On inflammatory hypothesis of depression: what is the role of IL-6 in the middle of the chaos?

Cytokines are a broad category of released proteins that act as signaling molecules to regulate inflammation and cellular activities [24, 42]. They are produced by different immune cells (e.g., macrophages, lymphocytes, mast cells), parenchymal cells, endothelial and epithelial cells, fibroblasts, adipocytes, and stromal cells within the periphery [24, 43]. Additionally, they are produced by microglia, astrocytes, and neurons in the brain [44]. Cytokines from the periphery (peripherally produced cytokines) can exert influences on inflammatory processes in the brain [45, 46]. Indeed, they can enter blood-brain barrier (BBB) and affect the brain via humoral (accessing the brain through leaky secretions of the BBB such as choroid plexus), neural (through stimulation of primary afferent nerve fibers in the vagus nerve), and cellular (through stimulation of microglia by pre-inflammatory cytokines to produce monocyte chemottractant protein-1 and recruit monocytes to the brain) pathways [47]. Most cytokines function in their immediate microenvironment. Few of them are involved in paracrine signaling which indeed is fundamental to the control of an inflammatory response within a given tissue or organ and the activation of a coordinated immune response that involves multiple cell types [48]. Apart from navigating the immune system to defend the body from pathogens, cytokines have a modifying effect on neurotransmission [49].

It’s also noteworthy that the same cytokines can be produced by multiple cell types. For example, white blood cells, endothelium, fat cells, and other cells can produce TNF-α [50]. Additionally, one single cell can release different cytokines. For instance, T Helper type 2 (T_H2) cells can produce IL-3, IL-4, IL-5, IL-6, and IL-13 [24]. Cytokines can have pleiotropic, redundant, synergistic, and antagonistic effects [51]. The phenomenon that a single cytokine can act on several different cell types is called pleiotropy [51]. For instance, IL-10 can activate T_H2 cells and B cells, yet inhibit macrophages and T helper type 1 (T_H1) cells. Thus, being immunostimulatory as well as being immunosuppressive [52]. Cytokines are redundant in their activity, i.e., similar functions can be exerted by different cytokines. For instance, interferon (IFN)-γ, IL-2, and TNF-α enhance cellular immunity and production of cytotoxic cell contacts [53]. Cytokines can also act synergistically, i.e., they can have combined effects when acting together. For instance, IL-3 and IL-4 amplify each other’s effects to induce growth, differentiation, and activation of mast cells in a synergistic manner [24]. Another phenomenon in cytokines signaling is antagonism. An example of cytokine antagonism is that cytokines of the IL-1 superfamily can antagonize IL-18 effects [54].

Four categories of cytokines are usually referred to in psychoimmunological literature. (1) T_H1 cytokines (IL-2, IL-12, IFN-γ) which induce cytotoxic cell contacts. (2) T_H2 cytokines (IL-4, (IL-5, IL-13) which lead to production of antibodies. (3) Pro-inflammatory cytokines (IL-1, IL-6, IL-8, IL-17, IL-21, IL-22, IFN-α, TNF-α) which further the progress of inflammation. (4) Anti-inflammatory cytokines (IL-10, transforming growth factor-beta (TGF)-β which are influenced by regulatory T cells and impede inflammatory process from escalating [24]. However, these categories are not distinct and it must be considered that cytokines can exert various effects on different cells and therefore, they may have pro- and also anti-inflammatory properties. For instance, IFN-α which has been listed as a pro-inflammatory cytokine can also have anti-inflammatory properties [55].

IL-6 was first identified as a differentiation factor for B cells which stimulates production of antibodies by activated B cells. Apart from regulation of acute inflammation, IL-6 is known to induce differentiation of B cells, and activation and population expansion of T cells [56]. Within the peripheral and central nervous system (CNS), IL-6 can act as a neuronal growth factor inducing neurite development and nerve regeneration [57]. IL-6 receptor (IL-6R) consists of the IL-6-binding chain which has two forms of transmembrane IL-6R and soluble IL-6R (sIL-6R) [58] and a gp130 signal-transducing chain [59]. Following binding to its receptor (IL-6R), IL-6 initiates to exert its multiple functions.

It is quite interesting that IL-6 exerts both pro- and anti-inflammatory properties [60, 61]. Indeed, its signaling is complex and can lead to both inflammatory and anti-inflammatory cascades depending upon the presence of either IL-6 receptor (IL-6R) or the membrane bound gp130 signal transducer and these are expressed at very different frequencies within specific cell type in the body [5]. Trans-signaling of IL-6, in which the soluble form of the IL-6 receptor (sIL-6R) is shed from the membrane bound receptors, is known to be pro-inflammatory [62]. The sIL-6R binds to IL-6 and is transported to any cell type on which gp130 is expressed [63]. While most soluble receptors (e.g., soluble receptor for TNFα) result in antagonistic action by competing for the ligand, the sIL-6R is agonistic and increases the types of cells through which IL-6 can signal. Additionally, IL-6 engages in classical signaling which is anti-inflammatory [63] and occurs through binding of IL-6 to the membrane bound cell surface receptor. Classical signaling of IL-6 solely occurs on some subsets of T cells, neutrophils and monocytes megakaryocytes, and hepatocytes [64]. In both classical and trans-signaling, the IL-6/IL-6R/gp130 complex uses two pathways to activate intracellular signaling namely the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway and the mitogen-activated protein kinase (MAPK) pathway [5].

Indeed, IL-6 has been mostly regarded as having pro-inflammatory properties; however, it has many anti-inflammatory functions which are necessary for resolution of inflammation [65]. For instance, IL-6 inhibits activity of the transcription factor named nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and expression of the chemokine receptor on dendritic cells which is needed for recruiting these cells to lymphoid tissues; thus, involving in resolution of inflammation [66]. Research findings showed that IL-6 has a crucial role in regulation of T helper17 (Th17)/regulatory T (Treg) cells [67]. In the presence of TGF-β, IL-6 is a vital signal for differentiation of naive T cells into Th17 cells which in turn are implicated in induction of autoimmune diseases [68, 69], and result in local tissue injury in chronic inflammatory disorders [70]. On the contrary, IL-6 can strongly inhibit the TGF-β-induced differentiation of Treg cells which in turn results in inhibition of autoimmunity and protects against tissue damage [71]. Functional dichotomy of IL-6 indicates that it may be responsible for maintaining the balance between pro- and anti-inflammatory responses, while having tissue-specific properties at the periphery and in the CNS [72].

Chemokines are small chemotactic cytokines that are identified to have significant roles in migration of immune cells, induction of direct chemotaxis, and propagation of inflammatory responses [73]. They are classified into four sub-families based on their structural criteria (i.e., the number and spacing of their two N-terminals, disulfide bonding participating cysteine residues). These four subfamilies include CXC, CC, C, and CX3C [74]. Furthermore, they can be categorized according to their biological activity, namely, the maintenance of homeostasis and the induction of inflammation. There are also chemokines which have dual functionality [75].

These small chemotactic cytokines are known to be secreted in response to inflammatory cytokines; thereafter, selectively recruiting lymphocytes, monocytes, and neutrophil-inducing chemotaxis by activating G-protein-coupled receptors (GPCRs) [76]. A growing body of evidence suggests that chemotactic cytokines are implicated in neurobiological processes relevant to psychiatric disorders such as synaptic transmission and plasticity, neuroglia communication, and neurogenesis [77]. Indeed, disruption of any of the mentioned functions which may take place by activation of the inflammatory response system has consistently been found to be relevant in pathogenesis of depression [73].

There are indeed both pre-clinical and clinical evidence in support of linking alterations in the chemokine network to depressive behavior [73]. In an animal model of depression, namely prenatal stressed rats, levels of CCL2, and CXCL12 chemokines were found to be upregulated in the hippocampus and prefrontal cortex, which was indeed suggestive of excessive microglial activation [78]. Additionally, Trojan et al. (2017) investigated the modulatory properties of chronic administration of anti-depressants on the chemokines. According to their results, chronic administration of anti-depressants has been shown to normalize the prenatal stress-induced behavioral disturbances together with the observed alterations in CXCL12 and their receptor. Indeed, they concluded that alterations of CXCL12 and their receptor and at less extend changes in CX3CL1–CX3CR1 expression will probably be normalized following chronic treatment with anti-depressants [79].

Moreover, several clinical studies found correlations between elevated levels of circulating inflammatory chemokines and depressive symptoms in patients with major depressive disorder [73, 80‐83]. According to the results of a comprehensive meta-analysis, peripheral concentrations of a number of chemokines including CCL2, CCL3, CCL4, CCL11, CXCL4, CXCL7, and CXCL8 can potentially discriminate between individuals with depression and those without [84]. Additionally, Ślusarczyk et al. (2016) provided a comprehensive account of the role of chemokines in processes underlying depressive disorder [85].

There are some difficulties faced by researchers in conducting cytokine research in psychiatry. The major problem seems to be heterogeneity of the obtained results. In other words, research outcomes are conflicting and challenging to interpret [24]. Moreover, research in this area is largely based on measurement of cytokine levels in the periphery and it is not completely clear how serum or plasma levels of cytokines reflect the situation in the brain [47]. Compellingly, results of studies that examined both peripheral and CFS levels of IL-6 found no correlations between the mentioned measures; thus, suggesting that peripheral levels of IL-6 may not directly reflect central IL-6 levels [86, 87].

It is also noteworthy that some environmental, social, biological, and medical factors may influence peripheral cytokine changes. For instance, one of the characteristics of obesity is chronic inflammation with the increased circulating levels of cytokines [88, 89]. Indeed, adipose tissue is reported to build up and activate lymphocytes and macrophages that secrete inflammatory factors [89, 90]. Interestingly, obese people show behavioral symptoms such as MDD and cognitive dysfunction at an increased rate in comparison with the general population [91, 92]. Therefore, one may argue that alterations in cytokine levels are somehow unspecific [24]. Additionally, there is a considerable overlap in cytokine values between patients in the acute phase of depression, patients in remission, and patients who are recovered [24]. Although the use of cytokines as potential biomarkers of depression has been discussed frequently in various studies, cytokine changes have been reported in other psychiatric disorders as well. For instance, increased levels of pro-inflammatory cytokines have been reported in generalized anxiety disorder [93‐95], obsessive-compulsive disorder [96], posttraumatic stress disorder [97, 98], and sleep disorder [99].

Moreover, cytokine levels change during pharmacotherapy of depression. Indeed, it has been suggested that treatment with anti-depressants can potentially lead to alteration in peripheral levels of cytokines. According to the results of a meta-analysis, anti-depressants, overall, cause decrease in peripheral levels of IL-6, IL-10, and TNF-α [100]. However, anti-psychotics which are used in psychotic depression, especially those with the highest risk of weight gain (e.g., clozapine and olanzapine), cause significant increase in the blood levels of pro-inflammatory cytokine [101]. Additionally, mood stabilizers such as lithium and carbamazepine have also been linked with an increase in the peripheral levels of cytokines [102]. In sum, as cytokine signaling often exhibits pleiotropic, redundant, synergistic, and antagonistic effects, it seems to be advisable to consider all cytokines that work together or against each other and therefore, take into account the whole range of cytokines instead of a single one.

The effects of cytokines on neurotransmitters have been studied extensively [49, 123]. Cytokines and their signaling pathways (e.g., p38 mitogen activated protein kinase) are reported to exhibit significant impacts on metabolism of multiple neurotransmitters such as serotonin, dopamine, and glutamate; thus, influencing their synthesis, release, and reuptake [49]. Indeed, cytokines can decrease synthesis of serotonin via activating the enzyme indoleamine 2,3 dioxygenase (IDO) which breaks the precursor of serotonin (i.e., tryptophan) to kynurenine (KYN) instead of metabolizing tryptophan to serotonin; thus, leading to serotonin depletion [3]. The process of serotonin depletion has been long associated with major depression [124, 125]. Moreover, cytokines can modulate serotonin signaling via elevating the expression and function of monoamine transporters. These transporters are known to re-uptake serotonin [126, 127].

IL-6 is known to influence neurotransmission by modulating the behavioral output of the brain; however, the exact mechanism is unknown. A previous study showed that IL-6 directly controls the levels of serotonin transporter (SERT) and therefore influences serotonin reuptake. Indeed, the researchers concluded that IL6-induced modulation of serotonergic neurotransmission through the signal transducer and activator of transcription 3 (STAT3) signaling pathway contributes to the role of IL6 in depression [128]. The activity of SERT forms serotonergic transmission which is implicated in depressive behavioral changes and pathophysiology of the disease [129]. By intensifying dopaminergic and serotonergic turnover in hippocampus and frontal cortex, IL-6 influences neurotransmission of catecholamines [130]. It seems that noradrenaline is not affected by IL-6; however, noradrenaline itself can induce expression of IL-6 in glial cells [131]. IL-6 together with other pro-inflammatory cytokines can activate kinurenine pathway which is involved in glutamatergic neurotransmission [132].

Previous studies showed that elevated levels of pro-inflammatory cytokines such as IL-6 may affect neurogenesis [133] and neural plasticity [134]. Imaging studies have shown that specific brain regions such as basal ganglia (which is involved in motor activity and motivation), the dorsal anterior cingulate cortex (ACC) (which has a central role in generation of anxiety), and the subgenual ACC (which is known to be involved in the development of depression) are influenced by cytokines [135, 136]. Additionally, high IL-6 expression levels demonstrated neuropathologic manifestations including neurodegeneration [137, 138].

There are many studies in which positron emission tomography (PET) has been applied to test translocator protein (TSPO) binding, a marker of neuroinflammation, in order to study neuroinflammatory hypothesis of depression [139‐143]. According to their results, neuroinflammation was present in various regions of the brain (e.g., neocortical grey matter, frontal cortex, prefrontal cortex, anterior cingulate cortex, insula, temporal cortex) as well as the hippocampus [139‐143].

In a recent study, Kakeda et al. (2018) evaluated possible relationship between serum levels of IL-1β, IL-6, IFN-γ, and TNFα and brain morphology in terms of brain cortical thinning and hippocampal subfield volumes during the first depressive episode in drug-naïve patients with MDD using a whole-brain SBM analysis. They found a significant inverse correlation between prefrontal cortex (PFC) thickness and serum IL-6 level in MDD patients. Indeed, high serum levels of IL-6 were correlated with reduced left subiculum and right CA1, CA3, CA4, GC-DG, subiculum, and whole hippocampus volumes in MDD patients. Additionally, thickness of the superior frontal and medial orbitofrontal cortices in patients with depression was significantly decreased compared to healthy controls. Since PFC contains high concentrations of IL-6 receptors, IL-6 mediated neurotoxicity might happen under conditions in which high serum IL-6 levels are present (i.e., early stages of MDD). Consequently, the authors advocated that the neuroinflammatory status in the early stage of MDD is associated with changes in the brain gray matter and IL-6 probably plays a key role in the morphological changes observed in the PFC during early stages of the disease. It is also noteworthy that serum IL-6 was the only cytokine among the tested cytokines that showed significant differences between the patients and controls in their study. Indeed, serum IL-6 levels were found to be significantly higher in MDD patients than in healthy controls [144]. In another study, Frodl et al. (2012) investigated possible effects of changes in the glucocorticoid and inflammatory systems on hippocampal volumes in patients with MDD. According to their results, MDD patients showed increased IL-6 levels and smaller hippocampal volumes compared to healthy controls. Positive effects of messenger RNA (mRNA) expression of glucocorticoid-inducible genes and further inverse effects of IL-6 concentration, on hippocampal volumes were also reported. Thus, they concluded that increased expression of IL-6 can probably predict decreased hippocampal volume [145].

As already mentioned, there is considerable amount of evidence regarding the central role of the highly plastic, stress-sensitive hippocampal region in pathogenesis of depression [146]. Indeed, grey-matter structures, including the hippocampus are vulnerable to atrophy in depression [147, 148]. Hippocampal volume reductions are most probably the result of remodeling of key cellular elements, involving retraction of dendrites, loss of glial cells, and decreased neurogenesis in the dentate gyros [149]. Factors underlying this cellular remodeling are known to be stress-induced increased levels of glucocorticoids, which are implicated in decreased neurogenesis [150]. Moreover, increased activity of the HPA axis resulting in decreased levels of glucocorticoids combined with resistance to glucocorticoid-induced negative feedback control is commonly observed in depression [151]. This dysregulation of glucocorticoid secretion along with the increased activity of excitatory neurotransmitters can potentially lead to cellular remodeling (which can be reversible) and hippocampal neurons cell death in patients with depression [152]. Since hippocampus has been identified to have a role in negative feedback inhibition of glucocorticoids, remodeling or neuronal damage may lead to less efficient inhibitory control of the corticotrophin-releasing hormone, resulting in elevated amounts of circulating glucocorticoids and further damage of the hippocampal neurons [153]. Taken together, it seems that further studies are required to elucidate the physiological mechanisms in which IL-6 might exert changes in the brain grey matter. A brief overview of the effects of cytokines including IL-6 on brain morphology is shown in Fig. 1.

Growing body of evidence suggests that abnormalities in the immune system are most probably relevant to pathogenesis and potential novel treatment of psychiatric disorders. Previous studies showed that alterations in the peripheral IL-6 levels might contribute to depressive-like behavior in animal studies [3, 112, 114, 154]. Moreover, IL-6 knockout mice showed resistance to development of depressive-like behavior [155] which gives further evidence for possible role of IL-6 pathogenesis of depression. High peripheral levels of IL-6 are even more apparent in patients with treatment-resistant depression. Additionally, correlations have been found between decrease in IL-6 levels and alleviation of depressive symptoms in patients who were responsive to the pharmacotherapy [156]. Moreover, results of a study on 222 stroke patients indicated significant associations between IL-6 periphery levels and development of MDD within 2 weeks and at 1 year following stroke. Furthermore, significant correlations were found between statin use and IL-6 on the presence of a depressive disorder at the 1st year. Indeed, preventive effects of treatment with statins (which are known to possess anti-inflammatory properties and potently reduce the cytokine-mediated IL-6 release [157]) against post-stroke depression was confirmed [158]. Thus, suppression of IL-6 activity could possibly lead to clinical recovery and may be considered as a novel pharmacotherapeutic option. Utilizing IL-6 receptor antibodies (for instance, Tocilizumab) or IL-6 antibodies (for instance, Sirukumab or Siltuximab) for reduction of IL-6 activity seems to be a novel strategy.

Blockade of IL-6 receptor by the humanized anti-IL-6 antibody, Tocilizumab has been used in treatment of rheumatoid arthritis (RA) [159‐163] and systemic juvenile idiopathic arthritis [164‐166]. Extensive clinical studies have established both short-term and long-term efficacy and safety of Tocilizumab [±conventional disease-modifying anti-rheumatic drugs (DMARDs)] in adults with moderate to severe RA. Additionally, Tocilizumab was shown to be effective as a monotherapy in patients with systemic juvenile idiopathic arthritis and also in patients whose disease has been refractory to other therapies [164]. Moreover, the safety profile of tocilizumab was reported to be consistent over time and also consistent with safety profile of other immunomodulatory agents [162]. It is also important to note that oral tocilizumab has been shown to inhibit experimental autoimmune encephalitis by elevating Th2 anti-inflammatory cytokines and decreasing pro-inflammatory Th1 cytokines [167]. With regard to crucial role of IL-6 in regulating metabolic homeostasis, side effects such as significant weight gain followed by hypertrygliceridemia and hypercholesterolemia may be observed in patients treated with tocilizumab [168]. Blockade of IL-6 trans-signaling, while classical IL-6R signaling stays intact seems to be crucial for the goal of maintaining gut mucosal integrity and epithelial regeneration [65]. Indeed, few randomized clinical trials were conducted on anti-depressant properties of tocilizumab. According to the results of a recent meta-analysis of anti-depressant activity of anti-cytokine therapies, treatment with tocilizumab showed statistically significant improvements in depressive symptoms [169].

Another promising human monoclonal antibody against Il-6, namely Sirukumab has been reported to be a safe and well-tolerated agent, capable of modulating the immune response in healthy populations as well as in patients with inflammatory disorders (e.g., rheumatoid arthritis). It targets the IL-6 signaling pathway by inhibition of both the pro- and anti-inflammatory effects of IL-6 [170]. Effects of Sirukumab on cytokine networks provide a well-founded rationale for its potential use in pharmacotherapy of psychiatric disorders promising possible advantages across varying domains of the biobehavioral research criteria [171]. In a phase 2, double-blind, placebo-controlled trial, the efficacy of Sirukumab and Siltuximab on depressive symptoms was studied in patients with rheumatoid arthritis or multicentric Castleman’s disease respectively. Compared with placebo, both IL-6 neutralizing antibodies were found to make significantly greater improvements on depressive symptoms in the patients [172]. Results of a recent mega-analysis of 18 randomized, placebo-controlled clinical trials of efficacy of immunomodulatory drugs on depressive symptoms in patients with inflammatory disorders demonstrated promising results (N = 10,743 participants). According to their findings, anti-IL-6 antibodies (sirukumab and siltuximab) had large and statistically significant effect sizes on core depressive symptoms before correction for physical health outcomes. Additionally, their effects remained significant in non-responders for the primary disease states evaluated [173]. Although further research is needed in this area, potential application of anti-IL-6 antibodies could possibly open new avenues in pharmacotherapy of MDD.

The human intestine harbors nearly 100 trillion bacteria [174] consisting assemblages of microorganisms associated with various niches in and on the body with long-term implications to health [175]. Evidence is emerging regarding correlations of microbial activities with progressive structural and functional processes in the brain of both animal models and humans [175]. There is a large body of evidence for the role of gut microbiota composition in pathogenesis of depression [176‐180]. Moreover, there is growing body of literature for the influence of the gut microbiome on cytokine signaling [181, 182].

The dominant gut microbial phyla are known to be Firmicutes and Bacteroideteds [183, 184]. The Firmicutes/Bacteroideteds ratio is of great relevance in signaling human gut microbiota status [185]. For instance, increased levels of Firmicutes/Bacteroideteds ratio have been reported in patients suffering from irritable bowel syndrome (IBD) and seem to have some correlations with development of depression and anxiety [186, 187]. Additionally, Firmicutes/Bacteroideteds ratio is associated with overall alterations in bacterial profiles at different life stages [185]. In a novel study, researchers reported decreased Firmicutes/Bacteroideteds ratio in mice following social defeat stress; thus, proposing possible role of Firmicutes/Bacteroideteds in depressive-like behavior. Furthermore, administration of anti-mouse IL-6 receptor antibody (MR16-1) attenuated the decreased ratio of Firmicutes/Bacteroideteds in susceptible mice. Thus, the researchers concluded that anti-mouse IL-6 receptor antibody may have anti-depressant-like effects by normalizing the Firmicutes/Bacteroideteds ratio via modulation of the immune system [3].

Decreased number of Oscillospira was detected in patients with depression [180] which suggests for possible role of Oscillospira in pathogenesis of depression. Two animal studies yielded same results. A recent study investigated therapeutic effects of finasteride on depressive-like behavior in rats together with 1 month of treatment withdrawal. Withdrawal from finasteride was associated with increased depressive-like behavioral responses. Therapeutic use of finasteride was linked with elevations in the phylum Bacteroidetes and in the family Prevotellaceae, and withdrawal was found to be correlated with decreases in the family Ruminococcaceae and the genera Oscillospira and Lachnospira [188]. In another study, socially stressed mice developing depression-like symptoms showed increases at the genus level of fecal Oscillospira. Interestingly, IV administration of anti-mouse IL-6 receptor antibody (MR16-1) normalized depression-like behavior and resulted in significant decrease in Oscillospira levels towards pre-stressor levels [3]. Moreover, increased number of Sutterella was reported in fecal samples [189] and intestinal biopsy samples of children with Autism spectrum disorder [190]. Additionally, elevated number of Staphylococcus and Sutterella were found in mice following social defeat stress. It is likely that Staphylococcus and Sutterella play a role in the depressive-like behavior via infection-induced inflammation. Interestingly, administration of anti-mouse IL-6 receptor antibody resulted in attenuation of elevated number of Staphylococcus and Sutterella following social defeat stress in mice [3].

These findings advocate that peripheral IL-6 may have a significant role in pathogenesis of MDD and blockade of IL-6 receptor in the periphery may exhibit rapid-onset effects by attenuating the altered composition of gut microbiota. Taking into account the role of gut-microbiota in immunomodulation, it is highly probable that gut-microbiota-brain- axis plays a role in anti-depressant actions of treatment with anti-IL-6 receptor [3]. A brief overview of the role of IL-6 together with gut microbiota in pathogenesis of depression is shown in Fig. 2.

The world-wide effect of the coronavirus disease 2019 (COVID-19) pandemic is enormous and is not solely limited to the increased mortality and morbidity rates, but also extends into the mental health of the global population [191]. Considerable amount of clinical data is emerging regarding the manifestation of depression in patients during [192‐194] and post-COVID 19 infection [192‐195]. It is estimated that about 48% of confirmed COVID-19 cases displayed overt psychological symptoms such as depression and often expressed feelings of regret, loneliness, helplessness, and irritation [196].

There is growing body of literature regarding dual role of IL-6 in COVID-19 infection and depression [192]. Normal plasma levels of IL-6 in adults range between 1 and 10 pg/ml; whereas in a systemic inflammation this amount increases to several ng/ml [197] and even higher concentrations were reported in COVID-19 patients [198]. Indeed, cytokine release syndrome (CRS) is common in COVID-19 patients and increased levels of serum IL-6 have been identified to be significantly associated with acute respiratory distress syndrome (ARDS), respiratory failure, and poor disease outcome in numerous studies [192, 199‐201]. Studies suggest that new onset depression is most probably caused by inflammation initiated during the active phase of the infection leading to a cytokine surge [202]. Indeed, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects primarily human monocytes and dendritic cells causing dendritic cell dysfunction, leading to T cell apoptosis and exhaustion; thus, contributing to the immunopathology [203]. Alpert et al. (2020) described two cases of COVID-19 patients with elevated amounts of IL-6 (25 pg/mL and 26.7 pg/mL respectively) who were diagnosed with major depressive disorder (according to the Diagnostic and Statistical Manual of Mental Disorder, 5th Edition (DSM-5)) during COVID 19 infection. Both patients’ depressive symptoms subsided about 6 weeks after initiation of anti-depressant pharmacotherapy and normalization of the inflammatory cytokines [192]. The authors concluded that lower cytokine activity ameliorates depressive symptoms as normalization of IL-6 plasma levels decreased depression with or without anti-depressants [192]. Moreover, Benedett et al. (2020) studied effects of treatment with cytokine-blocking agents on the psychopathological status of the patients with COVID-19 infection. Their results were in favor of the protective effects of treatment with cytokine-blocking agents in early phases of COVID-19 against the later onset of depression [204].

It is indeed crucial to maintain a multidisciplinary approach in management of the psychological effects of this debilitating pandemic. Treatment strategies addressing the immunopathology of SARS-CoV-2 infection will be promising during the acute phase of the disease [192, 205]. Currently, there are few studies considering psychological and neuropsychiatric implications of COVID-19; however, it is very likely to expect an increased incidence of mental pathologies both during and post-COVID-19 infection.