Evaluation of Trace Elements and Heavy Metals in Schizophrenic Patients in Iraq

 

Falah S. Al-Fartusie¹*, Saja N. Mohssan¹, Farhan A. Risan², Ahmed H. Yousif³

¹Department of Chemistry, College of Science, Mustansiriyah University, Baghdad, Iraq.

²College of Health and Medical Technology, Foundation of Technical Education, Baghdad, Iraq.

³Kimadia Company, Ministry of Health, Baghdad, Iraq.

 

ABSTRACT:

Schizophrenia is a mental disorder with abnormality in social behaviour and failure to understand what is real. It has been found that approximately 1% of the population worldwide is affected with schizophrenia. Although several studies have been conducted to assess and try to early detection of schizophrenia, however most of these studies still deficient. Therefore, this study was design to investigate and evaluate the expected association between the levels of trace elements (Se, Cu, Zn, Ni, Cr, Mn, Mg, Pb, Co, Fe and Al) and the risk of schizophrenia. Levels of these elements were determined in sera of 60 patients with schizophrenia using atomic absorption spectrophotometry technique and the alterations of these critical variables were analyzed in comparison with 60 healthy controls to try prediction of the occurrence and progression of disease. The results obtained showed a significant increase in the levels of Se, Cu, Ni, Cr and Mn, in contrast to significant decrease in the levels of Zn, Mg, Pb, Co and Al in schizophrenic patients compared to the healthy control group. The data analysis revealed the presence of valuable correlations between most of elements in schizophrenic patients. According to the finding of the present work, it can be suggested that these elements may have a vital role and prognostic significance in complex disorders leading to schizophrenia. The real mechanism responsible for the alterations in elements levels in patients with schizophrenia is unclear and requires additional evaluation. Therefore, further universal studies are wanted in order to advance understanding of the relationship between trace elements and their role in schizophrenia.

 

 

 

INTRODUCTION:

Schizophrenia is define as a chronic and severe mental disorderliness that effectson the thinking, feeling and behaviour of individual. It has been discovered that this disease may lead to an unusual person, with the mysterious hallucination of the mind, who becomes socially isolated in his own world [1,2]. In Latin, the word schizophrenia means of two minds.

 

 

 

 

 

 

It does not causes multiple personalities where schizophrenia and disorder of schizophrenic identity is considered to be no different.In fact, schizophrenic patients may look like those who have lost their contact with reality. It has been indicated that approximately 24 million people worldwide are infected with this disease. In fact, the disease affects both genders (males and females) in the same proportions [1].

 

The symptoms of schizophrenia are divided into three sections: positive symptoms (such as, delusion and hallucination), negative symptoms and cognitive symptoms of schizophrenia [3]. It is found that these symptoms can change with the disease progresses. According to these symptoms, there are five major subtypes are used to classify schizophrenia (Paranoid, Disorganized, Catatonic, Undifferentiated and Residual) [3]. Numerous physical and health problems have been observed, as well as other side effects, of many drugs consumed by schizophrenic patients, such as hypertension, diabetes and heart disorders [4,5].

 

Up to date, there is still ambiguity in understanding the real causes of schizophrenia as well as disease progression, but the prevailing belief is either an environmental or genetic disease [6,7]. It has been found that the existence of the disease in any member of family reflects the risk of injury of the individual by 10%,for example if one of the twins have schizophrenia the chance of injury to the other increases to become ranges from 40-60% [4].

 

Trace elements are naturally occurring inorganic material required in small amounts for the human body [8]. They have several important roles in human bodies, where some are essential cofactors for enzymes [9]. Some of them have structural roles and some of them play as electrons carrier in oxido-reduction reactions that have crucial roles in the generation and utilization of metabolic energy. Furthermore, some trace elements have important actions throughout biological processes, such as Fe which can transport oxygen in the body [10]. In fact, the excessive levels of trace elements can be toxic for health and has been found to cause many fatal diseases, such as cancers [8].

 

Recent years, elements contents in human body have been used as an aid for diagnosing various diseases [11-13]. Therefore the current work is aimed to examine a potential relationship between some elements concentrations that may be affected in patients with schizophrenia, and study the perturbations that may occur in these elements to use them as an indicator to predict for the risk, and progression, of disease.

 

MATERIALS AND METHODS:

Patients and Controls:

This study was conducted in Poison Centre at Ghazi Hariri Hospital for Specialized Surgery/Ministry of Health, Central service laboratory/College of Education for Pure Science/ Baghdad University and Chemistry department/College of Science/Mustansiriyah University, Baghdad, Iraq between December, 2016 and June, 2017. The study includes 60 patients with schizophrenia (age ranging from 40–60 years and the mean age 48.4 years). Sixty volunteers of control group (age ranging from 40–60 years and the mean age 50.9 years). Patient samples were collected from Al-Rashad Psychiatric Hospital/ Ministry of Health, Baghdad, Iraq.

 

Sample collection, preparation and analytical methods:

A 5 ml of blood were drawn,by vein puncture using disposable syringes, from each individual of patients with schizophrenia and volunteers as control. The collected sample was placed in gel tube andallowed to clot for 15-20 min at room temperature, then centrifuged at 5000 rpm for 10 minutes. The obtained serum transferredinto another test tube and storedin refrigerator at −20°C for subsequent analysis.

 

All standard elements and chemicals used in this study were supplied by Sigma-Aldrich, Germany. Serum elements content Cu, Zn, Mg, Cr, Fe, Co and Pb of all samples were estimated using flame atomic absorption spectrophotometer (FAAS, Model AA646, Shimadzu Corporation, Kyoto, Japan), whereas Se, Mn, Al and Ni were measured using flameless atomic absorption spectrophotometer (GFAAS, Model 210VGP, Buck Scientific, USA) [14]. Serum samples were diluted with 10-fold deionized distilled water (nanopure water (18.3Ω)) for Cu, Zn,Se,Co, Pb and Fe measurements. Determination of these elements was performed at wavelengths 324.7 nm, 213.9 nm, 196, 217, 287 and 248.3 nm, respectively.For Mg measurement,the samples were diluted 50-fold by lanthanum chloride (LaCl₂.7H₂O) and the assay was performed at wavelength 285.2 nm. Estimation of Ni, Mn and Cr concentrations was performed at wavelengths 232 nm, 379.5 nm and 357.9 nm, respectively, directly by injection the serum samples to the graphite tube of the GFAAS. A standard calibration curve was prepared for each element using the following concentrations (0.05, 0.1, 0.2, 0.4, 0.8, 1.6, and 2μg/ml).

 

Statistical Analysis:

The results were analyzed statistically using SPSS program version 22.0. Data were analyzed using descriptive statistics of the software andIndependent-Samples Student t test. The values were expressed as mean ± standard deviation (SD). In addition, Pearson’s correlation analysis was carried out to determine the relationships between all study variables. The statistical tests were considered to be significant at the p<0.05 with 95% Confidence Interval.

 

RESULTS AND DISCUSSION:

The collective results for quantitative analysis of the elements (Se, Cu, Zn, Ni, Cr, Mn, Mg, Pb, Co, Fe and Al) among two study groups are presented in Table 1. The data obtained indicated that the mean values of Se, Cu, Ni, Cr, Mn and Al (62.15, 155.52, 0.083, 0.195, 0.308 and 0.022 µg/dl, respectively) in schizophrenic patients were raised in comparison with those of control (45.94, 111.42, 0.046, 0.128, 0.164 and 0.019 µg/dl, respectively), as shown in Figures 1 and 2. This increase was found to be highly significant (p<0.001). In addition, the results indicated that the values measured in schizophrenic patients for Zn, Mg, Pb and Co (70.9, 103, 0.07 and 0.041 µg/dl, respectively) were lower than those of control (93.5, 163, 0.19 and 0.128 µg/dl, respectively), and statistically these differences were highly significant (p<0.001), Figures 1 and 2. The results also indicated that there is non-significant difference in Fe levels between control and patients (p>0.05).

 

The relationship between all parameters included in the present work was studied using Pearson’s correlation analysis and the collective results are presented in Table 2.The analysis revealed the presence of a positive correlation between the levels of Cu, Ni, Cr and Mn, with the level of Se of patients with schizophrenia. The analysis also revealed a negative correlation between the levels of Zn, Mg, Pb and Co, with the level of Se in patients group. In contrast, no correlation were observed between the level of Se and the levels of Al and Fe. Regarding to copper element, the results showed that higher levels of Cu were positively correlated with Ni, Cr and Mn. While were negatively correlated with Zn, Mg, Pband Co. Furthermore, the study revealed a positive correlation of Zn with Mg, Pb and Co, and negative correlation with Ni, Cr, Mn and Al.

 

The analysis also revealed a positive correlation between the high level of Ni with the levels of Cr, Mn and Al, and negative correlation with Mg, Pb and Co levels of schizophrenic patients. In addition, the data analysis showed a positive correlation between the high level of Cr and the levels of Mn and Al, opposed to negative correlation with Mg, Pb and Co levels. The results obtained showed the presence of positive correlation between the high level of Mn and the levels of Al, opposed to negative correlation with Mg, Pb and Co levels of patients. Also showed the presence of positive correlation between the low level of Mg and the levels of Pb and Co, while showed a negative correlation with Al levels of patients. There was also a negative correlation between the level of Al and the levels of Pb and Co of the patients. As well as a positive correlation of the Pb level with the levels of Co.

 

Table 1: Serum levels of elements (Se, Cu, Zn, Ni, Cr, Mn, Mg, Pb, Ni, Co, Fe and Al) in patients with schizophrenia patients and control group.

 

 

Figure 1: Diagram shows the mean values of serum Se, Cu, Zn and Mg levels (μg/dl) in schizophrenic patients and control subjects.

 

 

Figure 2: Diagram shows the mean values of serum Ni, Cr, Mn, Pb, Co and Al levels (μg/dl) in schizophrenic patients and control subjects.

 

 

 

 

Table 2: Correlations between variables in schizophrenic patients group (r value).‎

Element	Se	Cu	Zn	Ni	Cr	Mn	Mg	Al	Pb	Co	Fe
Se	1	0.353**	-0.29**	0.345**	0.384**	0.387**	-0.361**	0.126	-0.23*	-0.34**	0.080
Cu	0.353**	1	-0.72**	0.546**	0.649**	0.736**	-0.776**	0.360**	-0.67**	-0.54**	-0.02
Zn	-0.29**	-0.72**	1	-0.41**	-0.509**	-0.701**	0.717**	-0.35**	0.678**	0.531**	0.013
Ni	0.345**	0.546**	-0.41**	1	0.575**	0.449**	-0.483**	0.184*	-0.36**	-0.44**	0.100
Cr	0.384**	0.649**	-0.51**	0.575**	1	0.652**	-0.643**	0.281**	-0.49**	-0.51**	0.128
Mn	0.387**	0.736**	-0.701**	0.449**	0.652**	1	-0.788**	0.353**	-0.70**	-0.60**	-0.02
Mg	-0.36**	-0.78**	0.717**	-0.48**	-0.643**	-0.788**	1	-0.34**	0.703**	0.657**	-0.02
Al	0.126	0.360**	-0.35**	0.184*	0.281**	0.353**	-0.342**	1	-0.28**	-0.065	0.087
Pb	-0.227	-0.66**	0.678**	-0.36**	-0.49**	-0.700**	0.703**	-0.277**	1	0.501**	0.099
Co	-0.34**	-0.54**	0.531**	-0.44**	-0.51**	-0.604**	0.657**	-0.065	0.501**	1	0.055
Fe	0.080	-0.024	0.013	0.100	0.128	-0.019	-0.024	0.087	0.099	0.055	1

*Correlation is significant at the 0.05 level.

**Correlation is significant at the 0.01 level.

 

DISCUSSION:

There is still ambiguity in understanding causes of schizophrenia as well as disease progression. In recent years, metal and antioxidants contents in human body have been used as an aid for diagnosing various diseases. Therefore, the current work investigate a potential association between theserum contents of 11 elements and the risk of schizophrenia. It is found that the levels of these elements in sera of patients with schizophrenia differ significantly in comparison with those in controls. Therefore, follow up of these variables could be of great values and significant factors that can be rely on in the early diagnosis and predict the risk of schizophrenia.

 

Selenium is a necessary trace element for human body. The physiological function of selenium in the body is attributed mainly to its present in selenoproteins that have important roles in thyroid hormone metabolism, immune responses,oxidoreductions and antioxidant defence system [15]. It is found that selenium is important for normal brain function. Furthermore, it has been considered that selenium has a possible role in normal aging, schizophrenia, parkinson and alzheimerdisease [16,17]. In fact, high levels of selenium is toxic for human body. The results obtained in this study agree with the finding of a previous study conducted by (George et at.,2014) [18], who reported that serum concentration of Se was higher in schizophrenic patients in comparison to the control group. Some authors have pointed that differences in the Se level between schizophrenic patients and control were attributed to soil selenium contents and geographical locations [18,19]. However, monitoring of selenium is essential and requires further investigations to avert the counteractive effects resulting of metal high level in tandem with mental disease.

 

It has been reported previously by (Yanik et al., 2004; Rahman et al., 2009) [20,21] that theserum Cu level of schizophrenic patients was higher than in the healthy controls. These findings are consistent with the findings of the present work. On the other hand, it was found by (Liu et al., 2015) [22] that the serum concentration of Cu was lower in schizophrenic patients when compared to the control.Copper has an essential role in the activity of many physiological enzymes such as cytochrome c peroxidase and superoxide dismutase [23]. Furthermore, copper-containing enzymes (e.g.tyrosine hydroxylase and dopamine beta hydroxylase) are associated with the synthesis of dopamine and noradrenalinethat involved in the causes of schizophrenia [24]. Therefore, increased serum Cu may be associated with dopamine dysregulation in schizophrenia [25]. Similarly, and according to the findings of the present work, it is possible to refer that the high Cu levels may have a vital role in the development and pathogenesis of schizophrenia. In fact, although Cu has a vital role in the human body, high levels of Cucan cause an increase in toxic free radicals formation, which in turn may lead to increase the risk of schizophrenia.

 

The results of the present study have shown a significant reduced in the levels of Zn of schizophrenic patients when compared with the healthy controls, suggesting that this reduce may be a risk factor for development of schizophrenia or can facilitate the pathogenesis of schizophrenia. It was found that zinc has the ability to stabilize macromolecules against excess free radical production [26]. So, the low levels of Zn in serum of patients probably due to its sharing in the antioxidant defence system, where the patients with schizophrenia might be under higher oxidative stress. The results of the prsent workagree with the findings of previous studies [18,27,28], but disagree with the findings of another study [29]. It has been reported that prenatal nutrition deficiency may lead to increase the risk of schizophrenia in offspring [30]. These include zinc deficiency, therefore low levels of zinc can facilitate the pathogenesis of schizophrenia [31].

 

In fact and according to available information, this is the first attempt to study the relationship between nickel and schizophrenia. In the present study, it can be revealed that the high nickel levels may be correlating with an increased risk of schizophrenia. Ni is known as a carcinogenic agent [32], where exposure to nickel can cause a variety of negative effects on human health such as modifications to DNA, enhanced lipid peroxidation and production of reactive oxygen species [33]. Therefore, a comprehensive study is needed to determine whether the higher oxidative stress resulting of nickel exposure is a risk factor for schizophrenia.

 

Chromium is essential trace elements for human health. There are two forms of chromium: trivalent chromium and hexavalent chromium. Hexavalent chromium is a quite toxic agent that can cause skin problems and lung cancer [34]. In fact, the information regarding the toxicity of chromium is limited.It has been reported that hexavalent chromium is able to induce oxidative stress in human body by several pathways, which in turn lead to cells disruption [35]. The high levels of Cr recorded in the present study may be the reason for increased ROS production and then might be associated with the pathogenesis and aetiology of schizophrenia. The results of the present work agree with the findings of previous studies conducted by (Liu et at., 2015; Li et at., 2017) [22,36]. However, further universal studies,especially genetics studies, still needed to improve our knowledge about the relationship between Cr and its role in the aetiology of schizophrenia.

 

Manganese is an essential trace element in human body that has ability to act as a cofactor with many cellular enzymes, such as those with antioxidant activity. The Mn metabolism has been investigated, and was found that it has an important role in mental function. This element has a great interest of researchers in a variety of mental disorders, e.g. schizophrenia, wilson’s disease and pick’s disease [37]. Previous study has confirmed that excessive exposure to manganese stimulates neurotoxicity as a result of accumulation of this trace element in the mitochondria of brain [38]. It has been found that manganese toxicity might cause DNA fragmentation, where this case was observed in schizophrenia [39,40]. Furthermore, several studies have indicated that the manganese may play a role in the pathogenesis of mental disorders according to its toxic properties [41,42]. A previous study, has revealed that higher Mg levels were associated with an increased risk of schizophrenia [22]. Similarly, the present study exhibited higher manganese levels among schizophrenic patients in comparison with controls.

 

İt has been reported that the change in Mg level in patients with schizophrenia depends on several factors including age, disease duration, quality of food, type of treatment and the biological substances in which the concentration of magnesium is measured [43]. The level of magnesium in plasma and erythrocytes was measured for patients with paranoid schizophrenia. The researchers have found that the concentrations of magnesium in the red blood cells of patients are much lower than healthy people. The drugs, haloperidol or resperidone, increased the magnesium level in these cells and improved clinical status of the patients [44]. In fact, it has been reported that pimozide and fluphenazine drugs that used to treat schizophrenia lead to reduce plasma magnesium level. This decrease in Mg levels has been found to be related to a higher risk of sudden cardiac death in schizophrenic patients [45]. The results of the present work strongly support the previous findings. This gives further evidence that magnesium disturbances may play a substantial role in etiology of schizophrenia. However, the question remains how does that occur?.

 

The present work indicated decreased Pb levels in schizophrenic patients which is completely different from the findings of previous studies conducted by (Stanley and Wakwe, 2002; Arinola et al., 2010) [46,47]. It has been found that the brain systems responsible of social and emotional function can affected by Pb [48], but the mechanism of this effect is still not clear yet. In addition, it was found that the serotonin levels and metabolism can affected by Pb, where this case can lead to depression [49]. Therefore, a further work is suggested to decide whether the decrease levels of Pb is responsible of the aetiology of schizophrenia.

 

The information about the correlation between cobalt and schizophrenia is very rare. Co is important for human body as a key structural constituent of vitamin B₁₂. In fact, any decrease in cobalt content in the human body leads to a deficiency of vitamin B₁₂. It was found that the lack of vitamin B₁₂ leads to signs and symptoms, which include low capacity in thinking, changes in personality such as depression, frenzy, and psychosis, and can also cause feelings of abnormal sensations [50]. In this study, the results revealed a highly significant decrease of cobalt in schizophrenic patients. This findings suggested that Co content may be an important factor in the pathogenesis of schizophrenia.

 

The impact role of Fe on brain function, cognition and behaviour has been studied strongly [51]. Previous studies have reported lower Fe concentrations in schizophrenic patients compared to control group [20, 52]. Another study has reported a nonsignificant decrease in Fe concentration in schizophrenic patients [22]. In the present work, the association between Fe and an increased risk of schizophrenia was not significant.

 

Aluminium enters human bodies by food. It is distributed to different tissues in varying proportions. Approximately half of the amount is concentrated in the bones and quarter in the lungs as the aluminium reaches the brain via the cerebrospinal fluid [53]. In fact, the function of Al in human body is still not well understood. A previous study has reported that aluminium inhibited the activity of dopamine-beta-hydroxylase from bovine adrenal gland [54]. This enzyme has important role in the synthesis of dopamine and norepinephrine that involves in the aetiology of schizophrenia [24]. Moreover, it has been reported that Al is implicated in the aetiology of brain disorder such as Alzheimer's disease and other neurodegenerative disorders [55]. Similarly, the present study suggested that higher Al levels were associated with an increased risk of schizophrenia. However, more clinical experiments should carry out to explore the relationship between Al and schizophrenia.

 

CONCLUSION:

Trace elements have a substantial effect and play a vital role in a variety of necessary life processes, and was found to have a crucial role in the pathogenesis of some disease [56]. The objective of this study is to assess the levels of elements (Se,Cu, Zn, Ni , Cr, Mn, Mg, Pb, Co, Fe and Al) that may be valuable and may have prognostic significance in the early diagnosis, prognosis and therapy evaluation of schizophrenia. The results obtained show low levels of Zn, Mg, Pb and Co in serum samples of schizophrenic patients than in controls. In contrast, the results indicated high levels of Se, Cu, Ni, Cr, Mn and Al in the serum of schizophrenic patients than in those of healthy control subjects, while indicated no significant differ in iron level between patients and control subjects. The data analysis revealed the presence of a valuable correlation between most of elements in schizophrenic patients. These findings reflect the protective role that may played by elements (Zn, Mg, Pb and Co) in resistance of occurrence of schizophrenia, while the high levels of Se, Cu, Ni, Cr, Mn and Al may cause a threat of schizophrenia. Accordingly, it can be suggested that these elements may have a vital role and prognostic significance in complex disorders leading to schizophrenia. The real mechanism responsible for the alterations in elements levels in patients with schizophrenia is unclear and requires additional evaluation. Therefore, further comprehensive studies are wanted in order to advance our knowledge about the relationship between heavy metal and trace elements and their role in schizophrenia.

 

ACKNOWLEDGMENTS:

The authors would like to thank Mustansiriyah University (www.uomustansiriyah.edu.iq), Baghdad, Iraq, for its support in the present work.

 

 

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Accepted on 10.10.2018        © RJPT All right reserved

Research J. Pharm. and Tech 2019; 12(1): 185-191.