HYPOTHESIS OF NEUROINFLAMMATION IN SCHIZOPHRENIA

BACKGROUND

Schizophrenia is a debilitating mental disorder having a heterogeneous symptomatology that contains positive symptoms (delirium, hallucinations), negative symptoms and cognitive deficit (1). The social and economic impact of the disorder is huge, the symptoms being chronic and although new antipsychotic drugs have been released in the market, negative symptoms and cognitive deficit from schizophrenia are yet unresponsive to pharmacotherapy. The affection of life quality on a long term and the chronic deterioration of cognitive functions suggest the existence of some neurodegenerative characteristics within this disorder. The neurodegenerative process is tightly connected to the inflammation present at the level of central nervous system, and proinflammatory cytokines are considered to be etiologic factors for psychiatric diseases, including schizophrenia. An important role in the neuroinflammatory process is also played by microglia, an uncontrolled activity of proinflammatory cytokines and phagocytosis that may induce the appearance of schizophrenia in association with genetic vulnerability and the action of glutamatergic neurotransmitters. There are numerous studies which have investigated the potential effects of anti-psychotic drugs on inflammation and neurogenesis, the adjuvant anti-inflammatory therapy being studied subsequently as a treatment option to schizophrenia (2).
The study of neuroinflammation as an etiopathogenic mechanism in schizophrenia and other psychotic disorders is still at the beginning and subsequent studies are necessary to take into account certain systemic factors such as the metabolic syndrome as the side effect of some atypical antipsychotic drugs, smoking and hormonal balance determined by the hypothalamic-hypophysary axis (mainly the diurnal secretion of cortisol and cortisol awakening response). The goal of this review is to bring into focus the conclusions of the most important studies regarding the neuroinflammation and the role of i n f l a m m a t o r y m a r k e r s i n e t i o p a t h o g e n e s i s o f schizophrenia, the therapeutic implications of these discoveries as well as the limits of previous studies.

HISTORY
In 1987, Murray and Lewis proposed the hypothesis of neurodevelopment in schizophrenia, neurodevelopment anomalies which occur during the maturation of the central nervous system, and much earlier than the clinical expression of the disease being considered among the main causes of this disorder (1). It has been recently shown that in the initial phases of the disease, before or during the transition to constitute psychosis, progressive modifications of the cerebral structure continue to appear (3). These modifications are dynamic and much influenced by the affections of the cerebral substance occurred subsequently during the maturation of the nervous system. (4) Thereafter, the hypothesis of neurodevelopment was paralleled by the hypothesis of alteration of the immune response and neuroinflammation in the etiopathogenesis of schizophrenia (5). The increase of risk of occurrence of schizophrenia has been reported in the persons exposed to infections during the pre-birth period (6), and studies are going to be carried out so as to demonstrate the contribution of derangements of the immune system in the early stages of cerebral development to the increase of long-term risk for the psychotic type disorders. The correlation between pre- birth exposure to infection and the increase of schizophrenia risk is not currently associated to a specific pathogen agent. In this association numerous viral agents such as the flu virus, the measles virus, the polio virus, the herpes simplex virus, pathogen agents causing sinusitis, tonsillitis and pneumonia and the Toxoplasma Gondii parasite have been involved (1). Pre-birth exposure to the flu virus in case of lab mice induces a series of pharmacological and behavioral modifications in the adult mouse, similar to the positive and negative symptoms of schizophrenia (decrease of the adaptation capacity to sensorial and motor stimuli, decrease of the need to explore and social interaction and the increase of sensitivity to NMDA receptor antagonist treatment), the positive symptoms being improved in most cases by typical or atypical anti-psychotic drugs (7). Experimental studies carried out on rhesus monkey showed the decrease of the white substance in parietal zones of new-born babies from mothers infected with influenza virus (8). These experimental data may be subsequently corroborated with the results of epidemiologic studies on human beings showing that there might be a causality connection between the exposure in the uterus to infections and the appearance of cerebral dysfunctions in after-birth period, dysfunctions that may represent a subsequent risk factor in the development of schizophrenic process. The presence of viral and bacterial infections in pre-birth period has not only been associated to schizophrenia since neurosyphilis may also cause psychotic symptoms whereas streptococcal infections in children are connected to the development of obsessive- compulsive disorder (9). In uterus exposure to infections determines the persistent peripheral increase of proinflammatory cytokines together with the increase of microglial and astrocitary activation at the level of the nervous system in the rodents exposed before birth to influenza virus (13).

NEUROINFLAMMATORY HYPOTHESIS
Inflammation represents one of the primary mechanisms of the inborn immune system against infection and other physiological injuries such as tissular lesions and stress. It is characterized by the secretion of proinflammatory f a c t o r s s u c h a s p r o s t a g l a n d i n s , l e u k o t r i e n e s , proinflammatory cytokines and chemokines. Cytokines have a vast role in the recruiting and activation of lymphocytes and in the differentiation of the cells of the immune system and in homeostasis. Certain cytokines promote direct effector mechanisms such as the induction of cellular apoptosis and inhibition of protein synthesis. IL- 1β, IL-6 and TNF-α are essential for the inflammatory response as they activate the phagocytosis initiated by macrophages and dendritic cells thus increasing vascular permeability and facilitating the release of bradykinin and components of the complementary system. The synthesis of proinflammatory cytokines is strongly stimulated by the activation of the inborn immune system. In the central nervous system, microglia and astrocytes are the main immunocompetent cells regulating both the induction and limitation of the inflammatory process (1). Microglia have phagocytosis I the central nervous system as their main function by eliminating the neurons affected and the infectious agents. Microglia play an important role both in neuroprotection and in the pathology of the nervous system, it being also called as the “two-bladed sword”, the hyperactivity of microglia determining the hypersecretion of proinflammatory factors leading to a progressive process of neurodegeneration (10). Cytokines play a significant part in neurodevelopment. IL- 1β induces in rats the conversion of some precursor cells from midbrain towards a dopaminergic phenotype whereas IL-6 reduces the survival of serotoninergic neurons in fetal brain. On the other hand, IL-1β and IL-6 reduce the survival of dopaminergic neurons from midbrain at medium and low concentrations, whereas at high concentrations it determines the increase of survival of these neurons (11). TNF-α is neurotrophic for ventral midbrain dopaminergic neurons during early fetal development, but the same molecule has neurotoxic effects towards the end of fetal life (12). The exposure to an acute inflammatory process during fetal life may induce latent neuroinflammatory anomalies that may be unveiled by exposure to certain external stimuli along the afterbirth life. The inflammation in fetal life or immediately after birth subsequently determines the appearance of an inflammatory response more accentuated to immunologic or non0immunologic stressors. Microglia may be affected by the precocious inflammatory processes during the cerebral development and maturity, a hyperactivity of this type of cells appearing afterwards. These data are relevantin the development of schizophrenia since the etiology of this disorder is multifactorial by having both genetic bases and environmental influences and being much influenced by the impairment of cerebral development and maturation in early phases (1). In uterus exposure to infections and subsequently to inflammatory processes triggers the appearance of neuroinflammation in the fetal brain associated to physiopathological modifications. Fetal neuroinflammation modifies the neurodevelopment trajectories subjecting the cerebral substance to pathologic processes. After birth, there appear alterations of microglia and astrocytes which together with stressors of afterbirth life trigger the persistence of inflammation during the continuation of the maturation process of cerebral substance. This contributes to the progressive development of cerebral substance anomalies manifesting by behavioral disorders similar to psychosis. Immunomodulatory interventions aiming at fetal inflammation and the functional consequences of persistent inflammation during afterbirth life may alleviate or even prevent a subsequent psychiatric disorder based on these physiopathological processes (13).

CORTISOL INFLAMMATORY BIOMARKERS

Precocious response to treatment is one of the strongest predictors for the long-term prognosis in psychosis. Nowadays there are not any absolute predictors for response to treatment for the patients that are at their first psychotic episode. Stress and inflammation biomarkers show a high potential to become clinical predictors for the response to treatment since the stress plays an important role in the precipitation of onset and relapse of psychosis whereas the cortisol response to stress is abnormal at the onset of psychosis (14). The patients experiencing their first psychotic episode show anomalies in the activation of primary response to stress (hypothalamic-pituitary- suprarenal axis): CAR (cortisol awakening response) decrease with the decrease of reactivity to stress and a diurnal high level of cortisol. CAR decrease has been associated to a more accentuated cognitive deficit, as CAR was not corrected subsequently by antipsychotic treatment, what indicates that this might be a biological marker of psychosis. Psychotic individuals exhibit the increase of proinflammatory cytokine level in peripheral blood and cephalorachidian fluid, both at onset of disease and during its evolution. The increase of inflammatory response and the high level of cortisol are associated to the decrease of hippocampus in psychoses (15). A longitudinal study carried out by Mondelli et al. on patients experiencing their first psychotic episode showed that the patients who do not respond to treatment after 12 weeks, already had a serious decrease of CAR at onset of disease and high levels of IL-6 and IFN-γ as compared to the patients who responded to treatment, and these differences persisted for 12 weeks after the antipsychotic therapy (16).

THERAPEUTIC IMPLICATIONS

Due to the association between inflammation and schizophrenia, we might expect that antipsychotic drugs should have an anti-inflammatory effect. Despite all these, the anti-inflammatory effect is different for typical antipsychotic drugs from that of typical ones. Typical antipsychotic drugs reduce the proinflammatory cytokine level (IL-1β, IL-6, TNF-α) in aschizophrenic patients (17), studies on animals showing that haloperidol reduces significantly the production of IL-1β and TNF-α, and the decrease depends on the dosage (18). On the contrary, atypical antipsychotic drugs are associated to the increase of inflammatory response, many studies reporting the increase of proinflammatory cytokines at clozapine treatment (19). Repeated in vivo administration of atypical antipsychotic drugs such as clozapine or risperidone significantly increases the plasmatic concentrations of IL-6 and TNF-α. Short-term treatment with clozapine (on average 12 days) increases the plasmatic concentration of IL-6 (20). So far, there are contradictory data regarding the effect of antipsychotic drugs on the cytokine level and there is not any antipsychotic drug that may prove an absolute anti- inflammatory action. For example, clozapine and haloperidol suppress significantly the production of IL-2 and IFN-γ in vitro, whereas in vitro they suppress only the production of IL-2. This contradictory evidence may be owed to the metabolic side effects, since clozapine and olanzapine trigger obesity and glucose intolerance, disorders associated to a high level of proinflammatory cytokines and chronic inflammation. Olanzapine significantly increases the level of reactive C protein after
18 months of treatment what also results into the increase of cardiovascular risk (2). Despite all these, a meta- analysis of the relapse risk after the first psychotic episode in schizophrenia shows that the peripheral levels of IL-6, IL-1β and IFN-γ decreased significantly as compared to baseline following the antipsychotic drug treatment (21). These results support the hypothesis according to which both typical and atypical antipsychotic drugs suppress the m i c r o g l i a l a c t i v a t i o n b y i n h i b i t i n g c e r t a i n proinflammatory cytokines and nitric oxide (22). Despite numerous contradictions, all studies cited above finally show that, though the effects of antipsychotic drugs on inflammatory markers depend on the systemic inflammatory response and the type of antipsychotic drug used, the improvement of acute psychosis symptoms by means of antipsychotic drugs is associated to the decrease of inflammatory response. Despite all these, there comes the question whether high peripheral level of proinflammatory cytokines is associated to the general state of stress from the acute exacerbation of psychosis and whether the significant reduction of these markers was owed rather to the stabilization of psychiatric symptoms than to the direct effect of antipsychotic drugs on inflammatory mediators (2). Subsequent studies are necessary so as to highlight more clearly the effects of antipsychotic drugs on proinflammatory cytokines in schizophrenia. There are studies showing that antipsychotic drugs may have benefic effects on neurogenesis. Dawirs et al. have shown that haloperidol induces the proliferation of neuronal stem cells ay the level of gyrus dentatus (23), but subsequent studies failed to show this therapeutic effect of haloperidol (2). Despite all these, some atypical antipsychotic drugs (risperidone, paliperidone, olanzapine and clozapine) determine neurogenesis at hippocampus level (24).

ANTI-INFLAMMATORY MEDICATION

There have been so far six randomized studies that investigated the clinical effects of COX-2 inhibitor anti- inflammatory adjuvant treatment. Out of the six studies, two showed that COX-2 inhibitor treatment placebo did not have a significant efficacy whereas four studies showed a significant improvement at the inflammation level. Adjuvant anti-inflammatory medication was much more efficient in the amelioration of positive and negative symptoms of schizophrenia as compared to placebo (25). COX-2 inhibitors reduce the kynurenic acid level (KYNA) whereas COX-1 increases KYNA level. A recent meta-analysis shows that KYNA is a metabolic derivate of tryptophan and it contributes to the etiopathogenic process of schizophrenia, being an antagonist of NMDA receptor. Consequently, the COX-2 selective inhibition might theoretically inhibit a physiopathological process of schizophrenia. Several studies have shown that indomethacine, a non-steroidal anti-inflammatory drug with a strong inhibition of COX-1, may be associated to psychosis (27). On the other hand, IL-6 plays an important role in COX-2 activation suggesting that the anti- inflammatory treatment may improve physiopathological processes in schizophrenia by reducing IL-6 activity besides the decrease of COX-2 activity, what results in KYNA suppression. But there are several contradictions that cannot be explained by the studies cited above. In 2010, they carried out a randomized double-blind trial which showed that the adjuvant treatment with aspirin, which is a non-selective inhibitor of COX-1 and COX-2, is efficient in schizophrenia. (28). In 2012, they carried out a meta-analysis that contained 5 double-blind randomized placebo-controlled studies which associated non-steroidal anti-inflammatory drugs to antipsychotic therapy (4 studies with Celecoxib and 1 study with acetylsalicylic acid). The effect in terms of symptom improvement was moderate for the positive symptoms and low for the negative ones. The efficacy of acetylsalicylic acid proved to be similar to that of celecoxib. The main disadvantage of this meta-analysis is that it contained only 5 studies with a total number of 264 patients (30).

LIMITS AND CONCLUSIONS

There are still many unanswered questions in terms of the role of proinflammatory cytokines in the etiology of schizophrenia and many subsequent studies are necessary to highlight the complete mechanisms by which they exercise their role in the etiopathogenesis of this disorder. First of all if cytokines play a so important role in etiology of schizophrenia, we must expect a correlation between the high level of proinflammatory cytokines and clinical symptomatology. There are studies that showed that there is a connection between these two aspects (16, 17, 18) and studies which did not find any correlation between the high level of inflammatory cytokines and schizophrenia etiopathogenesis (2, 29). Other studies tried to show the existence of a connection between the high level of IL-6 and smoking in the schizophrenic patients, but results were contradictory and this aspect requires subsequent studies (2). Nowadays there is only one study trying to make the connection between the high level of cortisol and proinflammatory cytokines and the weak response to treatment in the patients experiencing their first psychotic episode, but it was carried out on a relatively small number of patients (n= 68) out of whom half were already under antipsychotic treatment at the moment of their inclusion into the study (16).

REFFERENCES

1. Meyer U. Developmental neuroinflammation and schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2013;42: 20-34.
2. Na KS, Jung HY, Kim YK. The role of pro-inflammatory cytokines in the neuroinflammation and neurogenesis of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2014;48: 277-86.
3. Cahn W, van Haren NE, Hulshoff Pol HE et al. Brain volume changes in the first year of illness and 5-year outcome of schizophrenia. British Journal of Psychiatry 2006;189: 381-382.
4. Cannon TD, van Erp TG, Bearden CE. Early and late neurodevelopmental influences in the prodrome to schizophrenia: contributions of genes, environment, and their interactions. Schizophrenia Bulletin 2003;29(4): 653-69.
5. Müller N, Riedel M, Ackenheil M, Schwarz MJ. Cellular and humoral immune system in schizophrenia: a conceptual re-evaluation. World J Biol Psychiatry 2000;1: 173–9.
6. Babulas V, Factor-Litvak P, Goetz R, Schaefer CA, Brown AS. Prenatal exposure to maternal genital and reproductive infections and adult schizophrenia. Am J Psychiatry 2006;163: 927–9.
7. Moreno JL, Kurita M, Holloway T et al. Maternal influenza viral infection causes schizophrenia-like alterations of 5-HT A and mGlu receptors in the adult offspring. J Neurosci 2011;31: 1863–72.
8. Short SJ, Lubach GR, Karasin AI et al. Maternal influenza infection during pregnancy impacts postnatal brain development in the rhesus monkey. Biol Psychiatry 2010;67: 965–73.
9. Feigenson KA, Kusnecov AW, Silverstein SM. Inflammation and the two-hit hypothesis of schizophrenia. Neurosci Biobehav Rev 2014;38: 72–93.
10. Block ML, Zecca L, Hong JS. Microglia-mediated neurotoxicity:
uncovering the molecular mechanisms. Nat Rev Neurosci 2007;8: 57–69.
11. Gilmore JH, Jarskog LF. Exposure to infection and brain development: cytokines in the pathogenesis of schizophrenia. Schizophr Res 1997;24: 365–7.
12. Doherty GH. Developmental switch in the effects of TNFalpha on ventral midbrain dopaminergic neurons. Neurosci Res 2007;57:
296–305.
13. Fatemi SH, Emamian ES, Sidwell RW et al. Human influenza viral infection in utero alters glial fibrillary acidic protein immunoreactivity in the developing brains of neonatal mice. Mol Psychiatry 2002;7(6): 633–40.
13. Hulshoff Pol HE, Kahn RS. What happens after the first episode? A review of progressive brain changes in chronically ill patients with schizophrenia. Schizophr Bull 2008;34: 354–66.
14. Belvederi Murri M, Pariante CM, Dazzan P et al. Hypothalamic- pituitary-adrenal axis and clinical symptoms in first-episode psychosis. Psychoneuroendocrinology 2012;37: 629–644.
15. Aas M, Dazzan P, Mondelli V et al. Abnormal cortisol awakening response predicts worse cognitive function in patients with first-episode psychosis. Psychol Med 2011;41(3): 463–476.
16. Mondelli V, Ciufolini S, Martino BM et al. Cortisol and Inflammatory Biomarkers Predict Poor Treatment Response in First E p i s o d e P s y c h o s i s . S c h i z o p h re n i a B u l l e t i n 2 0 1 5 ; d o i :
10.1093/schbul/sbv028
17. Kowalski J, Blada P, Kucia K, Madej A, Herman ZS. Neuroleptics normalize increased release of interleukin- 1 beta and tumor necrosis factor-alpha from monocytes in schizophrenia. Schizophr Res 2001;50: 169–75.
18. Moots RJ, Al-Saffar Z, Hutchinson D et al. Old drug,new tricks: haloperidol inhibits secretion of proinflammatory cytokines. AnnRheum Dis 1999;58: 585–7.
19. Halim ND, Weickert CS, McClintock BW, Weinberger DR, Lipska BK. Effects of chronic haloperidol and clozapine treatment on neurogenesis in the adult rat hippocampus. Neuropsychopharmacology
2004;29: 1063–9.
20. Maes M, Bocchio Chiavetto L, Bignotti S et al. Increased serum interleukin-8 and interleukin-10 in schizophrenic patients resistant to treatment with neuroleptics and the stimulatory effects of clozapine on serum leukemia inhibitory factor receptor. Schizophr Res 2002;54: 281–91.
21. Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B. Meta- analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry 2011;70: 663–71.
22. KatoT, MonjiA, HashiokaS, KanbaS. Risperidone significantly inhibits interferon-gamma induced microglial activation in vitro.
Schizophr Res 2007;92: 108 15.
23. Dawirs RR, Hildebrandt K, Teuchert-Noodt G. Adult treatment with haloperidol increases dentate granule cell proliferation in the gerbil hippocampus. J Neural Transm 1998;105: 317–27.
24. Nasrallah HA, Hopkins T, Pixley SK. Differential effects of antipsychotic and antidepressant drugs on neurogenic regions in rats.
Brain Res 2010;1354: 23–9.
25. Sommer IE, de Witte L, Begemann M, Kahn RS. Nonsteroidal anti- inflammatory drugs in schizophrenia: ready for practice or a good start? A meta-analysis. J Clin Psychiatry 2012;73: 414–9.
26. Wonodi I, Stine OC, Sathyasaikumar KV et al. Downregulated kynurenine 3-monooxygenase gene expression and enzyme activity in schizophrenia and genetic association with schizophrenia endophenotypes. Arch Gen Psychiatry 2011;68: 665–74.
27. Tharumaratnam D, Bashford S, Khan SA. Indomethacin induced psychosis. Postgrad Med J 2000;76: 736–7.
28. Laan W, Grobbee DE, Selten JP, Heijnen CJ, Kahn RS, Burger H. Adjuvant aspirin therapy reduces symptoms of schizophrenia spectrum disorders: results from a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2010;71: 520–7.
29. Cazzullo CL, Sacchetti E, Galluzzo A et al. Cytokine profiles in schizophrenic patients treated with risperidone: a 3-month follow- upstudy. Prog Neuropsychopharmacol Biol Psychiatry 2002;26: 33–9.
30. Sommer IE, de Witte L, Begemann M, Kahn R. Nonsteroidal Anti-Inflammatory Drugs in Schizophrenia: Ready for Practice or a Good Start?
A Meta- Analysis. J Clin Psychiatry 2012;73(4): 414–419.

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