines [62,67]. A meta-analysis based on 29 studies of serum cytokines [68] indicated increased sIL-2R, IL-6, and TNF-α levels, supporting the notion that elevated cytokine proinflammatory levels contribute to the pathophysiology of depression.

A recent review [69] raised the question whether a specific inflammatory profile underlies suicide risk. The authors summarized that although most studies showed a link between abnormally higher IL-1β, IL-6, TNF-α, transforming growth factor (TGF)-β1, vascular endothelial growth factor (VEGF), kynurenic acid (KYN), and lower IL-2, IL-4, and interferon (IFN)-γ levels in specific brain regions and suicidal behavior, the contribution of MDD as a mediator of the link between these cytokine abnormalities and suicidal behavior could not be excluded. Thus, obviously, additional studies to clarify if, and which immune pathways underlie suicidal behavior are needed.

As for neuroinflammation, in general, and cytokine levels, in particular, in bipolar disorder (BD), a meta-analysis of 30 studies [70] found significantly elevated plasma concentrations of IL-4, IL-6, IL-10, soluble IL-2 receptor (sIL-2R), sIL-6R, TNF-α, sTNFR1, and IL-1 receptor antagonist; IL-1β and IL-6 tended to show higher values in patients. While concentrations of IL-2, IL-4, sIL-6R, and INF-γ were unrelated to medication status, phasic difference was observed for TNF-α, sTNFR1, sIL-2R, IL-6, and IL-1RA, but not for IL-4 and IL-10. The data point at a "cytokine storm" in BD. Nevertheless, the authors of a recent systematic review of 51 articles that measured inflammatory markers in postmortem BD brain samples attested that an absolute statement cannot be concluded whether neuroinflammation is present in BD since a large number of studies did not evaluate the presence of infiltrating peripheral immune cells in the CNS parenchyma, cytokine levels and microglia activation in the same postmortem brain sample [71]. The authors claim that "Future analyses should rectify these potential sources of heterogeneity and reach a consensus regarding the inflammatory markers in postmortem BD brain".
