Understanding Schizophrenia: Genetic Causes And Treatment

Introduction:

Schizophrenia consists of two words “schizo” meaning “split” and “phrenia” meaning “mind”.Schizophrenia is a severe mental disorder (Van Den Heuvel & Fornito, 2014). A patient hears voices or sees things that don’t exist. A person who experiences this condition feels alone due to this loneliness he feels false perceptions and disconnects from the reality. About 1% people of the world face this disorder (Leucht, Burkard, Henderson, Maj, & Physical, 2007). TheWorld Health Organization (WHO) estimated that schizophrenia was the 5th (respectively 6th) leading worldwide cause of global disease burden in 2004 among males (respectively females), with 2.8% (respectively 2.6%) of total Years Lived With Disability (YLD) (WHO, 2004). Schizophrenia is a financial burden on society because of the potential for institutionalization and chronic use of treatments. It is described as a disease with large costs for individuals and society. While literature on the economic impact of schizophrenia is abundant (Silva, Hanwella, & Silva, 2012), few studies have focused on its humanistic burden, which not only concerns patients, but also caregivers, relatives, neighbors, and other individuals in a patient’s daily life (Millier et al., 2014).

Schizophrenia is a disorder of brain function, affecting one’s thoughts, feeling and acts. Symptoms develop either progressively or appear abruptly and vary from one patient to another. The dis-ease evolves in cycles of remissions and relapses. Symptoms consist of separation from reality with delusion formation, hallucinations, emotional dysregulation, and disorganized behavior, disorganized speech, disorganized thinking, loss of initiative and cognitive dysfunction. Over time, a small decline in mental function and social relationships occurs which leads to a marked personality change, social isolation, occupational disability, cognitive impairment, and poor health. schizophrenia is a major cause of suicide (Winnerbäck, 2010). It remains clear that the Quality of Life (QoL) of patients with schizophrenia is worse than that of the general population and worse than that of many patients with physical and other mental disorders (Bobes, Garcia-portilla, Bascaran, & Saiz, 2007). Depression is a common co-morbidity in schizophrenia and is described in the literature in conjunction with other disease outcomes, such as decreased QoL or higher risk of suicide. rates of depression prevalence in schizophrenia patients range from 25% to 81% (Siris, 2001). 

Treatments available for schizophrenia have many side effects and lead to many issues. first generation antipsychotics (FGA) can especially cause mild to severe problems with body movements, such as restlessness, tremors, and rigid muscles. Second generation antipsychotics (SGA) have reduced this burden. they have their own issues: over the years different surveys have shown that weight gain, metabolic syndrome, and cardiovascular disease are all related to the side effects of SGAs and to unhealthy behavior of patients caused by their illness (Seeman, 2009) (Sevy, Nathanson, Schechter, & Fulop, 1993). Cognitive impairment is a core feature of schizophrenia (Earl & Elizabeth, 2007). cognitive deficits include lack of attention, declarative memory, and higher-order problem solving. The speed of processing, working and long-term memory, executive function, and social cognition can also be affected (Allardyce, 2008). Patients with a social cognitive deficit are unable to communicate effectively and this contributed to increased social isolation (Allardyce, 2008). A Swedish study reports that life expectancy was reduced in patients with schizophrenia: at age 40 years, conditional life expectancy was 7 years less for patients with schizophrenia or affective psychosis when compared to general population (Borritz, 2001). main causes of mortality are suicide, cancer and cardiovascular disease (Bushe, Taylor, & Haukka, 2010).clozapine is the only antipsychotic medication that has demonstrated efficacy for the management of suicidality in schizophrenia (Hor, Taylor, Hor, & Taylor, 2010). Only a small proportion of societal violence is due to patients with schizophrenia. Of patients diagnosed with schizophrenia, 99.97% will not commit serious violence (Walsh, Buchanan, & Fahy, 1998). However, schizophrenia is associated with an increased risk for non-violent and violent crime and with aggressive behavior towards others (Bo, Abu-akel, Kongerslev, Helt, & Simonsen, 2011). Causes are not known properly but the scientists are trying to reveal the causes of this drastic disorder. the more the scientists enter in the deep study they found it more difficult to understand as it is complex disorder. it also runs from parents to offspring i.e in families. Known causes may include different factors like specific genes, environmental factors, social and psychological issues.

Functional or anatomical probing of individual psychiatric symptoms or symptom clusters within a psychiatric syndrome is a relatively recent endeavor. Schizophrenia symptomatology varies widely, affecting the cognitive, effective, and reality testing domains. Three sets of symptoms received particular attention: positive, negative and cognition-related symptoms. Negative symptoms of schizophrenia have been recognized for a long time as the most devastating among all symptoms clusters of schizophrenia. (Tandon et al., 2001) (Boutros, Mucci, Diwadkar, & Tandon, 2014)

Genetic causes:

DNA Methylation of EGR3 gene

DNA methylation has been incriminated in the pathologic process of schizophrenia. EGR3 is taken to be an effective candidate gene for schizophrenia (Hu, Hsu, Tsai, & Cheng, 2017). schizophrenia is a severe mental ailment which has a strong genetic cause (Singh, Kumar, Agarwal, Phadke, & Jaiswal, 2014). an alternative explanation for the pathogenesis of schizophrenia is the epigenetic alterations (Shorter & Miller, 2015).EGR3 gene plays important role in regulation of cognition and synaptic plasticity (Donovan, Tourtellotte, Milbrandt, & Baraban, 1999). this gene is expressed abnormally in the brains of patients of schizophrenia, thus considered as a susceptible gene (Huentelman et al., 2015). But further evidence does not prove the association of this gene with schizophrenia (Cheng et al., 2012). We took a hypothesis that effective regulatory region of EGR3 is DNA methylated in the pathophysiological process of schizophrenia.

Thus to support our hypothesis we conducted an experiment in which we did invitro DNA methylation to access the regulation of EGR3 gene; expected to be involved in schizophrenia. The two p promoter regions and intron region of the EGR3 were amplified from the genomic DNA using infused primers. the amplified PCR products were cloned into a luciferase reporter plasmid (pCpGfree-basic-Lucia). Bisulfite treatment of DNA was done in which genomic DNA samples were taken then2 microgram of the sample was treated with bisulfate and purified. Regulatory regions were amplified and then sequenced by using pyrosequencing assay. ANOVA test was performed to assess the differences in DNA methylation level of CpG site between schizophrenia patients controls. Results depict that DNA methylation may regulate the expression of EGR3 gene via trans-acting genetic modifiers (Hu et al., 2017). there are other epigenetic processes such as small RNAi regulation and post-translational modifications may also play alternative functions in the regulation of EGR3 expression and schizophrenia (Gavin & Floreani, 2014).

Treatment:

Chlorpromazine

Chlorpromazine discovered to cure the disease of schizophrenia study done to check the dopamine function disability in the mesolimbic dopamine pathway that increases production of dopamine that leads to severe mental disease and to lose the contact with reality (Singh et al., 2014)

The amphetamine that is a drug that temporarily quickens some vital processes of the central nervous system can also increase dopamine excretion that causes mental disability symptoms. the capacity of antipsychotic equal to the ability to work against dopamine D2/3 receptors loss of functional ability in dopamine is considering the common pathway that causes loss of severe reality contact of the brain in schizophrenia. The sign of mental disability remain unclear that caused increased synthesis of dopamine production (Yang & Tsai, 2017)

Speech And Language Therapies

Therapies are used to advance pragmatics in Schizophrenics: Pragmatics is a major component of language referring to the use of language in context. It involves verbal, paralinguistic and nonverbal aspects of communication, such as the ability to introduce a topic of conversation, respect turn-taking, detect emotions in someone else voice and adopt appropriate body posture and facial expression according to the social context (Pttutting, 1987) Pragmatics deficits are observed in many clinical populations such as individuals with schizophrenia. Individuals with schizophrenia display speech and language impairments that greatly impact their integration into society. importance of speech and language therapy (SLT) as part of rehabilitation curriculums for patients with schizophrenia emphasizing on the speech and language abilities assessed, the therapy setting and the therapeutic approach. This article reviewed 18 studies testing the effects of language therapy or training in 433 adults diagnosed with schizophrenia. Results showed that 14 studies out of 18 lead to improvements in language and/or speech abilities. Most of these studies comprised pragmatic or expressive discursive skills being the only aim of the therapy or part of it. the evidence tends to show that certain areas of language are treatable through therapy (Joyal, Bonneau, & Fecteau, 2016)

References

Allardyce, J. (2008). Long-term course and outcome of schizophrenia, 10–12.

Bo, S., Abu-akel, A., Kongerslev, M., Helt, U., & Simonsen, E. (2011). Clinical Psychology Review Risk factors for violence among patients with schizophrenia. Clinical Psychology Review, 31 (5), 711–726. https://doi.org/10.1016/j.cpr.2011.03.002

Bobes, J., Garcia-portilla, M. P., Bascaran, M. T., & Saiz, P. A. (2007). Quality of life in schizophrenic patients, 215–226.

Borritz, M. (2001). Life expectancies for individuals with psychiatric diagnoses, (January 1983), 328–337.

Boutros, N. N., Mucci, A., Diwadkar, V., & Tandon, R. (2014). Negative symptoms in schizophrenia: A comprehensive review of electrophysiological investigations. Clinical Schizophrenia and Related Psychoses, 8 (1). https://doi.org/10.3371/CSRP.BOMU.012513

Bush, C. J., Taylor, M., & Haukka, J. (2010). Mortality in schizophrenia : a measurable clinical endpoint. https://doi.org/10.1177/1359786810382468

Cheng, M., Chuang, Y., Lu, C., Chen, Y., Luu, S., Li, J., … Chen, C. (2012). Progress in Neuro-Psychopharmacology & Biological Psychiatry Genetic and functional analyses of early growth response ( EGR ) family genes in schizophrenia. Progress in Neuropsychopharmacology & Biological Psychiatry, 39 (1), 149–155. https://doi.org/10.1016/j.pnpbp.2012.06.004

Donovan, K. J. O., Tourtellotte, W. G., Milbrandt, J., & Baraban, J. M. (1999). The EGR family of transcription-regulatory factors : progress at the interface of molecular and systems neuroscience, 167–173.

Earl, T., & Elizabeth, B. Æ. (2007). Cognitive Impairments and the Prevention of Homelessness : Research and Practice Review, 375–388. https://doi.org/10.1007/s10935-007-0100-1

Gavin, D. P., & Floreani, C. (2014). Epigenetics of Schizophrenia : An Open and Shut Case. Epigenetics (1st ed., Vol. 115). Elsevier Inc. https://doi.org/10.1016/B978-0-12-801311-3.00005-6

Hor, K., Taylor, M., Hor, K., & Taylor, M. (2010). Journal of Psychopharmacology. https://doi.org/10.1177/1359786810385490

Hu, T. M., Hsu, S. H., Tsai, S. M., & Cheng, M. C. (2017). DNA methylation analysis of the EGR3 gene in patients of schizophrenia. Psychiatry Research, 251, 115–117. https://doi.org/10.1016/j.psychres.2017.02.014

Huentelman, M. J., Muppana, L., Corneveaux, J. J., Dinu, V., Pruzin, J., Reiman, R., … Gallitano, A. L. (2015). Association of SNPs in EGR3 and ARC with Schizophrenia Supports a Biological Pathway for Schizophrenia Risk, 1–17. https://doi.org/10.1371/journal.pone.0135076

Joyal, M., Bonneau, A., & Fecteau, S. (2016). Speech and language therapies to improve pragmatics and discourse skills in patients with schizophrenia. Psychiatry Research, 240, 88–95. https://doi.org/10.1016/j.psychres.2016.04.010

Leucht, S., Burkard, T., Henderson, J., Maj, M., & Physical, S. N. (2007). Physical illness and schizophrenia : a review of the literature, 317–333. https://doi.org/10.1111/j.1600-0447.2007.01095.x

Millier, A., Schmidt, U., Angermeyer, M. C., Chauhan, D., Murthy, V., Toumi, M., & Cadi-Soussi, N. (2014). The humanistic burden in schizophrenia: A literature review. Journal of Psychiatric Research, 54 (1), 85–93. https://doi.org/10.1016/j.jpsychires.2014.03.021

Putting, C. A. (1987). Prutting_Checklist_Article, 52 (May), 105–119. https://doi.org/10.1044/jshd.5202.105

Seeman, M. V. (2009). Secondary Effects of Antipsychotics : Women at Greater Risk Than Men, 35 (5), 937–948. https://doi.org/10.1093/schbul/sbn023

Sevy, S., Nathanson, K., Schechter, C., & Fulop, Q. (1993). Contingent Valuation and Preferences of Health States Associated With Side Effects of Antipsychotic Medications in Schizophrenia, 643–651.

Shorter, K. R., & Miller, B. H. (2015). Epigenetic mechanisms in schizophrenia. Progress in Biophysics and Molecular Biology, 118 (1–2), 1–7. https://doi.org/10.1016/j.pbiomolbio.2015.04.008

Silva, J. De, Hanwella, R., & Silva, V. De. (2012). The direct and indirect cost of schizophrenia in outpatients treated in a tertiary care psychiatry unit, 2 (January). 

Singh, S., Kumar, A., Agarwal, S., Phadke, S. R., & Jaiswal, Y. (2014). The genetic insight into schizophrenia: Past and future perspectives. Gene, 535 (2), 97–100. https://doi.org/10.1016/j.gene.2013.09.110

Siris, S. G. (2001). Suicide and schizophrenia. https://doi.org/10.1177/026988110101500209

Tandon, R., DeQuardo, J. R., Taylor, S. F., McGrath, M., Jobson, M., Eiser, A., & Goldman, M. (2001). Erratum: Phasic and enduring negative symptoms in schizophrenia: Biological markers and relationship to outcome (Schizophrenia Research (2000) 45 (191-201) PII: S0920996499001632). Schizophrenia Research, 51 (2–3), 185. https://doi.org/10.1016/S0920-9964 (01)00284-5

Van Den Heuvel, M. P., & Fornito, A. (2014). Brain networks in schizophrenia. Neuropsychology Review, 24 (1), 32–48. https://doi.org/10.1007/s11065-014-9248-7

Walsh, E., Buchanan, A., & Fahy, T. (1998). Violence and schizophrenia : examining the evidence, (1997).

Winnerbäck, K. (2010). Suicide in schizophrenia, 10 (7), 1153–1164.

Yang, A. C., & Tsai, S. J. (2017). New targets for schizophrenia treatment beyond the dopamine hypothesis. International Journal of Molecular Sciences, 18 (8). https://doi.org/10.3390/ijms18081689.