Schizophrenia: a Research Review and Discussion

Abstract

Schizophrenia spectrum disorders are types of psychological dysfunction associated with both common and diverse symptoms as well as treatment protocols across the spectrum. These disorders include but are not confined to schizophrenia, schizoaffective disorder, delusional disorder and schizophreniform disorder. Schizophrenia (SCZ) is a chronic, devastating, and lifelong disorder that is precipitated by genetic and environment risk factors. It is selected for the present analysis because it shares some symptoms, treatments, and genetic risk alleles with other disorders across the spectrum. In addition, it also manifests some symptoms, treatment protocols, and management challenges that are uniquely associated with other disorders (Schultze-Lutter, 2009). Therefore, the history, genetic factors, environmental influences, and available treatment options merit focused examination.

History

Schizophrenia was first identified as a disorder distinct from other psychotic disorders in 1887 by German psychiatrist, Emil Kraepelin who is credited as the founder of the field of psychiatric genetics based on his advancement of the notion that psychosis has a genetic/biological origin (Burton, 2012; Suris, Holliday & North, 2016). The formally recognized history of SCZ began largely at the turn of the twentieth century with the labeling of the disorder by Swiss psychiatrist, then student of eugenics, Paul Eugen Bleuler in 1910. The notion of a disorder that reflected a split (schizo) mind (phren) was based on what Bleuler saw as the separation of thinking and feeling exhibited by patients with the illness. Schizophrenia should not be confused with the condition of a split or multiple personality that, unlike SCZ often manifests swift changes in the characteristics of personality that are not normally associated with the schizophrenic patient. This is just one example of how the term schizophrenia has been inaccurately portrayed and accepted in society (Burton, 2012).

The history of SCZ, in fact, is replete with misunderstandings and/or the misuse/misapplication of the term to cover a myriad of personality irregularities marked by unusual behavior, which is typically negative and often rapidly changing in temperament and disposition. Unfortunately, erroneous misuse of the term schizophrenia also worked to set a precedent for the stigmatization of SCZ, and the marginalization of individuals suffering with the disorder. The risk of stigma and marginalization for mental illness goes as far back as antiquity, when even without labels, mental illness was associated with God’s punishment or possession by demons (Burton, 2012). Contributing to the misunderstanding/representation, standard diagnostic regarding the definition of SCZ did not exist in the United States nor did it globally until the development and publication of the DSM-III in 1980 (Suris, Holliday & North, 2016). Fortunately, the prospects for individuals currently suffering with SCZ are increasingly positive due to the advancement of technology as a diagnostic tool, enhanced social and psychological interventions, and more effective pharmaceutical treatments (Burton, 2012).

Epigenetic Causes

The epigenetics of SCZ work to explain the role that environmental factors play in changing the biologic expression of this chronic and debilitating disorder. Current studies have contributed to the identification of more than a thousand genes that are related to SCZ, and as many as 4116 genes identified as SCZ markers showing diverse patterns of expression. One of the most common and important epigenetic mechanisms that contributes to the symptomatic expression of SCZ is neurophysiological methylation, which has also been indicated in a variety of other progressive diseases (Sheng-An, & Kuo-Chuan, 2016). However, the diversity of genetic combinations allows for polymorphism of various genetic traits. Research has indicated the high-risk individuals carrying alleles on genes associated with this condition are vulnerable to symptomatic expression due to increased production on methylenetetrahydrofolate reductase (MTHFR) which decreases the amount of available catechol-O-methyltransferase (COMT) to facilitate degradation of dopamine. As such, elevated levels of dopamine continue occupying targeted receptors which increases focused attention altering perceptual abilities of the individual. In addition, those expressing this type of genetic mutation often have elevated levels of homocysteine in their plasma which potentiates greater risk of experiencing symptomatic expression of SCZ (Numata, Kinoshita, Tajima, Nishi, Imoto, & Ohmori, 2015).

As mentioned, multiple changes in expression of a single gene and/or a network of genes has been indicated as risk-factors in the vulnerability of an individual to experience symptoms of SCZ. However, the most highly contributions factors in symptomatic expression of SCZ involve frequency and duration of environmental exposures which dictate methylation of neurological connectivity which strengthens and/or weakens physiologic structure in the brain. Among these environmental factors, maternal stress during prenatal development have been indicated with potentiation of symptomatic development as well as paternal age and use of psychoactive substances during gestational period. Although genetic variants may predispose an individual to the possibility of developing symptomatic expression of SCZ along all diagnosable disorders along the spectrum, frequency and duration of adverse environmental exposures throughout the course of development have been indicated as the largest influence in the level of genetic expression (Shorter & Miller, 2015).

Symptoms and Treatments

Most often, symptoms of SCZ manifest in particularly obvious and abnormal behaviors that impact the thoughts and perceptual abilities of those who begin expressing symptoms of the disorder. The symptoms of SCZ are regularly categorized as positive of negative symptoms, in which positive indicates the addition of abnormal thoughts, feelings, and/or behaviors such as delusions and/or hallucinations. Conversely, expression of negative symptoms entails the removal of coherent thought, emotion, perception, and normal behavioral activity, which may also be classified as catatonic behavior. Included in the diagnostic criterion for SCZ are disorganized thought processing, motor function impairment, and perceptual disruptions that may manifest as visual, audible, and/or other sensational hallucinations. In such, these symptoms are often found to be caused by neurological dysregulation as a function of methanation and notated in study by the amount of white matter in particular areas of the brain. (Millan, Fone, Steckler, & Horan, 2014).

As previously mentioned, a review of historical patterns in research demonstrates that the diagnostic criteria, treatment, and research of various psychologic disorders such as SCZ have been misrepresentative throughout history. Though portions of current focus are on identifiable positive or negative symptoms, it should be noted that unlike most symptoms of SCZ, which may be highly-observable to others, those who endure psychosis are often unconsciously aware of the occurrence. However, at times symptoms indicating such a disturbance may be so subtle that others may remain ignorant to the descriptive markers/behaviors as subclinical symptoms are generally more private and unobserved by anyone by the individual suffering with the disorder. These basic symptoms are numerous and diverse, and they speak to the troubling aspect of self-observation among those with SCZ. Like the individuals who are diagnosed along the spectrum of Attentional Deficit Disorder (ADD), a primary example of symptomatic onset is intrusive thoughts which have no relevancy to the current focus and prevent acquisition of new knowledge because it interferes with informational processing and consolidation. Another example of the subclinical symptom is a disruption of organized speech, which is also affiliated with patterned amounts of neuronal connectivity in the temporal lobe as indicted with use of modern pictorial imaging. However, most instances of concern follow the symptomatic manifestation of an individual’s loss of function to produce coherent sentences when speaking, which indicates that neurological damage has already occurred undenounced to the patient (Schultze-Lutter, 2009). This is not to say that patients have no chance at recovering from the disorder/disease which developed due to vulnerability and environmental exposure. Instead, intervention at the earliest level can be paramount to the successfulness to acquire the skills necessary to identify symptoms and learn to overpower the temptation of all that encompasses elevated levels of dopaminergic activity.

Although treatment options for SCZ may include non-pharmacological therapies such as individual and group therapy and/or cognitive behavioral therapy, pharmacological treatment plans are imperative during time of psychosis. In the absence of effective rehabilitation programs progressive treatments are difficult to successfully implement. The first line of treatment for SCZ is the second-generation antipsychotics (SGAs) with the exception of the FDA approved clozapine, which is not used as a first choice because of some of the adverse effects that it can cause. The use of first-generation antipsychotics usually follows when the use of one or more SGAs is ineffective followed by the use of clozapine alone, clozapine with SGA, FGA or electroconvulsive therapy (ECT), FGA or SGA that has not been tried or a combination of each, respectively. At the same time, the research suggests that the pharmaceutical treatment of SCZ is bereft with challenges, not the least of which is the lack of adherence by schizophrenic patients to prescribed treatment modalities. Long-acting injectable antipsychotic medications are a common solution for schizophrenic patients who cannot be encouraged to comply with treatments that use oral medications (Patel, Cherian, Gohil & Atkinson, 2014). It should be emphasized that the outcomes of antipsychotic medications are often problematic, an issue that is addressed by Taipale, H., et al, illustrated in a study examining the association between application of medicinal antipsychotic treatment is highly associated with increased mortality among schizophrenic patients than others as their neurological pathways are differ in construction to others (2018).

Evaluation

Concerning the issue of potential treatment complications, researchers question the efficacy of pharmacologic treatment in potentially increasing or decreasing the mortality rate of those with SCZ. Given the nature of study, use of experimental studies would present ethical dilemmas in which the researchers would have to evaluate the morality of the project. In analyzing data drawn from a nationwide registry, the study of causation verses mortality rate among schizophrenic patients ages 16-64 years would require serious consideration when compared to the efficacy of long-acting antipsychotic injectables (LAI). In consideration of this, LAI’s have presented less than a 30% of death in comparison to orally administered medications. In addition, second generation LAIs and oral aripiprazole were found to have the lowest association with premature mortality rates. At this time it is not clear from the study whether it is the actual medication that is delivered to SCZ patients that increases or decreases mortality in this patient population or if it is the mode of administration. However, much research has indicated that the efficacy of a pharmacological engineered substance and method of delivery coincide with polymorphic genetic inheritance as expressed through environmental exposure which may vary by individual case. For example, most studies examining the issue of treating patients with SCZ eluded to the finding that compliance with treatment protocols is often difficult due to the patients understanding of emplaced treatment plan in addition to prior experiences (Taipale, et al, 2017).As elevated levels of dopaminergic activity is highly associated with the reward system which promotes all the feels good, SCZ patients who experience this level of satiation are likely to neglect and/or refuse implemented treatment plans as it would reduce the pleasurableness of this experience.

Some of the most compelling research on the combined impact of neurobiological expression and environmental factors in symptomatic expression of SCZ are studies which indicate the etiological role of relational to brain volume. With use of modern technology, studies indicate a reduction in white matter configuration as opposed to the volume of grey matter retained in proportional to developmental attributes. Unequivocally, the findings of these neurological structures can often indicate the extent of the neurological disordering which presents symptomatic features of the disorder. Illustrating this, twin studies have shown that volume of white matter in the hippocampal structure of the brain associated with perceptual memory and neuronal regeneration, and those with SCZ show a reduction of white matter/myelination in comparison to healthy subjects in the studied area (Piccioni, et al, 2017).

Environmental factors associated with a reduction in white matter may include a disruption in communication between hemispheric structures. In this case, the researchers have asserted correlation exists between a deficit in white matter in patients with SCZ that are monozygotic twins. However, developmental evaluations of symptomatic expression are found to be independent on environmental conditions of raise. As with other forms of expressive disorders, vulnerability is subject to genetic precursors and environmental experience. As such, this would suggest that the frequency and exposure to environmental conditions would impact the neurological activity which dictates physiological construction of necessary connections throughout areas of the brain which dictates myelination as a function of survival. In doing so, the central nervous system learns to adapt to its surrounding environment and passes this information onto the offspring of trailing generations (Piccioni, et al.,2017) Unfortunately, this type of inter-species pruning reduces the number of potential progressors as historical greats are the proprietor of this genetic connection to predisposition, and perceived societal norms to ensure for genetic expression of the sins of generations past.

Synthesis and Conclusion

Much like in modern society, those with SCZ have been erroneously stigmatize throughout history. However, modern technology has elucidated the significance of environmental conditions in facilitating the expression of innate genetic coding which ultimately decides the level/degree of experienced symptoms. Much like all beings are susceptible to contracting an illness (such as the Flu), they level of symptoms expressed and gravity of impact it has over one’s life is a function of tolerable immunity which is instilled from conception. As presented, there is an overwhelming amount of research evidence that provides for the manner in which neurological disorders such as SCZ develop. Knowing how impactful environment which we create are, it is in the best interest of future generations that current generations step back and reevaluated the ramifications of our actions.

References

Burton, N. (2017). A brief history of schizophrenia: Schizophrenia through the ages. Psychology

Today. Retrieved from https://www.psychologytoday.com/us/blog/hide-and-seek/201209/brief-history-schizophrenia

Millan, M. J., Fone, K., Steckler, T., & Horan, W. P. (2014).

Negative symptoms of schizophrenia: Clinical characteristics, pathophysiological substrates, experimental models and prospects for improved treatment. European Neuropsychopharmacology, 24, 645-692.

Numata, S., Kinoshita, M., Tajima, A., Nishi, A., Imoto, I., &

Ohmori, T. (2015). Evaluation of an association between plasma total homocysteine and schizophrenia by a Mendelian randomization analysis. BMC Medical Genetics, 16(54), 1-7.

Patel, K. R., Cherian, J., Gohil, K, & Atkinson, D. (2014).

Schizophrenia: Overview and treatment options. P&T: A Peer-Reviewed Journal for Managed Care & Formulary Management, 39(9), 638–645.

Picchioni, M. M., Rijsdijk, F., Toulopoulou, T., Chaddock, C.,

Cole, J. H., Ettinger, U., … McGuire, P. (2017). Familial and environmental influences on brain volumes in twins with schizophrenia. Journal of Psychiatry & Neuroscience: JPN, 42(2), 122–130.

Sheng-An, L., & Kuo-Chuan, H. (2016). Epigenetic profiling of

human brain differential DNA methylation networks in schizophrenia. BMC Medical Genomics, 9, 217–228.

Shorter, K. R., & Miller, B. H. (2015). Epigenetic mechanisms in

schizophrenia. Progress in Biophysics & Molecular Biology, 118(1/2), 1–7.

Schultze-Lutter, F. (2009). Subjective symptoms of schizophrenia

in research the clinic: The basic symptom concept. Schizophrenia Bulletin, 35(1), 5-8.

Suris, A., Holliday, R., & North, C. S. (2016). The evolution of

the classification of psychiatric disorders. Behavioral Sciences, 6(5), 1-10.

Taipale, H., Mittendorfer-Rutz, E., Alexanderson, K., Majak, M.,

Mehtälä, J., Hoti, F.,Jedenius, E., Enkusson, D., Level, A., Sermon, J. Tanskanen, A. & Tiihonen, J. (2018). Antipsychotics and mortality in a nationwide cohort of 29,823 patients with schizophrenia. Schizophrenia Research, 197, 274–280.

Annotated Bibliography

Burton, N. (2017). A brief history of schizophrenia: Schizophrenia through the ages. Psychology

Today. Retrieved from https://www.psychologytoday.com/us/blog/hide-and-seek/201209/brief-history-schizophrenia

In this article, the author offers a brief description of the history of SCZ. This is an informative article that provides a loose but compelling chronological examination of SCZ, how it has been addressed as well as perceived. Some of the most salient points of the article are those that inform on how SCZ was interpreted as madness in ancient civilizations. In some cases, perceived as a physical ailment addressed by diet and blood-letting and by others as a spiritual ailment to be addressed by religion. Overall, the article suggests that those who suffer with SCZ have a great opportunity for a normal life than ever.

Millan, M. J., Fone, K., Steckler, T., & Horan, W. P. (2014).

Negative symptoms of schizophrenia: Clinical characteristics, pathophysiological substrates, experimental models and prospects for improved treatment. European Neuropsychopharmacology, 24, 645-692.

This article offered an expansive review of the literature on the negative symptoms of SCZ; however, it did not describe a study. Instead, the primary goal of this article is to enlighten readers on the debilitating characteristics of the negative symptoms associated with SCZ. Although the authors offered details on both the positive and negative symptoms of SCZ, it goes much further to include the state of the research at this time as well as the prospects for the improvement of studies of SCZ’s negative symptoms. An especially compelling section of the article discusses that anomalies of cerebral structures that are associated with negative symptoms (NS). This section has special application to two studies on brain structure that are addressed in the present analysis.

[bookmark: _Hlk533281778]Numata, S., Kinoshita, M., Tajima, A., Nishi, A., Imoto, I., &

Ohmori, T. (2015). Evaluation of an association between plasma total homocysteine and schizophrenia by a Mendelian randomization analysis. BMC Medical Genetics, 16(54), 1-7.

This article addresses the question of whether an association exists between the single nucleotide polymorphism (SNP) (total plasma homocysteine) and SCZ. The authors conducted a meta-analysis of case-control studies comprising 11,042 schizophrenia suffers and 14,557 control subjects. The researchers combined the risk estimate for the association between the SNP and SCZ with the estimate from a meta-analysis of a genome-wide association studies. The results included a significant effect of the SNP on SCZ risk. The authors concluded that the results offer greater insight regarding the pathology and treatment of SCZ.

Patel, K. R., Cherian, J., Gohil, K, & Atkinson, D. (2014).

Schizophrenia: Overview and treatment options. P&T: A Peer-Reviewed Journal for Managed Care & Formulary Management, 39(9), 638–645.

Although it does not describe a study, this article is one of the most informative of all the sources used. The authors provide a succinct but thorough overview of SCZ that goes beyond just the treatment options that are currently in use. Rather, the article addresses key information like the pathophysiology, etiology, epidemiology and clinical presentation of SCZ. More than half of the article however is devoted to treatment options as well to the adverse effects of treatment medications on the endocrine, cardiovascular and central nervous systems. The authors offer a brief assessment of progress in the development of treatment protocols. Most disconcerting, however, is the fact that the life expectancy of SCZ patients remains as much as 10-25 years less than the average healthy individual.

Picchioni, M. M., Rijsdijk, F., Toulopoulou, T., Chaddock, C.,

Cole, J. H., Ettinger, U., … McGuire, P. (2017). Familial and environmental influences on brain volumes in twins with schizophrenia. Journal of Psychiatry & Neuroscience: JPN, 42(2), 122–130.

This article describes a study designed to identify the familial and environmental influences on brain volumes in twins with SCZ. The study involved the clinical assessment of and administration of an MRI to 168 twins making up a healthy control group and a patient or SCZ-affected group. The data from the assessment and MRIs were analyzed on between-group measures and genetic trait variance. The results showed that the SCZ patient twins had greater deficits in whole brain grey and white matter volume as well as in hippocampal volume. The authors’ conclusion presented major implications for future research investigation the as to the specific etiological imprinting of neurophysiologic structures in patients with SCZ .

Sheng-An, L., & Kuo-Chuan, H. (2016). Epigenetic profiling of

human brain differential DNA methylation networks in schizophrenia. BMC Medical Genomics, 9, 217–228.

This article described a study that investigated the role of DNA methylation in the causation of SCZ. The researchers capitalized on the increasing availability of post-mortem brain samples for research on SCZ-associated single nucleotide polymorphisms (SNPs) by analyzing the DNA methylation profiles of prefrontal cortex from healthy controls and schizophrenic patients. Their study involved the construction of a protein-protein interaction (PPI) network using genetic variants to examine the controlling interactions and possible pathways of genes. The results of the study indicated that SDMGs and SCZCGs may influence levels of gene expression potentiating symptomatic development of SCZ. The authors suggest that the typical hypomethylation of SDMG promoters presents important implications for therapeutic options that work to increase methylation of these and other weakly methylated promoters.

Shorter, K. R., & Miller, B. H. (2015). Epigenetic mechanisms in

schizophrenia. Progress in Biophysics & Molecular Biology, 118(1/2), 1–7.

This article is an informative source rather than a study and addresses covers various aspects of the epigenetics of SCZ. The article introduces the subject with a brief but important review of the literature on SCZ including its symptoms and the impact that they have on cognitive functioning and memory. The authors place special focus on the role of dopamine (DA) in SCZ, especially in the hyperactivity of the DA signaling system that promotes delusions and hallucinations. The discussions on DNA methylation in particular supports a much better understanding of how the epigenetic factors that impact single genes as well as gene networks. This is especially true of SCZ-risk genes, which in turn can contribute to the development of the disorder.

Schultze-Lutter, F. (2009). Subjective symptoms of schizophrenia

in research the clinic: The basic symptom concept. Schizophrenia Bulletin, 35(1), 5-8.

This was an informative article that provided information of the symptoms of schizophrenia. The author predicates the article on the increased interest in the subtle psychopathology that seemingly exceeds the larger and more overt positive and negative symptoms of SCZ. The author offers a systematic examination of the basic symptoms of schizophrenia that are defined as a subjective subclinical disturbance in such things as motivation, motor action, thinking and speech. These symptoms are diverse from the positive and negative symptoms of delusion and hallucinations and lack of motivation, desire or interest beautiful that are not easily observed by others. The author offers a list of these interesting introverted or introspective symptoms.

Suris, A., Holliday, R., & North, C. S. (2016). The evolution of

the classification of psychiatric disorders. Behavioral Sciences, 6(5), 1-10.

In this article, which is not an experimental study but rather an informative article, the authors describe their tracing of the history of classification and diagnostic systems for mental disorders. The description includes a brief discussion of the early history of classification systems and a more comprehensive investigation of the American System of Diagnostic Criteria. The authors do not provide a results or summary of their findings however their brief conclusions include the argument that the the validity of diagnostic criteria has been challenged insufficient differentiation between disorders. This contention presents serious implications for improved differentiation necessary to mitigate high rates of diagnostic comorbidity, non-specific treatment selection and failure to distinguish psychiatric disorders.

Taipale, H., Mittendorfer-Rutz, E., Alexanderson, K., Majak, M.,

Mehtälä, J., Hoti, F., Jedenius, E., Enkusson, D., Level, A., Sermon, J., Tanskanen, A., & Tiihonen, J. (2018). Antipsychotics and mortality in a nationwide cohort of 29,823 patients with schizophrenia. Schizophrenia Research, 197, 274–280.

This article describes a study designed to determine if antipsychotic treatment protocols are associated with increased or decreased mortality. This was accomplished through the analysis of patient data for all-cause mortality rates drawn from a nationwide registry. The researchers found that the use of oral medication was associated with a higher rate of mortality than injectable medication. It also identified second generation long-acting injectables as associated with the lowest mortality rates.

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