The Role of Inflammation in the Treatment of Schizophrenia

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The Role of Inflammation in the Treatment of Schizophrenia

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The Role of Inflammation in the Treatment of Schizophrenia

March 18,2020


https://www.frontiersin.org/articles/10 ... 00160/full

Background: Inflammation plays a major role in the onset and maintenance of schizophrenia. The objective of the present work was to synthetize in a narrative review the recent findings in the field of inflammation in schizophrenia and their application in daily practice.

Method: This review was based on the most recent meta-analyses and randomized controlled trials.

Results: The disturbed cytokines depend on the phase of the illness. A meta-analysis of cytokines in schizophrenia found higher levels of pro-inflammatory and anti-inflammatory cytokines in the peripheral blood in both patients with first-episode schizophrenia and relapsed patients than in healthy controls. Exploring detailed data on immune-inflammatory disturbances in SZ reveals that IL-6 is one of the most consistently disturbed cytokines. Other cytokines, including IL1, TNF, and IFN, are also disturbed in schizophrenia. Choosing a broad spectrum anti-inflammatory agent that may inhibit subsequent pathways might be particularly useful for the treatment of inflammatory schizophrenia. Highly sensitive C-Reactive Protein is a useful screening marker for detecting inflammation in SZ subjects. Anti-inflammatory agents have shown effectiveness in recently published meta-analyses. Only one study found a significant difference between celecoxib and placebo, but two found a trend toward significance on illness severity and one on positive symptoms. In addition, other published and unpublished data were included in another meta-analysis that concluded the significant effect of add-on celecoxib in positive symptoms in first episode patients. There is a lack of data to determine if aspirin is truly effective in schizophrenia to date. Other anti-inflammatory agents have been explored, including hormonal therapies, antioxidants, omega 3 fatty acids, and minocycline, showing significant effects for reducing total, positive, and negative score symptoms and general functioning. However, each of these agents has multiple properties beyond inflammation and it remains unclear how these drugs improve schizophrenia.

Conclusion: The next step is to tailor anti-inflammatory therapy in schizophrenia, with two main challenges: 1. To provide a more efficient anti-inflammatory therapeutic approach that targets specific pathways associated with the pathology of schizophrenia. 2. To develop a more personalized approach in targeting patients who have the best chance of successful treatment.

Introduction

Though conventional treatments have improved schizophrenia prognosis, they and the response rate of antipsychotics in schizophrenia remain unsatisfactory. The antipsychotics introduced in the 1950s have shown moderate global effectiveness with a mean effect size of 0.38 (1). The response rate of clozapine—the most effective antipsychotic—is only 33% after 3 months of treatment (1). Antipsychotics are effective on positive symptoms but unsatisfactory on negative/depressive symptoms, social functioning, and quality of life (1).

An explanation for this high rate of non-response and relapses relies on the observation that current pharmacological treatments are primarily based on the monoaminergic hypothesis, without involving the personalized medicine approach. According to this hypothesis, schizophrenia is principally due to a dopamine dysfunction in the brain (with an excess in the striatum ventral tegmental area and a deficit in the prefrontal cortex). All current antipsychotics target dopamine deficits in the brain. Yet clozapine, the antipsychotic that has shown the best effectiveness, has also one of the lowest potentials to reduce dopamine in the brain (2). This paradox remains unsolved to date.

The high rate of therapeutic failure in psychiatry can most likely be accounted for by the limitations pertaining to brain-orientated treatments. Current treatments do improve neurotransmitter deficits, but without addressing the source of these deficits. This may explain the high relapsing rates and chronic illness causes.

The objective of the present review was to synthetize the state of knowledge of the role of inflammation in the treatment of schizophrenia.


Materials and Methods

This review was based on the most recent meta-analyses and randomized controlled trials, and if these were not available, on preliminary data. The Medline® database was explored from its inception to September 10th 2019, without language restriction. The research paradigm was: (schizophrenia) AND (inflammation OR anti-inflammatory agents OR cytokines OR C reactive-protein). The references of each article were also checked. Given the broad spectrum of the subject, the systematic review design was not adapted to the present work and a narrative review form has been preferred. Thus, no flow-chart or study quality assessment has been provided.

Results

Two thousand two hundred seventy-eight articles were identified in the Medline search. Of them, 41 were included in the present review.

The Role of Inflammation in the Pathogenesis and Maintenance of Schizophrenia

The pathophysiological underpinnings of inflammation and its potential role in schizophrenia onset and maintenance have been previously synthetized (3). Schizophrenia is characterized by risk genes that promote inflammation, and by environmental stress factors and alterations of the immune system. Neuromediator alterations classically described in schizophrenia (dopamine, serotonine, glutamate) have also been identified in low-level neuro inflammation and may be key triggers of schizophrenia symptoms onset and maintenance (4). The contribution of chronic inflammation to major mental disorders has received increased attention, revealing a host of pharmacologic targets. Indeed, multiple recent reviews clearly demonstrate that schizophrenia is associated with a dysregulation of immune responses, as reflected by the observed abnormal profiles of circulating pro- and anti-inflammatory cytokines in affected patients (5). Impaired central nervous system volume and microglial activations in schizophrenia have been confirmed in neuroimaging studies (4).

Among potential sources of chronic low-grade inflammation, infectious agents and environmental toxins (including tobacco smoke and cannabis) have been identified (6–11). It may also be a secondary reaction to trauma-related neuronal lesions or a genetic effect (4).

Microglia constitute between 10 and 20% of all cells in the CNS and are the most important component of the local CNS immune system (12). Microglia is activated in case of injury or disease such as systemic infection, and is involved in the activation of cytokines, the key mediators of inflammation.

A variety of low-level stimuli including aging, neurodegeneration and stress can also cause microglia to be “sensitized” or “primed,” a process that elicits an exaggerated immune response (4). Once microglia are primed, an additional low-level stimulus, e.g., minor systemic inflammation, may exacerbate or re-exacerbate an immune response in the CNS with behavioral consequences (13).

Inflammatory Markers in Schizophrenia

Fibrin is a protein that is increased in inflammatory processes. Degradation products of fibrin have been found in postmortem brains of schizophrenia patients and in the cerebrospinal fluid (CSF) of about 50% of them (14). The density of microglia is significantly increased in schizophrenia [mostly in the temporal cortex (14)] yet with substantial heterogeneity between studies. Astrocytes and oligodendrocytes' densities did not differ significantly between schizophrenia and healthy controls. The results of postmortem histology are paralleled with an overall increase in expression of proinflammatory genes in SZ patients, while anti-inflammatory gene expression levels were not different between SZ patients and controls. These results strengthen the hypothesis that immune system disturbances are involved in the pathogenesis of schizophrenia.

A meta-analysis of cytokines in schizophrenia found higher levels of proinflammatory cytokines in the peripheral blood in both patients with first-episode schizophrenia and relapsed patients than in healthy controls, but it also found higher levels of some anti-inflammatory cytokines in these patients than in controls (15). The disturbed cytokines depend on the phase of the illness.

In first-episode psychosis, interferon-γ (IFN-γ), IL-1RA, IL-1β, IL-6, IL-8, IL-10, IL-12, sIL-2R, TGF-β, and TNF were all significantly increased, and levels of IL-4 were significantly decreased. Age, sex, illness duration, smoking, and BMI were all unrelated to IL-6 and TNF-α increase in first-episode psychosis.

In acute exacerbation of chronic SZ, an increase of IFN-γ, IL-1RA, IL-1β, IL-6, IL-8, IL-12, sIL-2R, TGF-β, and TNF alongside a decrease of IL-4 and IL-10 levels were found in SZ compared to controls.

In chronically ill SZ, IL-6, TNF, sIL-2R, IL-1β were increased and IFN-γ was decreased in SZ patients compared to controls, with no significant difference in the levels of IL-2, IL-4, or IL-10. Age, sex, illness duration, smoking, and BMI were all unrelated to the association between IL-6 and SZ. Of note, a meta-analysis of cytokines in the CSF of SZ showed increased levels of IL-6 and IL-8 (16).

Inflammation has been bilaterally associated with cortisol disturbances (17). Cortisol disturbances have shown associations with treatment non-response in schizophrenia and major depression, which is frequent in SZ patients (18).

In summary, IL-6 is the most consistent increased cytokine in all phases of schizophrenia, but a large bundle of other cytokines is found to be disturbed. These findings suggest that choosing a broad-spectrum anti-inflammatory agent that may inhibit subsequent pathways may be particularly useful for the treatment of inflammatory schizophrenia.

Anti-inflammatory Therapies Tested So Far in Schizophrenia

A detailed overview of the efficacy of anti-inflammatory treatment in schizophrenia was published in 2014 and provides one of the most convincing pieces of evidence that inflammation is involved in schizophrenia (19). This work has been recently updated (20). Sixty-two double-blind randomized clinical trials including 2,914 SZ patients were included in the latter.

The cyclooxygenase (COX) inhibitors were the first anti-inflammatory agents to be tested in schizophrenia in the early 2000's. The prostaglandin inflammatory cascade is activated by two COX enzymes named COX-1 and COX-2. The COX 1 is a permanent/state COX responsible for the baseline inflammatory response (e.g., reacting to a wound). The COX-2 is activated only in case of acute inflammation (in case of infection for example) (21).

That's why celecoxib, a specific COX-2 inhibitor, has been the first and most studied COX-targeted anti-inflammatory agent in schizophrenia. Four RCTs investigated the effects of celecoxib in 195 patients (22–24) with inconsistent findings. Only one study found a significant difference between celecoxib and placebo (24), but two found a trend toward significance on PANSS total score (p = 0.06 for both) and one on PANSS positive score (p = 0.05) (22). In addition, other published and unpublished data were included in another meta-analysis that concluded the significant effect of add-on celecoxib in SZ in PANSS total and PANSS positive scores in first episode SZ patients (25).

COX-1 inhibitor (low-dose aspirin) has been studied in two RCTs, with positive results on all PANSS scores in one study (26), and a positive but small effect on PANSS total- and positive score in the other (27). Aspirin is to date the anti-inflammatory agent that has shown the greatest potential for effectiveness in schizophrenia (20). This effect was driven by a high-baseline PANSS score subgroup. Yet the methodology of these trials has been questioned, especially due to the differences in antipsychotic treatments in each groups and the statistically significant but clinically non-significant effect reported in these trials (28). In summary, there is a lack of data to determine if aspirin is truly effective in SZ to date. Moreover, aspirin is at increased risk of ulcer and hemorrhagic side effects, limiting its prescription.

Other anti-inflammatory agents have been explored, yet with a broad spectrum of other properties. These agents included hormonal therapies, antioxidants, omega 3 fatty acids, and minocycline, an antibiotic that penetrates the brain. Overall, anti-inflammatory agents (mostly celecoxib, aspirin, minocycline) have shown significant effects for reducing total, (effect size = 0.41, 95% confidence interval (CI) = [0.26, 0.56]), positive (effect size = 0.31, 95% CI = [0.14, 0.48]), and negative (effect size = 0.38, 95% CI = [0.23, 0.52]) scores in the PANSS. General functioning was also significantly enhanced by overall anti-inflammatory agents. However, each of these agents has multiple properties beyond inflammation (e.g., hormonal for estrogens/pregnelonone, antibiotic/glutamatergic for minocycline, antioxidant for N-acetyl-cysteine) and it remains unclear how these drugs improve schizophrenia.

Discussion/Perspectives

Schizophrenia Patients With Chronic Low-Grade Peripheral Inflammation: The Best Candidates for Anti-inflammatory Treatment


To improve anti-inflammatory drug effectiveness, it is necessary to identify best candidate SZ patients using inflammatory markers. This is contrary to previous studies, which only included SZ patients using clinical criteria [for review see (21)]. This has led to high heterogeneity in previous meta-analyses (25). We have seen that defining an inflammation signature in schizophrenia was difficult due to the multiple cytokines that may be disturbed according to the state of the illness. We have recently published a review on the interest of hs-CRP to identify peripheral inflammation in schizophrenia (29). Hs-CRP is the most common peripheral marker of inflammation and is synthesized by the liver in response to IL-1 and IL-6 according to the following pathway. It has been reliably used in multiple randomized controlled trials for exploring the role of inflammation in treatment response (30–34). Recent data indicate that blood CRP concentrations have been associated with high central glutamate, which correlated with symptoms of anhedonia, one of the symptoms of schizophrenia (35).

In stabilized SZ patients, around one third exhibit high CRP levels (>3 mg/L) (36). These patients were found to have more resistance to conventional treatments and more cognitive impairment, which confirms the clinical interest of targeting this specific subgroup of patients (36, 37).

The blood–brain barrier protects the brain from peripheral inflammation, and the cytokines state in the blood does not reflect the situation in the brain. Yet different pathways exist between the peripheral and the CNS immune systems. Hs-CRP appears to be a good reflector of central inflammation in non-SZ populations (35). It seems also well-suited for guiding immunotherapies targeting IL-6 (35).

In summary, hs-CRP is a useful screening marker for detecting inflammation in SZ subjects.

Janus-Kinase Inhibitors (JAKinibs): A Promising Treatment for Inflammatory Schizophrenia

We have seen that schizophrenia was associated with a broad range of disturbed cytokines. These cytokines bind to receptors that activate downstream the so-called JAK/STAT signaling pathway (38) involved in gliogenesis, synaptic plasticity, microglia activation and neurogenesis, all implicated in the pathophysiology of schizophrenia (39). Moreover, depressive symptoms are frequent in schizophrenia and the antidepressant actions of current treatments have been confirmed to be mediated by JAK/STAT-dependent mechanisms (40). Small-molecule inhibitors of JAKs (jakinibs) have been shown as safe and efficacious options for the treatment of rheumatoid arthritis, psoriasis, and inflammatory bowel disease (41), and may be promising treatments for schizophrenia that should be evaluated.

To Destroy the Root Cause of the Evil: Addressing the Sources of Inflammation

Adding an anti-inflammatory agent may be not sufficient if the potential sources of inflammation are not addressed. Among them, tobacco smoking, Toxoplasma latent infection, microbiota disturbances, lack of physical activity, and poor diet have been identified as major modifiable sources of inflammation in SZ patients that should be addressed in schizophrenia daily care (7–10). Tobacco smoking cessation, Mediterranean or anti-inflammatory diets, and physical activity appear as promising interventions to be tested in inflammatory SZ patients, yet further studies are needed to determine their effectiveness.

Limits

This review has shown one major limit in the field of inflammation in schizophrenia, i.e., the definition of a consensual inflammatory signature to determine which patients may benefit from anti-inflammatory strategies. While TSPO-PET imaging appears as the gold standard to explore neuro-inflammation to date (42), its costs and its dissemination (limited by MRI availability and genotyping) prevents it from being widely distributed. Hs-CRP appears as a potentially good biomarker, but further studies should confirm if peripheral CRP is a good marker of central neuro-inflammation in schizophrenia, as suggested in one study in depression (35).

Conclusion

The next step is to tailor anti-inflammatory therapy with the best response and highest safety in schizophrenia. There are two main challenges:

- to provide a more efficient anti-inflammatory therapeutic approach that targets specific pathways associated with the pathology of schizophrenia. Exploring detailed data on immune-inflammatory disturbances in schizophrenia reveals that IL-6 is one of the most consistently disturbed cytokines in SZ. Other cytokines including IL1, TNF, and IFN are also disturbed in schizophrenia.

- to develop a more personalized approach in targeting patients who have the best chance of successful treatment. We hypothesize that SZ patients with chronic low-grade peripheral inflammation (SZ-CPI) defined by hs-CRP blood level ≥3 mg/L (a reliable marker used in previous works) make the best candidates for anti-inflammatory treatments.
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Re: The Role of Inflammation in the Treatment of Schizophrenia

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Schizophrenia May Be an Autoimmune Condition

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Re: The Role of Inflammation in the Treatment of Schizophrenia

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Inflammation and immunity in schizophrenia: implications for pathophysiology and treatment

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4595998/

Abstract

Complex interactions between the immune system and the brain might have important aetiological and therapeutic implications for neuropsychiatric brain disorders. A possible association between schizophrenia and the immune system was postulated over a century ago, and is supported by epidemiological and genetic studies pointing to links with infection and inflammation. Contrary to the traditional view that the brain is an immunologically privileged site shielded behind the blood–brain barrier, studies in the past 20 years have noted complex interactions between the immune system, systemic inflammation, and the brain, which can lead to changes in mood, cognition, and behaviour. In this Review, we describe some of the important areas of research regarding innate and adaptive immune response in schizophrenia and related psychotic disorders that, we think, will be of interest to psychiatric clinicians and researchers. We discuss potential mechanisms and therapeutic implications of these findings, including studies of anti-inflammatory drugs in schizophrenia, describe areas for development, and offer testable hypotheses for future investigations.

Introduction

Complex immune–brain interactions that affect neural development, survival, and function might have causal and therapeutic implications for many disorders of the CNS1–5 including psychiatric illness.2 Multiple sclerosis, previously thought to be solely neurological, is increasingly recognised as secondary to immune dysfunction.3 High concentrations of the circulating proinflammatory cytokine interleukin 6 in childhood have been reported to be associated with increased risk of subsequent psychosis and depression in young adult life,2 and elimination of autoantibodies against neuronal cell surface proteins by immunotherapy has led to symptomatic improvement in some cases of first episode psychosis.6 In this Review, we discuss whether research is entering a new era of immunopsychiatry that will change the understanding of the brain’s disorders, in which manifestations include, but are rarely restricted to, mental symptoms. Substantial evidence supports a role for the immune system in the pathogenesis of depression and schizophrenia, which is consistent with the well known clinical and aetiological (including genetic) overlap between these disorders. Here, we describe some of the important areas of research that implicate the innate and adaptive immune response in the pathogenesis of schizophrenia and related psychotic disorders through effects on neurotransmitters, neurodevelopment, and degeneration. We assess potential therapeutic implications of these findings and existing treatment studies of anti-inflammatory agents in schizophrenia.

The aim of this Review is not only to summarise key evidence about the link between immune system and schizophrenia, but also to identify gaps in knowledge and provide suggestions for improvement, including testable hypotheses for future investigations. The aim is also to give a holistic view, rather than an exhaustive review, of a landscape of increasing relevance to people with schizophrenia and those who treat them.

The immune system and the brain share some fundamental characteristics. Both are highly integrated, complex systems with memory, which develop through interactions with the external environment, are able to distinguish between self and non-self, and respond adaptively.7,8 Historically, the brain has been thought of as an immunologically privileged site, shielded behind the blood–brain barrier,9 but immune components of the brain, such as microglia that constitute about 10% of the brain cell mass (equal to neurons), derive from the haemopoietic system beyond the CNS.10 In response to systemic inflammation, microglia release cytokines that bind to specific receptors on neurons8 and affect neurotransmitters, synaptic plasticity, and cortisol concentrations, leading to changes in mood, cognition, and behaviour.1,5

The immune and infection link to psychosis


The immune system consists of a complex organisation of cells and mediators that has evolved largely to protect human beings from infection and malignancy.8 It can be broadly thought about as consisting of an innate response, acting as a rapid, non-specific first line of defence, and an adaptive response that is slower and antigen specific. The innate response is mediated by neutrophils and macrophages that recognise and clear invading organisms. Inflammatory cytokines, secreted by macrophages and other cells, help this process. The adaptive response involves immunological memory, and consists of T (thymic) lymphocytes that recognise antigens and cause lysis of infected cells, and B lymphocytes that secrete antibodies as part of the humoral response.8

Schizophrenia is a disabling disorder characterised by positive (delusions and hallucinations), negative (social withdrawal and apathy), and cognitive symptoms (poor executive function and memory). It affects around 1% of the population at some point in their lives, with onset characteristically during the period of brain development that follows puberty, and lasts until the end of the third decade.11 Schizophrenia is multifactorial; it is associated with multiple genetic loci that confer risk, in addition to developmental and postnatal risk factors.12 A possible association between schizophrenia and the immune system was postulated more than a century ago (panel 1), and is supported by epidemiological studies that suggest links with infection and systemic inflammation.13–16

Serologically confirmed prenatal maternal infection with any of several pathogens (including influenza, herpes simplex virus type 2, cytomegalovirus, and the intracellular parasite Toxoplasma gondii), clinically diagnosed non-specific viral and bacterial infections, and increased maternal C-reactive protein concentrations during pregnancy have all been associated with schizophrenia in the adult offspring.15,17 Reduced concentrations of acute-phase proteins in neonates might increase the risk of adult psychosis by increasing susceptibility to infections in early life.18 Acute-phase proteins are released as part of the innate immune response and consist of several mediators with different physiological functions.8 Exposure to neurotropic virus in early childhood is associated with increased risk of subclinical psychotic experiences in adolescence.19 The finding that the risk of schizophrenia is almost doubled in adult survivors of childhood CNS viral infection shows that the phase during which infection can increase the risk of future neuropsychiatric disorders is not confined to the prenatal period.14 Adult schizophrenia is also associated with increased rates of various infections, including those caused by T gondii.20

Childhood autoimmune conditions are associated with subclinical psychotic experiences in adolescents21 and schizophrenia in adults.22 The prevalence of autoimmune conditions is increased in people with schizophrenia and their unaffected first-degree relatives.23 Furthermore, risk of schizophrenia increases in a linear fashion with the number of severe infections in individuals with a previous history of autoimmune disease.22 Thus, the links between schizophrenia and a range of infections and autoimmune conditions suggest a common underlying pathway, probably involving the inflammatory immune response. In addition to its own effects on the brain, inflammation is thought to increase the permeability of the blood–brain barrier and to help with penetration of immune components into the brain.24

Support for an immune-mediated cause in schizophrenia comes from genome-wide association studies that report significant associations between schizophrenia and markers close to the major histocompatibility complex (MHC) region on chromosome 6.25,26 This region contains many immune-related genes, including those involved in antigen presentation and inflammatory mediators. A 2014 genome-wide association study27 identified 108 genetic loci (83 previously undetected) associated with schizophrenia. Broadly, these represent genes expressed in the brain and immune cells involved in adaptive immunity (CD19 and CD20B lymphocytes), in addition to the MHC. Moreover, associations with the immune-related genes remained significant after the MHC region was excluded, suggesting that these findings were not driven by the strong association at the MHC. Another genome-wide association study28 reported substantial genetic overlap involving the MHC region between schizophrenia and multiple sclerosis, a condition characterised by immune dysfunction.

Immune system in the pathogenesis of schizophrenia and related psychosis

The abnormalities of the immune system seen in schizophrenia and related psychosis are diverse and overlapping, and involve many immune components. Here, we discuss components of the innate immune response (cytokines and microglia), and components of the adaptive immune response (lymphocyte subsets and anti-neuronal cell surface antibodies). We do not cover autoimmunity involving various brain regions, thyroid, thymus, and antibodies to dietary antigens such as gliadin and casein. Key questions pertaining to the entire field have been summarised in panel 2.

Heterogeneity between studies might point towards uncertainty or suggest heterogeneity in the causes and pathogenesis of the schizophrenia syndrome. Changing of the focus of research from syndrome to symptom, or constellation of symptoms, would be helpful to fully understand the role of inflammation and immunity in neuropsychiatric disorders. Many current studies have inadequately accounted for confounding factors such as body mass and smoking. More studies have focused on blood rather than CNS immune markers, and few have examined associations between immune markers and either symptoms or cognition in schizophrenia. Rarer still are longitudinal studies of immune markers and schizophrenia that comment on cause and effect between immunity and psychiatric syndrome. Associations between immune markers, stress, and cortisol in schizophrenia are also poorly understood. Despite these gaps in the literature, present knowledge is consistent with a role for the immune system in the pathophysiology of schizophrenia and related psychotic disorders.

Inflammatory cytokines


Meta-analyses of many cross-sectional studies show that schizophrenia is associated with disruption of the cytokine milieu and the propensity for the production of proinflammatory cytokines.16,29,30 Longitudinal studies of inflammatory markers and subsequent psychotic disorders are scarce. Findings from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort2 suggest that increased serum concentration of the proinflammatory cytokine interleukin 6 at age 9 years is associated with twofold increased risk of development of a psychotic disorder at age 18 years. The study also reports a robust dose-response association between increased interleukin 6 concentrations in childhood and subsequent risk of subclinical psychotic experiences in young adulthood, which persists after several potential confounders are taken into account, including sex, body mass, and psychological and behavioural problems preceding the measurement of childhood interleukin 6.2 No associations between serum C-reactive protein concentrations at baseline and future psychiatric disorders were seen, but another longitudinal study31 reported increased risk of late, or very late, onset schizophrenia for increased serum C-reactive protein concentrations at baseline. Further longitudinal studies are needed to confirm whether the increase in serum concentrations of proinflammatory cytokines in schizophrenia and related psychosis is the cause or consequence of illness, although these findings suggest causal mechanisms.

Antipsychotic-naive first-episode psychosis30 and acute psychotic relapse16 are also associated with increased serum concentrations of interleukin 6 and other proinflammatory cytokines, such as tumour necrosis factor α (TNFα), interleukin 1β, interferon γ, and decreased serum concentrations of anti-inflammatory cytokine interleukin 10, which are normalised after remission of symptoms with antipsychotic treatment.16 Reduced interleukin 2 (involved in immune regulation) production in vitro by T cells collected from patients with schizophrenia was thought to be indicative of autoimmune causes of psychosis.32 However, acute psychosis is associated with no substantial changes in serum interleukin 2 concentrations.16 The concentration of soluble interleukin 2 receptor increases in schizophrenia,16,30 which is likely to be a compensatory mechanism that inhibits interleukin 2 production. Thus, the data are consistent with an increase in proinflammatory cytokines in acute psychosis. However, few studies have adjusted for important immune-modulatory factors such as body mass or smoking,16 or examined cytokines in cerebrospinal fluid, where an increase in interleukin 6 concentration33,34 has been reported in schizophrenia. One study35 reported increased serum interleukin 6 concentrations in people with an at-risk mental state for psychosis compared with healthy controls. Some data suggest that serum cytokine concentrations, including interleukin 6, are associated with illness severity, duration, and antipsychotic therapy,16,36–39 but little is known regarding the associations between stress, cortisol and cytokine concentrations in different stages of schizophrenia. Therefore, more studies are needed to understand the associations between cytokine concentrations, disease prodrome, progression, and treatment response. Longitudinal studies of first-episode psychosis, individuals at clinical high risk for development of psychosis, and those with treatment refractory illness would be useful to examine these issues. Rather than merely reporting group differences in cytokine serum or cerebrospinal fluid concentrations, future studies should examine associations between cytokines, cognitive and social functioning, comorbid physical illness, and structural and functional brain indices in people with psychosis and healthy controls.

In rodents, studies have noted physiological roles for cytokines in memory and learning, including long-term potentiation, synaptic plasticity, and neurogenesis.40 Mild systemic inflammation has been reported to produce impairments in spatial memory in human beings via its action on glucose metabolism in the medial temporal lobe.41 Whether cytokine-mediated inflammatory processes underlie cognitive dysfunction in schizophrenia, an integral part of the syndrome, is an important hypothesis that needs investigation.

Longitudinal associations between interleukin 6 and both psychosis and depression might indicate a transdiagnostic effect.2 A longitudinal association between serum C-reactive protein, a marker of systemic inflammation, and subsequent symptoms of posttraumatic stress disorder has been reported.42 Thus, understanding the early-life biopsychosocial determinants of cytokine serum concentrations would be crucial to elucidate whether increased concentrations of cytokines could explain the association between early-life adversity and the risk of various psychiatric illnesses in adulthood.43

Studies in mice have shown how peripheral cytokines, such as interleukin 6, can affect the brain (figure 1).1,4 In the neural pathway, circulating interleukin 6 binds to receptors on the vagus nerve, and the signal reaches hypothalamic brain nuclei via the brainstem by retrograde axonal transport. Once within the CNS, the cytokine signal is amplified, which activates microglia, leading to the secretion of proinflammatory cytokines, chemokines, and proteases within the brain.1 These messengers activate IDO1, an enzyme that metabolises tryptophan along the kynurenine pathway, leading to increased concentrations of kynurenic acid and its metabolite quinolonic acid, both of which are involved in glutamatergic neurotransmission.44 Cytokines also increase oxidative stress by raising the concentration of toxic nitric oxide, and activate the hypothalamic–pituitary–adrenal axis, leading to the release of cortisol.1,5 These effects could contribute to the negative, cognitive, and positive symptoms of schizophrenia, and also to the impaired mood, cognition, and perception that are important parts of other psychiatric disorders. Indeed, non-specific peripheral immune activation caused by injection of lipopolysaccharide in healthy volunteers increases serum interleukin 6 concentrations, in addition to inducing low mood, anxiety, and reduced cognitive performance.45 Furthermore, cytokines have substantial effects on microglia that, in turn, are crucial for the maintenance of effective neuronal and synaptic health.10

Microglia


Microglia, the resident immune cells of the brain, constitute 10% of all non-neuronal or glial cells, which in turn constitute 90% of the adult human brain.10 Similar to macrophages, these cells originate from myeloid precursor cells and are thought to migrate into the CNS during the early neonatal period.46 In the healthy brain, microglia retain a downregulated phenotype (resting state),47 yet continue to survey and respond to the surrounding brain microenvironment. If the brain is subject to injury, inflammation, or in response to systemic inflammation, microglia develop an activated phenotype characterised by morphological changes, upregulation of surface receptors, the potential to activate T cells, and the release of various inflammatory mediators, including cytokines.48

Neuroinflammation is characterised by the activation of microglia cells, which show an increase in the expression of the translocator protein (TSPO). Neuroimaging studies using PET and a TSPO ligand provide evidence for neuroinflammation in recent-onset schizophrenia,49 and in acute exacerbations of schizophrenia.50 These studies49,50 report increased binding of this ligand in the entire grey matter and hippocampus, suggesting that neuroinflammation might contribute to grey matter volume loss and cognitive deterioration in schizophrenia. However, such studies are few in number and the existing studies have included small numbers of people with schizophrenia and healthy controls. An alternative explanation for increased binding of the TSPO ligand could be its affinity for activated astrocytes, which are seen in schizophrenia but are unrelated to neuroinflammation.50 Many patients with schizophrenia are treated with benzodiazepines, which can also affect the binding of this ligand. Thus, identification of reliable markers of microglial activation is needed so they can be used for in-vivo imaging or measured in blood to investigate whether microglial activation corresponds with clinical severity and treatment response.

Previously activated microglia can respond more strongly to a new stimulus.51 Microglia are likely to retain an immune memory of the neuropathology, which in turn is associated with heightened responsiveness to new systemic inflammation.48 Thus, early developmental insults such as childhood CNS or severe systemic infection might have a priming effect on microglia,51 increasing microglial activation and psychosis risk after subsequent infections. Whether the association between early-life CNS infection and adult schizophrenia14 could be explained by changes in microglia can be tested using longitudinal birth cohorts. Induced pluripotent stem cell technology has been successfully used to create neurons by reprogramming human fibroblast cells; neurons derived from patients with schizophrenia have diminished neuronal connectivity and decreased neurite number and glutamate receptor expression compared with neurons derived from healthy controls.52 Whether this technology can be used to study non-neuronal brain cells such as microglia remains to be seen.

Antineuronal cell surface autoantibodies


A possible role of brain-reactive autoantibodies in the causation of schizophrenia has been discussed since the early 20th century.53 Autoantibodies against components of various brain regions, cellular proteins, and dietary antigens, such as gliadin and casein, in serum and cerebrospinal fluid have been seen in schizophrenia and related psychosis.54,55 Antibodies against neuronal cell-surface targets, N-methyl-D-aspartate (NMDA) receptor, and components of the voltage-gated potassium channel complex have been reported in some patients with first episode psychosis and schizophrenia defined according to the diagnostic and statistical manual of mental disorders, fourth edition (DSM-IV).6,56–59 Some of these antibodies have been typically associated with anti-NMDA receptor encephalitis, a progressive illness that often starts with psychotic symptoms or seizures, and subsequently manifests other neurological and autonomic features.60 When present in patients with encephalitis, the antibodies are deemed to be pathogenic, and removal of the antibodies is associated with clinical improvement. Early identification of the antibodies and treatment with immunotherapy has been reported to predict good clinical outcome.61 Whether this finding applies for patients with antibodies and a purely psychiatric presentation remains to be tested, although a few case descriptions exist to support this.6 Randomised controlled trials of immunotherapy as an adjunct of standard antipsychotic treatment for antibody-associated cases of psychosis are needed to examine this question.

Could NMDA receptor antibody seropositivity in some people with psychosis be, in fact, undiagnosed anti-NMDA receptor encephalitis? Diagnostic misclassification is unlikely to be the sole explanation for this finding because almost none of the NMDA receptor antibody seropositive cases of psychosis have IgG class NMDA receptor antibodies against the NR1 subunit alone (one of the subunits of this antibody).59,62 An association between NMDA receptor antibody and schizophrenia is biologically plausible; in healthy volunteers, blockade of this receptor with ketamine produced psychotic symptoms.63 Furthermore, a 2014 study of schizoprenia64 reported that de-novo mutations, in the form of chromosomal copy number changes, affect glutamatergic post-synaptic proteins that form part of the receptor.

NMDA receptor antibody seropositivity is not restricted to patients with schizophrenia alone. Patients with psychiatric disorders, such as schizophrenia, depression, and bipolar disorder, are collectively about three times more likely to have elevated NMDA receptor antibody titres than controls, based on high-specificity (but not low-specificity) seropositivity thresholds.62 This underscores the need for further cross-sectional and longitudinal studies of psychiatric cases and healthy controls, which employ standardised assay methods and seropositivity threshold definitions. Preclinical studies are also needed to elucidate pathogenic mechanisms of these antibodies in psychosis and other mental illnesses.

T lymphocytes

T cells are thymus-derived lymphocytes which, very simply, can be thought of as either CD8-expressing cytotoxic cells or CD4-expressing helper cells, and can have both proinflammatory and anti-inflammatory roles. Evidence suggests a role for T cells in the causes of schizophrenia. Acute psychosis is associated with the activated phenotype of lymphocytes within the CNS compared with controls.65 In post-mortem studies, immunohistology has allowed direct visualisation of both increased T cell and B cell numbers within the hippocampus in patients with schizophrenia.66 These changes were especially evident in those patients with predominantly negative, rather than positive symptoms.67 However, inconsistencies exist between studies as to whether schizophrenia is associated with increased or decreased numbers of lymphocytes in the peripheral circulation. A 2013 meta-analysis68 reported increased numbers of cells positive for CD56 (a marker of natural killer cells and activated T cells), and an increased CD4/CD8 T cell ratio in schizophrenia. The study also underscored important limitations of the existing data. Many studies do not control for immune-mediating variables, such as smoking, body mass, stress-associated cortisol concentrations, and medication. Findings from individual studies are difficult to compare because they report percentages rather than cell numbers.

Well controlled studies reporting absolute cell numbers are needed to fully understand any associations between T cells and schizophrenia. Since schizophrenia is a heterogeneous condition, different T-cell subtypes might be associated with differing symptoms. Thus studies of T cells might be more informative after stratification of cases by symptom profile. To fully understand the role of T cells in schizophrenia, an understanding of the function of these cells is also needed. Future studies should assess the cytokine profile of these cells, their activation status, and gene expression profiles.

How might immune dysregulation lead to the manifestation of schizophrenia?


Effects on neurotransmitters


Studies in mice suggest an association between prenatal infection and inflammation and disturbance of neurotransmitter systems (glutamate, dopamine, and γ-aminobutyric acid [GABA]) in the offspring.69 However, little is known about the direct effects of the inflammatory immune response on neurotransmitter systems in human beings. NMDA receptor antagonism and glutamatergic hypofunction have long been proposed as underlying mechanisms for psychotic symptoms and cognitive dysfunction in schizophrenia.63,70 Evidence suggests that proinflammatory cytokines increase the concentration of kynurenic acid, which is a metabolite of tryptophan and the only naturally occurring NMDA receptor antagonist in the human CNS (figure 2).71,72

Studies of the cyclooxygenase (COX) pathway might lead to a better understanding of the role of kynurenic acid in psychosis. COX1 inhibition increases the concentration of kynurenic acid, while COX2 inhibition decreases this concentration.73 This finding might explain some of the side-effects of COX1 inhibitors, such as psychotic symptoms and cognitive dysfunction. Furthermore, celecoxib (a selective COX2 inhibitor) has been reported to improve clinical symptoms in schizophrenia.74,75 Therefore, systematic evaluation of the neuropsychiatric side-effects of COX1 and COX2 inhibitors from existing randomised controlled trial data would be useful.

The association between neurotransmitters and immune mediators can be reciprocal and a few publications have reported immunoregulatory functions for dopamine.76 T cells express dopamine receptors, the stimulation of which promotes upregulation of adhesion molecules and cytokine production.77,78 Increased expression of the dopamine D3 receptor and increased synthesis of the proinflammatory cytokine interferon γ by lymphocytes have been reported in unmedicated patients with schizophrenia.79 The opposite has been reported in Parkinson’s disease,80 a condition characterised by CNS dopamine depletion. Further studies are needed to understand the effects of inflammation on neurotransmission and vice versa in both healthy people and people with psychiatric disorders.

Effects on neurodegeneration


That a neurodegenerative process is active in schizophrenia beyond that seen in healthy people is suggested by progressive clinical deterioration, cognitive decline, and loss of cortical grey matter in combination with histopathological evidence of neuronal atrophy and reductions in the number of neuronal synapses and dendrites.81–83 Activated microglia are increasingly recognised as an important component in the pathogenesis of other degenerative brain conditions, such as Alzheimer’s disease, in which they seem to have wide-ranging effects.48 Could microglial activation also contribute to neurodegeneration in schizophrenia? Microglial activation interferes with neuronal survival by increasing oxidative stress and decreasing neurotrophic support.5 Schizophrenia is associated with changes in serum, plasma, and red blood cell markers of oxidative stress.84 A population-based longitudinal study85 reported a strong association between delirium and subsequent dementia and cognitive decline in older adults, which is not mediated by classical neuropathologies associated with dementia. Systemic inflammation, a common cause of delirium, might underlie this association. Indeed severe systemic illness in the elderly has been reported to be associated with subsequent cognitive decline and functional deterioration.86,87 In the future, studies should examine whether inflammatory processes could explain progressive cognitive decline and brain volume loss in some cases of schizophrenia.

Effects on neurodevelopment

Interference with brain development from early-life infection/inflammation is consistent with a neurodevelopmental view of schizophrenia.88,89 The association of adult schizophrenia with a variety of early-life infections14,15 suggests that a common pathway is probably involved: the proinflammatory immune response. This notion is supported by studies in mice. Simulated viral or bacterial infection, or direct injection with interleukin 6, in pregnant mice has been reported to produce intermediate phenotypes related to schizophrenia in the adult offspring.90 Some of these phenotypes, such as deficits in sensory gating and abnormal latent inhibition, are reversible by treatment with clozapine.91 Since infections are widespread in the general population, interactions with genetic or other factors are likely. Indeed, an additive effect of family history of psychosis and prenatal infection in the causation of schizophrenia has been reported in a Finnish cohort.92 In future, studies should examine the gene–infection interaction, and whether a sensitive period exists during development when exposure to infection is more harmful.

Genome-wide association studies and epidemiological studies indicate some overlap of genetic susceptibility between schizophrenia and serious infection.26,93 Childhood infection might have a priming effect on microglia (discussed previously). Thus, early-life infection, by affecting gene expression or in the presence of preexisting genetic liability, might lead to a distinct or pathological immune response. This might, in turn, lead to CNS alterations that make these individuals susceptible to developing psychotic illness subsequently in life. Studies with detailed phenotypic characterisation of early development and immune and genetic data are necessary to test this hypothesis.

The human microbiome and the gut–brain axis: an emerging area of interest

The intestinal microbiota consists of a vast bacterial community that resides primarily in the lower gut and lives in a symbiotic association with the host. A bidirectional neurohumoral communication system, known as the gut–brain axis, integrates the host gut and brain activities. The intestinal microbiota is thought to affect brain development and function via this axis, and thus might be relevant for neuropsychiatric disorders.94,95 Bacterial colonisation of germ-free mice increases metabolism of tryptophan, leading to more than doubling of concentrations of 5-hydroxy tryptophan and its metabolites, including kynurenic acid (which is relevant for psychosis as previously described). A study in mice96 suggests that manipulation of the intestinal microbiota can alter host cognitive function and behaviour.

The vagus nerve—which plays a central part in relaying of the systemic cytokine signal to the brain—might also be important for gut–brain communication. In mice, the anxiolytic and antidepressant effects of ingesting a specific strain of Lactobacillus can no longer be seen after vagotomy.97 Evidence shows increased intestinal inflammation in individuals with schizophrenia compared with controls, and similarly, in people with first episode psychosis who have not taken antipsychotics compared with those receiving antipsychotics.98 Studies in rats99 and human beings100 suggest that manipulation of the gut microbial composition affects systemic cytokine concentrations. Thus, intestinal microbiota might affect the brain and behaviour by changing systemic cytokine concentrations in schizophrenia. This hypothesis is important and warrants examination. In the future, studies should examine the associations between intestinal microbiota and behavioural, cognitive, and neurochemical phenotypes in psychiatric disorders and healthy controls.

Therapeutic implications of an immunological understanding of schizophrenia

The present understanding of the association between the immune system and risk of psychotic disorders holds promise for novel approaches for detection, treatment, and prevention. These approaches might include development or repurposing of drugs to target inflammatory pathways, immunotherapy for antibody-associated cases of psychosis and other mental illnesses, and stratification of patients by their immune phenotype to inform treatment decisions and measure treatment response. Indeed, a 2014 molecular study101 reported two distinct subgroups of patients with schizophrenia characterised by predominant abnormalities in either immune molecules or growth factors and hormones.

Randomised controlled trials of anti-inflammatory drugs as adjuncts to standard therapy have shown promising results in schizophrenia (table),74,75,102–118 although such trials are few and have often involved small samples.119 Celecoxib has been reported to improve cognitive function in the early stages of schizophrenia,106,108 but the use of COX2 inhibitors is problematic because they can increase risk of heart disease.120 Minocycline, a centrally acting tetracyclic anti-inflammatory drug, has been reported to improve negative symptoms and cognitive function in schizophrenia.111,112 Large multicentre trials are needed, with stratification of patients by their immune phenotype. This approach proved useful in a randomised controlled trial of infliximab (a TNFα antagonist) in treatment-resistant depression, in which no overall efficacy was noted but infliximab improved depressive symptoms in patients with high concentrations of inflammatory markers at the start of the trial.121 The absence of clinical benefit from conventional antidepressants has been suggested to be related to activation of the inflammatory system.122 In future, randomised controlled trials should focus on specific patient groups characterised by, for example, resistance to conventional antipsychotics, presence of a defined pattern of immune activation, such as a predominantly proinflammatory molecular signature, or symptom profile, such as predominant negative symptoms or cognitive dysfunction.

Identification of specific inflammatory pathways for neuropsychiatric symptoms would provide novel targets for therapeutic intervention.123 Mouse studies44 suggest a mechanistic role for quinolonic acid, an NMDA receptor agonist, in inflammation-induced depression. Furthermore, randomised controlled trials of NMDA receptor antagonists, ketamine, and compound AZD6765 have shown promising results for treatment-resistant depression.124–126 Although the safety and tolerability of ketamine might restrict its applicability in clinical setting, these findings provide further support for a role for inflammation in major mental illness.

New therapeutics for immunologically stratified psychosis might be based on molecules and targets that are already well known in other therapeutic areas, allowing repurposing of existing anti-inflammatory drugs.127 Collaboration between industry and academia would be important to realise the potential of immune-modulatory molecules for the treatment of major mental illness. In future, studies should assess the prophylactic potential of immunological drugs in individuals at high risk of developing psychosis. Longitudinal associations between higher concentrations of interleukin 6 and subsequent risks of psychosis,2 depression,2 heart disease,128 and type 2 diabetes129 suggest that control of inflammation might reduce the risk of several chronic adult diseases, and thus, have a huge beneficial effect at the population level.

Conclusion

Inflammation and immune dysfunction might contribute to cognitive, negative, and positive symptoms in schizophrenia.
We have described several hypotheses and potential areas of interest for future research regarding the immunological aspects of schizophrenia. Addressing these issues would contribute to understanding the disease mechanism and development of new effective interventions. However, success would need collaborative work between several disciplines. Although animal model studies have much to offer in terms of understanding specific biological systems, these findings need to be confirmed in human beings. This underscores the scope for translational research in schizophrenia over the coming years, encompassing immune, genetic, microbiological, and other biomarkers.
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