Schizophrenia – a Genetic and Environmental Review

Introduction

Schizophrenia is defined as a severe brain disorder characterized by disturbances of thoughts, perceptions, volition, and cognition, which affects about 1% of the world population today (Ozawa et al., 2006, p. 546). The disorder can be incapacitating to those who live with it and prevent normal societal function. Despite its frequency in the population, scientists and medical professionals still struggle to find a conclusive explanation for why some develop schizophrenia. This may be in part due to its ties to both environmental and genetic factors. Throughout the literature there are extensive hypotheses on what the contributing factors to development of the disorder are, but a consensus remains that no one factor defines susceptibility. Environmentally, Adult onset of schizophrenia seems to be linked to neonatal care. Maternal viral infection (Ozawa et al., 2006) as well as maternal vitamin D deficiency from improper diet and sunlight intake (Pluta, 2010) leads to small but significant increases in offspring disorder development. Genetic pre-disposition is also a well-known factor to be considered. Currently well researched, disruption of dopaminergic pathways in schizophrenic patients are becoming more prevalent as it seems to play a crucial role in symptomology of the disorder. More specifically, abnormal dopamine function appears to give rise to much of the positive symptoms (psychosis) (Abi-Dargham et al., 2000).

In addition to the factors that increase likelihood of development, treatment is heavily discussed in the literature. Medication is a crucial baseline component to treatment as it can keep patients functional, so that other psychosocial therapies can occur. Unfortunately, the symptomology that demands medication also prevents approximately 50% of patients from maintaining a regimen. Increased numbers of environmental treatments are being researched to rectify this (Velligan et al., 2008). Schizophrenia is generally a hard disease to measure because its symptoms vary widely across the population. The 2 domains that most of the symptoms fit within are positive are negative. Positive symptoms are analyzed using the Brief Psychiatric Rating Scale. This scale accurately places how severe a patient's symptoms (psychosis, delusions, etc.) are and detects changes over time. The Scale for the Assessment of Negative Symptoms (SANS) rates how severely a patient presents in the 5 categories on the scale. (Lindenmayer, Harvey, Khan, & Kirkpatrick, (2007). Unfortunate limitations to these measurement scales are that patients frequently go on and off medications making it hard to monitor improvement in symptoms over time. Also, patients can cross lines from one subtype to another as well as more minor subtypes, making categorization difficult. Genetic Studies The effect of dopamine on Schizophrenia has recently begun to be heavily investigated in the scientific community.

Dopamine receptors, specifically D2 appear to be a probable contributing factor to the classic symptoms of Schizophrenia. The receptor availability of dopamine was measured in patients at the standard level as well as after drug administration to reduce available dopamine in 36 subjects. 18 of these subjects were Schizophrenic patients and the other 18 were matched controls. The dopamine receptor availability in each subject was measured with single-photon computerized emission tomography (SPECT) and the drug administered to reduce dopamine concentration was ?±-methyl-para-tyrosine (?±-MPT). Upon the first initial analysis, no significant difference in standard dopamine receptor availability was noted between the Schizophrenic and control subjects. However, after a decrease in available dopamine, significant results arose (Abi-Dargham et al., 2000). Upon depletion of dopamine with ?±-MPT, there was a significant increase in receptor availability in both Schizophrenic patients and control subjects. This is an intuitive explanation as a decrease in dopamine would trick the brain into believing it needs more receptors to reach it's normal level of dopamine binding. However, the increase in dopamine receptor availability was significantly higher in patients with Schizophrenia (19% ?± 11%) compared to the control subjects (9% ?± 7%) after the drug treatment. This data is illustrated below (Figure 1). Through this data it can be deduced that if much of the dopamine was reduced by ?±-MPT, then there would be a difference of 8% ?± 6%, compared to 15% ?± 7% of D2 receptors filled in the control vs. Schizophrenic patients, respectively. This data provides significant evidence that contributes to the literature on dopamine involvement with Schizophrenic symptomology. Dopamine appears to be highly involved with the D2 receptor in patients with Schizophrenia, but not as much in the normal population (Abi-Dargham et al., 2000).

In addition to dopaminergic activity, other underlying molecular mechanisms may also play a role in schizophrenia development. Microarray technology was utilized to examine gene expression patterns in 24 schizophrenic or control patients. This technology can pinpoint differential gene expression patterns, and the underlying molecular mechanisms can then be examined. Experimental analysis was conducted on subjects diagnosed with chronic schizophrenia and controls, all of whom died from natural causes. After death the dorsolateral prefrontal cortex of the subjects was dissected into ~0.5cm tissue cubes. In the 89 genes that showed differential expression patterns in schizophrenic vs. control subjects, a categorical pattern emerged. The majority of these genes were involved in mechanism of signal transduction, neurotransmission, neuronal development, synaptic plasticity, and most prominently myelination (Hakak et al., 2001). Of these 5 categories, all but myelination appear to have an increase in gene expression compared to the control. Although not conclusively followed up with, this data indicates that multiple, if not all these genes may play a role in the symptomology of schizophrenia. The downregulation of the myelination genes plays a role in this theory, as the 5 genes in this category all aid in formation of oligodendrocytes. Commonly known, oligodendrocytes produce myelin in the central nervous system. The primary function of myelin is to aid in cell signaling and protect neurons. With deficient production, this can cause significant changes in brain circuitry. In addition, the authors noted that in humans, myelin production by oligodendrocytes within the region examined (prefrontal cortex) begins to occur from late adolescence to early adulthood. This coincides with the period that both men and women begin to report symptoms of schizophrenia development. The conclusion can be drawn that this deficiency may go unnoticed for much of the early stages of life, but as myelin production begins this could be a tipping point for disease onset (Hakak et al., 2001).

In addition to disruptions in neurological pathways, specific gene loci have begun to be implicated in risk for schizophrenia development. Over 100 of these loci have now been located, however this research remains generally fragmented (Harrison, 2015). This has remained the case because no one aberrant gene can be directly correlated to schizophrenia development. It has been maintained in the literature that multiple aspects of genetic predisposition linked to specific environmental triggers must be connected to lead to a schizophrenia diagnosis. Previous human and animal studies have linked the DISC1 gene to mental illness and schizophrenic phenotype. This gene is involved in numerous activities, making it hard to decipher which aspect of its disfunction may lead to this symptomology. A shortened DISC1 transgene from a human source was inserted under the ?±CaMKII promoter in C57BL/6 mice. Expression of this gene leads to dominant negative phenotype. Two lines of transgene mice were created and compared to one wildtype line. The ?±CaMKII promoter was chosen specifically because of its role in gene expression in the prefrontal cortex and hippocampus. From 3-8 months of age several behavioral analyses exams and in vivo MRI scans were conducted to survey a wide variety of characteristics in the tg C57BL/6 mice (Hikida et al., 2007). A staple phenotype in a large percentage of schizophrenic patients is abnormal sizing of the lateral ventricles. In vivo MRI scanning of tg line 10 at 6 weeks and 3 months showed significantly larger left lateral ventricles compared to wildtype. In the same line, the ratio between left and right ventricles as well as lateral ventricles to whole brain volume was shown to be larger in tg compared to wildtype, however, this only became significant at 3 months of age. (Figure 2).

Behavioral analyses also showed that tg mice had lower pre-pulse inhibition (a measure of cerebral cortex sensorimotor gating) and increased hyperactivity compared to wildtype. These are common characteristics in schizophrenic patients, however other common characteristics such as anxiety, impaired motor coordination, and working memory were not affected (Hikida et al., 2007). Inserting a shortened DISC1 transgene into C57BL/6 mice resulted in tg mice lines that demonstrated significant pathogenic and behavioral traits seen in patients of schizophrenia. This does well to contribute to the present literature that the DISC1 is implicated in some aspects of schizophrenic symptomology and development. Because this transgene came from a human source this gives a strong external validity for generalization to the human population, but as always there may be limitations such as the way this pathology and behavior may shift after years of medical treatment or psychological therapy (Hikida et al., 2007). Environmental Studies Schizophrenia is strongly theorized to be linked to both genetic and environmental causes. A well-known environmental factor that could lead to fetal development of schizophrenia is maternal contraction of viral infection. Evidence from previous studies provided evidence to suggest that maternal viral infection during developmental stages in pregnancy lead to higher rates of fetal schizophrenic development. This viral infection appears to be non-specific as research has been done on influenza, polio, rubella, and measles may all have the same effect.

This information led researchers to believe that maternal immune response, particularly inflammatory cytokines, may affecting fetal neurological development rather than the viral infection itself. To simulate this environmental factor in schizophrenic development, double-stranded RNA polyriboinosinic-polyribocytidilic acid (poly I:C) was utilized. This method was used to replicate a viral infection because it causes a non-disease specific immune reaction. BALB/c mice were bred in the lab and from 2-weeks to 3-weeks post copulation pregnant females were injected with the RNA daily (Ozawa et al., 2006). To measure if the offspring of the poly I:C injected mothers demonstrated characteristics comparable to Schizophrenia, 3 criteria were measured. These were maturational delay, damage to dopaminergic systems, and cognitive impairment. Along with cognitive impairment, the effects of two common anti-psychotic drugs on this were measured. These drugs were clozapine and haloperidol. After injection the pregnant mothers were observed to gain less weight than expected as well as produce a lower number of pups. The offspring of these mice were measured to have significantly damaged dopaminergic systems as well as cognitive impairment only after maturing into adults. Clozapine and haloperidol also helped to curb the symptoms of the cognitive impairment (Ozawa et al., 2006).

This is a very useful animal model for understanding the association between gestational viral infection and offspring schizophrenia risk, however limitations apply to a comparison to a human model. The most significant limitation being that it is still not conclusively known at what stages of pregnancy an infection has the most risk on the fetus. This may skew data that could be obtained in a human study because women may be less inclined to report or remember a viral infection in early stages of pregnancy as they may not realize the effect it has on a fetus that is not showing yet. Interestingly, while the immune system is more susceptible to contracting viruses in colder months like winter and spring, this is also the time of year that vitamin D deficiencies are also most common. This time of year, also coincides with significantly more babies born that will develop Schizophrenia in adulthood. The most direct way to gain vitamin D is through the skin being exposed to sunlight. This obviously becomes less feasible in the winter. Through the processing of vitamin D in the human body, 25-hydroxyvitamin D3 (25[OH]D3) is produced. Infant blood samples from the Newborn Screening Biobank were analyzed for concentrations of (25[OH]D3). 424 Danish, schizophrenic and control matched pairs were used (Pluta, 2010). The data indicated a significant variation in the amount of 25[OH]D3 present in newborn blood throughout different months of the year. There was also a significant association between developing Schizophrenia in adulthood and the amount of 25[OH]D3 present in the blood at time of birth. In comparison to the fourth quintile of infants, infants with the highest 20% (first quintile) of 25[OH]D3 at time of birth had a 1.71% relative risk of developing schizophrenia in adulthood, while those in the lowest 20% (fifth quintile) of 25[OH]D3 at time of birth had a relative risk of 2.1% in comparison to the fourth quintile.

The relative risks of the development of schizophrenia in controls is shown below (Figure 3). The most interesting component of the research is that while prenatal vitamin D plays a significant role in the future development of schizophrenia, the trend is not linear. Compared to the fourth quintile both the first and fifth quintiles had a higher risk of disease development. It did appear, however, that vitamin D deficiency plays a more prominent role (Pluta, 2010). Through literature analysis it becomes apparent that both genetic and environmental factors play a significant role in the development of schizophrenia. In the realm of treatment for this disease, a multitude of drug treatments are available, some of which are argued to treat better than others (Leucht, 2009). It is also important to consider the effect of environment on drug treatment and patient care for schizophrenia in general. While schizophrenia is a disease that somewhat demands drug treatment to keep patients normally functional, the adherence to medication is a significant problem in the population. The symptomology that demands drug adherence also promotes patient disassociation from treatment. Three different environmental treatment approaches were taken on subjects with diagnosed schizophrenics. These treatments were full-CAT treatment, Pharm-CAT, and TAU (treatment as usual). Cognitive adaptation training (CAT) is a personalized treatment designed to promote patients maintaining a medication schedule through a specific environmental setup and organization in the home.

Pharm-CAT is essentially the same, however the organization only pertains to specifically medication-related lifestyle components (Velligan et al., 2008). The initial regimens lasted for a period of 9 months and medication adherence was measured through counting of untaken pills during periodic home visits. After this time-period the CAT environments were not removed, but home visits were for another 6 months. Adherence to medication treatments was shown to be significantly higher in both Full-CAT and Pharm-CAT patients compared to usual treatment patients during all stages of the experiment. However, in the area of functional outcomes, Full-CAT patients only performed better than Pharm-CAT in the initial 9 months of the study, and only Full-CAT patients outperformed traditional patients once home-visits were removed (Velligan et al., 2008). This study provides significant data to support how helpful individualized environments can be to medication adherence and normal functioning in patients with Schizophrenia. In all cases patients with any form of CAT treatment outperformed those undergoing their usual treatment. However, this treatment did get less effective when visitors stopped checking in on the patients. This is an important distinction, as a limitation to this treatment is that it does not appear to significantly effective in promoting self-sufficiency in schizophrenic patients (Velligan et al., 2008).

References

Abi-Dargham, A., Rodenhiser, J., Printz, D., Zea-Ponce, Y., Gil, R., Kegeles, L., . . . Laruelle, M. (2000). Increased Baseline Occupancy of D2 Receptors by Dopamine in Schizophrenia. Proceedings of the National Academy of Sciences of the United States of America, 97(14), 8104-8109. Hakak, Y., Walker, J., Li, C., Wong, W., Davis, K., Buxbaum, J., . . . Fienberg, A. (2001).

Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia. Proceedings of the National Academy of Sciences of the United States of America., 98(8), 4746-4751. Harrison, P. (2015). Recent genetic findings in schizophrenia and their therapeutic relevance. Journal Of Psychopharmacology, 29(2), 85-96. Hikida, T., Jaaro-Peled, H., Seshadri, S., Oishi, K., Hookway, C., Kong, D., . . . Sawa. (2007). Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans. Proceedings of the National Academy of Sciences of the United States of America., 104(36), 14501-14506. Leucht, S., Komossa, K., Rummel-Kluge, C., Corves, C., Hunger, H., Schmid, F., . . . Davis, J. (2009).

A Meta-Analysis of Head-to-Head Comparisons of Second-Generation Antipsychotics in the Treatment of Schizophrenia. The American Journal of Psychiatry., 166(2), 152-163. Lindenmayer, Harvey, Khan, & Kirkpatrick. (2007). Schizophrenia: Measurements of Psychopathology. Psychiatric Clinics of North America,30(3), 339-363. Ozawa, Hashimoto, Kishimoto, Shimizu, Ishikura, & Iyo. (2006). Immune Activation During Pregnancy in Mice Leads to Dopaminergic Hyperfunction and Cognitive Impairment in the Offspring: A Neurodevelopmental Animal Model of Schizophrenia. Biological Psychiatry, 59(6), 546-554. Pluta, R. (2010).

Neonatal Vitamin D Status and Risk of Schizophrenia: A Population-Based Case-Control Study. JAMA, 304(18), 1996. Tseng, K., Lewis, B., Lipska, B., & O'Donnell, P. (2007). Post-Pubertal Disruption of Medial Prefrontal Cortical Dopamine“Glutamate Interactions in a Developmental Animal Model of Schizophrenia. Biological Psychiatry.,62(7), 730-738. Velligan, D., Diamond, P., Mintz, J., Maples, N., Li, X., Zeber, J., . . . Miller, A. (2008). The Use of Individually Tailored Environmental Supports to Improve Medication Adherence and Outcomes in Schizophrenia. Schizophrenia Bulletin, 34(3), 483-493.

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