Inflammatory Pathways in Psychiatric Disorders: The case of Schizophrenia and Depression

Abstract

Purpose of Review:

A better understanding of the key molecules/pathways underlying the pathophysiology of depression and schizophrenia may contribute to novel therapeutic strategies. In this review, we have discussed the recent developments on the role of inflammatory pathways in the pathogenesis of depression and schizophrenia.

Recent Findings:

Inflammation is an innate immune response that can be triggered by various factors, including pathogens, stress and injury. Under normal conditions, the inflammatory responses quiet after pathogen clearance and tissue repair. However, abnormal long-term or chronic inflammation can lead to damaging effects. Accumulating evidence suggest that dysregulated inflammation is linked to the pathogenesis of neuropsychiatric disorders. In this review, we have discussed the roles of complement system, infiltration of peripheral immune cells into the central nervous system (CNS), the gut-brain axis, and the kynurenine pathway in depression and schizophrenia.

Summary:

There is a large body of compelling evidence on the role of inflammatory pathways in depression and schizophrenia. Although most of these findings show their roles in the pathophysiology of the above disorders, additional studies are warranted to investigate the therapeutic potential of various immune signaling targets discussed in this article.

Introduction

Inflammation is the immune system’s natural response to factors such as pathogens, stress, and injury. Acute inflammation is essential for normal health, contributing to pathogen clearance, tissue repair, and restoration of homeostasis. However, prolonged or chronic inflammation can lead to tissue damage or disease [1, 2]. Accumulating evidence indicate that chronic inflammation is linked to the pathogenesis of psychiatric disorders, which is evidenced by increased levels of inflammatory mediators in patients with neuropsychiatric disorders such as schizophrenia and depression [3-7]. Supporting the above findings, rodent models of chronic stress also have shown increased pro-inflammatory cytokines levels [8, 9]. Although medications such as antidepressants can often significantly improve symptoms in patients, 10%-30% of patients with depression do not respond to conventional treatments of antidepressants and psychotherapy [10-12]. Interestingly, high levels of cytokines such as IL-6 were found in non-responders to antidepressant therapy [13]. Moreover, anti-inflammatory agents can effectively reduce major depressive symptoms [14]. Similar to depression, anti-inflammatory therapies have be shown to reduce symptom severity in patients with schizophrenia [15, 16]. These evidence support the hypothesis that chronic inflammation plays a key role in the pathophysiology of depression and schizophrenia. In this article, we have reviewed the recent developments on the role of complement system, infiltration of peripheral immune cells into the CNS, the gut-brain axis, and the kynurenine pathway in the pathophysiology of depression and schizophrenia.

The complement system

The complement system plays a central role in nonspecific innate immune defense [17]. It consists of a series of proteins (known as complement “components”) that are activated via three major pathways – classical, alternative, and lectin – each with their own specific recognition molecule that leads to activation of the cascade. All pathways ultimately lead to the cleavage of complement component 3 (C3) into C3a and C3b [17]. The complement system has been classically known for its ability to kill bacteria and induce antibody generation by B cells, and only recently have we begun to better characterize its roles outside of bactericidal activity. For example, complement components can directly activate immune cells; increase activation of endothelial cells to promote binding of immune cells; participate in toll-like receptor (TLR) pathways; and more. C1q (a component that participates in the classical pathway) works in tandem with C3 to tag apoptotic cells for clearance by phagocytes, and intracellular C3a helps maintain homeostasis. The various roles of complement are reviewed by Merle et al., 2015 [18].

Complement components that are produced in the liver or other peripheral locations can only reach the CNS through a compromised blood-brain barrier [19]. However, cells of the CNS have demonstrated the potential to natively produce complement components. Glial cells such as microglia and astrocytes have been shown to synthesize most components of the classical and alternative pathways, leading to a functional complement system in the CNS modulated by pro-inflammatory cytokines such as IL-1B and TNF-alpha [20, 21], though it is typically not operating at a high level of activity [22]. In general, complement in the CNS demonstrates protective effects such as regulation of homeostasis, synaptic growth, clearance of debris, etc.; but it can also be harmful in the context of uncontrolled inflammation (the role of complement in the CNS is reviewed by Woodruff et al. (2010) [22]). Due to its various effects and its key role in inflammation, the complement system theoretically has the possibility to be involved with the development of neuropsychiatric disease. However, studies linking the two are limited.

Depression

The studies addressing the link between complement and depression are few in number, but the current evidence suggests that complement activity may be abnormally upregulated in depressed patients. In preclinical studies, C3 deficiency seems to be protective against the development of depressive symptoms. C3-KO mice demonstrate resiliency towards anxiety, and protection against age-related cognitive declines in learning and special memory [23, 24]. More recently, data from our laboratory have shown a direct link between stress and C3 upregulation in mice [25]. Inhibition of C3 or the use of C3-KO mice prevented the development of depressive-like behaviors following chronic stress; and overexpression of C3 replicated depressive-like behaviors even in the absence of a chronic stress paradigm. The results strongly implicate a role for C3 in the formation of depressive-like behaviors.

As for clinical evidence, a handful of previous studies found associations between serum complement levels and depression, but results are somewhat inconsistent. Plasma levels of C3 (and its breakdown products) and C4 were higher in depressed patients compared to healthy subjects [26, 27]. Berk et al. [28] found elevated serum C4 in depressed subjects but no significant difference in C3 levels. Another study [29] looked at data from 313 healthy male patients who had enrolled in the Air Force Health Study, a 20-year study designed to evaluate the health consequences of dioxin exposure. The authors derived a composite score of anger, hostility, and depression, and found that participants with high composite scores at baseline showed a significant increase in serum C3 levels over a period of 10 years when compared to patients with low composite scores. However, serum C4 levels were unchanged. A study in Japan found significantly increased C5 levels in the CSF of patients with major depressive disorder (MDD) and schizophrenia (but not bipolar disorder) versus controls [30]. Review of a gene expression database consisting of 64 patients with depression (vs. 64 controls) revealed upregulation of complement factor B (a key component of the alternative pathway) compared to controls, among elevated levels of other acute phase reactants [31].

Schizophrenia

Schizophrenia has a stronger association with complement (reviewed by Woo et al. [32]), especially with the classical and the lectin pathways [33]. The bulk of the evidence lies in genetic studies rather than the measurement of serum complement levels or activity. Multiple genome-wide association studies in schizophrenia have brought focus to areas of the major histocompatibility complex, including the area encoding C4 [32]. Sekar et al. [34] found that the risk of schizophrenia increased with the expression of C4A, a gene for C4. Their subsequent investigation of post-mortem brain samples supported this finding and demonstrated increased C4A mRNA in the brains of schizophrenic patients. Also, C4 localized to synapses in the prefrontal cortex (PFC) and hippocampus of human brain samples and thus may be involved in synaptic pruning, possibly contributing to the decreased synapse number commonly found in schizophrenic patients [34]. In independent studies that followed, C4A and C4B have both been found upregulated in schizophrenic patients [32]. Prasad et al. [35] used phosphorus magnetic resonance spectroscopy to show that increased copy number of C4A genes predicted decreased neuropil in areas of the frontal lobe, parietal lobe, and thalamus in small cohorts of patients with schizophrenia.

Genes for complement modulators, rather than complement components themselves, are also associated with schizophrenia [36]. CSMD1 is a classical-pathway protein complex that inhibits deposition and causes degradation of C3 [37]. It was also found to be especially associated with schizophrenia in genome-wide association studies [36, 38].

Non-genetic evidence is more scarce. Schizophrenic patients have demonstrated increased activity of the alternative pathway, which was further increased in patients undergoing antipsychotic treatment; however, classical pathway activity was not increased [39]. The authors proposed that increased alternative pathway activation may be involved in the destruction of neuronal tissue by inducing apoptosis. More recently, a longitudinal study performed by Focking et al. [40] in a cohort of teens showed evidence linking psychotic episodes at age 18 with increased levels of several complement proteins measured years earlier at age 12. These proteins were associated with the classical and alternative pathways.

Infiltration of peripheral immune cells into the CNS

Although the immune system of the CNS was traditionally considered separate from that of the periphery, a staunch body of literature now supports the fact that the two influence each other much more than previously believed [41]. The blood-brain-barrier (BBB) is the name given to the junctions between peripheral blood vessels and areas of the brain, and it is notable for its strict control over the substances allowed to pass into the CNS. During inflammatory states, the BBB may become “leaky,” and substances can pass more freely between the CNS and peripheral circulation. Kealy et al. [42] review evidence that BBB abnormalities are associated with neuropsychiatric disease in both clinical and preclinical studies. The increased permeability allows peripheral inflammatory factors to cross into the CNS and potentially contribute to the development of symptoms. Some patients with psychiatric disorders such as depression and schizophrenia exhibit markers of increased BBB permeability upon analysis of the CSF-to-serum albumin ratio [43]. Mice those were significantly more vulnerable to stress exhibited downregulation of claudin-5, a protein present in tight junctions that is important for BBB integrity, in the nucleus accumbens (NAc). Human patients with depression also have reduced expression of claudin-5 in the NAc [44].

Moreover, the literature has found that not only are cytokines diffusing through the leaky BBB, but so are immune cells themselves. For example, peripheral monocytes originating from the bone marrow or the spleen can enter the brain [45]. Some of those bone-marrow-derived monocytes may even differentiate into microglia afterward [46, 47]. Lines of research, mostly preclinical, show that infiltration of these immune cells may be involved in rodent models of depression and schizophrenia.

Depression

Monocytes are immune cells derived from myeloid progenitors; they migrate to target tissues and differentiate into macrophages. Monocytes have been associated with infiltration into the brain in rodent models of stress (reviewed by Weber et al. [48]). Wohleb et al. [49] showed that repeated social defeat (RSD) induced recruitment of peripheral monocytes to the brain in a manner dependent on receptors CCR2 and CX₃CR1. Notably, this recruitment was necessary for the development of anxiety-like behavior; mice depleted of peripheral monocytes did not develop anxiety-like behavior. The peripheral immune cells trafficked to stress-responsive regions of the brain such as the PFC, amygdala, and hippocampus, and expressed high levels of IL-1β and characteristics of activated microglia [46, 49], suggesting that the peripheral cells differentiated into microglia. Endothelial activation and subsequent recruitment of monocytes has been shown as necessary for the development of anxiety-like behavior [50]. Threat appraisal regions such as the central amygdala and the CA3 region of the hippocampus demonstrated local activation of microglia that subsequently recruited peripheral monocytes through an expression of CCL2. Blood vessels in these threat appraisal regions also expressed adhesion factors (VCAM-1, ICAM-1, etc.) to promote monocyte transmigration. Once recruited, monocyte secretion of IL-1β and activation of IL-1R1 on the endothelial surface were particularly important for the development of anxiety-like behavior [50].

Evidence for the infiltration of non-monocyte immune cells in models of stress is remarkably less established. A recent study had investigators inject mice with kynurenine, a product of tryptophan breakdown whose levels have been shown to increase in depression. Kynurenine injection exacerbated LPS-induced depressive-like behaviors and increased the amount of Ly6C^hi peripheral monocytes in the brain but did not affect the infiltration of neutrophils or T-cells [51]. However, one rodent study showed infiltration of neutrophils (enhanced by higher concentrations of leptin) into the brains of mice that were demonstrating LPS-induced depressive behaviors. Obliterating neutrophil levels with specific antibodies, but leaving lymphocyte levels intact, correspondingly abolished depressive behaviors after LPS injection [52]. Additionally, Th17 cells are a type of T-helper cell whose levels were increased in the brains of mice displaying depressive behaviors. These Th17 cells found in the brain have been theorized to originate from the periphery and infiltrate into the brain through the choroid plexus [53], although there are currently no studies providing direct evidence of this particular proposal.

Schizophrenia

Increased BBB permeability has been associated with schizophrenia as well, with evidence showing microvascular dysfunction and the influx of peripheral cytokines into the CNS [54]. However, studies on the infiltration of peripheral cells are few. Cai et al. [55] demonstrated the direct presence of macrophages in the brains of schizophrenic patients. The samples had been divided into two groups based on previously-collected peripheral levels of inflammatory markers – “high inflammation” brains vs. “low inflammation.” Brains in the “high inflammation” category were more likely to show increased vascular endothelial adhesion factors, as well as the presence of macrophages in the brain parenchyma and vasculature of the ventral medial prefrontal cortex. The authors suggest that there may be a subtype of schizophrenia-related to increased infiltration of inflammatory cells into the brain.

Additional studies provide weaker, indirect evidence. Najjar et al. [54] review BBB dysfunction in schizophrenia, with findings of upregulated adhesion factors in endothelial cells suggesting peripheral immune cell activation and direction to the brain. Studies have shown increased peripheral monocyte counts in the blood of patients with schizophrenia [56], as well as one study showing a correlation between high monocyte and neutrophil counts with baseline PANSS-P score [57]. Taken altogether, increased peripheral cell counts in the context of upregulated adhesion factors suggest a potential for peripheral infiltration. However, there is no strong direct evidence connecting peripheral immune cell infiltration into the CNS with the development of schizophrenia.

Gut-Brain Axis

The gut-brain axis is bi-directional, with both systems exerting influence on the other. Patients with a history of traumatic brain injury (TBI), stroke or Parkinson’s disease show alterations in the composition of their gut microbiome [58-60]. And conversely, alterations in the gut microbiome may influence behavior, cognition, and induce physiological changes in the CNS. A rodent study by Frohlich et al. [61] showed that mice treated with oral antibiotics had deficits in novel objection recognition, but retained performance on spatial memory. Analyses of brain matter showed deficits in tight junction proteins, suggesting increased BBB permeability.

Mechanistically, the link between the gut and the brain is unsurprisingly complex, with multiple interconnected systems currently under investigation. These include but are not limited to the involvement of the vagus nerve and altered levels of active bacterial metabolites, both of which may affect BBB permeability or neurotransmitter concentrations through long-distance signaling. Additionally, the immune system is not exempt from the influence of gut microbiota. Gut bacteria are intimately linked with the development and maturation of immunity. Germ-free mice present with irregularities across multiple branches of the immune response that are reversible through fecal transplantation [62]. Recent evidence on how the bidirectional communication between the gut and the brain influences the immune system to contribute to psychiatric disease is the topic of this section.

Depression

The composition of the gut microbiome has been linked to depression in both preclinical and clinical studies, reviewed by Hao et al. [63] and Caspani et al. [64]. Mice whose gut microbiomes have been depleted through oral antibiotics, as well as mice specifically bred to be germ-free, show a variety of behavioral and cognitive abnormalities including both elevated and reduced anxiety/depressive behaviors depending on the treatment paradigm; and depressed patients show altered levels of various strains of gut bacteria [64-66]. Results on microbiome diversity or richness in depressed patients versus healthy controls are mixed, with some studies showing reduced diversity and others showing no difference [65, 66].

As mentioned above, the immune system is one arm by which the contents of the gut can influence the CNS. Preclinical studies in mice treated with antibiotics have shown increased pro-inflammatory cytokines and activation of NF-kB signaling, along with an increase in depressive or anxiety behaviors [63]. The increase in peripheral inflammation may be explained by the “leaky gut” hypothesis, which postulates that a precipitating event increases gut wall permeability and leads to displacement of bacterial antigens into the bloodstream that activates host immunity. Stress or depression may be one such precipitating event. Depressed patients showed increased IgA and IgM against lipopolysaccharide (LPS) of gut bacteria [67]. A social stress paradigm in mice reduced the diversity of the gut microbiome and increased circulating peripheral proinflammatory cytokines [68]. However, an antibiotic treatment used to wipe out the microbiome blocked the expected increase in bloodstream proinflammatory cytokines. The authors suggest that the gut microbiome may be a key intermediate in activating peripheral inflammation after stress paradigms, possibly through the sequence of events put forward by the leaky gut hypothesis. Another rodent study with oral antibiotics showed no increase in plasma cytokines or in cytokines in areas of the brain, such as the amygdala or hippocampus [61].

Ampicillin treatment increased anxiety-like behaviors in mice and increased microglia and monocytes in the brain [69]. The authors suggest that after translocation of bacterial antigens into the bloodstream, monocytes in the periphery are sent to the brain, possibly influencing anxiety-like behaviors. van de Wouw et al. [70] review evidence that gut microbiota is essential for hematopoiesis and affects the production of metabolites such as short-chain fatty acids (SCFAs) that affect monocyte inflammatory behavior. Infiltration of peripheral monocytes in the brain has been linked to the development of behavioral disturbances in rodent models of psychiatric disease, as covered in a previous section of this review.

Schizophrenia

While studies on the role of the microbiome in schizophrenia are fewer than their counterparts on depression, the relevant hypotheses are so far comparable. A recent review of the relationship between the microbiome and schizophrenia is by Golofast, Vales [71].

Subjects with schizophrenia showed significant differences in gut microbiome composition compared to healthy controls, with some strains specific enough to be used as diagnostic markers. In addition, patients with schizophrenia exhibited lower microbial diversity and richness compared to healthy controls [72, 73]. The abundance of a few specific strains was found to correlate to symptom severity as measured by the Positive and Negative Symptom scale (PANSS).

The exact mechanisms by which the gut microbiota contribute to the development of schizophrenia are not entirely known but are likely related to long-distance signaling and activation of the immune system. When a fecal transplant from schizophrenic patients was performed to mice, they showed reduced anxiety-like behaviors as well as decreased glutamate and increased GABA in the hippocampus, suggesting behavioral changes stemming from alterations in neurotransmitter levels and amino acid and lipid metabolism [73]. There is also some evidence of increased gut permeability leading to immune activation in schizophrenic patients, who demonstrated increased serum soluble CD14 levels but unchanged lipopolysaccharide-binding protein (LBP) levels; both used as surrogate markers of bacterial translocation [74]. In a sample of 80 schizophrenic patients, negative symptoms (as measured by PANSS) were correlated with increased IgA and IgM against antigens from Gram-negative gut bacteria such as K. pneumonia, which the authors suggest may be evidence that a subtype of schizophrenia with predominately negative symptoms may be related to bacterial translocation [75]. Gut bacteria may also directly affect the gut-associated immune system. Peripheral blood levels of double-negative (DN) mucosal-associated invariant T-cells (MAITs), a type of T-cell abundant in the intestinal mucosa whose development is dependent on gut bacteria [76], were significantly decreased in a sample of 32 schizophrenic patients free from antipsychotic treatment for three months [77]. However, DN MAITs showed increased activity in the same sample, which the authors propose may be due to apoptotic death.

The Kynurenine Pathway

The kynurenine (KYN) pathway is a metabolic pathway that leads to the production of nicotinamide adenine dinucleotide (NAD+) by degrading tryptophan (TRP). It is well known that KYN pathway-mediated TRP degradation controls inflammation by regulating the immune system [78, 79]. The KYN pathway breaks down 95% of ingested TRP, and the remaining TRP is used for protein and serotonin synthesis. Dysregulation of the KYN pathway affects TRP degradation, which in turn leads to altered metabolism of serotonin, melatonin, and KYN. The two major etiologies of KYN pathway dysregulation are related to 1) genetic dysfunction, and 2) inflammatory conditions. Alterations in this pathway have been associated to the pathogenesis of a broad variety of chronic inflammatory disorders [80, 81].

Depression

Accumulating evidence from both pre-clinical and clinical studies indicate a potential role of the KYN pathway and its metabolites in depression [82, 83]. The HAMD-24 scores which measure the severity of depression were negatively correlated with levels of tryptophan, kynurenic acid, and kynurenic acid / quinolinic acid in patients with MDD [82]. Increases in quinolinic acid, but decreases in kynurenic acid levels were found in CSF samples of suicidal patients; and low kynurenic acid were strongly associated with severe depressive symptoms in these subjects [84]. A recent study has found a strong association between plasma and CSF KYN pathway metabolites in unmedicated depressed subjects [85]. They found that plasma TNF levels were associated with plasma KYN and KYN/TRP, which was in turn associated with CSF KYN, kynurenic acid, and quinolinic acid in these patients [85]. In an earlier study, peripheral IFNα-stimulated increases in brain KYN and quinolinic acid were correlated with depressive symptoms [86]. The serum levels of kynurenine and the ratio of kynurenine to tryptophan were inversely associated with striatal volumes in the MDD subjects [87]. Altered kynurenine metabolism has also been linked to sleep disturbance and depression [88]. In rodent studies, chronic social stress has been shown to increase blood and brain kynurenine pathway activity, which was reversed by inhibition of indoleamine 2,3-dioxygenase [89]. Another study using mouse spared nerve injury model has found critical roles of brain IL-1 signaling and activation of neuronal kynurenine 3-monoxygenase in the development of depressive-like behavior in neuropathic pain [90]. In vivo and in vitro studies have shown the role of high mobility group box 1 (HMGB1) in LPS-induced depressive behavior through the KYN pathway. Furthermore, inhibiting the release of HMGB1 by ethyl pyruvate treatment reduced the activation of enzymes in the KYN pathway and the depressive behavior [91]. Together, the above findings from clinical and pre-clinical studies provide strong evidence on the role of KYN pathway in inflammation-associated depressive symptoms (Table 1).

Table. 1:

Comparison of the findings on inflammatory pathways in depression and schizophrenia.

Inflammatory Pathways	Depression	Schizophrenia	Comments
Complement System	Preclinical studies: ↑C3 levels in the mouse model of depression [25]. C3-KO mice demonstrated enhanced spatial learning [23]; lack of age-related cognitive decline [24] and resilience to chronic stress-induced depressive-like behavior [25]. Clinical studies: ↑ C3 and C4 plasma levels [26-28] ↑C3 levels but not C4 in 10 years of longitudinal study [29]. ↑C5 levels in CSF [30]. ↑Complement factor B (alternative pathway) in plasma [31]. ↑C3 levels in PFC [25].	Clinical studies: ↑C4A mRNA levels in post-mortem brain samples [32, 34]. ↑activity of C1, C3, C4 [33]. Association of complement control-related genes CSMD1 and CSMD2 [36, 37]. Hyperactivation of the alternative complement pathway [39].	Complement system plays both protective and destructive roles in the CNS. Use of complement system as a clinical biomarker and/or treatment target needs additional research.
Infiltration of Peripheral Immune Cells in CNS	Preclinical studies: ↑Monocyte infiltration to the brain [48, 49, 51]. Kynurenine increased monocyte infiltration not neutrophils or T-cells [51]. ↑Endothelial activation and adhesion factors [50]. ↑Th17 cells in the brain [53].	Clinical studies: ↑Macrophages in brain [55]. ↑Monocyte counts in blood [56]. ↑Neutrophils, monocytes, and CRP in blood [57].	Studies on infiltration of peripheral immune cells into CNS could provide novel mechanism underlying neuroinflammation in depression and schizophrenia
Gut-Brain Axis	Preclinical studies: ↓Diversity of the gut microbiome and ↑circulating peripheral proinflammatory cytokines [68]. Ampicillin treatment ↑microglia and monocytes in brain [69]. Clinical studies: Altered levels of various strains of gut bacteria [64-66]. Leaky gut and ↑IgA and IgM levels [67]	Clinical studies: ↓Microbial diversity and richness [72, 73]. ↑Gut permeability with ↑CD14, IgA and IgM levels [74, 75]. Changes in frequencies of MAIT cells [77].	The mechanisms by which gut-brain axis ties into the increased inflammation associated with depression and schizophrenia need to be investigated.
Kynurenine Pathway	Preclinical studies: Chronic social stress ↑KYN pathway activation [89]. ↑kynurenine3-monooxygenase expression [90]. Clinical studies: ↓Kynurenic acid in plasma and CSF [82, 84]. Association of inflammation with peripheral and CNS KYN pathway metabolites [85, 86]. Association of Striatal volume with KYN pathway activation [87] Sleep disturbance [88]	Clinical studies: ↑Kynurenic acid in postmortem and CSF samples [92,93] ↑pro-inflammatory cytokines correlated with ↑ kynurenine and IL-1β in plasma [97]. Dysregulation of kynurenine metabolism linked to brain volume loss and attention impairment [99]. Relationship between gut microbiota and kynurenine metabolism [100].	Further studies should identify the origins and heterogeneity of the KYN pathway-related abnormalities in depression and schizophrenia.

Schizophrenia

Post-mortem brain and CSF studies have reported increased levels of kynurenic acid in patients with schizophrenia [92, 93]. Kynurenic acid blocks glutamate receptors, and its elevation affects neurotransmitter release similar to that of psychotomimetic agents such as phencyclidine [94, 95]. Moreover, inhibition of the KYN pathway prevents behavioral disturbances and oxidative stress in an animal model of schizophrenia [96]. Further, a significant correlation between kynurenine and IL-1β has been found in plasma of schizophrenia patients [97]. Kynurenine pathway metabolites can cross the placenta in mice, as researchers confirmed increases in kynurenine levels in fetal plasma and brain following maternal kynurenine treatment [98]. Dysregulation of kynurenine metabolism has been linked to brain volume loss and attention impairment in schizophrenia [99]. In an elegant study, researchers have shown the relationship between gut microbiota and kynurenine metabolism in the pathogenesis of schizophrenia. Transplantation of fecal microbiota from drug-free patients with schizophrenia into specific pathogen-tree mice could cause dysregulated kynurenine metabolism and schizophrenia-like behavioral abnormalities [100].

Conclusion

Despite significant advances in depression and schizophrenia research, therapeutic options are limited and insufficient for many patients; therefore, novel therapeutic approaches appear necessary. We have presented major upcoming areas of interest in depression and schizophrenia research, emphasizing the role of the immune system in each: the complement system, peripheral infiltration of immune cells, the gut-brain axis, and the kynurenine pathway (Figure 1). Because the complement system plays both protective and destructive roles in the CNS, it has potential use as a clinical biomarker or pharmacologic target pending further research. Establishing the significance of peripheral immune cells in the development of psychiatric disorders could lead to the development of novel therapeutic approaches. Further studies are warranted to understand the mechanisms linking gut-brain axis to neuroinflammation and changes in neuroplasticity. Finally, additional studies should identify the origins and heterogeneity of the KYN pathway abnormalities in depression and schizophrenia. In conclusion, further research on the above key inflammatory pathways could yield novel strategies for the treatment of depression and schizophrenia.

Figure. 1-.

Schematic depicting inflammatory pathways in depression and schizophrenia.