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Inflammation Theories in Psychotic Disorders: A Critical Review Jaana Suvisaari1,* and Outi Mantere1,2 1

Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland; 2Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland Abstract: Recent research suggests that inflammation and immunity may have a role in the etiology of psychotic disorders. There is evidence of proinflammatory activation of the innate immune system and an activation of the T-cells of the adaptive immune system in both schizophrenia and bipolar disorder. Studies of antipsychotic-naïve patients with firstepisode psychosis have found that inflammation is present already at this stage. Some of these abnormalities resolve after the initiation of treatment, suggesting that they are state markers of acute psychosis, but other abnormalities persist. There is also evidence for prenatal infections being involved in the etiology of schizophrenia. Several hypotheses link inflammation and immunity with psychotic disorders. In this review, we focus on hypotheses related to prenatal development, disturbed regulation of neurogenesis, microglial activation, autoimmunity and microbial environment, and consider the potential confounding effects related to stress, childhood adversities, lifestyle and medical comorbidity as well as some methodological limitations. We also review the current evidence for the effectiveness of anti-inflammatory medication in the treatment of psychotic disorders.

Keywords: Autoimmunity, bipolar I disorder, infections, inflammation, microglia, psychotic disorders, schizophrenia. INTRODUCTION Inflammation and immunological dysfunction may have a role in the etiology of psychotic disorders. There is evidence of both proinflammatory activation of the innate immune system and an activation of the T-cells of the adaptive immune system in both schizophrenia and bipolar disorder [1]. This has been shown by monocyte and T-cell activation studies, by elevations in serum and cerebrospinal fluid (CSF) cytokines and other inflammatory markers, and by findings of increased expression of genes related to inflammatory pathways in monocytes [1-5]. In addition, there is evidence that inflammatory or immunological activation during prenatal development increases the risk of schizophrenia and other psychotic disorders [6]. Many theories have aimed to integrate various findings in the field into a coherent theory on how inflammation and immunity may be involved in the etiology and pathogenesis of schizophrenia and major mood disorders. In this review, we aim to describe alternative explanations to how inflammation and immunity might be linked to schizophrenia and bipolar I disorder. IMMUNE SYSTEM: AN OVERVIEW The immune system is divided into innate and adaptive immune system. Innate immune system recognizes molecular patterns shared by many microbes and toxins that are not present in the host and provides the fast initial host response against pathogens. The innate immune system includes physical barriers, such as epithelial cell layers, tears, saliva and the secreted mucus layer that overlays the epithelium of the gastrointestinal, respiratory and genitourinary tracts, *Address correspondence to this author at the Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, P.O. Box 30, FIN-00271 Helsinki, Finland; Tel: +358-295248539; Fax: +358-295247155; E-mail: [email protected] 2212-3989/13 $58.00+.00

defense cells of the innate immune system, and soluble proteins and bioactive small molecules that are either constitutively present in biological fluids, such as complement proteins, or are released from cells when they are activated, like cytokines. Components of the innate immune system contribute to the activation of adaptive immunity. The adaptive immune system is antigen-specific and is based on the antigen-specific receptors on the surfaces of T and B lymphocytes that are encoded by genes that are assembled by somatic rearrangement of the receptor genes [1, 7]. Cells of the innate immune system consist of neutrophils, monocytes that further differentiate into macrophages or dendritic cells, eosinophils, basophils and mast cells. Neutrophils are phagocytic cells that accumulate at sites of infection and tissue injury and, when activated, produce interleukin (IL)-8 and tumor necrosis factor (TNF)-. Macrophages are phagocytic cells that are mobilized after neutrophils and persist for long periods at sites of chronic infection or inflammation. Classically activated magrophages produce interferon (IFN)-, IL-6, IL-12 and TNF-, but there is also an alternative activation pathway induced by Th2-type cytokines. Alternatively activated macrophages decrease inflammation and promote tissue repair and produce antiinflammatory cytokines IL-10, IL-1 receptor antagonist (IL1RA) and transforming growth factor (TGF)-. Eosinophils are involved in the immune response against helminthes and parasites and in allergic responses. Basophils and mast cells are involved in immune response against helminthes, in hypersensitivity responses and in allergic immune responses. Tissue macrophages, such as microglial cells in neural tissue, and dendritic cells are antigen presenting cells that take up microbial antigens, process them and present them in forms that can activate T-cells. These antigen-presenting cells are the interphase between innate and adaptive immunity [1, 7].

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Adaptive immunity consists of B lymphocytes and T lymphocytes, which in turn have several subtypes. T cells are divided by their selective surface expression of either CD8 molecules which bind to HLA class I molecules or CD4 molecules that bind to HLA class II molecules. The majority of the CD8+ T cells are cytotoxic against cells with intracellular pathogens and tumor cells but some of them also downregulate immune response (suppressor cells). The CD4+ T cells are called helper T cells (Th) because they are important in providing help to other immune cells. There are several subtypes of Th cells. Th1 cells support cell-mediated immune responses and activate macrophages via IFN-. Th2 cells support humoral and allergic responses and play a major role in the transformation of B cells into plasma cells. They secrete IL-4, IL-5, IL-9 and IL-13. Th17 cells contribute to host defense against bacterial and fungal infections and secrete IL-17. An important group of helper T cells are the regulatory T cells. The main regulatory T-cell subsets are the CD4+CD25+FOXP3+Tregs (natural Tregs), the Tr1 cells which produce IL-10, and Th3 cells which produce TGF-. Regulatory T cells are important in immune tolerance and in the prevention of autoimmunity. Activated T cells, but not regulatory T cells, produce IL-2, while Tregs express high levels of IL-2 receptor’s subunit. It has been suggested that the main function of IL-2 is to induce production of Treg cells and thereby to maintain peripheral T-cell tolerance [7-9]. B lymphocytes produce antibodies (immunoglobulins (Ig)). When naïve B cells are activated by Th cells, the activated B cells differentiate into either memory B cells or plasma cells. Plasma cells start producing antibodies. Naïve B cells express IgM and IgD on their cell surfaces. As B cells mature under the influence of T cells, T-cell cytokines induce isotype switching: IL-10 to IgG1 and IgG3, IL-4 and IL-13 to IgE, TGF- to IgA and IFN- to IgG2. B cells become either plasma cells, secreting high levels of antibodies, or memory cells which can survive for years or even a lifetime and allow stronger and more rapid secondary response to a secondary infection with the same pathogen [7]. ROLE OF CYTOKINES IN BRAIN DEVELOPMENT AND FUNCTION Cytokines have several other functions besides the coordination of the host response to infection. They are small proteins that are secreted by both cells of the immune system and many other cells. They have been shown to be particularly important for neural development and function [10-12]. During the fetal development, they contribute to the temporal regulation of neurogenesis and gliogenesis, to progenitor migration, proliferation and axon pathfinding, and to the development of microglia [10, 12]. They participate in the regulation of neuronal cell survival, synapse modulation and elimination, neural stem cell renewal, differentiation and brain repair [10, 13, 14]. Some cytokines have stressor-like effects on CNS, including changes in tryptophan metabolism, hypothalamo-pituitary-adrenocortical axis, and brainderived neurotrophic factor expression [15, 16]. An important role of cytokines is their involvement in neuroplasticity. This includes both acute, synapse –specific forms of associative plasticity, which is thought to contribute

Suvisaari and Mantere

to synapse refinement and memory, and slower, global forms of non-associative plasticity in response to chronic changes in activity (homeostatic plasticity or synaptic scaling), which is thought to stabilize neuronal networks by keeping excitation and inhibition in balance [12]. An imbalance of this regulation could be present at illness onset, when changes in the expression or function of immune mediators could lead to an interruption of their normal neuroplastic functions, or/and inappropriate reactivation of normal neuroplastic function [12]. Hippocampal neurogenesis is of special interest for psychiatric disorders because the new neurons exert critical functions in the hippocampus and help in explaining particular aspects of learning and memory [17]. PRENATAL CYTOKINE HYPOTHESIS AND OTHER HYPOTHESES RELATED TO PRENATAL DEVELOPMENT Fetal immune system starts to develop during the second trimester. Inflammatory response would be harmful to the fetal development, and therefore cells of the innate immune system such as macrophages are hyporesponsive during fetal development, while regulatory T cells are abundant. If fetal proinflammatory response occurs, it associates with intrauterine growth restriction, premature rupture of the membranes, and preterm labour. IgG production is very scarce during fetal development, whereas maternal IgG is transferred over placenta during the third trimester to give immunological protection to the newborn during the first 6 months of life when the newborn’s own capacity to adaptive immunity is still limited. Unfortunately, also possible maternal autoantibodies are transferred and can cause e.g. neonatal lupus erythematosus in offspring of mothers with the disease [18]. A wealth of epidemiological research suggests that prenatal infections increase the risk of schizophrenia [19, 20]. This association seems to hold for a variety of pathogens, although it is not entirely consistent for any of them [19, 20]. While findings linking specific infections to schizophrenia have mostly been from first- and second-trimester infections [19], elevations in cytokine levels in mothers of offspring who developed schizophrenia have been observed from second and third trimester samples [21, 22]. Besides infections, also other prenatal exposures have been linked to increased risk of developing schizophrenia. These include obstetric complications [23], severe traumatic events like war [24] or loss of parent [25], and starvation [26, 27]. A recent study also found that high maternal anti-gliadin antibodies increased the risk of schizophrenia in the offspring [28], which could reflect shared genetic risk with celiac disease but might also be related to the effect of nutrition or harmful effect of maternal antibodies. Several hypotheses have been set to explain why these prenatal exposures increase the risk of schizophrenia. The most prevailing of them suggests that maternal immune activation harms the developing fetal brain [19, 20, 29]. The theory suggests that cytokines produced by the mother, or at a later stage of pregnancy by the fetus itself, would disturb normal fetal brain development, in which cytokines have an important role [10] The cytokine hypothesis is suggested to be the common pathway behind all pregnancy-related expo-

Inflammation in Psychotic Disorders

sures associated with increased schizophrenia risk. Many obstetric complications, like pre-eclampsia and preterm labor, are associated with elevations in serum proinflammatory cytokines as well as placental inflammation [30, 31], and also psychosocial stress during pregnancy is associated with elevated production of pro-inflammatory cytokines [32]. Animal models have elegantly shown the substantial effects of prenatal infection on brain development. Influenza virus infection of pregnant mice at different stages of fetal development results in changes in gene expression in various brain areas both pre- and postnatally, brain structural abnormalities, neurotransmitter changes and behavioral abnormalities [20]. The effects depend on the timing of infection. Influenza infection during early development also causes structural abnormalities to the placenta, such as thrombi and increased presence of immune cells [20]. However, an infection by a pathogen is not necessary for these changes to occur: a viral mimic, PolyI:C, which elicits the immune system to respond in a similar manner as in viral infection, and LPS, which mimics bacterial infection, cause similar abnormalities when given to pregnant mice [20]. These findings support the hypothesis that it is the maternal immune response that harms fetal development. Moreover, recent research suggests that placental proinflammatory signaling in early pregnancy is particularly harmful for fetal brain development [33]. Another possibility is that maternal antibodies that cross the placenta harm fetal brain development. This could occur through several mechanisms: antibodies acting as receptor agonists or antagonists, antigen modulation or interaction with the fetal immune system [34]. Maternal autoantibodies associated with chronic autoimmune diseases are associated with considerably increased risk of pregnancy complications [35]. Meyer et al. [36] have hypothesized that fetal neuroinflammation is a common mechanism linking schizophrenia and autism and accounts for the shared phenotypic features in the disorders, including deficits in social behavior and emotional processing and in cognitive functioning. They suggest that in schizophrenia, the fetal system gains control over the inflammation while in autism, a chronic inflammation develops that persists into neonatal life and accounts for the early onset of symptoms. In schizophrenia, fetal inflammation would leave a predisposition to respond more vigorously to subsequent challenges, like stress or immune rechallenge. While it remains to be proved that such latent vulnerability exists in schizophrenia, animal models have shown that immune challenge early in life can permanently alter postnatal immune functions [36]. SCHIZOPHRENIA AS A DISTURBED REGULATION OF NEUROGENESIS The existence of a neurodegerative component in psychotic disorders is not unequivocal. However, there are brain structural abnormalities in both schizophrenia and bipolar disorder [37], and while some of the changes are related to genetic predisposition and are observed also in unaffected co-twins, others are disease-specific and show progression over the course of illness [38-40]. The progression of brain

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structural abnormalities predicts the onset of psychosis in people at clinical [41] or genetic [42] high risk of psychosis, and structural brain abnormalities continue to progress several years after the onset of schizophrenia [43]. Thus, it is postulated that psychotic disorders could result in part from a dysregulation of adult neurogenesis. The hippocampal neurogenesis may be more clearly associated with bipolar disorder [44, 45]. However, even in schizophrenia, childhood experiences are important for the outcome, which could be mediated by an effect on later neurogenesis [17]. MeyerLindenberg argued that progressive volume change could be related to enduring dysfunction of experience –dependent plasticity in cortex subsequent to abnormalities in long-range connectivity in key neurocircuits implicated in schizophrenia, including dorsolateral prefrontal cortex and the hippocampal formation [46]. This would be especially challenged in adolescence, when connectivity patterns mature through myelinization of long range tracts, followed by reductions in gray matter, and schizophrenia could result from persistent maladaptive synaptic plasticity in adolescent brain [46]. Also, dysregulation of neuroplasticity in the hippocampus could result in cognitive problems associated with psychotic disorders [17]. Physical exercise appears to stimulate the hippocampal precursor cells from which adult neurogenesis originates to increased proliferation and maintenance over time, whereas environmental enrichment, as well as learning, predominantly promotes survival of immature neurons [17]. MICROGLIA HYPOTHESIS The microglia hypothesis suggests that there is microglial hyperactivity in schizophrenia [47, 48]. Bilbo and Schwarz have further hypothesized that a prenatal infection leaves subsets of microglia permanently in an activated state, and a subsequent immune challenge in adulthood causes exaggerated response from the primed microglial cells [49]. Prolonged microglial hyperactivity in the adulthood may then lead to neuronal apoptosis and brain damage [48, 50]. The microglia have also a role in adult neurogenesis, and they regulate the balance between pro- and antineurogenetic molecules [51]; thus, microglia also have a role in the theory of schizophrenia as a dysregulation of adult neurogenesis. There is some evidence suggesting that microglial cells are activated in schizophrenia. Microglial activation in vivo can be detected using (11)C-(R)-PK11195, a peripheral benzodiazepine receptor ligand, in positron emission tomography (PET). Using this method, two small studies have found evidence of ongoing inflammation in the brain of patients with schizophrenia compared to matched controls, one in hippocampus [52] and the other in the total gray matter [53]. Some studies have found elevated levels of IL-1 [54] and glial protein S100B [55] in the CSF of patients with schizophrenia, and the number of macrophages and activated lymphocytes was increased in people with acute psychotic episode [56, 57]. Other cytokines that have been analyzed from the CSF but have not been significantly elevated include IL2, IL-12 and IL-6 [58]. Post-mortem studies have found some evidence for microglial activation or increased microglial density in schizophrenia in different brain areas [48]. However, more research is still needed to verify that there is chronic microglial activation in schizophrenia.


SCHIZOPHRENIA, BIPOLAR I DISORDER AND AUTOIMMUNITY Autoimmune diseases are characterized by a breakdown of tolerance to self-antigens and a development of immune response to self-molecules that leads to tissue injury and damage. When autoimmune diseases develop, there usually is a genetic susceptibility combined with a triggering event, which may be an infection or other type of tissue injury [59]. Several autoimmune diseases are associated with increased risk of developing schizophrenia, while the association with bipolar disorder is more controversial [60]. According to a large population-based Danish study, having any autoimmune disease increases the risk of schizophrenia 1.29-fold [61]. The risk varies, being highest in autoimmune hepatitis (2.75-fold), while rheumatoid arthritis was not associated with increased risk of schizophrenia [61]. Autoimmune diseases in first-degree relatives also increase the risk of schizophrenia, suggesting a common genetic background [60]. In the study by Benros et al., autoimmune diseases increased the risk of schizophrenia 1.29-fold and hospitaltreated infections 1.60-fold, and the risk was increased 2.25fold in people with autoimmune disease and hospital-treated infections, suggesting a synergistic effect of these exposures [61]. It might be that hospital-treated infection triggered autoimmunity or that hospital-treated infection and autoimmunity are both markers of the presence of immune dysregulation that increases susceptibility to schizophrenia. Some autoimmune diseases are characterized by organspecific autoantibodies that target antigens in the damaged organ, while others are characterized by autoantibodies directed against systemic antigens like nuclear proteins [59]. Psychotic symptoms in autoimmune diseases are associated with certain types of autoantibodies, like anti-glutamate receptor antibodies and anti-P antibodies [62, 63]. Several studies have examined the presence of autoantibodies in schizophrenia, finding increases in both systemic and organspecific autoantibodies, e.g. antinuclear and antibrain antibodies [59]. These findings have been reviewed in detail be Goldsmith and Rogers [59]. It has been proposed that brain reactive antibodies might be especially relevant in schizophrenia [59, 61]. In the study by Benros et al., autoimmune diseases with suspected presence of brain reactive antibodies were associated with higher risk of schizophrenia than other autoimmune diseases (1.48-fold vs. 1.19-fold, respectively) [61]. Diamond et al. have suggested that antibodies that react with the brain could cause immune-mediated alterations in brain structure and function even in the absence of overt inflammation and immune cell infiltration [34]. Antibodies might e.g. act as receptor agonists or antagonists or alter the density of the target antigen on the cell surface [34]. In their own work, they showed elegantly that at low concentration, the NMDA-receptor-reactive autoantibodies are positive modulators of receptor function that increase the size of NMDA-receptor-mediated excitatory postsynaptic potentials, whereas at high concentration, the autoantibodies promote excitotoxicity through enhanced mitochondrial permeability transition [64]. NMDAR activation was required for producing both the synaptic and the mitochondrial effects [64]. In the adult brain, there needs to be an insult to the blood-brain


barrier to allow access of autoantibodies to brain tissue. During the fetal development, when the blood brain barrier is not fully developed, maternal brain-reactive antibodies might harm fetal brain development through any of the above mentioned mechanisms [34]. This mechanism could be relevant also in psychotic disorders. There is genetic evidence that supports the involvement of autoimmunity in the etiology of schizophrenia. All four large meta-analyses of the GWAS studies in schizophrenia have found the best hit to be in the major histocompatibility complex area [65-67], and although the area is difficult to study, the association is now believed to be genuine. It seems likely that the association involves both HLA and other genes in the area. Another genetic finding that may be related to autoimmunity is the high risk of schizophrenia associated with velocardiofacial syndrome, although the autoimmune aspect of velocardiofacial syndrome has received little attention in schizophrenia research. Velocardiofacial syndrome is caused by a microdeletion of chromosome 22q11.2 and is associated with considerably increased risk of both autoimmune diseases and schizophrenia [68, 69]. An unknown genetic aspect of velocardiofacial syndrome causes thymic aplasia or hypoplasia and consequent T-cell deficiency [18], which explains the high risk of autoimmune diseases associated with the syndrome. To our knowledge, it has not been investigated whether immunological deficiencies could be one factor that explains the high risk of schizophrenia (up to 30%) in people with velocardiofacial syndrome. Regulatory T cell function is impaired in most autoimmune diseases [9]. Drexhage et al. have suggested that regulatory T cells might be involved in schizophrenia and bipolar I disorder, and specifically their activation would be protective against the proinflammatory state and possibly increased autoreactivity that is otherwise present in these disorders [1, 4]. They found that the number of regulatory T cells was increased in patients with recent onset schizophrenia, and regulatory T-cell activation correlated with better outcome [4]. One consistent finding in psychotic disorders is elevation in the serum concentration of soluble IL-2 receptor, which would also fit with regulatory T cell activation since activated Treg cells shed the receptor from their cell surface to bind IL-2 and thereby regulate immune response [1]. ROLE OF MICROBIAL ENVIRONMENT The incidence of many inflammatory, atopic and autoimmune diseases, like asthma, type 1 and 2 diabetes and allergies has raised dramatically in recent decades. It has been hypothesized that loss of contact with micro-organisms that were once ubiquitous in both external and internal human environment might explain the link between modernity and increased inflammatory/atopic disease [70]. It was suggested that these micro-organisms, so-called “old friends” induced and maintained immune suppression by stimulating regulatory T-cells, leading to increased production of antiinflammatory cytokines. “Old friends” trained the immune system in tolerance because they provided essential services for their host, like gut microbiota. Adequate exposure to these micro-organisms primed regulatory T-cells and helped to maintain an appropriate balance of regulatory and effector


T-cells and reduced proinflammatory signaling [71]. Raison et al. have hypothesized that the loss of contact to “old friends” might expose vulnerable individuals to inappropriately aggressive inflammatory response to psychosocial stress, which would increase the risk of depression [71]. Recent research confirms that there is an interaction between intestinal microbiota, gut, and central nervous system, the so-called microbiome-gut-brain axis [72]. It has been suggested that the investigation of the microbiome-gut-brain axis may find etiologically important links and even provide novel targets for intervention in psychiatric illnesses [73]. There is evidence from animal studies that some intestinal microbes cause anxiety- and depression-like behavior and modulate GABA-ergic, glutaminergic NMDA and serotonergic 5HT1A receptors in the brain [74-77], whereas germfree mice exhibit reduced anxiety-like behavior [74, 77]. Furthermore, some enteric pathogens may cause memory impairment [78]. In human studies, there is evidence of intestinal mucosal dysfunction in depression [79], and one clinical trial has found that probiotics reduce depressive symptoms [80]. The possible relevance of the “old friends” hypothesis and the role of microbiome-gut-brain axis in psychotic disorders is largely an unexplored area. Recently, Severance et al. [81] examined the role of gastrointestinal inflammation in schizophrenia. They found elevated levels of IgG antibodies to Saccharomyces cerevisiae in both recent-onset and chronic schizophrenia, and these antibodies correlated with the presence of anti-casein and anti-gluten antibodies [81]. Other studies have also found elevated antibodies against food in people with schizophrenia [82]. These findings suggest that people with psychotic disorders might suffer from gastrointestinal inflammation and “leaky gut”, and encourage investigating the role of gut microbiota in psychotic disorders further. INFLAMMATION AS A MARKER OF CARDIOVASCULAR AND METABOLIC COMORBIDITY AND LIFESTYLE Schizophrenia and other psychotic disorders are associated with high prevalence of type 2 diabetes, metabolic syndrome, and obesity [83-88], all diseases in which inflammation has a key role [89, 90]. In visceral obesity, white adipose tissue contains excessive number of macrophages which are in a chronically inflamed state and produce various cytokines and other inflammatory molecules, and also enlarged adipocytes produce e.g. TNF- [90, 91]. Lifestylerelated and socioeconomic factors that could also contribute to the association between psychotic disorders and inflammation include smoking [92], alcohol use [93], poor physical condition and low muscle strength [94, 95], sleep [88], and low socioeconomic status in childhood [96] and adulthood [97]. Could inflammation then be just a marker of medical comorbidity and poor lifestyle? We examined this in a population-based study [5]. We analysed the levels of tumor necrosis factor alpha (TNF-), interleukin-1 receptor antagonist (IL-1RA), interleukin-2 (IL-2) and its soluble receptor's alpha subunit (sIL-2R), interleukin-6 (IL-6), and sensitive CRP in people with schizophrenia, other nonaffective psy-


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choses (ONAP), affective psychoses and controls matched by age, sex, and region of residence [5]. The sample was derived from a large general population survey which included a thorough examination of health and lifestyle. We found that IL-1RA and CRP were the strongest markers of metabolic comorbidity both among persons with psychosis and controls. Their levels correlated strongly with BMI and waist circumference, and serum insulin, triglyceride and HDL levels. TNF- and sIL-2R showed similar but weaker correlations. Antipsychotic medication use was also associated with increased CRP, TNF- and IL-1RA but did not influence the other cytokines we measured. After adjusting for other measures related to cytokine elevations, schizophrenia remained as a significant predictor of only sIL-2R and the other psychotic disorders showed no independent associations [5]. Consistently with these findings, the CATIE study found in patients with schizophrenia that all individual criteria of metabolic syndrome were associated with elevated CRP, and higher CRP values correlated positively with the number of metabolic syndrome criteria [98]. These findings indeed suggest that elevations in markers of innate immunity are related to medical comorbidity, most notably to visceral obesity and diabetes. The correlations we observed are concordant with those observed in general population studies examining factors related to inflammation [99-101]. However, our findings from a cross-sectional study do not inform about the causative pathway. It could be that chronic inflammation has been one of the factors contributing to medical comorbidity in people with psychotic disorders. Studies of patients with first-episode psychosis who have been antipsychotic-naïve have found evidence of inflammation present already at this stage [58]. Some of these abnormalities resolve after the initiation of treatment, suggesting that they are state markers of acute psychosis, but other abnormalities persist and might contribute to the development of metabolic abnormalities [58]. One suggestion is that all psychotic disorders can be viewed as multi-system inflammatory diseases, with inflammatory dysregulation as a common etiological factor with metabolic illnesses [88]. INFLAMMATION AS A MARKER OF STRESS IN PSYCHOTIC DISORDERS Psychosocial stress activates innate immune system [102] and impairs regulatory T cell functioning [103]. People with psychotic disorder or psychotic-like symptoms are known to be more sensitive to stress, and daily life stress is associated with increase in the intensity of psychotic symptoms [104]. Genetic risk for psychosis is also associated with increased vulnerability to stress. Siblings of patients with psychotic disorder have higher cortisol levels and elevated cortisol response to negative daily events compared to controls [105], and elevated cortisol also predicts the onset of psychosis in at-risk adolescents [106]. One may speculate that this vulnerability to stress worsens chronic inflammation, or that predisposition to aggressive inflammatory response may be one factor contributing to stress sensitivity. Acute psychosis is a state associated with considerable stress, which is reflected in elevations of markers of acute stress, like cortisol [107]. Cortisol levels decrease with symptom improvement in first-episode psychosis [108].


Both in first-episode psychosis and in acute psychotic relapse, proinflammatory cytokines are increased, most consistently IL-6 and TNF- [58]. In addition, patients with acute relapse have decreased levels of the anti-inflammatory cytokine IL-10 [58]. In stable medicated outpatients, some proinflammatory cytokines like IL-6 are no longer increased [58], whereas several anti-inflammatory cytokines remain elevated [5, 109], suggesting that inflammation may be to some extent a marker of acute stress related to acute psychosis, while anti-inflammatory activation may be an adaptive response. Adverse life experiences which may be one factor contributing to chronic inflammation in psychotic disorders. Childhood adversities are known to be more common in people with psychotic disorder [110, 111] and are a risk factor of psychotic disorders [112]. Childhood adversities, in turn, are associated with elevated serum proinflammatory cytokines in the adulthood [113, 114, 115]. Moreover, exposure to childhood adversities leads to pronounced inflammatory response to acute stress in adult life [116]. Consistently, there is evidence that inflammatory markers are higher in first-episode psychosis patients who have experienced childhood maltreatment than in those without such exposure [117]. Taken together, acute stress, increased stress sensitivity, and early adverse life events may all be contributing to inflammation in patients with psychotic disorders. ANTI-INFLAMMATORY AND NEUROPROTECTIVE TREATMENT TRIALS IN PSYCHOTIC PATIENTS Perospirone, ziprasidone and quetiapine seem to have an anti-inflammatory effect via the inhibition of microglial activation [118]. Anti-inflammatory effects of mood stabilizers [50, 119-121] and antidepressants [122] are also well documented. The effectiveness of mood stabilizers as adjunctive treatment in schizophrenia has not been proved [123, 124]. In contrast, antidepressants seem to be effective in treating negative symptoms in schizophrenia [125, 126]. According to a recent meta-analysis, nonsteroidal antiinflammatory drugs are effective adjuvant drugs in schizophrenia, with a mean effect size of 0.43 [127]. The metaanalysis was based on five trials, of which four had used celecoxib and one aspirin [127] The effect may be larger in patients with evidence of inflammation [128]. Celecoxib may also be effective in bipolar depression [129]. However, celecoxib and other selective COX-2 inhibitors, as well as non-steroidal anti-inflammatody drugs, can markedly increase serum lithium concentrations leading to toxicity [130]. N-acetylcysteine is an antioxidant precursor to glutathione. Besides being an antioxidant, it also modulates glutaminergic activity and has anti-inflammatory properties [131]. N-acetylcystein has been used as an adjunctive medication in clinical trials of both schizophrenia and bipolar disorder. It had beneficial effects on negative symptoms and global functioning in schizophrenia in a double-blind randomized study including 84 patients [132]. In bipolar disorder, it alleviated depressive symptoms in a double-blind randomized placebo-controlled trial with 75 patients [133] and in an open trial with 149 patients [134].


Polyunsaturated fatty acids (PUFAs) are the major constituents of cell membrane phospholipids. They have important biological roles in receptor binding, neurotransmission, signal transduction, and eicosanoid synthesis. Reduced PUFA levels have been found in mood disorders and schizophrenia. Adjunctive treatment with omega-3 fatty acids, particularly eicosapentaenoic acid, has shown positive effects in schizophrenia in some studies, but this effect was not statistically significant in a meta-analysis [135]. In ultra high risk patients, PUFA’s are likely to delay the illness onset according to a meta-analysis [136] and a randomized controlled trial with 81 ultra high risk patients [137]. Interestingly, PUFA supplementation also resulted in weight loss, decreased fasting insulin, TNF-alfa and leptin in obese prepubertal and pubertal children [138]. Pregnenolone is a neurosteroid with pleiotrophic actions on rodents including the enhancement of learning and memory, neuritic outgrowth, and myelination. Addition of pregnenolone results in elevations in downstream neurosteroids such as allopregnanolone, that for instance increases neurogenesis, decreases apoptosis and inflammation. Three pilot RCT’s suggest effects of adjunctive pregnolone on psychotic symptoms [139]. Dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) are steroids synthesized in human adrenal glands. Their biological actions include neuroprotection, neurite growth and antagonistic effects on oxidants and glucocorticoids [140]. Abnormal DHEA and DHEAS concentrations are found in several neuropsychiatric conditions. An RCT lasting 6+6 weeks and including 55 schizophrenia patients showed DHEAS to be a positive and DHEA a negative predictor of cognitive functions [141]. An RCT including 40 schizophrenic patients found improvement in negative symptoms, depression and anxiety [142]. Minocycline is an antibiotic that can modulate glutamateinduced excitotoxity, and has antioxidant, anti-inflammatory and neuroprotective effects. Case reports and small randomized trials [143] as well as one RCT with 94 schizophrenic patients [144] suggest possible positive effect on psychotic or negative symptoms in schizophrenia. L-theanine possesses neuroprotective, mood-enhancing, and relaxation properties. Augmentation to antipsychotic therapy shows effect on positive symptoms in 60 patients with schizophrenia or schizoaffective disorder in an 8-week, double-blind, randomized, placebo-controlled study [145]. In summary, anti-inflammatory compounds show good to suggestive evidence of effect as an adjunctive treatment in schizophrenia and other psychotic disorders and deserve further research. It is likely that treatment response differs according to the stage of the disorders. RECOMMENDATIONS FOR FUTURE STUDIES One important lesson from the studies conducted thus far is that inflammation and immune activation changes during the course of illness and is influenced by a multitude of factors, including medication, lifestyle and medical comorbidity [58, 109]. The source of peripheral inflammatory markers detected from the serum might change accordingly, since adipocytes are an important source of proinflammatory cyto-


kines in people with visceral obesity [91], which most people with chronic psychotic disorders develop over time [83]. Furthermore, inflammatory factors have pleiotrophic effects, meaning that one protein can control multiple, apparently unrelated phenotypic features [12], and have differing effects in peripheral and brain tissues. Regulation of inflammatory processes in the periphery is known much better than the area specific processes in the brain, including the developing brain as well as the brain in childhood, adolescence and adults. The few studies that have compared patients with a high risk and a present or chronic psychosis find differences according to the stage of illness in neuroinflammatory proteins and in neuroimaging results [146]. Therefore, in order to understand the role of inflammation and immunological mechanisms in disease progression, longitudinal studies of high risk patients, patients with a prodromal state, adolescents with somatic illnesses without psychiatric symptoms, as well as first episode patients are needed. Inflammatory markers and cognitive functions are correlated, but treatment trials so far have mostly been unsuccessful in improving cognitive deficits. Thus, a more detailed knowledge of how the effects of activated inflammatory response system are extended to disease-relevant cognitive changes is needed. This might include synaptic plasticity, which is an important substrate for learning and memory by modulating synaptic architecture and function. Alternatively, although not necessarily exclusively, it may be related to changes in the central kynurenine pathway [147].


hospitalizations were adjusted for [153]. The risk reduction was related to paternal non-psychotic disorders, suggesting a link between paternal impulsive behavior and maternal HSV-2 immunization [153]. In another study by the same group, parental hospital treated infections were found to be a risk factor of schizophrenia regardless of whether they occur in prenatal period or at other times [154], suggesting that the underlying risk factor might be immunological abnormality that predisposes to severe infections. Studies that have been able to use maternal serum samples are scarce, and although the existing ones are based on large general population samples, the number of affected individuals in these cohorts is relatively small. It is also worth mentioning that the sample storage methods should be taken into account in the analysis and reporting when analyzing serum samples that have been stored for a long time and often at -20°C or -25°C. Even when samples are stored at -80°C, most cytokines degrade up to 50% of less of baseline values within 2-3 years of storage [155]. Furthermore, plasma and serum cytokine levels are often somewhat different, multiple freeze-thawing cycles affect cytokine levels (either by increasing or decreasing their level), and timing of the sampling also affects cytokine levels because of diurnal variation [155]. Quality control of the platforms that are used is important, because large differences have been found between different commercial platforms [155]. These factors probably have contributed to negative findings in some studies, as well as to differences between studies in cytokine concentrations, and they should be taken more rigorously into account in further studies.

Theories of inflammatory mechanisms are grossly unspecific for psychotic disorders. The same theories and findings are presented for major depression [148, 149] and bipolar disorder [88]. Since both include psychotic patients, differences between psychotic and non-psychotic as well as affective and non-affective psychoses are of interest. Studies across categorical diagnoses are needed to find differences between episodic and chronic courses of illness, and associations of inflammatory proteins with affective as compared to psychotic symptoms. It is possible that processes that include inflammatory proteins reflect more general neurodevelopmental competence and general cognitive ability of the brain shared partly by all psychiatric illnesses.

CONFLICT OF INTEREST

Adjunct treatments aimed at increasing neurogenesis at several levels of regulation as described by Kempermann [17] should be a focus of interest in high risk population and after illness onset. Treatment could include enrichment of environmental stimuli by physical and psychological exercise [150], melatonin [151] but also known antiinflammatory medications [152] as well as traditional medications used in mood disorders. Also, potential effects of reduced metabolic load on psychological wellbeing are worth studying.

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65

Dr. Suvisaari has served as a consultant for JanssenCilag. Dr. Mantere has received reimbursement for attending a symposium from Lundbeck. ACKNOWLEDGEMENTS We thank professor Outi Vaarala for valuable comments. This study has been supported by grants from the Päivikki and Sakari Sohlberg Foundation, the Finnish Cultural Foundation and the Sigrid Jusélius foundation (Dr. Suvisaari). REFERENCES

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Received: March 12, 2012

Revised: January 28, 2013

Accepted: June 01, 2013

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