The Biochemical, Cognitive, and Psychiatric effects of Anticholinergics Benzhexol Hydrochloride and Biperiden Hydrochloride in Schizophrenic Patients

It is estimated that 45 million people suffer from schizophrenia around the world; it is among the top ten leading causes of disability. By 2050, this number will have grown to approximately 71 million people. Mental illnesses contribute more to the global burden of disease than all cancers combined. The present study has been planned to evaluate the effect of anticholinergic parkinol (benzhexol hydrochloride) and akineton (biperiden hydrochloride) on erythrocyte acetyl cholinesterase (AChE) activity and serum activities of gamma-glutamyl transferase (GGT), alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP) in schizophrenic patients treated with haloperidol, and also to study the effect of the previously mentioned two anticholinergics on both the cognitive functions and psychiatric symptoms in such patients. The study was carried out on 30 male schizophrenic patients who were divided into two main groups (group 1 and group 2) each of 15 patients of comparable age. The present results revealed that the total score of (PANSS) showed a significant decrease in all studied groups. The total score of (MMSE) showed a significant increase in all studied groups. The AChE activity did not show any significant difference in all comparisons in all studied groups. In our study, there was a significant elevation of serum GGT, ALT, AST and ALP levels in some groups of treated patients as compared to pretreatment groups. The results obtained in our study showed a significant increase in serum GGT, ALT, AST, and ALP levels in groups treated with either (haloperidol+benzhexol hydrochloride) or (haloperidol+biperiden hydrochloride) as compared to the corresponding levels in groups treated with haloperidol only, respectively. From all results we can concluded that the biochemical parameters used in this study are useful in detecting any side effects of antipsychotic and anticholinergic drugs on liver functions. The treatment with (haloperidol+benzhexol hydrochloride) and (haloperidol+biperiden hydrochloride) are effective in decreasing the positive and negative symptoms of schizophrenia. INTRODUCTION Schizophrenia is a psychiatric diagnosis that describes a mental disorder characterized by impairments in the perception or expression of reality and by significant social or occupational dysfunction. A person experiencing schizophrenia is typically characterized as demonstrating disorganized thinking, and as experiencing delusions or auditory hallucinations(1). The report from the WHO on the diagnosis of schizophrenia according to the 779 Bull High Inst Public Health Vol.37 No. 3 [2007] International Classification of Diseases Revision Ten (ICD-10) stated that no strictly pathogenic symptoms can be identified, and it is useful to divide the various symptoms of schizophrenia into groups that have special importance for diagnosis and often occur together(2). It is estimated that 45 million people suffer from schizophrenia around the world(3); it is among the top ten leading causes of disability. No population is free of schizophrenia. By 2050, this number will have grown to approximately 71 million people(4). Mental illnesses contribute more to the global burden of disease than all cancers combined(5). The prevalence of schizophrenia is much greater in densely populated, large, urban areas of industrialized countries(6,7). There is a strong evidence that using certain drugs can trigger either the onset or relapse of schizophrenia in some people(8). Some of these drugs are amphetamines, hallucinogens, and cannabis(9). The antipsychotic drugs are a chemically diverse group of heterocyclic compounds, which ameliorate many symptoms of schizophrenia(10). The side effects of antipsychotic drugs have always been a major concern for clinicians and the appreciation of the importance in the treatment of schizophrenia has increased steadily over the years(11). Most conventional antipsychotic drugs have central nervous system effects, particularly extrapyramidal symptoms (EPS), hypotension, changes in liver function, antiadrenergic side effects, sexual dysfunction, and weight gain(12). The effect of conventional antipsychotic is presumed to be associated with dopamine D2-receptor blockade(13), that cause extrapyramidal side effects(14). One explanation of extrapyramidal disorders is an imbalance between dopaminergic and cholinergic systems in the brain(15). Antipsychotics (e.g., haloperidol) induced pseudo-parkinsonism that has the same clinical appearance as


INTRODUCTION
International Classification of Diseases Revision Ten (ICD-10) stated that no strictly pathogenic symptoms can be identified, and it is useful to divide the various symptoms of schizophrenia into groups that have special importance for diagnosis and often occur together (2) .
It is estimated that 45 million people suffer from schizophrenia around the world (3) ; it is among the top ten leading causes of disability. No population is free of schizophrenia. By 2050, this number will have grown to approximately 71 million people (4) . Mental illnesses contribute more to the global burden of disease than all cancers combined (5) .
The prevalence of schizophrenia is much greater in densely populated, large, urban areas of industrialized countries (6,7) . There is a strong evidence that using certain drugs can trigger either the onset or relapse of schizophrenia in some people (8) . Some of these drugs are amphetamines, hallucinogens, and cannabis (9) .
The antipsychotic drugs are a chemically diverse group of heterocyclic compounds, which ameliorate many symptoms of schizophrenia (10) . The side effects of antipsychotic drugs have always been a major concern for clinicians and the appreciation of the importance in the treatment of schizophrenia has increased steadily over the years (11) . Most conventional antipsychotic drugs have central nervous system effects, particularly extrapyramidal symptoms (EPS), hypotension, changes in liver function, antiadrenergic side effects, sexual dysfunction, and weight gain (12) . The effect of conventional antipsychotic is presumed to be associated with dopamine D2-receptor blockade (13) , that cause extrapyramidal side effects (14) . One explanation of extrapyramidal disorders is an imbalance between dopaminergic and cholinergic systems in the brain (15) . Antipsychotics (e.g.,  (16) .
Benzhexol hydrochloride (Parkinol) and biperiden hydrochloride (Akineton) are anticholinergic drugs which are used for the treatment of extrapyramidal side effects induced by antipsychotics (17,18) .
Acetylcholine (Ach) has an important function in the cholinergic system where it acts as a transmitter of impulses on the cholinergic synapses (19) .The cholinergic system is one of the most important modualtory neurotransmitter systems in the brain (20,21) .
Cholinesterase (ChE), which is an enzyme, breaks acetylcholine down into choline and acetate and the most significant action of the ChEs physiologically is the hydrolysis of Ach to choline and acetic acid (22) . and alkaline phosphatase activity in serum using ALP Kit from Human (33) .
Statistical analyses were performed using the SPSS version 9. Repeated measurement ANOVA was used to compare the means of the different studied groups.
Correlation between variables of all groups was also studied.

RESULTS
Statistical analyses of total score of the positive and negative symptoms scale (PANSS) are shown in Table ( Table ( biperiden. This is in accordance with many studies which showed that anticholinergic medication used to treat EPS, can also impair cognitive processes related to learning and memory (38,39) . But this was not happened in case of benzhexol treated group which is in agreement with other study which stated that anticholinergic medication used to control emergent EPS have benign cognitive profiles that do not interfere with normal cognitive processes (40) . were treated with antipsychotic drugs (47) . It also showed the possibility that GGT is to some extent induced by haloperidol itself (48) .

Results
In our study the increase of ALT activities in the groups (1b), (1c) and (2b) and the increase of AST activities in groups (1b) and (2b) are in accordance with the results of several studies. They showed that transaminase enzyme levels increase during treatment with haloperidol and other neuroleptics and usually return to normal (49) .
Green et al., study revealed that ALT and AST levels were found to be higher in patients treated with haloperidol (50) .This increase in these enzyme activities may be attributed to the fact that many medications produce hepatic injury by competitively interfering with cellular metabolism (51) . Our results showed a significant positive correlation between ALT and AST activity levels.
The high levels of ALP activity in the studied groups are in agreement with that reported by Moradpour and co-workers who showed that the treatment by conventional antipsychotic drugs was characterized by high ALP levels (52) .  (55) .
In this study, the results showed no