**Author details**

[66]. In cancer etiology, the promoter hypermethylation also plays a major role by aberrant transcription of critical regulator genes such as tumor suppressor genes with the implications

Epigenetic mechanism produces DNA methylation which alters gene expression without altering underlying DNA sequence. *Epigenetic changes may be passed on for multiple generations by cell division* [68]. Evidences of linkage analysis in schizophrenic family suggest a hereditary susceptibility [69]. The methylation of DNA confers long-term epigenetic silencing which could be reprogrammed by demethylation of DNA repair [70]. It is implicated that the epigenetic change, especially from the differentially expression genes, regulates the methylation

Recent study suggests that the hypomethylated genes are predominant in schizophrenia. Reducing hypomethylation of SDMGs or SCZCGs could be a novel therapeutic treatment method for schizophrenia. There might be the protective factors as per the etiology of cancer [25], in which most promotors are hypermethylated. Some hypermethylating agent, such as vitamin B1, induces upregulation of methyltransferase and reversion of hypomethylation as an adjuvant treatment in schizophrenia [71]. It has postulated that deficiency of vitamin B1 may result in genetic methylation and biochemical lesion relating to neurotransmitter metab-

**2.7. Mitochondrial dysfunction in schizophrenia by genetic interaction network**

tance of mitochondria dysfunction in the manifestation of schizophrenia [73].

by the DRD2-NDUFS7 and the FLNA-ARRB2 interactions [5].

By the analysis of transcriptome profiles in postmortem brain tissues and interactions between differential expression candidate genes, the novel finding of potential complexes and pathways could facilitate the investigation of potential schizophrenic pathoetiology. Recent researches focus on theories related to the hypofunction of mitochondria which may contribute to the pathogenesis of schizophrenia, especially negative symptoms such as anhedonia, lack of emotional expression, flattening, poor social and interpersonal activities, and poor self-care. Some advanced techniques propose the replacement of mitochondria; even restoration of mitochondrial function might be potential treatment for alleviation of the negative symptoms of schizophrenia. Since the mitochondria are responsible for vital biological processes such as energy metabolism, calcium buffering, and apoptosis, it indicates the impor-

The genetic profile of mitochondria and energy metabolism in the analysis of brain samples may contribute to reveal the novel insight to the etiology of schizophrenia [73, 74]. The genetic interactions and intermediate mediators among mitochondrial genes and many underexpressed SCZCGs indicate the genetic predisposition of mitochondria dysfunction in schizophrenia. The genetic interactions between mitochondria and schizophrenia may be revealed

In SDMG, NDUFA10 has been found to be associated with the abnormalities of mitochondrial function in schizophrenia [75]. It plays a key role in respiratory electron transport chain responded to the exposure of antipsychotics [76]. NDUFA10 mutation causes mitochondrial complex I deficiency. It is associated with the progressive neurodegenerative disease such as

for the hypomethylation factors in the novel treatment strategy of cancer [67].

of SDMGs and the production of corresponding protein complexes.

52 Schizophrenia Treatment - The New Facets

olism in the brain, leading to psychotic manifestations [72].

Kuo-Chuan Huang1, 2, Theresa Tsun-Hui Tsao<sup>3</sup> , Tse-Yi Wang<sup>4</sup> and Sheng-An Lee<sup>5</sup> \*

\*Address all correspondence to: shengan@mail.knu.edu.tw

1 Department of Psychiatry, Beitou Branch, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan

2 Department of Nursing, Ching Kuo Institute of Management and Health, Keelung, Taiwan

3 Department of Psychiatry, College of Medicine, National Taiwan University Hospital ,Taipei, Taiwan

4 Molecular Anthropology and Transfusion Medicine Research Laboratory, Mackay Memorial Hospital ,Taipei City, Taiwan

5 Department of Information Management, Kainan University, Taoyuan, Taiwan

### **References**


[18] Nishioka, M., et al., *DNA methylation in schizophrenia: progress and challenges of epigenetic studies*. Genome Med, 2012. **4**(12): p. 96.

**References**

54 Schizophrenia Treatment - The New Facets

[1] Kallmann, F.J., *The genetics of schizophrenia*. 1938, Oxford, England: J. J. Augustin. xvi, 291. [2] Gejman, P.V., A.R. Sanders, and J. Duan, *The role of genetics in the etiology of schizophrenia*.

[3] Allen, N.C., et al., *Systematic meta-analyses and field synopsis of genetic association studies in* 

[4] Wu, Y., Y.G. Yao, and X.J. Luo, SZDB: a database for schizophrenia genetic research.

[5] Huang, K.C., et al., *Transcriptome alterations of mitochondrial and coagulation function in schizophrenia by cortical sequencing analysis*. BMC Genom, 2014. **15**(Suppl. 9): p. S6.

[6] Farrell, M.S., et al., *Evaluating historical candidate genes for schizophrenia*. Mol Psychiatry,

[7] Collins, A.L., et al., *Hypothesis-driven candidate genes for schizophrenia compared to genome-*

[8] Schwieler, L., et al., *Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia–significance for activation of the kynurenine pathway*. J Psychiatry Neurosci,

[9] Miller, B.J., et al., *Meta-analysis of cytokine alterations in schizophrenia: clinical status and* 

[10] Jacobs, B.M., *A dangerous method? The use of induced pluripotent stem cells as a model for* 

[11] Sadowska-Bartosz, I., et al., *Antioxidant properties of atypical antipsychotic drugs used in the* 

[12] Rudan, I., *New technologies provide insights into genetic basis of psychiatric disorders and* 

[13] Schreiber, M., M. Dorschner, and D. Tsuang, *Next-generation sequencing in schizophrenia and other neuropsychiatric disorders*. Am J Med Genet B Neuropsychiatr Genet, 2013.

[14] Kato, T., *Whole genome/exome sequencing in mood and psychotic disorders*. Psychiatry Clin

[15] Nestler, E.J., et al., Epigenetic basis of mental illness. Neuroscientist, 2016 Oct;22(5):447-63. [16] Lim, D.H.K. and E.R. Maher, *DNA methylation: a form of epigenetic control of gene expres-*

[17] Li, Y., et al., *Genome-wide methylome analyses reveal novel epigenetic regulation patterns in* 

*schizophrenia and bipolar disorder*. Biomed Res Int, 2015. **2015**: p. 201587.

*schizophrenia: the SzGene database*. Nat Genet, 2008. **40**(7): pp. 827–34.

*wide association results*. Psychol Med, 2012. **42**(3): pp. 607–16.

*antipsychotic effects*. Biol Psychiatry, 2011. **70**(7): pp. 663–71.

*treatment of schizophrenia*. Schizophr Res, 2016. **176**(2-3): pp. 245–51.

*explain their co-morbidity*. Psychiatr Danub, 2010. **22**(2): pp. 190–2.

*schizophrenia*. Schizophr Res, 2015. **168**(1-2): pp. 563–8.

Psychiatr Clin North Am, 2010. **33**(1): pp. 35–66.

Schizophr Bull, 2016 Jul 22. pii: sbw102.

2015. **20**(5): pp. 555–62.

2015. **40**(2): pp. 126–33.

**162B**(7): pp. 671–8.

Neurosci, 2015. **69**(2): pp. 65–76.

*sion*. Obstet Gynaecol, 2010. **12**(1): pp. 37–42.


[52] Romero, P., et al., *Computational prediction of human metabolic pathways from the complete human genome*. Genome Biol, 2005. **6**(1): p. R2.

[35] Mathivanan, S., et al., *An evaluation of human protein-protein interaction data in the public* 

[36] Caspi, R., et al., *The MetaCyc database of metabolic pathways and enzymes and the BioCyc collection of pathway/genome databases*. Nucleic Acids Res, 2012. **40**(Database issue): pp.

[37] Orchard, S., et al., *The MIntAct project–IntAct as a common curation platform for 11 molecular interaction databases*. Nucleic Acids Res, 2014. **42**(Database issue): pp. D358–63.

[38] Kanehisa, M., et al., *Data, information, knowledge and principle: back to metabolism in KEGG*.

[39] Kandasamy, K., et al., *NetPath: a public resource of curated signal transduction pathways*.

[40] Thomas, P.D., et al., *PANTHER: a browsable database of gene products organized by biological function, using curated protein family and subfamily classification*. Nucleic Acids Res, 2003.

[41] Hornbeck, P.V., et al., *PhosphoSitePlus, 2014: mutations, PTMs and recalibrations*. Nucleic

[42] Schaefer, C.F., et al., *PID: the Pathway Interaction Database*. Nucleic Acids Res, 2009.

[43] Croft, D., et al., *Reactome: a database of reactions, pathways and biological processes*. Nucleic

[44] Jewison, T., et al., *SMPDB 2*.*0: big improvements to the Small Molecule Pathway Database*.

[45] Wingender, E., *The TRANSFAC project as an example of framework technology that supports* 

[46] Hsu, S.D., et al., *miRTarBase: a database curates experimentally validated microRNA-target* 

[47] Law, V., et al., *DrugBank 4*.*0: shedding new light on drug metabolism*. Nucleic Acids Res,

[48] Thiele, I., et al., *A community-driven global reconstruction of human metabolism*. Nat

[49] Kutmon, M., et al., *WikiPathways: capturing the full diversity of pathway knowledge*. Nucleic

[50] Viswanathan, G.A., et al., *Getting started in biological pathway construction and analysis*.

[51] Jupe, S., et al., *Reactome – a curated knowledgebase of biological pathways: megakaryocytes and* 

*the analysis of genomic regulation*. Brief Bioinform, 2008. **9**(4): pp. 326–32.

*interactions*. Nucleic Acids Res, 2011. **39**(Database issue): pp. D163–9.

*domain*. BMC Bioinform, 2006. **7**(Suppl. 5): p. S19.

Nucleic Acids Res, 2014. **42**(Database issue): pp. D199–205.

Acids Res, 2015. **43**(Database issue): pp. D512–20.

Acids Res, 2011. **39**(Database issue): pp. D691–7.

Nucleic Acids Res, 2014. **42**(Database issue): pp. D478–84.

Genome Biol, 2010. **11**(1): p. R3.

**37**(Database issue): pp. D674–9.

2014. **42**(Database issue): pp. D1091–7.

Biotechnol, 2013. **31**(5): pp. 419–25.

Acids Res, 2016. **44**(D1): pp. D488–94.

PLoS Comput Biol, 2008. **4**(2): p. e16.

*platelets*. J Thromb Haemost, 2012. **10**(11): pp. 2399–402.

**31**(1): pp. 334–41.

D742–53.

56 Schizophrenia Treatment - The New Facets


## *Toxoplasma gondii* **and Schizophrenia: A Relationship That Is Not Ruled Out** *Toxoplasma gondii* **and Schizophrenia: A Relationship That Is Not Ruled Out**

Antonio Sorlozano-Puerto and Jose Gutierrez-Fernandez Antonio Sorlozano-Puerto and Jose Gutierrez-Fernandez

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/66018

#### **Abstract**

[68] Bird, A., *Perceptions of epigenetics*. Nature, 2007. **447**(7143): pp. 396–8.

J Med Genet B Neuropsychiatr Genet, 2009. **150B**(6): pp. 827–35.

Nature, 2007. **447**(7143): pp. 425–32.

Mol Cells, 2012. **33**(2): pp. 105–10.

*ease*. Eur J Hum Genet, 2011. **19**(3): pp. 270–4.

pp. 26–32.

58 Schizophrenia Treatment - The New Facets

3633–41.

[69] Paunio, T., et al., *Linkage analysis of schizophrenia controlling for population substructure*. Am

[70] Reik, W., *Stability and flexibility of epigenetic gene regulation in mammalian development*.

[71] Ghufran, M.S., K. Ghosh, and S.R. Kanade, *Aflatoxin B1 induced upregulation of protein arginine methyltransferase 5 in human cell lines*. Toxicon, 2016. **119**: pp. 117–21.

[72] Osiezagha, K., et al., *Thiamine deficiency and delirium*. Innov Clin Neurosci, 2013. **10**(4):

[73] Karry, R., E. Klein, and D. Ben Shachar, *Mitochondrial complex I subunits expression is altered in schizophrenia: a postmortem study*. Biol Psychiatry, 2004. **55**(7): pp. 676–84. [74] Martins-de-Souza, D., et al., *Proteome analysis of schizophrenia patients Wernicke's area* 

[75] Park, C. and S.K. Park, *Molecular links between mitochondrial dysfunctions and schizophrenia*.

[76] Ji, B., et al., *A comparative proteomics analysis of rat mitochondria from the cerebral cortex and hippocampus in response to antipsychotic medications*. J Proteome Res, 2009. **8**(7): pp.

[77] Hoefs, S.J., et al., *NDUFA10 mutations cause complex I deficiency in a patient with Leigh dis-*

[78] Mnif, L., R. Sellami, and J. Masmoudi, *Schizophrenia and Leigh syndrome, a simple comorbid-*

[79] Dikshit, R. and P. Tallapragada, *Bio-synthesis and screening of nutrients for lovastatin by Monascus sp*. *under solid-state fermentation*. J Food Sci Technol, 2015. **52**(10): pp. 6679–86.

[80] Ghanizadeh, A., et al., *Lovastatin for the adjunctive treatment of schizophrenia: a preliminary randomized double-blind placebo-controlled trial*. Psychiatry Res, 2014. **219**(3): pp. 431–5. [81] Lerner, V., P.J. McCaffery, and M.S. Ritsner, *Targeting retinoid receptors to treat schizophre-*

*ity or the same etiopathogeny: about a case*. Pan Afr Med J, 2015. **22**: p. 333.

*nia: rationale and progress to date*. CNS Drugs, 2016. **30**(4): pp. 269–80.

*reveals an energy metabolism dysregulation*. BMC Psychiatry, 2009. **9**: p. 17.

Over recent years, it has been proposed that some diseases of unknown origin, such as schizophrenia, may be caused by persistent chronic infections coupled with a genetic component and may be perpetuated by the immune system. This hypothesis is supported by epidemiological and biological evidence on the exposure of schizophrenics to infec‐ tious diseases during prenatal or postnatal periods, including *Toxoplasma gondii*, chla‐ mydia, human herpes virus, human endogenous retroviruses, parvovirus B19, mumps, and flu viruses. This growing list of microbes will undoubtedly continue to increase in the future. Linking infection to schizophrenia is a complex challenge that requires further experimental and epidemiological research. *T. gondii* is the infectious agent that has most frequently been related to neuropsychiatric disorders, including schizophrenia, and it is considered to represent a highly useful model to analyze the influence of a microorgan‐ ism on human behavior and the development of psychiatric disease. It may also help to detect patient subpopulations susceptible to treatment with specific antimicrobials by improving definition of the differential phenotype of the disease, and it offers the possibility of a preventive approach.

**Keywords:** schizophrenia, *Toxoplasma gondii*, antibodies, behavior, cytokine, neurotransmitter, gene‐infection interaction

#### **1. Introduction**

Over the past few years, it has been proposed by some authors that schizophrenia may be caused by central nervous system (CNS) disorders during neurodevelopment (i.e., congeni‐ tal) or during the postnatal period, at least in some patient subgroups [1]. These disorders may be related to environmental exposure to toxic products, radiation, stress, fetal hypoxia,

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

nutritional problems, infections (especially when chronic and persistent), and/or, according to more recent data, gut microbiota [2, 3]. Any of these exposures could possibly affect cogni‐ tive functions and behavior patterns with important neuropsychiatric consequences, includ‐ ing irreversible neurological lesions leading to neuronal dysfunction, behavior problems, mental retardation, learning difficulties, or mood disorders [4–9]. Participation by microbial agents in the development of schizophrenia is suggested by medical evidence, with prenatal or perinatal infection being the most frequent cause of severe congenital malformations and mental impairment [10]. Their involvement is also supported by epidemiological evidence on the exposure of schizophrenic patients to *T. gondii*, chlamydia, human herpes virus, human endogenous retroviruses, parvovirus B19, and rubella, mumps, or influenza viruses, among other microorganisms [11].

According to current pathogenic models, microorganisms may produce various inflamma‐ tory and/or immunological disorders in the infected brain, giving rise to neurotransmitter synthesis disorders with important clinical repercussions [7]. Schizophrenia has been related to the production of inflammatory cytokines that alter the synthesis of dopamine and other neurotransmitters [12] and to fetal neuronal tissue damage due to the transplacental trans‐ fer of maternal antibodies, which might underlie development of the disease decades later [13]. This association with inflammatory and immunologic disorders has been observed in studies of animal models and human cells. Thus, maternal infection of mice and rats during pregnancy was associated with behavioral disorders in the offspring that were very similar to those reported in schizophrenic patients. Various studies in murine models revealed an association between prenatal infection and marked deficits in sensory information process‐ ing, in the expression of certain neurotransmitters (e.g., dopamine) and of cytokines, and in the immune function, all of which emerged in the offspring. Their onset is at an age equiva‐ lent to human adolescence and is earlier, with more severe effects, in male *versus* female rats, and these alterations can be reverted by the administration of antipsychotic drugs. In short, the fetus can be damaged by numerous infectious agents, whether or not they are primarily neurotropic, which may favor in a direct or immune‐mediated manner the development of neurological damage, disorders in neurotransmitter expression, and modifications in sensory information processing [14].

There is intense and increasing research interest in the relationship between schizophrenia and infectious agents. Irreversible mild or severe neurophysiologic alterations may result from fetal infection, maternal infection with secondary fetal involvement *via* inflammatory and/or immunological mechanisms, or postnatal infection and may lead to the emergence of schizophrenia over the years. The full elucidation of these associations may allow specific antimicrobial treatments to be added to current symptomatic (or antipsychotic) treatments for these patients [5], potentially offering a preventive and curative approach to the disease, given that they would act on known and treatable etiologic factors.

*T. gondii* is the infectious agent that has most frequently been related to neuropsychiatric disor‐ ders, including schizophrenia, and it is considered to represent a useful model to analyze the influence of a microorganism on human behavior and the development of psychiatric disease [15]. It is an obligate intracellular protozoa belonging to the *Coccidia* subclass of the phylum *Apicomplexa* and causes toxoplasmosis. Its definitive hosts are cats and other felines, which are the only animals in which the sexual stage of their life cycle takes place (in intestines), forming oocysts that are eliminated through the feces. Hot‐blooded vertebrates such as birds and other mammals, including humans, are intermediate hosts. Humans can become infected by various pathways, such as: the intake of undercooked meat containing latent forms of the parasite (bradyzoites in tissue cysts), fresh food (e.g., fruit and vegetables), or water contami‐ nated with oocysts from cat feces; blood transfusions; transplantation of solid organ or stem cells, or transplacental transmission. Upon reaching tissues, *T. gondii* rapidly replicates in the form of tachyzoites until tissue proliferation and expansion of the parasite are impeded by the immune response, after which its replication slows and it remains in tissue cysts in latent or bradyzoite form. Cysts are most frequently found in skeletal muscle, myocardium, CNS, and eyes and are responsible for persistent infection [16, 17].

nutritional problems, infections (especially when chronic and persistent), and/or, according to more recent data, gut microbiota [2, 3]. Any of these exposures could possibly affect cogni‐ tive functions and behavior patterns with important neuropsychiatric consequences, includ‐ ing irreversible neurological lesions leading to neuronal dysfunction, behavior problems, mental retardation, learning difficulties, or mood disorders [4–9]. Participation by microbial agents in the development of schizophrenia is suggested by medical evidence, with prenatal or perinatal infection being the most frequent cause of severe congenital malformations and mental impairment [10]. Their involvement is also supported by epidemiological evidence on the exposure of schizophrenic patients to *T. gondii*, chlamydia, human herpes virus, human endogenous retroviruses, parvovirus B19, and rubella, mumps, or influenza viruses, among

According to current pathogenic models, microorganisms may produce various inflamma‐ tory and/or immunological disorders in the infected brain, giving rise to neurotransmitter synthesis disorders with important clinical repercussions [7]. Schizophrenia has been related to the production of inflammatory cytokines that alter the synthesis of dopamine and other neurotransmitters [12] and to fetal neuronal tissue damage due to the transplacental trans‐ fer of maternal antibodies, which might underlie development of the disease decades later [13]. This association with inflammatory and immunologic disorders has been observed in studies of animal models and human cells. Thus, maternal infection of mice and rats during pregnancy was associated with behavioral disorders in the offspring that were very similar to those reported in schizophrenic patients. Various studies in murine models revealed an association between prenatal infection and marked deficits in sensory information process‐ ing, in the expression of certain neurotransmitters (e.g., dopamine) and of cytokines, and in the immune function, all of which emerged in the offspring. Their onset is at an age equiva‐ lent to human adolescence and is earlier, with more severe effects, in male *versus* female rats, and these alterations can be reverted by the administration of antipsychotic drugs. In short, the fetus can be damaged by numerous infectious agents, whether or not they are primarily neurotropic, which may favor in a direct or immune‐mediated manner the development of neurological damage, disorders in neurotransmitter expression, and modifications in sensory

There is intense and increasing research interest in the relationship between schizophrenia and infectious agents. Irreversible mild or severe neurophysiologic alterations may result from fetal infection, maternal infection with secondary fetal involvement *via* inflammatory and/or immunological mechanisms, or postnatal infection and may lead to the emergence of schizophrenia over the years. The full elucidation of these associations may allow specific antimicrobial treatments to be added to current symptomatic (or antipsychotic) treatments for these patients [5], potentially offering a preventive and curative approach to the disease,

*T. gondii* is the infectious agent that has most frequently been related to neuropsychiatric disor‐ ders, including schizophrenia, and it is considered to represent a useful model to analyze the influence of a microorganism on human behavior and the development of psychiatric disease [15]. It is an obligate intracellular protozoa belonging to the *Coccidia* subclass of the phylum *Apicomplexa* and causes toxoplasmosis. Its definitive hosts are cats and other felines, which

given that they would act on known and treatable etiologic factors.

other microorganisms [11].

60 Schizophrenia Treatment - The New Facets

information processing [14].

Primary infection usually takes place during childhood, when only a small percentage of people show symptoms, which are mild and include general discomfort, lethargy, cervical lymphadenopathy, and/or eye disease, among others. Most parasitized individuals remain asymptomatic for a long time period, even throughout their life, and host the latent form of *T. gondii*. However, chronic infection can be reactivated in immunocompromised individu‐ als (AIDS, transplanted, and oncology patients, etc.), giving rise to various symptoms and even, in death. This reactivation is often associated with nervous system symptoms, such as Guillain‐Barré syndrome, diffuse encephalopathy, meningoencephalitis, or brain abscesses [17, 18]. Human parasitizations, although generally considered asymptomatic, may cause behavioral disorders and the development of a psychiatric disease such as schizophrenia due to damage resulting from the initial infection, from the host immune response to the parasite, or from the persistence of cysts in the CNS [19]. Accordingly, the concept of asymptomatic chronic parasitization is currently under debate [20].

*T. gondii* is a plausible candidate as an infectious origin of schizophrenia and has attracted considerable research attention for the following reasons: the possibility of its transplacen‐ tal transmission; its marked neurotropism; its capacity for persistent infection, remaining in latent form but with the possibility of reactivation; its association with brain development disorders and anomalies; its relationship with behavior disorders in animal and human mod‐ els; and *in vitro* evidence of the inhibition of its growth in cell culture by antipsychotic drugs.
