High levels of pro-inflammatory substances such as cytokines have been described in the blood and cerebrospinal fluid of schizophrenia patients. Animal models of schizophrenia show that under certain conditions an immune disturbance during early life, such as an infection-triggered immune activation, might trigger lifelong increased immune reactivity. A large epidemiological study clearly demonstrated that severe infections and autoimmune disorders are risk factors for schizophrenia. Genetic studies have shown a strong signal for schizophrenia on chromosome 6p22.1, in a region related to the human leucocyte antigen (HLA) system and other immune functions. Another line of evidence demonstrates that chronic (dis)stress is associated with immune activation. The vulnerability-stress-inflammation model of schizophrenia includes the contribution of stress on the basis of increased genetic vulnerability for the pathogenesis of schizophrenia, because stress may increase pro-inflammatory cytokines and even contribute to a lasting pro-inflammatory state. Immune alterations influence the dopaminergic, serotonergic, noradrenergic, and glutamatergic neurotransmission. The activated immune system in turn activates the enzyme indoleamine 2,3-dioxygenase (IDO) of the tryptophan/kynurenine metabolism which influences the serotonergic and glutamatergic neurotransmission via neuroactive metabolites such as kynurenic acid. The described loss of central nervous system volume and the activation of microglia, both of which have been clearly demonstrated in neuroimaging studies of schizophrenia patients, match the assumption of a (low level) inflammatory neurotoxic process. Further support for the inflammatory hypothesis comes from the therapeutic benefit of anti-inflammatory medication. Metaanalyses have shown an advantageous effect of cyclo-oxygenase-2 inhibitors in early stages of schizophrenia. Moreover, intrinsic anti-inflammatory, and immunomodulatory effects of antipsychotic drugs are known since a long time. Anti-inflammatory effects of antipsychotics, therapeutic effects of anti-inflammtory compounds, genetic, biochemical, and immunological findings point to a major role of inflammation in schizophrenia.
Cyclooxygenase-2 (COX-2) inhibition as an anti-inflammatory therapeutic approach in schizophrenia
Modern anti-inflammatory agents have been explored in schizophrenia. The cyclooxygenase-2 (COX-2) inhibitor celecoxib was studied in a prospective, randomized, double-blind study of acute exacerbations of schizophrenia. The patients receiving celecoxib add-on to risperidone showed a statistically significantly better outcome than the patients receiving risperidone alone; the clinical effects of COX-2 inhibition in schizophrenia were especially pronounced in cognition (Müller et al., 2005). The efficacy of therapy with a COX-2 inhibitor seems most pronounced in the first years of the schizophrenic disease process (Müller, 2010; Müller et al., 2010). A recent study also demonstrated a beneficial effect of acetylsalicylic acid in schizophrenic spectrum disorders (Laan et al., 2010). A meta-analysis of the clinical effects of non-steroidal anti-inflammatory drugs in schizophrenia revealed significant effects on schizophrenic total, positive and negative symptoms (Sommer et al., 2012), while another meta-analysis found a significant benefit only in schizophrenia patients with a short duration of disease or in first manifestation schizophrenia (Nitta et al., 2013).
Further immune-related substances in the therapy of schizophrenia
Because of the role of microglia activation in inflammation, minocycline, an antibiotic and inhibitor of microglia activation, is an interesting substance for the treatment of schizophrenia. The improvement of cognition by minocycline has been described in animal models of schizophrenia (Mizoguchi et al., 2008) and in two double-blind, placebo-controlled add-on therapy trials in schizophrenia patients (Levkovitz et al., 2010; Chaudhry et al., 2012). In clinical studies, positive effects on schizophrenic negative symptoms were noted as well (Chaudhry et al., 2012). Case reports documented positive effects of minocycline on the whole symptom spectrum in schizophrenia (Ahuja and Carroll, 2007).
Acetylcysteine (ACC) and other substances, including omega-3 fatty acids, that have anti-inflammatory and other effects also provide some benefit to schizophrenia patients (overview: Sommer et al., 2014)
First pilot experiences with cytokine interferon gamma (IFN-γ), which stimulates the monocytic type 1 immune response, as a therapeutic approach in schizophrenia are encouraging (Grüber et al., 2014), although side effects, including unwanted immune effects, have to be carefully monitored and the results are only preliminary. On the other hand, such a hypothesis-driven therapeutic approach opens interesting perspectives for the development of therapeutic substances based on etiopathology.
‘Altered expression of neuro-immune genes and increased levels of cytokines are observed, especially in patients with comorbid depression’ and first episode psychosis (FEP) ‘patients with depression show a different gene expression profile reinforcing the theory that depression in FEP is a different phenotype’ 
Inhibition of kynurenine aminotransferase II reduces activity of midbrain dopamine neurons  and ‘lowering brain KYNA levels might be a novel approach in the treatment of psychotic disorders’
Previous studies on schizophrenia have detected elevated cytokines in both brain and blood, suggesting neuroinflammation may contribute to the pathophysiology in some cases. We aimed to determine the extent to which elevated peripheral cytokine messenger RNA (mRNA) expression: (1) characterizes a subgroup of people with schizophrenia and (2) shows a relationship to cognition, brain volume and/or symptoms. Forty-three outpatients with schizophrenia or schizoaffective disorder and matched healthy controls were assessed for peripheral cytokine mRNAs (interleukin (IL)-1β, IL-2, IL-6, IL-8 and IL-18), intelligence quotient, memory and verbal fluency, symptom severity and cortical brain volumes integral to language (that is, Broca’s and Wernicke’s areas). IL-1β mRNA levels were 28% increased in schizophrenia compared with controls (t(82)=2.64, P<0.01). Using a two-step clustering procedure, we identified a subgroup of people displaying relatively elevated cytokine mRNA levels (17/43 people with schizophrenia and 9/42 controls). Individuals with schizophrenia in the elevated cytokine subgroup performed significantly worse than the low-cytokine subgroup on verbal fluency (F(1,40)=15.7, P<0.001). There was a 17% volume reduction of the left pars opercularis (POp) (Broca’s area) in patients with elevated cytokines compared with patients with lower cytokines (F(1,29)=9.41, P=0.005). Negative linear relationships between IL-1β mRNA levels and both verbal fluency and left POp volume were found in schizophrenia. This study is among the first to link blood biomarkers of inflammation with both cognitive deficits and brain volume reductions in people with schizophrenia, supporting that those with elevated cytokines represent a neurobiologically meaningful subgroup. These findings raise the possibility that targeted anti-inflammatory treatments may ameliorate cognitive and brain morphological abnormalities in some people with schizophrenia.
“Group comparisons of peripheral circulating cytokines (signaling peptides of the immune system mediating the inflammation response) between individuals with schizophrenia and controls have consistently identified higher mean levels of interleukin (IL)-6, IL-1β, tumor necrosis factor and other cytokines in schizophrenia and even greater elevations during acute psychosis. We have recently provided evidence of central immune activation with cytokine messenger RNAs (mRNAs) for IL-6, IL-8 and IL-1β upregulated in brain tissue of ~40% of individuals who were chronically ill with schizophrenia. Demonstrating that a proportion of individuals with schizophrenia have abnormal cytokine profiles in blood, similar to what was previously described in post-mortem brain samples, would further support the relevance of inflammation to pathophysiology in a subgroup of those with the disease.”
“Our study found evidence for a biological subgroup of people with schizophrenia who display elevated peripheral cytokine mRNA levels, poor verbal fluency and decreased Broca’s area brain volumes. Our finding that ~40% of individuals in a community clinical sample had a pattern of relatively elevated cytokine expression in peripheral blood is consistent with our previous post-mortem brain tissue observations, in which we found that ~40% had elevated cytokines in the prefrontal cortex. Peripheral cytokine changes appear to be related to brain dysfunction given that the elevated cytokine subgroup with schizophrenia showed worse verbal fluency and a more pronounced volumetric reduction of Broca’s area. Our results suggest that there may be a meaningful biotype of patients with schizophrenia and increased cytokines who can be identified using easily accessible markers; however, as our study is a proof of concept, independent replication in larger samples will be required.”
“Out of all of the cytokine mRNAs that we measured peripherally, only IL-1β was significantly elevated in schizophrenia. IL-1β is a powerful classical proinflammatory cytokine, which has been described as a master regulator of other immune cells and immune processes. Our cluster analysis concurs with this in that individuals with elevated IL-1β tend to also have elevations in other cytokines forming a fingerprint, or a pattern. The possibility that patients with schizophrenia are abnormally sensitive to immune activation mediated by IL-1β is supported by our findings of robust correlations between elevated IL-1β mRNA levels, lower verbal fluency scores and reduced Broca’s area volumes.”
“Our finding that decreased verbal fluency and Broca’s area volume is related to immune activation suggests that targeted treatment of some individuals with schizophrenia displaying the elevated cytokine biotype with anti-inflammatory agents may be beneficial for cognitive deficits, especially verbal fluency. As current treatments have little beneficial effect on language dysfunction in schizophrenia, anti-inflammatory agents may yield greater efficacy on this prominent deficit of the illness. In support of this, although Alzheimer’s disease is a different disorder and any comparison with schizophrenia must be treated with caution, it is noteworthy that anti-inflammatory treatment resulted in a decrease in cytokine levels and improved verbal fluency.”
It’s nice to have a growing sense of friendship and social inclusion these days. Reflecting back, I can definitely relate to strong feelings of ‘social defeat’ and I know the negative consequences it carries. I’ve internalised a lot of things that my ‘voices’ still try to ‘socially defeat’ me with everyday, so it’s a constant struggle to keep positive and not let ‘them’ (or me…) emotionally defeat myself, or impact on the progress I’m making socially and with returning to study.
Epidemiological data suggest that the experience of being excluded from the majority group (or social defeat) may be the common denominator of social risks associated with schizophrenia .
Here are a few recent articles relating to social defeat that I found interesting [see an extensive review here]:
The dopaminergic system:
“Dopamine dysregulation involving striatal dopamine sensitization may represent a common mechanism, linking multiple environmental exposures to underlying biological mechanisms of psychosis (Yuii et al., 2007 and Collip et al., 2008). Additionally, previous research suggests a reciprocal relationship between prefrontal and striatal dopaminergic dysfunction in schizophrenia. A number of researchers have suggested that prefrontal dopaminergic dysfunction may partly be the result of dysregulated input from the midbrain dopamine system (Braver et al., 1999, Braver and Cohen, 2000 and Tanaka, 2006). On the other hand, according to the tonic-phasic dopamine theory introduced by Grace (1991), when the tonic activity is low, stressful stimuli are not optimally regulated by the PFC, resulting in increased phasic dopamine release in the striatum.”
The social defeat (SD) hypothesis of schizophrenia posits that repeated experiences of SD may lead to sensitisation of the mesolimbic dopaminergic system and to precipitation of psychosis. When exposed to social threat, defeated rats have elevated levels of extracellular dopamine in the nucleus accumbens and repeated experiences of SD lead to behavioral sensitisation and enhanced behavioral response to dopamine agonists :
“…If the results of the animal studies can be extended to humans, chronic exposure to SD may lead to sensitization of the mesolimbic dopamine system and/or overactivity of this system, and thus foster the development of psychosis “
Schizophrenia remains a major burden on patients and society. The dopamine hypothesis attempts to explain the pathogenic mechanisms of the disorder, and the neurodevelopmental hypothesis the origins. In the past 10 years an alternative, the cognitive model, has gained popularity. However, the first two theories have not been satisfactorily integrated, and the most influential iteration of the cognitive model makes no mention of dopamine, neurodevelopment, or indeed the brain. In this Review we show that developmental alterations secondary to variant genes, early hazards to the brain, and childhood adversity sensitise the dopamine system, and result in excessive presynaptic dopamine synthesis and release. Social adversity biases the cognitive schema that the individual uses to interpret experiences towards paranoid interpretations. Subsequent stress results in dysregulated dopamine release, causing the misattribution of salience to stimuli, which are then misinterpreted by the biased cognitive processes. The resulting paranoia and hallucinations in turn cause further stress, and eventually repeated dopamine dysregulation hardwires the psychotic beliefs. Finally, we consider the implications of this model for understanding and treatment of schizophrenia. [full text]
“Position in the social hierarchy affects the recovery of the dopamine
system after isolated animals are returned to the social group; dominant, but not subordinate, monkeys show reversal of the striatal dopamine changes”
“Stress also increases striatal dopamine release in human beings, although not in all studies. This inconsistency could be related to the severity of the stressor—findings from animal studies suggest that mild stressors do not always increase striatal dopamine concentrations. Furthermore, increased dopamine release is associated with greater cortisol response to a challenge.”
Adolescent social defeat stress produces deficits in adult mPFC DA activity and corresponding behavioral and cognitive dysfunction .
Research indicates that the mu opioid receptor is an important mediator of behavioural flexibility and responses to psychosocial stress . Kappa-opioid receptors expressed in DAergic systems regulate the effects of acute, but not chronic, social stress in mice .
Preexisting individual differences in the sensitivity of the peripheral immune system may predict and promote vulnerability to social stress . Interleukin-1β was rapidly increased in key limbic structures (paraventricular nucleus of the hypothalamus, PVN; amygdala) in response to stress challenges that involve application of an aversive/noxious stimulus but not in response to social stress. On the contrary, social stressors appear to increase release of another pro-inflammatory cytokine, interleukin-6 (IL-6), in both plasma and brain :
“Although IL-1, IL-6, and TNF-α are considered to be the classic proinflammatory cytokines – and all appear to be modulated in the CNS by stressor exposure – these are by no means the only neuroimmune factors impacted by stress. For example, monocyte chemoattractive protein-1 (MCP1/CCL2) is a chemokine expressed in the CNS in response to a number of stress challenges and likely plays a key role in recruitment of monocytes from the blood into the CNS (Blandino et al., 2009; Wohleb et al., 2013). Prostaglandins also appear to be highly active in cortical regions after stress (Garcia-Bueno et al., 2008). Thus, a multitude of distinct neuroimmune signaling pathways appear to be activated in response to stressful circumstances, and these effects often depend upon specific individual subject characteristics such as sex, age, strain and prior stress history.”
“In addition to stress-related increases in expression of cytokines and other inflammatory signaling molecules, stress exposure is often accompanied by other cellular manifestations of neuroimmune activation, such as dynamic changes in microglial activation state. Microglia play a prominent role in immune surveillance within the CNS, and are often viewed as the “first responders” in response to infection and/or damage. Prior studies have shown that microglia are highly responsive to stress, with evidence to date suggesting that microglia exhibit priming-like effects following stress exposure as evidenced by enhanced or accelerated activational responses to subsequent immune challenge either in vivo (Johnson et al., 2002) or ex vivo (Frank et al., 2010). An enhanced functional activation state of microglia is also associated with altered expression of cell surface markers that are known to modify or regulate microglia reactivity to antigens (Blandino et al., 2009; Frank et al., 2007). Other studies have shown that chronic stress enhanced microglial proliferation (Nair & Bonneau, 2006) and migration into the CNS (Wohleb et al., 2013). Although it is not clear whether these changes in microglia are the cause or consequence of cytokine expression, it is clear that microglial activation is associated with increased cytokine expression, and exogenous cytokine administration often enhances microglial activation. In this sense, it is notable that IL-1 in particular is often described in the neuroinjury literature as an immediate early gene indicative of microglial activation state. “
Microglia from mice exposed to repeated social defeat had higher mRNA expression of IL-6, TNF-α, and IL-1β, and these increases were reversed by imipramine treatment .
Infliximab (a TNF-α inhibitor) decreased anhedonia and despair-like behavior in the rat unpredictable chronic mild stress (UCMS) model of depression .
Lorazepam and clonazepam, aside from exerting anxiolytic and antidepressant effects, may have therapeutic potential as neuroimmunomodulators during psychosocial stress .
Central immune alterations in passive strategy following chronic defeat stress have been studied .
Social defeat causes long lasting anxiety behaviour :
Directions for future therapeutics:
” …administration of specific pathway inhibitors such as IL-1 receptor antagonist (intra-cerebroventricular; i.c.v.) has been shown to block behavioral deficits indicative of learned-helplessness (Maier & Watkins, 1995), and the enhanced HPA axis response produced by inescapable tailshock (Johnson et al., 2002a). In our hands, IL-1 receptor antagonist reversed the suppression of social interaction produced by prior stressor exposure, and blocked the release of aversive odor cues emitted by stressed rats (Arakawa et al., 2009). Agents with more global anti-inflammatory properties, such as alpha-melanocyte stimulating hormone (α-MSH), have been shown to rescue stress-induced reductions in food intake and HPA axis aberrations (Milligan et al., 1998). IL-10, a potent anti-inflammatory cytokine, has also been shown to reverse sickness-like behavioral responses in a guinea pig model of maternal separation (Hennessy et al., 2011), and sensitization of febrile responses produced by this maternal separation experience was reversed with naproxen, a relatively selective inhibitor of cyclooxygenase-2 activity (i.e. the enzyme responsible for production of mature prostaglandin E2 synthesis) – a final common mediator of many inflammation-related effects (Hennessy et al., 2015). Although there is some recent evidence suggesting that antagonists to the P2X7 (purinergic) receptor can reverse some stress-related effects (presumably due to blocking IL-1 release), these effects are generally modest, perhaps because they are blocking only one cytokine within the context of many (Catanzaro et al., 2014; Lord et al., 2014). Thus, one very fruitful avenue of future studies will be the development of novel therapeutics targeting inflammatory signaling pathways that can be used to ameliorate adverse health consequences of stress. The key challenge for production of these therapeutics will be the formulation of agents that either (a) readily cross the blood-brain barrier (BBB) or (b) can be coupled to some form of vector (viruses, nanoparticles, etc.) in order to promote CNS penetration of the drugs.”
In the past decade, there has been renewed interest in immune/inflammatory changes and their associated oxidative/nitrosative consequences as key pathophysiological mechanisms in schizophrenia and related disorders. Both brain cell components (microglia, astrocytes, and neurons) and peripheral immune cells have been implicated in inflammation and the resulting oxidative/nitrosative stress (O&NS) in schizophrenia. Furthermore, down-regulation of endogenous antioxidant and anti-inflammatory mechanisms has been identified in biological samples from patients, although the degree and progression of the inflammatory process and the nature of its self-regulatory mechanisms vary from early onset to full-blown disease. This review focuses on the interactions between inflammation and O&NS, their damaging consequences for brain cells in schizophrenia, the possible origins of inflammation and increased O&NS in the disorder, and current pharmacological strategies to deal with these processes (mainly treatments with anti-inflammatory or antioxidant drugs as add-ons to antipsychotics).
Reviewed in the article are the multiple and interrelated mechanisms that have been suggested as possibly involved in brain cell damage or neurodegeneration in SCHZ. Based on current findings, these possible mechanisms include:
Microglial activation or increased microglial cellular density.
Oxidative/nitrosative stress and neuroinflammation
Uncontrolled activation of the hypothalamic/pituitary/adrenal axis
Excitotoxicity and disrupted glutamate metabolism
Mitochondrial dysfunction and energy deficits
Reduced levels of neurotrophins
Effects on glucose transport and metabolism
“Augmentation of antipsychotic therapy with antioxidants may an effective and safe add-on strategy in SCHZ patients. Table 2 summarizes double-blind, randomized, placebo-controlled clinical trials with antioxidant augmentation in SCHZ. Other strategies such as vitamin E (Michael et al., 2002) and lipoic acid (Kim et al., 2008) augmentation have shown encouraging results, but in small samples. Besides clinical assessments, it is also important to identify objective markers such as EEG findings to monitor the efficacy of the treatment (Lavoie et al., 2008, Carmeli et al., 2012 and Ballesteros et al., 2013).
If increased inflammation of the brain contributes to the symptoms of SCHZ, reduction of inflammatory status may improve the clinical picture. A recent update has reviewed the randomized controlled trials on efficacy of anti-inflammatory agents in SCHZ, including aspirin, celecoxib, davunetide, estrogens, and minocycline (Sommer et al., 2011). Table 3 summarizes the main double-blind, randomized, placebo-controlled clinical trials with anti-inflammatory augmentation in SCHZ.
Aspirin showed significant effects on the primary outcome (total PANSS score change), while celecoxib, minocycline, and davunetide showed no significant effect. As some of these studies included a small and heterogeneous number of samples, these results should be interpreted with caution. A recent meta-analysis of these studies showed that NSAID supplementation is not superior to placebo in PANSS total score change from baseline, but suggestive effects were observed in studies on aspirin in inpatients and in FEP (Nitta et al., 2013). However, augmentation with acetylsalicylic acid may have the additional benefit of reducing cardiac and cancer mortality in SCHZ (Sommer et al., 2011). Other ongoing clinical trials (FDA, EMA) include combination therapies (add-on antipsychotics) with salsalate, fluvastatin, simvastatin, methotrexate, resveratrol, hydrocortisone, and ibuprofen.
While the focus has traditionally been on antagonizing the proinflammatory pathways, little effort has been made to investigate the anti-inflammatory side of the balance, including stimulation of deoxyPGs or PPARγ activity. Of special interest is the possible use of some thiazolidinediones, potent agonists of PPARγ, widely used as insulin-sensitizing drugs for the treatment of type 2 diabetes (Lehmann et al., 1995). This pharmacological modulation of PPARγ, which may also may directly regulate glutamatergic neurotransmission at the NMDA receptor level (Salehi-Sadaghiani et al., 2012 and Almasi-Nasrabadi et al., 2012), has been suggested as a putative treatment for neurocognitive deficits associated with mood and psychotic syndromes (McIntyre et al., 2006), and it can be considered a multi-faceted therapeutic target due to its anti-inflammatory, antioxidant, anti-excitotoxic, and pro-energetic profile (García-Bueno et al., 2010). However, in a recent pilot clinical trial, the PPARγ synthetic ligand rosiglitazone failed to improve cognitive deficits in clozapine-treated patients with SCHZ, so more evidence is needed to design new trials (Yi et al., 2012).”
“We are still far from having ideally effective and safe treatments to offer our patients. There is therefore a need for a change in the drug discovery strategy, mainly based on a better understanding of pathophysiology (Insel, 2010 and Lewis and Gonzalez-Burgos, 2006). It is still too soon to consider proinflammatory cytokines and/or their signaling pathways a possible novel strategy to treat psychosis (Potvin et al., 2008), although there are already ongoing trials of adjunctive monoclonal antibody anti/pro-inflammatory cytokine therapy (infliximab, tocilizumab) in major depression and SCHZ, whose results could directly implicate inflammation in the pathophysiology of psychiatric disease (Raison et al., 2013 and Miller, 2013). Furthermore, current studies using new anti-inflammatory and antioxidant pharmacological approaches are still in the early stages.”
Interestingly, when given separately to patients with low erythrocyte PUFA levels “EPA and vitamins E+C [can] induce psychotic symptoms in patients… Combined, these agents seem safe.” 
Psychiatric disorders, including major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia, affect a significant percentage of the world population. These disorders are associated with educational difficulties, decreased productivity and reduced quality of life, but their underlying pathophysiological mechanisms are not fully elucidated. Recently, studies have suggested that psychiatric disorders could be considered as inflammatory disorders, even though the exact mechanisms underlying this association are not known. An increase in inflammatory response and oxidative stress may lead to inflammation, which in turn can stimulate microglia in the brain. Microglial activation is roused by the M1 phenotype, which is associated with an increase in interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). On the contrary, M2 phenotype is associated with a release of anti-inflammatory cytokines. Thus, it is possible that the inflammatory response from microglial activation can contribute to brain pathology, as well as influence treatment responses. This review will highlight the role of inflammation in the pathophysiology of psychiatric disorders, such as MDD, BD, schizophrenia, and autism. More specifically, the role of microglial activation and associated molecular cascades will also be discussed as a means by which these neuroinflammatory mechanisms take place, when appropriate.
“One theory suggests that maternal immune activation during pregnancy is a risk factor for the progeny to develop schizophrenia in adulthood (Brown, 2011). The findings from preclinical studies using models of prenatal infection and maternal immune activation through polyinosinic-polycytidylic (Poly I:C) or LPS can have a negative impact on offspring brain development (Missault et al., 2014, Reisinger et al., 2015 and Wischhof et al., 2015). Van den Eynde et al. (2014) demonstrated that offspring rats born to Poly I:C had an increase in microglia accompanied by schizophrenic-like behavior. Influenza exposure during the first gestational trimester significantly increased the risk of schizophrenia in adulthood (Brown et al., 2004). Other studies showed an association between Toxoplasma gondii and early-onset schizophrenia ( Mortensen et al., 2007), and maternal genital/reproductive infections during periconception increased the risk of schizophrenia in offspring ( Babulas et al., 2006). On this vein, several models have attempted to explain how prenatal infection can increase the risk of schizophrenia. A theory suggests that the host immune response through cytokines could mediate the effects of infection ( Girgis et al., 2014). During infection the innate immune cells are also activated by endogenous constituents that are normally released from injured cells, including ATP, S100 molecules, histones and HSPs, which are known as DAMPs ( Lu et al., 2014 and Wiersinga et al., 2014). Thus, microglia can be stimulated by numerous components including DAMPs or pro-inflammatory mediators to produce cytokines, chemokine, and induce oxidative stress. This prolonged and excessive microglial response may lead to deleterious effects on neuronal plasticity and apoptosis, leading to behavioral and cognitive deficits through exogenous as well as endogenous components ( Barichello et al., 2013 and Hu et al., 2014).
Microglial activation and an increase in microglial cells in the brain of schizophrenic patients have been reported in post-mortem studies (Bayer et al., 1999 and Radewicz et al., 2000). An increase in microglial cells was also demonstrated in schizophrenic patients who had committed suicide (Steiner et al., 2008). A positron emission tomography (PET) study showed microglial activation in recent-onset schizophrenics within the first 5 years of disease (van Berckel et al., 2008). Moreover, microglial activation through Iba-1 and iNOS in the hippocampus of adult rats was observed in an animal model of schizophrenia induced during the neonatal period. This microglial activation was accompanied by prepulse inhibition (PPI) and working memory impairment that were reversed by antipsychotic clozapine treatment (Ribeiro et al., 2013). However, in the prefrontal white matter from schizophrenic patients, Iba-1 expressing microglial cells were found only in three out of 20 schizophrenia samples compared to controls (Hercher et al., 2014).
Schizophrenia is known to be associated with alterations in the immune system, such as increased cytokine levels. In a meta-analysis, IL-1β, IL-6, and TGF-β (which also has neuroprotective and anti-inflammatory effects in the CNS) were augmented during an acute relapse in patients and in the first-episode of psychosis. These alterations in cytokines were normalized with antipsychotic treatment (Miller et al., 2011). Another meta-analysis revealed a link between polymorphism in the IL-1β gene and abnormal white and gray matter volume in schizophrenia (Najjar and Pearlman, 2015).
Schizophrenic patients have also shown DAMPs in the serum or in the cerebrospinal fluid (CSF). Micromolar concentrations of S100B protein (a protein involved with cell cycle progression and differentiation) can induce apoptosis in neurons and astrocytes in response to the activation of the advanced glycation end-products receptor (RAGE) (Steiner et al., 2009). S100B protein has been shown to be augmented in the serum and in the CSF of untreated schizophrenic patients (Schmitt et al., 2005).
Heat shock 70-kDa proteins (HSP70s) are molecular chaperones and also microglial activators, which regulate biological processes and are associated with the pathophysiology of schizophrenia. Antibodies against HSP70 have been found in the serum of schizophrenic patients, which is suggestive of inflammation (Kim et al., 2001 and Kim et al., 2008). Extracellular HSP70 mediates the innate immune responses of brain through toll-like receptors (TLRs). TLRs activate the nuclear transcription factor kappa B (NF-κB), which plays a key role in the expression of genes responsible for the development of cell and inflammation. These transcription factors also are capable of activating the promoter region of many pro-inflammatory genes, including genes expressed by the M1 microglial phenotype (Tato and Hunter, 2002 and Saijo and Glass, 2011).”
“…inhibition of pro-inflammatory cytokines or enhancement of anti-inflammatory mediators in schizophrenic patients may be a beneficial strategy to prevent the devastating consequences of this illness with respect to neuronal damage and function. We propose that inhibition of the activity of DAMPs and/or administration of specific anti-inflammatory agents may lead to amelioration of symptoms of this debilitating illness.”
Recent findings strongly support the idea to use anti-inflammatory drugs such as minocycline to target microglia activation as an adjunctive therapy in schizophrenic patients.
In both schizophrenia and depression immunological imbalance results in increased prostaglandin E2 (PE2) production and probably also in increased cyclooxygenase-2 (COX-2) expression – COX-2 inhibition is a potential therapeutic strategy .
“Classical inflammatory cytokines, such as IL-1β, TNF-α and IL-6, by activating their cognate receptors in target cells, induce intracellular pathways which differ depending on the cell type, and often result in divergent pathophysiologic outcomes. In the nervous system, cytokines have physiological functions that include neurite outgrowth, neurogenesis, neuronal survival, synaptic pruning during brain development, and they regulate the strength of synaptic transmission and synaptic plasticity”
The versatility in VGCs enables them to regulate various cellular pathophysiologic processes, ranging from neuronal excitability and synaptic transmission to neuronal death or survival. Cytokines are among the molecules that influence VGCs properties, and as such they are now regarded as novel neuromodulators. The modulation of VGCs by cytokines is reviewed extensively in the article.
Modulation of receptor-coupled ion channels in CNS by cytokines:
In hippocampal neurons, IL-1R1 co-localizes with the N-methyl-d-aspartate receptor
NMDAR stimulation increases the IL-1R1 interaction with the NR2B subunit
increases the GABAergic tone, thus altering the synaptic strength at GABAergic synapses.
modulates exocytosis of several neurotransmitters such as norepinephrine, glutamate, GABA and adenosine
there is evidence of presynaptic effects of IL-1β on glutamatergic terminals resulting in modulation of glutamate release.
precludes the cannabinoid CB1 receptors ability to inhibit glutamate release in corticostriatal brain slices, an effect that presumably increases neuronal network excitability.
induces defects in GABAergic neurotransmission in forebrain
has predominant excitatory effects mediated by enhancement of NMDA-induced neuronal Ca2+ influx, increased glutamate release, and inhibitory effects on GABAergic neurotransmission.
has specific interactions with AMPAR mediated by TNF-R1 (reversed by activation of cannabinoid CB1 receptors)
promotes the endocytosis of GABA-A receptors expressing the β2/3 subunits, thereby reducing inhibitory synaptic transmission
modulates glutamate and GABA receptor subunit compositions at neuronal membranes
can modify extracellular glutamate levels indirectly, by inducing glutamate release from microglia and astrocytes
Recently it was found that infliximab (a TNF-α inhibitor) decreased anhedonia and despair-like behavior in the rat unpredictable chronic mild stress model of depression, suggesting that inflammation might play an important role in stress related illnesses . TNF-α is important to the sensitivity of the behavioral response to administration of antidepressants . It has been suggested that pro-inflammatory cytokines enhance serotonin transporter activity, and possibly also dopamine transporter activity in the brain .
reduces glutamate excitotoxicity
reduces mGLUR2/3 metabotropic receptor expression
reduces AMPAR-GLUR2 subunit and L-type Ca2+ channel proteins
alters the functional properties of hippocampal synaptic network activity, especially under conditions of strong synaptic drive
reduces NMDA-activated neuronal firing in rat cerebellar slices, an effect associated with decreased NR1 subunit phosphorylation
Elevated IL-6 levels may play the role in cognitive impairment and serve as potential inflammatory biomarker of deterioration in schizophrenia . IL-6 directly controls SERT levels and consequently serotonin reuptake  and can regulate 5-HT2A receptor function .
Extensive research implicates disturbed immune function and development in the etiology and pathology of schizophrenia. In addition to reviewing evidence for immunological factors in schizophrenia, this paper discusses how an emerging model of atypical immune function and development helps explain a wide variety of well-established – but puzzling – findings about schizophrenia. A number of theorists have presented hypotheses that early immune system programming, disrupted by pre- and perinatal adversity, often combines with abnormal brain development to produce schizophrenia. The present paper focuses on the hypothesis that disruption of early immune system development produces a latent immune vulnerability that manifests more fully after puberty, when changes in immune function and the thymus leave individuals more susceptible to infections and immune dysfunctions that contribute to schizophrenia. Complementing neurodevelopmental models, this hypothesis integrates findings on many contributing factors to schizophrenia, including prenatal adversity, genes, climate, migration, infections, and stress, among others. It helps explain, for example, why (a) schizophrenia onset is typically delayed until years after prenatal adversity, (b) individual risk factors alone often do not lead to schizophrenia, and (c) schizophrenia prevalence rates actually tend to be higher in economically advantaged countries. Here we discuss how the hypothesis explains 10 key findings, and suggests new, potentially highly cost-effective, strategies for treatment and prevention of schizophrenia. Moreover, while most human research linking immune factors to schizophrenia has been correlational, these strategies provide ethical ways to experimentally test in humans theories about immune function and schizophrenia.
Bolstering immune function
One treatment strategy suggested by the hypothesis would be to employ practices that bolster immune function, by helping schizophrenia patients to follow procedures that have been shown to reduce inflammatory responses and improve defense against infection. These include, for example, insuring a balanced diet and ample levels of sunlight exposure, to insure adequate levels of vitamin D. A complementary approach would insure that patients practice regular moderate exercise and stress management—a regimen that some controlled experiments have found to reduce inflammation and improve resistance to infectious diseases.
Diagnosing and treating unrecognized infections and immune disorders
Because the hypothesis suggests that schizophrenia patients’ symptoms may sometimes be promoted by unrecognized and/or untreated infections, another strategy could involve more careful testing for untreated infections, and trials with targeted anti-viral or antibiotic regimes. Similarly, treating previously unrecognized immune disorders, or investigating medications to reduce high levels of pro-inflammatory cytokines, could be an informative test. As part of their disability, schizophrenia patients are less likely to seek out medical care and/or follow treatment recommendations. Thus, it may become important to regularly screen for infections as part of standard psychiatric care. Of note, adherence to anti-viral, antibiotic, or anti-inflammatory medication regimes may be greater than adherence to antipsychotics, as they tend to be better-tolerated, and carry less illness-related fear and stigma.
New prevention strategies
Reducing exposure to new infections
Primary prevention by optimizing prenatal care and nutrition
This chapter is built on increasing evidence that individuals diagnosed with a wide range of currently recognized psychiatric diseases show significant increases in peripheral inflammatory biomarkers and CNS markers of immune activation, while simultaneously evincing reduced effectiveness of immune elements important for protection against pathogens. From this foundational assumption, a number of central unanswered questions regarding the relationship of immunity to emotional and cognitive functioning and behavior are explored. Tentative conclusions are reached that in addition to being impacted by mental events, immune activity may contribute to the development of a wide range of psychiatric disorders, and may tend to promote different disorders at different stages of the life course.
Evidence That the Immune System is Involved in Psychiatric Disease Pathogenesis
Behavioral Abnormalities Associated with Immune Activation
Long-Term Behavioral Abnormalities Associated with Immune Activation Prenatally or in Early Life
Mechanisms by which Immune Activation (Inflammation) Produces Behavioral Disturbance
Effects of Inflammation on Neuroendocrine Mechanisms
Effects of Inflammation on Brain Biochemical Pathways Relevant to Psychiatric Disease
– Monoamine Neurotransmitter Function
Mechanisms of Inflammatory Effects on Monoamine Metabolism
– Indoleamine 2,3-Dioxygenase
– Mitogen-Activated Protein Kinase
– Glutamate and γ-Aminobutyric Acid
Effects of Inflammation on Functional Brain Neurocircuitry
– Basal Ganglia
– Anterior Cingulate Cortex
Evidence that Patterns of CNS Activity Associated with Psychiatric Disease Affect Immune Functioning in Health-Relevant Ways
Psychosocial Stress and Promotion of the Proinflammatory Phenotype
Stress Outflow Mechanisms by Which Psychosocial Stress Affects Immunity
– Hypothalamic–Pituitary–Adrenal Axis
– Autonomic Nervous System
Evidence that Environmental Factors that Promote Psychiatric Morbidity May Do So By Altering Immune Function
Role of Disrupted Human–Microbial and Human–Parasitic Relationships in the Development of Psychiatric Disease
Evidence that Psychiatric Conditions Are Associated with Alterations in Peripheral and CNS Immune Activity
Neuropsychiatric disorders (e.g., autism, schizophrenia) are partially characterized by social cognitive deficits, including impairments in the ability to perceive others’ emotional states, which is an aspect of social cognition known as theory of mind (ToM). There is also evidence that inflammation may be implicated in the etiology of these disorders, but experimental data linking inflammation to deficits in social cognition is sparse. Thus, we examined whether exposure to an experimental inflammatory challenge led to changes in ToM. One hundred and fifteen (n=115) healthy participants were randomly assigned to receive either endotoxin, which is an inflammatory challenge, or placebo. Participants completed a social cognition task, the Reading the Mind in the Eyes (RME) test, at baseline and at the peak of inflammatory response for the endotoxin group. The RME test, a validated measure of ToM, evaluates how accurately participants can identify the emotional state of another person by looking only at their eyes. We found that endotoxin (vs. placebo) led to decreases in performance on the RME test from baseline to the peak of inflammatory response, indicating that acute inflammation can lead to decreases in the ability to accurately and reliably comprehend emotional information from others. Given that deficits in ToM are implicated in neuropsychiatric disorders, including those which may have an inflammatory basis, these results may have implications for understanding the links between inflammation, social cognition, and neuropsychiatric disorders.