Oxidative Stress and the Level of Antioxidant Enzymes in Schizophrenia


Doctoral Thesis / Dissertation, 2012

169 Pages, Grade: 10


Excerpt


Index

Chapters

1. Introduction

2. Review of literature

3. Material & methods

4. Observation

5. Discussion

6. Summary & conclusion

7. Bibliography

8. Annexure

ACKNOLEDGEMENT

It gives me an immense pleasure to put on record my profound gratitude to my revered teacher and supervisor Dr. Suhail Ahmed Azmi MD, Associate professor, Department of Psychiatry, J.N. medical college and ‘Hospital, A.M.U., Aligarh for his sagacious guidance and intellectual stimulation throughout my academic career. "His scholarly suggestions, research acumen, keen interest and affectionate Behavior have been an unending s ource of inspiration to me. The present woriy owes its existence to him right from its conception upto the present state. His place as a physician exemplary excellence and perfection has motivated' me to try to live upto somewhere near his perfectionist standard's. It has been ready an honor for me to worfwith a his perfectionist person of his stature so earty in my career.

I am obliged my Co-superviser Prof NagmulIslam, P hdD, Professor (Department of (Biochemistry, J.N Medical college, AMU Aligarh for his never ending support and timely suggestions to get the accurate laboratory results. His supervision has been the driving force throughout this study. I greatly appreciate his scientific knowledge and productivity.

I am also obliged my Co-supervisor P rof RK Gaur, M.D, Professor, (Department of psychiatry, JN Medical College A.M.U., Aligarh has Been most patient in rendering help I often needled', this worff owes its present shape to his screening, so thoroughly that I feet many minor errors have Been eliminated' due to his expertise.

I wish to take this opportunity to express my sincere thanks and obligation to my respected teacher, p rof . Abu Qamar, Professor and Chairman, (Department of (Psychiatry, J.NM.C., A.M.U, Aligarh , for his reassuring presence, able guidance, tremendous concern and constant encouragement in academic excellence.

I wish to acknowledge the help and support I received from seniors & colleagues Dr. Amir Usmani, (Dr Nadeem Ansari. , (Dr. Sheshank. ganwar and (Dr. AbidRjzvi in collecting cases and blood' samples and they are also been a resource of encouragement andguidance whenever I needed, My sincere and special thanks to Dr Anees, D r. Abèas, D r. Salman and D r. Urfi for helping me in understanding and carrying out tin statistical analysis and there valuable advices during moments of doubt., I would not miss this opportunity to thank gmy wife, my friends (SkHamid & Md Ali) and my neighbours Khansa & Umar whose constant pray and smile keeps me happy and hardworking whenever I f eel sad'.

Lastly, the Job is unfinished' if I do not thanlgny patients for their cooperation and to the blessings of the almighty who has enabled me to complete this wor( with perfection.

I dedicate this work to my parents and wife for their love and affection.

INTRODUCTION

Schizophrenia is a clinical syndrome of variable, but profoundly disruptive, psychopathology that involves cognition, emotion, perception, and other aspects of behavior. The expression of these manifestations varies across patients and over time but the effect of the illness is always severe and is usually long lasting. The disorder usually begins before age 25, persists throughout life, and affects persons of all social classes. In the United States, the lifetime prevalence of schizophrenia is about 1 percent, which means that about 1 person in 100 will develop schizophrenia during their lifetime. The prevalence of schizophrenia in India is 2.5/1000 as reported by Ganguli in 2000 and 2.7/1000 by Reddy et al in 1998. Both patients and their families often suffer from poor care and social ostracism because of widespread ignorance about the disorder. Although schizophrenia is discussed as if it is a single disease, it probably comprises a group of disorders with heterogeneous etiologies and it includes patients whose clinical presentations, treatment response, and courses of illness vary. Clinicians should appreciate that the diagnosis of schizophrenia is based entirely on the psychiatric history and mental status examination. There is no laboratory test for schizophrenia.

A growing body of evidence suggests that peripheral activities of antioxidant enzymes and lipid peroxidation are abnormal in schizophrenic subjects. Mahadik found increased lipid peroxidation products and altered defence system in both chronic and drug-naive first episode schizophrenics. The accumulated results indicate that oxidative stress is integral to this disease and not the result of neuroleptic treatment.

Oxidative damage inflected by reactive oxygen species is also referred to as oxidative stress. Oxidative stress is a result of increased formation of free radicals and/or reduced antioxidative system capacity. Neurons are particularly vulnerable to radical-mediated damage. High oxygen consumption, lipid content and transition metals are particular risk factors. Free radicals contribute to neuronal loss in cerebral ischemia and haemorrhage, and may be involved in degeneration of neurons in normal aging, epilepsy, Parkinson's disease, Alzheimer's disease, and possibly in schizophrenia. In addition to their pathological role, free radicals have critical physiological functions in neuronal development, differentiation and signal transduction, all of which may be altered in some cases of schizophrenia. The effect of oxidative modification of neuronal phospholipids, DNA, and proteins on their function (i.e., membrane transport, loss of mitochondrial energy production, gene expression and, therefore, receptor-mediated phospholipid-dependent signal transduction may explain altered information processing in schizophrenia.

The evidence behind oxidative stress mechanisms in schizophrenia can be grouped into three categories: first, those studies that illustrate disturbed oxidative homeostasis through oxidative enzyme genetic polymorphism and quantification of antioxidants, free radicals and markers of oxidative damage; second, those demonstrating antioxidant mechanisms of established antipsychotic drugs; third, those showing benefits from antioxidant therapies.

Reduced levels of the major antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px), have also been found in patients with schizophrenia compared with controls (Ben Othmen et al., 2007; Li et al., 2006; Ranjekar et al.,2003). Others have reported unchanged levels for these three enzymes (Srivastava et al., 2001), or altered concentrations of individual enzymes (Abdalla et al.,1986; Akyol et al., 2002; Altuntas et al., 2000; Dietrich- Muszalska et al.,2005; Herken et al.,2001; Kuloglu et al.,2002c; Zhang et al.,2006a). A strong negative correlation between blood GSH-Px and structural measures of brain atrophy was also reported by an early study (Buckman et al.,1987).

Estimating levels of oxidative reactive products provide another useful strategy to determine the impact of oxidative stress. Published studies have predominantly examined products of lipid peroxidation and DNA oxidation as markers of oxidative damage. A widely used method of measuring lipid peroxidation is the performance of thiobarbituric acid reactive substances (TBARS) assays. TBARS are low molecular-weight substances, consisting largely of malondialdehyde (MDA), which are formed from the decomposition of unstable lipid peroxidation products and react with thiobarbituric acid to form fluorescent adducts (Fukunaga et al.,1998). TBARS have been reported to be elevated in the plasma (Akyol et al.,2002; Dietrich-Muszalska and Olas, 2007; Kuloglu et al., 2002c; Mahadik et al., 1998; Ranjekar et al.,2003; Zhang et al.,2006a), erythrocytes (Altuntas et al., 2000; Herken et al.,2001), leucocytes (Srivastava et al.,2001) and platelets (Dietrich- Muszalska et al.,2005) of schizophrenia patients, in conjunction with abnormalities in antioxidant levels, and depleted essential polyunsaturated fatty acids, which are especially prone to lipid peroxidation (Arvindakshan et al.,2003b; Khan et al.,2002)

Studies from India also reported significantly lower levels of the two antioxidant enzymes were found in schizophrenics compared to normal controls, with an increased oxidative stress as indicated by high blood MDA levels. The condition worsened with advancing age, smoking, among literate masses, and in chronic schizophrenics; whereas gender did not show any effect (Dadheech et.al 2008).Another study reported Haloperidol caused more oxidative stress along with a significant reduction of important antioxidant parameters. Plasma ascorbate was found to be the chief antioxidant on which the activity of both plasma SOD and alpha tocopherol were dependent under oxidative stressful conditions ( Om P.Singh et.al 2008).

Antioxidant effects of established antipsychotic agents provide indirect evidence for oxidative pathophysiological mechanisms in schizophrenia. Abnormalities in levels of antioxidants and oxidative products have been reported to reverse over the course of treatment with atypical antipsychotics, coinciding with symptomatic improvement (Dakhale et al., 2004; Zhang et al.,2003).

Clinical trials investigating adjunctive antioxidants in the treatment of schizophrenia have utilized vitamins C and E, Ginkgo biloba extract (EGb), and NAC.

So the present study was carried out in department of Psychiatry, Jawahar Nehru medical college, Aligarh. We have taken 50 drug naïve schizophrenic patients attending for the first time in OPD. They were diagnosed according to ICD-10 criteria for schizophrenia. They were assessed using PANNS scale for severity of disease and PSLES for stressful life events after through clinical history, physical examination and mental examination. After that there blood samples were drawn and following markers were analysed - Malondialdehyde(MDA), Gluthathione peroxidase (GSH-PX), Superoxide dismutase (SOD).They were compared with 50 age and sex matched normal healthy controls with the following objectives:-

1. To study the oxidative stress and the level of antioxidant enzymes Superoxide dismutase (SOD) and Glutathione peroxidase (GSH-PX) in schizophrenia.
2. To study the relation of sociodemographic characteristics of schizophrenic patients with the oxidative stress and antioxidant enzymes.
3. To compare the number of stressful life events within six months and during life time in schizophrenic patients with normal healthy controls.
4. To study the effect of life events experienced by schizophrenic patients on the oxidative stress and level of antioxidant enzymes.
5. To study the relation between PANNS score with oxidative stress and antioxidative enzymes in schizophrenic patients.

REVIEW OF LITERATURE

Schizophrenia

Schizophrenia is a clinical syndrome of variable, but profoundly disruptive, psychopathology that involves cognition, emotion, perception, and other aspects of behavior. The expression of these manifestations varies across patients and over time but the effect of the illness is always severe and is usually long lasting. The disorder usually begins before age 25, persists throughout life, and affects persons of all social classes. Both patients and their families often suffer from poor care and social ostracism because of widespread ignorance about the disorder. Although schizophrenia is discussed as if it is a single disease, it probably comprises a group of disorders with heterogeneous etiologies and it includes patients whose clinical presentations, treatment response, and courses of illness vary. Clinicians should appreciate that the diagnosis of schizophrenia is based entirely on the psychiatric history and mental status examination. There is no laboratory test for schizophrenia (Synopsis, Kaplan & saddock,10th edition)

History

Written descriptions of symptoms commonly observed today in patients with schizophrenia are found throughout history. Early Greek physicians described delusions of grandeur, paranoia, and deterioration in cognitive functions and personality. It was not until the 19th century, however, that schizophrenia emerged as a medical condition worthy of study and treatment. Two major figures in psychiatry and neurology who studied the disorder were Emil Kraepelin (1856a€“1926) and Eugene Bleuler (1857a€“1939). Earlier, Benedict Morel (1809a€“1873), a French psychiatrist, had used the term dA©mence prA©coce to describe deteriorated patients whose illness began in adolescence.

Emil Kraepelin

Kraepelin translated Morel's dA©mence prA©coce into dementia precox, a term that emphasized the change in cognition (dementia) and early onset (precox) of the disorder. Patients with dementia precox were described as having a long-term deteriorating course and the clinical symptoms of hallucinations and delusions. Kraepelin distinguished these patients from those who underwent distinct episodes of illness alternating with periods of normal functioning which he classified as having manic- depressive psychosis. Another separate condition called paranoia was characterized by persistent persecutory delusions. These patients lacked the deteriorating course of dementia precox and the intermittent symptoms of manic-depressive psychosis.

Eugene Bleuler

Bleuler coined the term schizophrenia, which replaced dementia precox in the literature. He chose the term to express the presence of schisms between thought, emotion, and behavior in patients with the disorder. Bleuler stressed that, unlike Kraepelin's concept of dementia precox, schizophrenia need not have a deteriorating course

Epidemiology

In the United States, the lifetime prevalence of schizophrenia is about 1 percent, which means that about 1 person in 100 will develop schizophrenia during their lifetime. The Epidemiologic Catchment Area study sponsored by the National Institute of Mental Health reported a lifetime prevalence of 0.6 to 1.9 percent. According to DSM-IV-TR, the annual incidence of schizophrenia ranges from 0.5 to 5.0 per 10,000, with some geographic variation (e.g., the incidence is higher for persons born in urban areas of industrialized nations). Schizophrenia is found in all societies and geographical areas, and incidence and prevalence rates are roughly equal worldwide. In the United States, about 0.05 percent of the total population is treated for schizophrenia in any single year, and only about half of all patients with schizophrenia obtain treatment, despite the severity of the disorder.

The prevalence of schizophrenia in India is 2.5/1000 as reported by Ganguli in 2000 and 2.7/1000 by reddy et.al in 1998.

Incidence Rates per 1,000 population, age 15-54, for a Broad and a Narrow Case Definition of Schizophrenia

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ICD, International Classification of Diseases; Catego S+, Diagnostic class for schizophrenia patients with highly discriminating (first-rank) symptoms according to the computer algorithm Catego. (From World Health Organization Ten-Country Study, 1992 and Wing JK, Cooper JE, Sartorius: Measurement and classification of psychiatric symptoms Cambridge University Press; 1974.)

Gender and Age

Schizophrenia is equally prevalent in men and women. The two genders differ, however, in the onset and course of illness. Onset is earlier in men than in women. More than half of all male schizophrenia patients, but only one-third of all female schizophrenia patients, are first admitted to a psychiatric hospital before age 25. The peak ages of onset are 10 to 25 years for men and 25 to 35 years for women. Unlike men, women display a bimodal age distribution, with a second peak occurring in middle age. Approximately 3 to 10 percent of women with schizophrenia present with disease onset after age 40. About 90 percent of patients in treatment for schizophrenia are between 15 and 55 years old. Onset of schizophrenia before age 10 or after age 60 is extremely rare. Some studies have indicated that men are more likely to be impaired by negative symptoms (described below) than are women and that women are more likely to have better social functioning than are men prior to disease onset. In general, the outcome for female schizophrenia patients is better than that for male schizophrenia patients. When onset occurs after age 45, the disorder is characterized as late-onset schizophrenia (Kaplan & sddock).

IN INDIA

The mean age of onset of schizophrenia did not significantly differ between males (29.2±8.8 years) and females (30.8±11.4 years) (t = 1.12; p = 0.27). Among those with an age of onset <33 years, females had a significantly earlier onset; among those with an age of onset >33 years, females had a significantly later onset.(Basappa et.al,2008)

Etiology

Genetic Factors

There is a genetic contribution to some, perhaps all, forms of schizophrenia, and a high proportion of the variance in liability to schizophrenia is due to additive genetic effects. The modes of genetic transmission in schizophrenia are unknown, but several genes appear to make a contribution to schizophrenia vulnerability. Linkage and association genetic studies have provided strong evidence for nine linkage sites: 1q, 5q, 6p, 6q, 8p, 10p, 13q, 15q, and 22q. Further analyses of these chromosomal sites have led to the identification of specific candidate genes, and the best current candidates are alpha-7 nicotinic receptor, DISC 1, GRM 3, COMT, NRG 1, RGS 4, and G 72. Recently, mutations of the genes dystrobrevin (DTNBP1) and neureglin 1 have been found to be associated with negative features of schizophrenia. (Brien riley et.al 2006)

MLC1 Gene Is Associated with Schizophrenia and Bipolar Disorder in Southern India reported by Ranjana et al., in 2005.

Prevalence of Schizophrenia in Specific Populations

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(Kaplan & saddock)

Biochemical Factors

Dopamine Hypothesis

The dopamine hypothesis proposes that the symptoms of schizophrenia are due to dopaminergic overactivity. This might arise due to excess dopamine itself or to an elevated sensitivity to it, e.g. because of increased numbers of dopamine receptors. The hypothesis originated with the discovery that all effective antipsychotic drugs are dopamine (D2) receptor antagonists, and that dopamine-releasing agents such as amphetamine can produce a paranoid psychosis. It received support from findings of increased dopamine content and higher densities of D2 receptors in schizophrenia (summarized in Roberts et al., 1997). However, despite the longevity of this hypothesis there is still no consensus as to the nature of the supposed abnormality or any evidence that dopamine has a causal role in the disorder (Davis et al., 1991; Joyce and Meador-Woodruff, 1997). There are two main difficulties. First, antipsychotics have marked effects on the dopamine system, seriously confounding all studies of medicated subjects. Secondly, the molecular characterization of the dopamine receptor family has greatly increased the number of potential sites of dysfunction and the mechanisms by which it might occur in schizophrenia. There is no doubt that D2 receptor densities are increased in schizophrenia, but considerable doubt as to what proportion is not attributable to antipsychotic treatment (Zakzanis and Hansen, 1998), especially given that PET studies of D2 receptors in drug- naive, first-episode cases are largely negative (Nordstro’m et al., 1995). There are reports of altered D1 (Okubo et al., 1997) and D3 (Gurevich et al., 1997) receptors in schizophrenia, but these are either unconfirmed or contradicted by other studies (see Harrison, 1999 b). The D4 receptor has proved particularly controversial following a report that its density was increased several-fold in schizophrenia, seemingly independently of medication(Seeman et al., 1993). However, it appears that the result was due to a ‘D4-like site' rather than the true D4 receptor (Reynolds, 1996; Seeman et al., 1997).

In summary, the status of dopamine receptors in schizophrenia is still contentious. In contrast, there is emerging evidence for a presynaptic dopaminergic abnormality in schizophrenia, with PET and single photon emission tomography displacement studies indicating an elevated dopamine release in response to amphetamine (Laruelle et al.,1996; Breier et al., 1997; Abi- Dargham et al.,1998), implying a dysregulation and hyperresponsiveness of dopaminergic neurons. This is a potentially important finding which needs further investigation.

Summary of recent neurochemical findings in schizophrenia

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5-Hydroxytryptamine (5-HT; serotonin)

The idea that 5-HT is involved in schizophrenia has long been advocated because the hallucinogen LSD is a 5-HT agonist. Current interest centres on the role of the 5-HT2A receptor (Harrison and Burnet, 1997) because a high affinity for the receptor may explain the different therapeutic and side-effect profile of novel antipsychotics (Meltzer, 1996), and polymorphisms of the gene are reported to be a minor risk factor for schizophrenia (Williams et al., 1997) and response to the atypical antipsychotic drug clozapine (Arranz et al., 1998). Neurochemically, many studies have found lowered 5-HT2A receptor expression in the frontal cortex in schizophrenia (Harrison, 1999 b), and there is a blunted neuroendocrine response to 5-HT2 agonists (Abi-Dargham et al., 1997). An elevated number of cortical 5-HT1A receptors is also a replicated finding (Burnet et al., 1997). Both the 5-HT1A and 5-HT2A receptor alterations are seen in unmedicated subjects post-mortem, but a preliminary PET study has not shown any change in 5-HT2A receptors in younger,medication-free patients (Trichard et al., 1998), suggesting that the abnormalities may emerge during the course of the illness. Hypotheses to explain 5-HT involvement in schizophrenia include alterations in the trophic role of 5-HT in neurodevelopment, impaired 5- HT2A receptor-mediated activation of the prefrontal cortex, and interactions between 5-HT and dopamine (Kapur and Remington, 1996).

Glutamate

Phencyclidine and other non-competitive antagonists of the NMDA (N- methyl-D-aspartate) subtype of glutamate receptor produce a psychosis closely resembling schizophrenia (Javitt and Zukin, 1991). This has driven the hypothesis of glutamatergic dysfunction in schizophrenia. In support, there is now considerable evidence for abnormalities in pre- and postsynaptic glutamate indices (Table 5). For example, in the medial temporal lobe, glutamatergic markers are decreased and there is reduced expression of non-NMDA subtypes of glutamate receptor (Kerwin et al., 1990; Eastwood et al.,1995 b, 1997 b; Porter et al., 1997). However, a different pattern is seen in other brain regions, affecting other glutamate receptor subtypes (Roberts et al.,1997), precluding any simple conclusion regarding the nature of glutamatergic abnormality in schizophrenia (Tamminga,1998). Mechanisms proposed to explain glutamatergic involvement in schizophrenia centre on its interactions with dopamine (Carlsson and Carlsson,1990), subtle forms of excitotoxicity (Olney and Farber,1995) and a developmental abnormality of corticocortical connections (Deakin and Simpson,1997).

Neuropathology

In the 19th century, neuropathologists failed to find a neuropathological basis for schizophrenia, and thus they classified schizophrenia as a functional disorder. By the end of the 20th century, however, researchers had made significant strides in revealing a potential neuropathological basis for schizophrenia, primarily in the limbic system and the basal ganglia, including neuropathological or neurochemical abnormalities in the cerebral cortex, the thalamus, and the brainstem. The loss of brain volume widely reported in schizophrenic brains appears to result from reduced density of the axons, dendrites, and synapses that mediate associative functions of the brain. Synaptic density is highest at 1yr age, then is pared down to adult values in early adolescence. One theory, based in part on the observation that patients often develop schizophrenic symptoms during adolescence, holds that schizophrenia results from excessive pruning of synapses during this phase of development.(Kaplan)

Cerebral Ventricles

Computed tomography (CT) scans of patients with schizophrenia have consistently shown lateral and third ventricular enlargement and some reduction in cortical volume. Reduced volumes of cortical gray matter have been demonstrated during the earliest stages of the disease. Several investigators have attempted to determine whether the abnormalities detected by CT are progressive or static. Some studies have concluded that the lesions observed on CT scan are present at the onset of the illness and do not progress. Other studies, however, have concluded that the pathological process visualized on CT scan continues to progress during the illness. Thus, whether an active pathological process is continuing to evolve in schizophrenia patients is still uncertain(stenton et.al).Key neuropathological findings and the strength of evidence are given in the table just given below.

Cerebral asymmetry and neuropathology in schizophrenia

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For additional references see Falkai and Bogerts (1993) and Crow (1997). *With clear evidence for lateralised change (e.g. diagnosis X side interaction on ANOVA). ^Studies where the change was found bilaterally. ^Planum temporale area reduced unilaterally, but volume reduced bilaterally. ^Relative to affective disorder controls.

(P.J Harrison, Brain (1999), 122, 593-624)

Certainty and doubt in schizophrenia

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Neuropathology and the neurodevelopmental model

The concept of developmental insanity was proposed by Clouston in 1891 (Murray and Woodruff, 1995) and elaborated in neuropathological terms early this century (Southard, 1915). However, it is only in the past decade that a neurodevelopmental origin for schizophrenia has become the prevailing pathogenic hypothesis for the disorder; indeed the principle is now largely unchallenged (Murray and Lewis,1987; Weinberger, 1987, 1995). The model receives support from various sources, the neuropathological data forming an important component of the evidence (Table 4) (Harrison,1997 a; Raedler et al., 1998).The most influential and specific form of the theory is that the pathology of schizophrenia originates in the middle stage of intrauterine life (Roberts, 1991; Bloom, 1993; Roberts et al., 1997). An earlier timing is excluded since overt abnormalities in the structure and cellular content of the cerebral cortex would be expected if neurogenesis were affected, whilst the absence of gliosis is taken to mean that the changes must have occurred prior to the third trimester. The conclusion that, by default, the pathological process originates in the second trimester is bolstered by reference to certain of the cytoarchitectural abnormalities of schizophrenia. However, this ‘strong' form of the neurodevelopmental model is weak on two grounds. First, because of the limitations of the absence-of-gliosis reported by several studies(Roberts et al., 1986, 1987; Stevens et al., 1988 b; Casanova et al., 1990; Arnold et al., 1996). Secondly, the types of cytoarchitectural disturbance adduced in favour are those of neuronal disarray, heterotopias and malpositioning suggestive of aberrant migration (Kovelman and Scheibel, 1984; Jakob and Beckmann, 1986; Arnold et al., 1991 a; Akbarian et al.,1993 a, b), processes which occur at the appropriate gestational period; yet, as described above, none of these cytoarchitectural abnormalities has been unequivocally established to be a feature of schizophrenia. By comparison, the other cytoarchitectural findings, such as alterations in neuronal size and synaptic and dendritic organization, could well originate much later, being susceptible to ongoing environmental influences (Jones and Schallert, 1994; Moser et al., 1994; Saito et al., 1994; Andrade et al., 1996; Kolb and Whishaw, 1998), ageing (Huttenlocher, 1979; Braak and Braak, 1986; Masliah et al., 1993; de Brabander et al., 1998) and perhaps also to genetic factors (Vaughn et al., 1977;Williams et al., 1998). Other versions of the neurodevelopmental theory of schizophrenia postulate additional or alternative abnormalities in processes such as cell adhesion, myelination and synaptic pruning (e.g. Keshavan et al., 1994 a; Benes et al., 1994;Akbarian et al., 1996; Arnold and Trojanowski, 1996; Lewis,1997) or allow for a mixture of maturational and degenerative processes (e.g. Murray et al., 1992; Garver, 1997). Overall, a parsimonious view is that the extant cytoarchitectural abnormalities and lack of gliosis are indicative merely of an essentially neurodevelopmental as opposed to neurodegenerative disease process, rather than as pointing directly to a particular mechanism or timing. It is only by consideration of the pathological features in conjunction with the other evidence (given in the table just below) that a strong case for a significant early childhood, including foetal, component to schizophrenia can be made. Even then, it is unknown whether neurodevelopmental deviance is either necessary or sufficient. Moreover, any such model has a problem explaining the onset and outcome of the disorder: how is an abnormality in the cortical cytoarchitecture, present since early in life and presumably persistent, reconciled with the onset of symptoms in adulthood and a typically relapsing and remitting course thereafter? Regarding the explanation for the timing of psychosis, one can take refuge in the similar difficulties in explaining some epilepsies, and point to the fact that pathological and behavioural effects can clearly be long delayed after relevant neonatal lesions (Beauregard et al., 1995; Lipska and Weinberger, 1995; Saunders et al., 1998).It can also be argued that the expression of psychotic symptoms requires a brain which has reached a certain stage of biochemical and anatomical maturation. Explaining the course of the disorder is more difficult and entirely speculative. It may be hypothesized that the aberrant circuitry is rendered ‘unstable' (e.g. is more susceptible to neurochemical fluctuations which precipitate recurrence) or is unable to undergo normal plasticity in response to age-related and environmental factors (Stevens, 1992; De Lisi, 1997;Lieberman et al., 1997).

Key points of evidence for a neurodevelopmental origin of schizophrenia

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Psychosocial and Psychoanalytic Theories

If schizophrenia is a disease of the brain, it is likely to parallel diseases of other organs (e.g., myocardial infarctions, diabetes) whose courses are affected by psychosocial stress. Thus, clinicians should consider both psychosocial and biological factors affecting schizophrenia.

The disorder affects individual patients, each of whom has a unique psychological makeup. Although many psychodynamic theories about the pathogenesis of schizophrenia seem outdated, perceptive clinical observations can help contemporary clinicians understand how the disease may affect a patient's psyche.(Kaplan)

Expressed Emotion

Parents or other caregivers may behave with overt criticism, hostility, and over involvement toward a person with schizophrenia. Many studies have indicated that in families with high levels of expressed emotion, the relapse rate for schizophrenia is high. The assessment of expressed emotion involves analyzing both what is said and the manner in which it is said. The relapse rate is 3-7 times more in high expressed emotions group(Gordon et.al,1990)

Stressful Life events

Life events have been defined as those "whose advent is either indicative of/or requires significant change in the ongoing life pattern of the individual' (Holmes & Rahe, 1967). Life event research continues to be an area of active work for understanding the aetiology, development or relapse of psychiatric disorders. Major efforts have been directed at finding the role of life events in the evolution of depressive illness (Paykel et al., 1969; Brown & Harris 1978) and schizophrenia (Brown & Birley 1968; Al Khani et al., 1986; Chung et al., 1986). Norman and Malla (1993a) in a review pointed out presence of a relationship between life events and changing symptomatology over time in patients of schizophrenia. Al Khani et al. (1986) reported a higher frequency of events in married female schizophrenics in the 6-month period preceding assessment. A similar observation was made by Gureje & Adewunmi (1988) that married females reported a higher rate of life events. A recent study by Das et al. (1997) had reported higher levels of stress and higher number of life events, in the one-year preceding relapse, in relapsed schizophrenics as compared to stable schizophrenics. The psychological stressors and stressful life conditions have a greater triggering pathophysiologic role in acute and transient psychosis (ATPD) than in Bipolar Affective Disorder, manic phase (Rudraprosad et al., 2007). Socioenvironmental stressors may precipitate schizophrenic attacks and such events tend to cluster in the two to three week period immediately preceding illness onset (R. Day et.al 1987).

Diagnosis

ICD-10(International classification of diseases) Diagnostic Criteria for Schizophrenia

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A. The general criteria for Schizophrenia (above) must be met.
B. Delusions or hallucinations must be prominent (such as delusions of persecution, reference, exalted birth, special mission, bodily change or jealousy; threatening or commanding voices, hallucinations of smell or taste, sexual or other bodily sensations).
C. Flattening or incongruity of affect, catatonic symptoms, or incoherent speech must not dominate the clinical picture, although they may be present to a mild degree.

Hebephrenic schizophrenia

A. The general criteria for Schizophrenia (above) must be met.
B. Either (1) or (2):

(1) Definite and sustained flattening or shallowness of affect;
(2) Definite and sustained incongruity or inappropriateness of affect.

C. Either (1) or (2):

(1) Behaviour which is aimless and disjointed rather than goal- directed;
(2) Definite thought disorder, manifesting as speech which is disjointed, rambling or incoherent.

D. Hallucinations or delusions must not dominate the clinical picture, although they may be present to a mild degree.

Catatonic schizophrenia

A. The general criteria for Schizophrenia (above) must eventually be met, though this may not be possible initially if the patient is uncommunicative.
B. For a period of at least two weeks one or more of the following catatonic behaviours must be prominent:

(1) Stupor (marked decrease in reactivity to the environment and reduction of spontaneous movements and activity) or mutism;
(2) Excitement (apparently purposeless motor activity, not influenced by external stimuli);
(3) Posturing (voluntary assumption and maintenance of inappropriate or bizarre postures);
(4) Negativism (an apparently motiveless resistance to all instructions or attempts to be moved, or movement in the opposite direction);
(5) Rigidity (maintenance of a rigid posture against efforts to be moved);
(6) Waxy flexibility (maintenance of limbs and body in externally imposed positions);
(7) Command automatism (automatic compliance with instructions).

C. Other possible precipitants of catatonic behaviour, including brain disease and metabolic disturbances, have been excluded.

Undifferentiated schizophrenia

A. The general criteria for Schizophrenia above must be met.
B. Either (1) or (2):

(1) There are insufficient symptoms to meet the criteria of any of the sub-types.
(2) There are so many symptoms that the criteria for more than one of the subtypes listed in B(1) above are met.

Residual schizophrenia

A. The general criteria for Schizophrenia (above) must have been met at some time in the past, but are not met at the present time.
B. At least four of the following 'negative' symptoms have been present throughout the previous twelve months:

(1) Psychomotor slowing or under activity;
(2) Definite blunting of affect;
(3) Passivity and lack of initiative;
(4) Poverty of either the quantity or the content of speech;
(5) Poor non-verbal communication by facial expression, eye contact, voice modulation or posture;
(6) Poor social performance or self-care.

Simple schizophrenia

A. Slowly progressive development over a period of at least one year, of all three of the following:

(1) A significant and consistent change in the overall quality of some aspects of personal behaviour, manifest as loss of drive and interests, aimlessness, idleness, a self-absorbed attitude, and social withdrawal.
(2) Gradual appearance and deepening of "negative" symptoms such as marked apathy, paucity of speech, underactivity, blunting of affect, passivity and lack of initiative, and poor non-verbal communication (by facial expression, eye contact, voice modulation and posture).
(3) Marked decline in social, scholastic, or occupational performance.

B. Absence, at any time, of any symptoms referred to in and of hallucinations or well formed delusions of any kind, i.e. the subject must never have met the criteria for any other type of schizophrenia, or any other psychotic disorder.
C. Absence of evidence of dementia or any other organic mental disorder listed in section.

(The ICD-10 Classification of Mental and Behavioural Disorders. Geneva: World Health Organization; 1992.)

Oxidative stress

Introduction

An imbalance between oxidants and antioxidants in favour of the oxidants, potentially leading to damage, is termed 'oxidative stress' (Sies,1985,1986). Oxidants are formed as a normal product of aerobic metabolism but can be produced at elevated rates under pathophysiological conditions. A quasi-steady state is maintained by an intricate pattern of antioxidants. The antioxidaint defense is, in part, calpable of adapting to chalenging needs.

Oxidants

Molecular oxygen can be reduced to water. The intermediate steps of oxygen reduction are the formation of the superoxide anion radical, hydrogen peroxide and the hydroxyl radical, corresponding to the steps of reduction by one, two and three electrons, respectively. Further, ground state molecular(triplet)oxygen, as a diradical, can be electronically excited to singlet molecular oxygen. Oxygen radicals can occur as alkyl or peroxyl radicals, e.g. in lipids. Also, there is nitric oxide, one of the gasseous radicals of biological interest. Peroxynitrite, a non radical reactive species, is formed from the nitric oxide and superoxide anion radicals (sies,1991).

Oxidants are also generated by different types of radiation, with X- irradiation generating the hydroxyl radical and irradiation with ultraviolet light generating electronically excited states with subsequent radical formation. Ultrasound and microwave radiation can also generate reactive oxygen species. Even shear stress, e.g. in homogenization, is known to generate radicals.

The half-lives of the major reactive oxygen species are vastly different, underscoring the necessity for different types of defense mechanisms (Sies, 1993). Highest rate constants for the reaction with target molecules are found for the hydroxyl radical; its reactions are diffusion limited, i.e. they take place practically at the site of generation. In contrast, some peroxyl radicals are relatively stable, with half-lives in the range of seconds. Such molecules may diffuse away from their site of generation and thus transport the radical or oxidant function to other target sites. In cell metabolism, clandestine oxidants may exist and may be transported to distant target sites where they exert oxidant activity. This would include compounds or enzymes with activities that are innocuous in one environment but can be activated to generate oxidants under other conditions.

The human diet contains many compounds of an oxidant and antioxidant nature (Ames, 1983). In the present context, it is important to note that there are dietary compounds which act as potential oxidants, including a variety of quinones, capable of redox cycling, and substrates for enzyme systems which generate oxidants.

Antioxidants

In their definition of the term, Halliwell & Gutteridge (1989) state that an antioxidant is 'any substance that, when present at low concentrations compared with that of an oxidizable substrate, significantly delays or inhibits oxidation of that substrate'. This definition includes compounds of a non-enzymatic as well as an enzymatic nature. Clearly, the diversity of antioxidants matches that of pro-oxidants. The principles underlying the antioxidant was reported by Sies, 1993.

Prevention

A first line of defense against reactive oxygen species is, of course, protection against their formation, i.e. prevention. There are numerous strategies in biology designed to evade oxidative stress, ranging from the plankton that descends from the surface of the sea water to lower levels of solar irradiation, to the packaging of DNA in chromatin to shield the genetic material by providing alternative targets. Microbes have developed specialized strategies to prevent oxygen dependent killing by phagocytes. Regarding radical formation, first it should be mentioned that some of the enzymes prone to generate free radical species are ingeniously designed. Cytochrome oxidase, which carries out most of the cellular oxygen reduction, does not release superoxide or other radicals, even though it contains iron and copper ions. Likewise, the three­dimensional structure of the enzyme ribonucleotide reductase keeps the radical character of the tyrosyl function in subunit B from spreading to the environment by forming an appropriate 'cage'. Furthermore, the prevention of initiation of chain reactions includes the binding of metal ions, in particular iron and copper ions. Metal chelation is a major means of controlling lipid peroxidation and DNA fragmentation. Thus, the metal-binding proteins ferritin, transferrin, coeruloplasmin and others, e.g. metallothionein, are of central importance in the control of potential radical-generating reactions. Another strategy to increase the resistance to metal ion dependent oxidation is to modify the potential target site (sies,1993).

Protection of cells from incident radiation may occur through specialized pigments, e.g. the melanins for ultraviolet radiation or the carotenoids for electronically excited states such as singlet oxygen. However, these and other strategies are not completely preventative, because they operate by decreasing the yield of a given challenging agent with less than 100 % efficiency.

In this regard, there are many enzymatic systems in cells and body fluids to control the level of reactive species which otherwise might generate a cascade of products which, in turn, would lead to attacking oxidants. One important group of such enzymes is the glutathione S-transferases. This family of enzymes catalyses the reaction of the major low molecular mass thiol, glutathione, with reactive electrophiles to form thioethers, called S- conjugates. Biologically reactive electrophilic intermediates can be formed in a variety of metabolic pathways, notably those involving cytochrome P450, and are of interest in toxicology and pharmacology (NAD(P)H: quinone oxidoreductase; Schulz, Eickelmann & Sies, 1996).

A strategy of preventative antioxidation could therefore be formulated as prevention by diversion, i.e. by channelling an attacking species into a less harmful product, hence lowering the risk of further damage. In the extreme, this could involve whole cells, one example being the intestinal mucosal cells. These cells are exposed to a variety of reactive intermediates and xenobiotics, and the rate of accumulation of products of oxidative damage in these cells is high. The turnover and elimination of whole cells prevents further spread of the challenging species. This type of prevention overlaps in part with the concept of interception.

Interception

Non-enzymatic antioxidants

This is the domain of the antioxidants as defined in a more narrow sense. The basic problem is to intercept a damaging species, once formed, to prevent it from further deleterious reactions. This is the process of deactivation. For radical compounds, the final deactivation consists of the formation of non-radical and non-reactive end-products. Due to the nature of the free radicals, there is a tendency towards chain reaction ('radicals beget radicals'). A second objective of biological importance is to transfer the radical function away from more sensitive target sites to compartments of the cell in which an oxidative challenge would be less deleterious (Briviba,1994). In general, this means transferring the oxidizing equivalents from the hydrophobic phases into the aqueous phases, e.g. from the membrane to the cytosol or from lipoproteins to the aqueous phase of the plasma. Biologically, the most efficient intercepting antioxidants combine optimal properties for both these objectives: first, they react with initial free radicals, such as lipid peroxyl radicals, at suitable rates; and second, they are capable of interacting with water­soluble compounds for their own regeneration. This combined action then transfers the radical function away from further potential targets. In biological membranes, where a high-efficiency back-up system is present, there may be the need for only one to three antioxidant molecules per 1000 potential target molecules. Such intercepting chain-breaking antioxidants are often phenolic compounds. (R, R, R) a-Tocopherol is probably the most efficient compound in the lipid phase (Traber & Sies, 1996).

Enzymatic antioxidants

All cells in eukaryotic organisms contain powerful antioxidant enzymes. The three major classes of antioxidant enzymes are the superoxide dismutases, catalases and glutathione (GSH) peroxidases. In addition, there are numerous specialized antioxidant enzymes reacting with and, in general, detoxifying oxidant compounds. Indirect antioxidant functions carried out by enzymes are: (a) the back-up function, e.g. the replenishment of GSH from glutathione disulphide (GSSG) by the flavoprotein GSSG reductase; and (b) the transport and elimination of reactive compounds, e.g. the glutathione S-transferases and the transport systems for the glutathione S-conjugates. Different subcellular sites and different cell types may contain varying amounts of the antioxidant enzymes (Soboll,1995).

Antioxidant enzymes: properties and biological implications

Superoxide dismutase

Superoxide dismutase is the antioxidant enzyme that catalyses the dismutation of the highly reactive superoxide anion to O2 and to the less reactive species H2O2. Peroxide can be destroyed by Catalase or Glutathione peroxidase reactions (Fridovich,1995) , (L.M. Sandalio et.al,1997) and (H.D. Teixeira et.al,1998).

Abbildung in dieser Leseprobe nicht enthalten

In humans, there are three forms of SOD: cytosolic Cu/Zn-SOD, mitochondrial Mn-SOD, and extracellular SOD(EC-SOD) (J. Sandstróm et.al,1994) and ( E. Sun et.al,1995). SOD destroys O2- by successive oxidation and reduction of the transition metal ion at the active site in a Ping Pong type mechanism with remarkably high reaction rates (B. Meier, et al, 1998).

Mn-SOD is a homotetramer (96 kDa) containing one manganese atom per subunit that cycles from Mn (III) to Mn (II) and back to Mn (III) during the two step dismutation of superoxide (L.A. MacMillan-Crow et al, 1998). The respiratory chain in mitochondria is a major source of oxygen radicals. Mn-SOD has been shown to be greatly induced and depressed by cytokines, but is only moderately influenced by oxidants (P. Stralin et.al,1994). Inactivation of recombinant human mitochondrial Mn-SOD by peroxynitrite is caused by nitration of a specific tyrosine residue (F. Yamakura et.al, 1998).

Cu/Zn-SOD (SOD-1) is another type of enzymes that has been conserved throughout evolution. These enzymes have two identical subunits of about 32 kDa, although a monomeric structure can be found in a high protein concentration from E. coli (A. Battistoni et al, 1996). Each subunit contains a metal cluster, the active site, constituted by a copper and a zinc atom bridged by a histamine residue (A. Battistoni et al, 1998), (R.B. Leah et al, 1998) and (M.E. Stroppolo et al, 1998).

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Details

Title
Oxidative Stress and the Level of Antioxidant Enzymes in Schizophrenia
College
Jawaharlal Nehru University  (ALIGARH MUSLIM UNIVERSITY)
Course
MD PSYCHIATRY
Grade
10
Author
Year
2012
Pages
169
Catalog Number
V913268
ISBN (eBook)
9783346223760
ISBN (Book)
9783346223777
Language
English
Keywords
oxidative, stress, level, antioxidant, enzymes, schizophrenia
Quote paper
Mohammed Reyazuddin (Author), 2012, Oxidative Stress and the Level of Antioxidant Enzymes in Schizophrenia, Munich, GRIN Verlag, https://www.grin.com/document/913268

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