International Journal of Mental Health & PsychiatryISSN: 2471-4372

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Review Article, Int J Ment Health Psychiatry Vol: 1 Issue: 2

Schizophrenia Research in Saudi Arabia: Appraisal and Perspectives

Mohammed Rizwan1*, Rashad Al Sunosy2 and Ayesha Alvi3
1Department of Biochemistry, Faculty, Jazan University, Jazan, Kingdom of Saudi Arabia
2Department of Genetics and Molecular Biology, Faculty of Applied Medical Sciences, Jazan University, Jazan, Kingdom of Saudi Arabia
3Substance Abuse Research Centre, Jazan University, Jazan, Kingdom of Saudi Arabia
Corresponding author : Dr. Mohammed Rizwan
Assistant professor, Department of Biochemistry, Faculty of Nursing PO Box-2914, Jazan University, Jazan, Kingdom of Saudi Arabia
Tel: 00966-73174383
E-mail: [email protected]
Received: August 24, 2015 Accepted: September 29, 2015 Published: October 03, 2015
Citation: Rizwan M, Al Sunosy R, Alvi A (2015) Schizophrenia Research in Saudi Arabia: Appraisal and Perspectives. Int J Ment Health Psychiatry 1:2. doi:10.4172/2471-4372.1000107

Abstract

Kingdom of Saudi Arabia (KSA) is the largest Arab state lying in west Asia. It has an organized health care system with a wide network of health clinics, with special hospitals to cater mental disorders including schizophrenia. Research on schizophrenia in KSA is scanty and covers limited aspects of the disease there is no known epidemiological data on the prevalence of schizophrenia in the kingdom.

This concept review summarizes the research studies carried out in Saudi Arabia retrieved from Pub Med and some local journals on schizophrenia. It also suggest the priority areas in schizophrenia research with special reference to Saudi population in domain such as molecular and genetic aspects, consanguinity and its impact on transmission dynamics of schizophrenia, Genome Wide Association Studies (GWAS), quality of life in schizophrenia, role of religion effecting the quality of life of schizophrenia patients and their relatives.

Keywords: Schizophrenia research; Saudi Arabia; Molecular and genetic aspects; Consanguinity; Quality of life in schizophrenia patients

Keywords
Schizophrenia research; Saudi Arabia; Molecular and genetic aspects; Consanguinity; Quality of life in schizophrenia patients
Introduction
Schizophrenia is a brain disabling disorder of severe nature which usually starts in early adult life and often follows a chronic disabling course. It is characterized by distortions in the form and content of thinking and perception which manifest itself through delusions, hallucinations and loosening of associations, and variation in mood. The signs and symptoms are diverse, depending on various factors, and they usually encompass almost every aspect of cognition and behavior. These symptoms are classified as positive or negative symptoms which are associated with disorder such as hallucination and delusion are generally called as positive, whereas qualities such as motivation, drive which are taken away by the disease falls in the category of negative symptoms. Schizophrenia was estimated to be the 10th leading cause of non-fatal burden in the world in 1990, accounting for 2.6% of total YLD, around the same percentage as congenital malformations [1]. In the Version 1 estimates for the Global Burden of Disease 2000 study, published in the World Health Report 2001 [2].
Kingdom of Saudi Arabia (KSA) is the largest (in terms of area) Arab state of western Asia with population of a nearly 20 million. Health care system in KSA is organized and controlled by government with a network of 2037 health center spread across the country [3]. With specialized center for mental related disorders known as Al-Amal hospitals. Mental care hospitals are located in different region and cater the needs of the patients.
Prevalence of Schizophrenia in KSA
Interestingly no epidemiological data is available for the prevalence of schizophrenia in Saudi Arabia the Saudi ministry of health reported that 22.4% patients reporting to outpatient services for mental disorders are suffering from schizophrenia related disorders (it does not specify schizophrenia) ministry of health 2008 [4]. However WHO in 2004 has estimates of Disability-adjusted life year DALY rate, due to schizophrenia, in KSA is 270 which are quit high [5].
Research Scenario in KSA
Research on schizophrenia in Saudi Arabia is scanty, and has been mostly focused on either the role of consanguinity [6] with limited number of samples, or with the disease manifestations such as auditory hallucination [7] or in the areas of quality of life and related aspects. Although there exist the single study about the HLA-DRB1 association with schizophrenia in Saudi Arabian patients, carried out by Kadasah et al 2011 the study examined ,the association between HLA-DRB1 alleles frequency and schizophrenia in Saudi population by screening the DRB1 region of histocompatibility complex, by Sequence specific primers (PCR/SSP) in 180 schizophrenia patients and 200 matched controls, it revealed that the frequency of DRB1*03 allele was significantly higher in schizophrenia patients as compared to controls, whereas a significantly lower frequency of DRB1*06 was observed in schizophrenia patients as compared to controls. The study further explore molecular sub-typing of the most prevalent allele DRB1*03 (30.56%) which revealed the presence of DRB1*030101, *030102 alleles showing the positive association between DRB1*03 (DRB1*030101, DRB1*030102) with schizophrenia and a negative association of DRB1*06 [8]. However the study was inconclusive in the fact that whether the DRB1*03 alleles have a direct causal role in the etiology of schizophrenia or they are in direct linkage disequilibrium with another true susceptibility locus. A larger cohort study would have given a more clear picture as schizophrenia is a complex disorder, and it is evident from other studies that many factors might act together to produce the final outcome.
Barring this lone study on genetic aspect of schizophrenia in Saudi population the pub med in depth search didn’t yield any results.
However population specific study of Human leukocyte antigen (HLA) DRB1 alleles in Kuwaiti Arabs with schizophrenia was carried by Haider MZ, et al 2000 determining the frequency of human leukocyte antigen DRB1 alleles in a cohort of 194 Kuwaiti Arabs consisting of 80 schizophrenia patients and 114 ethnically matched healthy controls. 12 DRB1 alleles with a statistically significant difference in the frequency of alleles DRB1(*)04 and DRB1(*)13 between the schizophrenia patients and controls were revealed . Allele frequency of DRB1(*)04 in schizophrenia patients was 14% compared with nearly 7% in controls .For DRB1(*)13, the allele frequency was found to be 18% in schizophrenia patients compared with 9% in the controls. For alleles, DRB1(*)03, DRB1(*)07, and DRB1(*)16 the frequency was higher in controls compared with schizophrenia patients. The frequency of DRB1(*)01, DRB1(*)08, DRB1(*)10, DRB1(*)11, and DRB1(*)15 alleles was almost identical in schizophrenia patients and controls [9].
Another study pertaining to the role of inflammation in schizophrenia among Arab population was recently carried out by Al- Asmari A et al. they search for alterations in cytokine levels and perturbation in antioxidative defense systems in Arab schizophrenic patients they argued that theories have been proposed including developmental/neurodegenerative processes, neurotransmitter abnormalities, viral infection, and immune dysfunction, as causative factor of schizophrenia. However the exact cause is still is unclear. A relationship between inflammation and schizophrenia has been supported by abnormal cytokine production and altered antioxidant status. Hence the study was aimed to examine the alterations in serum oxidative-antioxidative status and cytokine levels of schizophrenic patients. A total of 91 schizophrenic patients from Saudi Arabia and 50 age- and sex-matched healthy controls participated in the study it was observed that there was a significant increase in the levels of tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 and a decrease in the levels of interferon-γ in schizophrenic patients as compared to control subjects. Similarly lipid peroxides were elevated in serum, while totalsulfhydryl levels were decreased. Also, the activities of superoxide dismutase and glutathione peroxidase were decreased, while the activities of catalase, glutathione reductase, and myeloperoxidase were found to be elevated in serum among schizophrenic and nonschizophrenic patients respectively [10]. The study concluded that inflammation resulting from dysregulation of cytokines and altered antioxidant systems may play a critical role in the etiology of schizophrenia.
Investigation on other aspect of schizophrenia are rare however present in the literature such as role of consanguinity or cousin marriages was investigated by Chaleby. They studied the rate and degree of consanguinity in the parents of 143 schizophrenics who satisfied the DSM-III diagnostic criteria, and compared it with the same number of controls matched for age, sex and socioeconomic class. A family history of disorders suggestive of schizophrenia in the offspring of consanguineous parents, who were schizophrenic, was compared with the incidence of a similar history in the schizophrenic offspring of non-consanguineous parents. There was no statistically significant difference in the former, but there was in the latter. Their finding supports the observations of other researchers that a familial tendency towards schizophrenia and the possibility of recessive or a multigene pattern of inheritance does exist.
Similarly a comparative study on the aspect of auditory hallucination and its coping was carried out by Wahass S the authors compare the coping of auditory hallucinations between western (British) and non-western (Saudi Arabian) patients [7]. The rationale was that the majority of schizophrenic patients from western backgrounds develop strategies to cope with the positive symptoms of their condition. However, there is little evidence to indicate how these coping mechanisms are affected by cultural background. Hence they interviewed seventy schizophrenic patients from Saudi Arabia (SA) and the United Kingdom (UK) who reported auditory hallucinations to explore the ways in which they coped with their voices and sounds. Patients from both cultures had several coping mechanisms, but these varied between cultures. The majority of SA patients used strategies associated with their religion whereas UK patients were more likely to use distraction or physiologically based approaches. The majority of patients were slightly or not at all confident about the effectiveness of their coping strategies.
Other than these there are two studies on quality of life of patients with schizophrenia 2 [11] and life events and schizophrenia [12] can be found in the literature.
However the above review of literature suggests that schizophrenia research requires more focused and comprehensive efforts in general and with special reference to Saudi population, in particular. Following are the broad areas which can be explored.
Demographical Survey
Almost all countries have inventory for the affected population. The published literature survey is suggestive of an urgent demographical analysis and epidemiological survey to ascertain number of individual affected with schizophrenia this will paw the ways to formulate strategy to address various issues pertaining to structural adjustments in health care services provided to the mentally ill patients in KSA.
Genetics and Molecular Aspects of Schizophrenia
The GWAS era has opened the windows of myriad yet important markers for complex genetic disorders where in markers can be tested for their robust co relations with the clinical outcomes. Similarly GWAS also suggest the strong role of population specificities in genotype phenotype relation, as aforementioned schizophrenia is a complex pathology which arises due to complex heritable trait and environmental factors, these traits may be common among populations and may be different as well i.e. traits which contributes significantly to the development of pathology in one population may not confer the same level of severity as causal stimuli in the other population may be absent or may not confer the pathology in other population . Recent technical achievements in whole genome-wide association studies call for in depth population specific studies to dissect the underlying genetic factors. As it’s well-known, now that schizophrenia is essentially a polygenic and complex disorder. Most likely there may be more than 100 genes, contributing to the disease risk. A recent multi-stage genome-wide association study [13] identified 22 risk loci and points towards 8,300 independent singlenucleotide polymorphisms which may contribute to the risk accounting collectively for 32 % in liability. There also exists a strong indication that in some patients, in some populations, a deletion or insertion of a larger chromosomal region [so-called copy number variation (CNV)] might play a crucial role in early onset or progression of schizophrenia pathogenesis. CNV could be important, particularly in sporadic cases with schizophrenia, because the frequency of de novo mutations is higher with these CNVs. Further studies, with specific populations and combining much larger sample sizes using newer technology, such as deep sequencing, will be essential in order to obtain a more comprehensive understanding of the genetic foundations of schizophrenia in Saudi population.
Population Specific Linkage Analysis and Marker Validations
Chromosome 6, has long been implicated in pathology of schizophrenia because the 6p22–p24 locus has been shown to have strongest associations in 265 Irish families. But later on this association was found to be not convincing when a narrow or abroad disease definition was used [14]. However other studies showed this association with certain regions of chromosome 6 [15-18]. Another study involving 10 Canadian families, evaluated 28 genetic markers using ASP analysis and is found no evidence for linkage, however it has been noted that D6 S 1960 marker was associated with the positive symptom scale scores (on the positive and negative Symptoms Scale for schizophrenia (PANSS) suggesting that this locus might be related to the severity of psychotic symptoms [19]. In another study using linkage disequilibrium analysis a susceptible locus at D6S1960 on 6p was found when 115 ASPs with microsatellite markers were assessed [20]. Considering locus heterogeneity and moderately broad disease definition 186 multiplex families were analyzed, using linkage analysis, it revealed a significant LOD score and genome-wide significance of 5%–8%, which supports the notion that a susceptibility locus on chromosome 6 may play more substantial role in schizophrenia [21]. However involvement of susceptibility loci of chromosome 6 has contrasting reports .This contrast becomes more evident when 22 extended Canadian families, with high frequencies of schizophrenia were subjected to a genome-wide scan, a highly significant evidence of linkage to chromosome 1(and not on chromosome 6,) in the region 1q21–q22, between the markers D1S1653 and D1S1679 was observed and this evidence in agreement with the recessive model of inheritance with parametric analysis, using narrow disease definition. [22]
A part from above mentioned region several other studies of genome wide scan showed regions on chromosome arm 1q with specifically involving the DISC1 gene which plays more crucial role in the development of schizophrenia [23,24]. Ironically, a recent study which involved a large sample size and was multicentric found no linkage at this locus [25].
Arinami et al. studies the Japanese patients with schizophrenia and found that D2 receptor bear a substitution from serine to cysteine at position 311 and reported an increased frequency of the Cys 311 variant [26,27]. However this study was not able to withstand the replicative trial by other groups and it was noticed that the substitution is associated to a greater degree with certain clinical subtypes (disorganized schizophrenia) rather than schizophrenia [28-30].
The above review of literature is strongly suggestive of the heterogeneous nature of genetic elements which confers the susceptibility to schizophrenia calling for the population specific understanding of the genetic markers involved in schizophrenia.
Quality of Life (QoL) Analysis
QoL analysis of patient with schizophrenia is an emergent need. Currently there exist two studies with regards to QoL in schizophrenia [9,31]. These studies have smaller sample size and considered only sociodemographical angle. There must be a larger cohort study. With both qualitative and quantitative aspects included. Studies addressing quality of life analysis using both qualitative and quantitative data will be important in addressing several issues of how Schizophrenia is handled in KSA both at clinical and social level.
There can be a specific angle of religion and its impact on quality of life of the people and their families with schizophrenia, as KSA observes deep religious practices in all domain of its social life.
Consanguinity in KSA and Schizophrenia
The overall rate of consanguinity in KSA ranged from 52.1% to 67.7%. The most frequent are first cousin marriages (28.4%) followed by distant relative marriages (15.2%) and second cousin marriages (14.6%). There are slight differences in the consanguinity rates in different provinces of the kingdom but they are highest in gulf region any way. Given to the fact that schizophrenia is polygenic disorder it would be more than interesting to investigate what transmissions dynamics is followed with such a deep consanguinity, considering consanguinity alone. This will also help policy makers and campaigners against consanguinity to be used as a toll for mass awareness.
Family Twin and Adoption Studies
It has been convincingly demonstrated that influence of genetic factors in the development of schizophrenia is more than what previously were thought. Hence family, twin, and adoption studies are integral part to know whether schizophrenia in Saudi population fall in line with other reports. This has got rationale in the fact that the consanguinity ratio in KSA is one of the highest in the world. Considering factors such as twin status, family history of high consanguinity among Saudi population may yield useful insights.
Conclusions
• There are very few studies related to schizophrenia with specific reference to Saudi population
• GWAS studies are increasingly suggestive of population specific variants of genes which contribute to the development of complex inherited disorders such as schizophrenia
• There is only one study with regards to genetic aspects of schizophrenia focusing only on DRB1 locus
• Recent genetic markers conferring susceptibility or severity or early onset of schizophrenia awaits validation in Saudi population
• Collection of sufficiently large samples and better methods of pedigree ascertainment is required to get meaningful insights into transmission dynamics of susceptibility conferring genetic elements .
• Application of large-scale family-based association tests across the whole genome would yield reliable data.
• To detect the small gene effects particularly with reference to Saudi population a combination of path, segregation and linkage analysis is necessary and would may yield concrete conclusions.
• Being heterogeneous in nature resolution of genetic heterogeneity requires further work on phenotypic classification for schizophrenia, to identify clinical features/characteristics which are important to delineate genetically distinct groups.

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