Free radical mechanisms in schizophrenia and tardive dyskinesia

Neuroscienceand BiobehavioraiReviews,Vol. 18, No. 4, pp. 457--467,1994 Copyright©1994ElsevierScienceLtd Primedin the USA.All fightsreserved 0149-7634/94$6.00 + .00

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Free Radical Mechanisms in Schizophrenia and Tardive Dyskinesia J E A N L. C A D E T t A N D L I N D A A. K A H L E R

Molecular Neuropsychiatry Section, N I H / N I D A , Addiction Research Center, Baltimore, M D 21224

(Received 29 N o v e m b e r 1989)

CADET, J. L. AND L. A. KAHLER. Free radical mechanisms in schizophrenia and tardive dyskinesia. NEUROSCI BIOBEHAV REV 18(4)457-467, 1994.-The present article discusses the distribution of free radical processes in the central nervous system (CNS). Specifically, we discuss the involvement of oxyradicals in the normal metabolism of catecholamine. We also review some proposals related to the possible importance of these compounds in the development of neuropsychiatric and movement disorders such as schizophrenia and neuroleptic-induced tardive dyskinesia (TD), respectively. Clinical studies have shown that antioxidant treatment can attenuate the movement abnormalities observed in TD. Further studies are necessary to evaluate the status of specific scavenging systems in these two disorders. The prophylactic use of antioxidants in patients who are treated with neuroleptics needs also to be considered. Free radicals Antioxidants Superoxide dismutase Glutathione Catecholarnines Schizophrenia Neuroleptics Tardive dyskinesia

INTRODUCTION

Glutathione peroxidase Catalase Nitric oxide Glutamate

neuropsychiatric diseases, namely Schizophrenia and tardive dyskinesia.

IN spite of recent advances in neurobiology, a thorough understanding of the major problems in the clinical neurosciences remains elusive. One issue concerns the elucidation of the processes involved in the selective morbid anatomy associated with various neurodegenerative disorders such as the dementias and the movement disorders. For example, although molecular biological techniques have already impacted significantly on the approaches which are being taken toward these disorders, much work remains to be done to evaluate the mechanisms by which gene products cause selective neuronal loss. Furthermore, the functional importance of the biochemical abnormalities found in the central nervous system of these patients has yet to be understood. Because endogenous or exogenous neurotoxins may be important in causing these diseases, theoretical frameworks are being developed to clarify the complexities of neuropsychiatric and movement abnormalities. These disorders may be special cases of general toxic mechanisms directed against specific neurochemical substructures. Herein, we elaborate on some ideas which deal with the involvement of oxyradicals in two

FREE RADICALMECHANISMSIN THE CENTRAL NERVOUSSYSTEM

Source of Oxyradicals Free radicals are reactive substances which have an odd number of electrons. Aerobic organisms take up oxygen, which is then used by the mitochondrial enzyme cytochrome oxidase in a process that results in the formation of water (79,88-90). This process results in the formation of the superoxide radical (O2--), of hydrogen peroxide (H202), of the hydroxyl radical (. OH) and the hydroxyl ion (OH-)(14,26,145). The superoxide anion is also produced by autoxidation of compounds such as catecholarnines (55-59), tetrahydrobiopterins (135), and ferrodoxins (128). The mitochondrial electron transport chains and reactions catalyzed by enzymes such as aldehyde oxidase, indoleamine dioxygenase, monoamine oxidase, and xanthine oxidase also yield the superoxide anion (79). H202 is toxic to various cell types through processes of

i Requests for reprints should be addressed to Jean Lud Cadet, M.D., Molecular Neuropsychiatry Section, NIH/NIDA, Addiction Research Center, P.O. Box 5180, Baltimore, MD 21224. 457

458 enzyme oxidation or through the initiation of lipid peroxidation. Hydrogen peroxide is produced in reactions catalyzed by amino acid oxidase and monoamine oxidase (165), or through the autoxidation of ascorbate or catecholamines (58). The toxicity of H202 is thought tO be related to its reaction with transition metals to form the hydroxyl radical (170). The hydroxyl radical can react with many biochemical substances including amino acids, nucleic acids, phospholipids, and sugars (8,112,125,170). For instance, when •OH interacts with membrane lipids, it initiates the formation of lipid peroxides which can then react with metals. This type of reaction helps to propagate the chain of lipid peroxidation. This process results in destabilization of cell membranes which then become permeable to certain ions such as calcium. This process eventually causes cell death. High concentrations of various metals are found in brain regions such as the substantia nigra and basal ganglia (92,113,146) which have been implicated in the pathogenesis of neurodegenerative and movement disorders. In addition, these structures contain very high concentrations of catecholamines which can be neurotoxic via the production of oxyradicals during their catabolism.

Involvement of Reactive Species in Catecholamine Metabolism The neurotoxicity and participation of catecholamines in the production of oxyradicais is well documented (54-59,167, 182,200,201). H202 is produced during reactions catalyzed by MAO, one of the enzymes involved in catecholamine metabolism (181). The selective neurotoxicity of catecholamines is related to the production of free radicals and antioxidants such as phenylthiourea, benzoate, and ethanol can partially attenuate the toxic effects of some of these reactive species (54-59). Graham and his collaborators (83,84) had demonstrated that the cytotoxicity of the catecholamines is related to their rate autoxidation to form quinones (i.e., 6-hydroxydopamine > dopamine > norepinephrine > epinephrine). The rate of cyclization to less reactive leukochromes was in the reverse order from this list. Reactions involving nucleophilic attacks of protein side-chains by their quinone by-products are also involved (83,84). Intermediate reactive species of molecular oxygen may be important in the pathobiology of many diseases (34,51,69,8891,122,144). Inhalation of pure oxygen for long periods of time leads to alveolar damage, lung fibrosis, and the adult respiratory distress syndrome (69,91). Free radicals have also been implicated in myocardial infarction (122,166), cancer (144), and aging (144).

Scavenging Systems Aerobic organisms possess dctoxification systems such as enzymes (e.g., catalase, glutathione peroxidase, superoxide dismutase) and antioxidants (e.g., vitamin E, vitamin C) which protect them from the widespread oxidative processes that occur during normal cellular functions (2,57,78,105,123, 158,179,194). For example, the dismutation of 02- is catalyzed by superoxide dismutases which eliminate the reactive species much faster than its spontaneous rate of dismutation (79). Hydrogen peroxide is produced during the dismutation of 02- and is itself eliminated by catalase and peroxidases (57,79). Vitamin E, vitamin C, selenium, and glutathione are also very important in controlling the toxic effects of free radicals. Vitamin E is present on cellular membranes which it stabilized by antago-

CADET AND KAHLER nizing the process of lipid peroxidation (194,197). It protects ceils by scavenging free radicals during the peroxidation of unsaturated fatty acids through a reaction that leads to the formation of the stable vitamin E radical, which itself can be reduced by vitamin C. Selenium is a component of the active site of the enzyme glutathione peroxidase (158). Because cells depend on these antioxidant mechanisms to survive, any state that stresses these systems beyond their capacity to compensate will cause deleterious effects. Such conditions could be due to excess transition metals, increased catecholamine, or lack of precursor amino acids needed to synthesize the protein scavengers. The following discussion deals with the possible participation of free radicals in a neuropsychiatric disorder, schizophrenia and a drug-induced movement disorder, tardive dyskinesia. SCHIZOPHRENIA

The Dopamine Hypothesis of Schizophrenia The introduction of chlorpromazine, a drug that caused dramatic improvement in many schizophrenic patients stimulated a revolution in thinking regarding the etiology of schizophrenia (1,16,48,64,96,160). The mode of action of these drugs was soon demonstrated to involve interactions with dopamine receptors (47,121). The blockade of dopamine receptors occurs at neuroleptic concentrations similar to those effective in the treatment of schizophrenia. Also, the ability of different neuroleptic drugs to block dopamine receptors was found to correlate with their antipsychotic potency (60, 142,168). Moreover, amphetamine can cause a state very similar to paranoid schizophrenia (9,10,12,16,61,67,75,98,161, 199). The subsequent discovery that amphetamine could cause release of catecholamines stimulated suggestions that dopaminergic hyperactivity may be involved in some schizophrenic patients (see ref. 155 for more discussion). Dopamine agonist can effect the symptoms of schizophrenia (11,32,82,101). Postmortem studies have provided partial support for the dopamine hypothesis. There are significant increases in the levels of dopamine in the nucleus accumbens, caudate nucleus and amygdala of the brains of a subgroup of schizophrenic patients in comparison to controls (20,22,93,118,150). The elevation of dopamine content appears to be highest in the brains of younger schizophrenic patients (118). On the other hand, significant decreases in cerebrospinal fluid homovanillic acid (HVA) have been found in a subgroup of schizophrenic patients with ventricular enlargement (183,184). Patients who were without brain atrophy and who had evidence of increased dopamine concentration exhibited more psychotic symptoms and had a shorter duration of illness than those patients with evidence of decreased dopamine levels. Wise and Stein had also reported that some schizophrenic patients have a significantly lower activity of DBH in their brains (196). Although the validity of the dopamine hypothesis of schizophrenia has been questioned, it is clear that any future theories of schizophrenia will have to consider the role of dopamine, both in terms of the functional increases and decreases reported in different groups of patients. More recently a number of investigators have suggested that DA-glutamatergic interactions may form the basis of the disorder (46).

Defect Symptoms and the Course of Schizophrenia Because the hypercatecholaminergic hypotheses of schizophrenia are insufficient to explain the existence of negative symptoms and the response of these abnormalities to catechol-

FREE RADICAL MECHANISMS aminergic drugs, the existence of different forms of schizophrenia has been postulated (65,161). Crow's (65) conjecture has become particularly popular. A simplified version suggests that there may be two broad forms of schizophrenia: one consisting mainly of positive symptoms but with few or no structural brain abnormalities (type I schizophrenia), and a second marked by a predominance of negative symptoms accompanied by structural brain abnormalities (type II schizophrenia). Crow has suggested that the dopamine hypothesis may offer an explanation for type I schizophrenia, but is inadequate to account for type II schizophrenia. This dichotomization does not account for the spectrum of symptoms observed in many schizophrenic patients. It does not explain why some type I patients progress to the type II form, a process sometimes referred to as "schizophrenic burn-out" or the development of a "residual" or "schizophrenic defect state". In recent years, some studies have supported the notion that "burn-out" occurs in at least a subgroup of schizophrenic patients (30,126,143,175,191). For example, in a study of the initial clinical presentation of 166 schizophrenic patients, Mellor reported that 72070 had positive symptoms (126). Patients with predominantly positive symptoms had a mean duration of illness of 5.1 yr whereas those with negative symptoms had a mean duration of 8.6 yr. Stephens had concluded that schizophrenia, defined meticulously, still has a relatively poor outcome despite modern psychotherapeutic treatments (175). The possibility has also been suggested that some patients may show a decrease in pathology during the involutional years (30). Pfohl and Winokur also reported that positive symptoms such as hallucinations and delusions had an early onset and tended to resolve with the passage of time (143). Negative symptoms such as flat affect, poor social interaction, or inability to work occurred much later and tended to be more persistent. Long-term follow-up studies are difficult to interpret because, sometimes, it is not clear if the development or emergence of negative symptoms is considered to represent an improvement over acute positive symptomatology, or a decline in functioning. In any case, the evidence suggests that, some schizophrenic patients who initially manifest a preponderance of positive symptomatology may show, with the passage of time, a reduction in such symptoms along with the occurrence of more negative s y m p t o m s - t h e development of "burn-out'.

Neuropathological Abnormalities in Schizophrenia Interest in the neuropathology of schizophrenia has been rekindled, in large part, because neuroleptics are of limited efficacy in the treatment of schizophrenia. Recent postmortem and neuroradiological studies have identified pathologic changes in the areas of the brains of these patients (137,154). Because of the importance of dopaminergic transmission to the basal ganglia and the frontal lobes of the brain, the evidence for pathology in these two areas of the brain will be briefly discussed. Frontal lobe pathology. The frontal lobes have long been areas of interest in the study of schizophrenia (17). For example, some recent investigations have suggested that cortical pathology, especially of the frontal lobes, may play a significant role in the manifestation of the schizophrenic syndrome (192). Schizophrenic patients also have deficit in neuropsychological tests (173). Neuropathological studies have reported alterations in the frontal cortex and cingulum of schizophrenic patients (24,60,

459 129,176,180). Some of the abnormal findings in schizophrenic brains were very similar to what had been observed in vitamin E-deficiency states (129). This comparison is important to the theme of our review since vitamin E is a very important free radical scavenger. Basal ganglia pathology. Evidence has accumulated which also implicates basal ganglia dysfunction in schizophrenia. The idea of basal ganglia pathology in schizophrenia is supported by the fact that some chronic schizophrenics who have not been treated with neuroleptic drugs may exhibit the presence of abnormal movements (often choreoathetoid, sometimes parkinsonian) (127,138,149,171,172). The reported overall prevalence of spontaneous movements appears to be in the range of 4070 to 7°70 of schizophrenic patients (49). The movements often appeared to be clinically similar to movements described in tardive dyskinesia, but in many cases the movements were described in tardive dyskinesia, but in many cases the movements were not described in detail (see ref. 42 for more detail). Pathological changes have been found in the basal ganglia of patients with schizophrenia and catatonia (13,23,24,99,120, 132,185). These abnormalities included fatty degeneration of neurons and actual neuron loss.

The Free Radical Hypothesis of Schizophrenia The so-called positive symptoms of schizophrenia appear to predominate during the early stages of the schizophrenic syndrome, whereas the apathetic "defect" stage may arise later. The dopamine excess hypothesis was initially posited to explain the positive symptoms while structural abnormalities in the brains of schizophrenic were thought to account for the burnout state. This original proposition attempted to dichotomize the group of schizophrenias into dopamine- and nondopamine-related syndromes. The functional dopamine excess theory is consonant with some biochemical and clinical studies, but does seem to falter, at a first approximation, when it comes to explaining the development of the defect abnormalities of schizophrenic patients. It has been proposed, however, that an extension of the dopamine hypothesis that takes into consideration the production of toxic by-products of catecholamines such as semiquinone, hydrogen peroxide, and hydroxyl radical, may explain the development of the defect symptoms and the decrease in CSF HVA reported in some patients (35,38). It was thus suggested that if the brains of some schizophrenic patients are characterized by areas of oscillating or even chaotic (94), elevated dopamine content, the potential formation of toxic by-products during catecholamine catabolism might eventually lead to neuronal damage in these regions of the brain. This hypothesis provides a pivot for proposals such as those of Klein (107), Stein and Wise (174), and Wyatt (198). Klein had suggested that acute mania and schizophrenia have a common core of activation derangement, because both disorders respond similarly to antipsychotic treatment (107). He suggested further that, in the case of schizophrenia, such an activation derangement may interact with an abnormal CNS or may induce a state of autointoxication, and that neuroleptics may normalize a pathologic feedback loop in the brains of these patients. Stein and Wise (174) suggested a role for 6-hydroxydopamine in schizophrenia primarily on the basis of the effect of chronic 6-hydroxydopamine on self-stimulation and other reward behaviors in rats, and on the ability of chlorpromazine to antagonize the norepinephrine-depleting effects of 6-hydroxydopamine. Wyatt has also come to a similar conclusion about the role of

460 6-hydroxydopamine in the phenomenology of schizophrenia (198). Although the existence of 6-hydroxydopamine in vivo has been questioned because of its instability, Seiden and Vosmer (162) have recently reported that acute methamphetamine administration in rats can cause the formation of 6hyroxydopamine. Methamphetamine can cause depletion of monoamines in the brain (159,190). This depletion can be attenuated by the use of antioxidant vitamin C (190) and in transgenic mice that have high levels of the scavenging enzyme CuZn superoxide dismutase (43). If there is excessive dopamine metabolism in schizophrenia, it is thought that a small portion of the dopamine would be metabolized to 6-OHDA. This amount of 6-OHDA might be sufficient to cause freeradical-based cell destruction over long periods of time. Nevertheless, since the rate of formation of other quinone by-products of the catecholamines is faster than the conversion of dopamine to 6-OHDA (3), the more parsimonious explanation may be that formation of semiquinone and oxyradicals (hydrogen peroxide, hydroxyl radicals) may be the responsible culprits involved in the production of the abnormalities observed in the brains of schizophrenic patients. This notion is consistent with the finding that some schizophrenics have low DBH activity in their brains since hydrogen peroxide can indeed inhibit the enzyme DBH. The possibility that excitotoxic substances might play a role in the development of these changes needs also to be considered. If this is the case, the toxic effects might be through the production of the free radical, nitric oxide (NO), since glutamate appears to effect the nervous system through the arginine-NO system (68). The progression of the biochemical and neuroanatomical changes may be reflected in varying combinations of positive and negative symptoms associated with pathology in structures such as the frontal lobe, the basal ganglia, the limbic systems, and the brainstem core (133). Recent neuropathological studies of the brains of schizophrenic patients have reported pathologic changes in these regions (13,23,31,99,116,120,129,153,176, 180,185). One of these reports drew attention to the similarities of these changes to those observed in vitamin E deficiency states (129). In previous attempts to account for the neuroanatomical distribution of the pathology seen in the brain of schizophrenic patients, Cadet had suggested that most of these areas form subsets or are projection areas from the so-called isodendritic core of the brainstem (33,35). The isodendritic core is characterized by a group of cells which have extensive overlapping dendrites and interdigitate freely with passing fibers (147,148). They also project extensively to subcortical nuclei (basal ganglia) and to the neocortex (frontal cortex) (76,115). Some of these structures include the locus ceruleus, the substantia nigra, the substantia innominate, and the hypothalamus. Pathological changes have been reported in some structures in the brains of schizophrenic patients. The free radical extension of the dopamine hypothesis allows us to explain the occurrence of the pathology in these regions of the isodendritic core. It must be noted that it has previously been suggested that Parkinson's disease, the pathology of which (13) probably involves free radical (35,56), may also be a disorder of the isodendritic core (35,157). This contention is supported by the recent report that drug-naive schizophrenic patients show signs of Parkinsonism (44). The subset of patients who begin with defect symptoms and in those who initially present with mixed symptomatology, it is conceivable that the concentration or turnover of dopamine might have been high enough to cause cellular damage but not high enough exceed the symptomatic threshold for

CADET AND KAHLER psychosis. Some of these patients might be deficient in free radical scavenging mechanisms. When one considers the fact that the brain contains large amounts of unsaturated lipids, it is easy to imagine that, in a pathologic condition such as schizophrenia, which may be characterized by the formation of reactive chemical species in the brain, overloading of the scavenging systems may actually occur. Alternatively, there may be more than one type of defect symptoms in schizophrenia. While the early onset defect states might be related to a hyperdopaminergic state in inhibitory brain systems and might be responsive to neuroleptic medications, the later-onset "burn-out" states might be the results of structural damage which occurs in hyperdopaminergic areas over many years. One obvious criticism of the free radical hypothesis in schizophrenia is that it is somewhat indirect. However, this situation is analogous to that of other medical conditions for which a free radical mechanism has been proposed. Moreover, there are clinical and laboratory findings in schizophrenia, previously difficult to explain or reconcile with the dopamine hypothesis, that the free radical hypothesis may help to interpret. For example, it has been reported that some schizophrenic patients have increased copper and ceruloplasmin in their blood and in the hair (27). Increased copper in the brains of some of these patients could catalyze the formation of free radicals from dopamine and react with H202 to yield •OH. These toxins could then result in cell damage. Initially, such deficit might appear as excessive dopaminergic transmission because of compensatory stimulation of dopaminergic neurons. In the end, however, the neurons would die. While metal chelation may be helpful in the early stage of the illness inthe groups of patients with increased copper concentrations,it probably would not be effective in the late state of the disease.

Implications of the Free Radical Model Increased catecholamine content or metabolism in the brains of schizophrenic patients may be associated with the production of excessive free radicals that might result in a chaotic state in neuronal function. Defect symptoms might result from these changes. This hypothesis does not offer an explanation for the initial presence of the hypercatecholaminergic state at the beginning of the illness but attempts to account for some aspects of the course of the disease. The excess dopamine might be the result of a variety of pathologic processes involving enzymes, neurohumoral or immunological factors, or viruses. The timing of presentation and the course of the illness may vary significantly depending on the developmental stage during which the damage was done. This hypothesis may be of preventive interest. The use of antioxidants may be indicated in the treatment of schizophrenia because such an approach may protect the brain from the toxic effects of oxyradicals. This approach would be consistent with the reports that vitamin C and vitamin E can provide partial protection against the toxic effects of methamphetamine (190) and of 6-OHDA (37), on the dopamine system. TARDIVE DYSKINESIA Tardive dyskinesia is characterized by various abnormal movements which develop after the chronic use of antipsychotic drugs (71,102-104,164). Initially described as "dyskinesie facio-buccio-lingui-masticatrice" (164), the concept now includes nonrepetitive choreic and choreoathetoid movements of fingers (piano playing), hands, and of the legs and trunk. Tardive dyskinesia has to be differentiated from some neurological disorders including Huntington's chorea, drug-

FREE RADICAL MECHANISMS induced chorea, and levodopa-induced dyskinesias. The use of neuroleptics is a sine qua non for the diagnosis of tardive dyskinesia to be made.

Neuropathological Findings after Chronic Neuroleptics Chronic treatment with neuroleptics can cause some neuropathological changes in the CNS (5,18,19,50,70,81,85,95,97, 108-111,119,134,139,140,156). Most studies, however, have concentrated on the biochemical or behavioral alterations associated with chronic administration of the drugs. Aksel (5) had reported that the cells of the caudateputamen, the thalamus, and the cerebellum showed chromatolysis, degeneration of the cytoplasm and of the nuclei, and accumulation of chromatin around the nuclear membrane after the chronic use of chlorpromazine in rabbits and cats. Chlorpromazine also causes moderate chromatolytic changes, increased satellitosis, and neuronophagia in the cortex, the lenticular nuclei, the thalamus, and the hypothalamus in rats and monkeys (156). The pons, the medulla, and the cerebellum were also affected. Electron microscopy revealed increased osmiophilia and reduction in the size of the mitochondria, the cytoplasm of neurons and their processes. Chlorpromazine and haloperidol cause significant alterations in the synaptic areas of the basal ganglia (108-111). Haloperidol causes deposition of granular and fibrillary material in the postsynaptic dendrites and vacuolization of presynaptic axon terminals (110). More recently, Benes and her co-workers (18,19) have demonstrated that there was a significant shift in the distribution of axon terminals in the brains of rats chronically treated with haloperidol. The brains of patients treated with neuroleptics show varying degrees of chromatolysis, satellitosis, and neuronophagia in the basal ganglia, the cerebellum, and the cerebral cortex. Patients who suffer from persistent dyskinesia demonstrated more gliosis in the midbrain and in the brainstem and more cell degeneration in the substantia nigra (53; reviewed in ref. 39). Forty-six percent of patients who suffer from persistent dyskinesia secondary to the use of neuroleptics showed swelling of large neurons, satellosis, neuronophagia, and proliferation of astroglia in the caudate nucleus (100). The putamen and giobus pallidus were less affected but showed evidence of central chromatolysis and cytoplasmic ballooning. The neuropathological abnormalities were observed in 57070 of patients who had suffered from dyskinesia prior to death, but in only 7°70 of the patients without movement disorders and 4070 of age-matched psychotics who had no history of long-term neuroleptic treatment. Although the mechanisms by which neuroleptics may cause pathologic changes in the brain are still uncertain, the possibility remains that toxic species may play a role in these changes.

Models of Tardive Dyskinesia Several models have been put forward to explain the development and persistence of TD. The most popular model is that of postsynaptic dopamine receptor supersensitivity. This hypothesis suggests that, because of chronic blockade of the receptors by antagonists, there develops a compensatory increase in the number of binding sites for dopamine in the basal ganglia (6,54,102,103). Chronic treatment with neuroleptics does result in increases in striatal dopamine receptors (see references in 103 and 186-189) and neuroleptic-treated animals do develop a behavioral supersensitivity to dopamine agonist such as apomorphine and amphetamine (187-189). Nevertheless, the validity of the dopamine receptor hypothesis

461 is hampered by the fact that these binding sites increase in number within days of starting treatment with the neuroleptics, whereas TD develops after several months to years after initiation of drug treatment. Moreover, the dopamine receptor hypothesis does not explain the persistence of TD because it is known that, after withdrawal of neuroleptics, the number of dopamine receptors returns to normal in animals that have been treated with these agents. Finally, because doparnine autoreceptors are also upregulated during chronic neuroleptic use, they might have compensated for the changes in the postsynaptic membranes. Some of these issues have been discussed at length by others (77,102,186-189). The possibility that the GABAergic system may also play a role in the development of tardive dyskinesia has also been recently discussed (77). Chronic neuroleptic administration results in a significant reduction of GAD, the enzyme that catalyzes the synthesis of GABA (86). Only animals which showed the reduction in the enzyme level had dyskinetic movements (87). The role of the GABAergic system is supported by the finding that some GABA agonist may have beneficial effects on TD (178). It has been suggested that it might be a degenerative process which causes the abnormalities seen in the GABA system (77). This suggestion is consonant with the hypothesis that chronic use of neuroleptics may be associated with the production of endogenous toxins which are associated with deleterious effects on the brain.

Free Radical Hypothesis of Tardive Dyskinesia Because neuroleptics cause an increase in the turnover of dopamine, both enzymatic and nonenzymatic events could lead to the formation of cytotoxic compounds which might negatively affect neurotransmission and cellular viability. These active species would disturb not only the dopamine systems but also the surrounding GABAergic, cholinergic, or peptidergic neurons. Interactions of neuroleptics with these systems have not been yet fully evaluated either in vitro or in vivo. Moreover, because chlorpromazine can cause increases in the levels of manganese in the central nervous system (21,193), this ion may lead to the exacerbation of catecholamine-induced oxyradical damage in the brain. This idea is consonant with the findings that the interaction of phenothiazine derivatives with trace metals can generate free radicals (reviewed in refs. 39,40). Further support for this hypothesis is provided by the report of increased iron in the brain of a patient who suffered from TD (45). Probably more important than cell death, other mechanisms may serve as substrates for the development of TD (106). For example, the production of cytotoxic species during chronic usage of neuroleptics may lead to the initiation of membrane lipid peroxidation, a process, which could lead to the de-stabilization of the cell membrane. This proposition is in accord with the data of Cohen and Zubenko who demonstrated that in vitro exposure of normal human platelets to psychotropic drugs caused changes in the structural order of the cell membranes (202,203). Striatal ceils of rats treated with neuroleptics also showed abnormal physicochemical properties (55). Patients who suffered from TD after chronic neuroleptic treatment showed similar abnormalities whereas patients without TD did not (204). It is thus conceivable that patients who develop TD may have started with low levels of some free scavenging mechanisms and thus were not able to protect themselves from the damaging effects of the toxins produced during treatment with neuroleptics. Such patients may also be more at risk to develop parkinsonian symptoms during their treatment.

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Because free radicals are thought to be involved in the development and course of idiopathic Parkinson's disease (35, 56), it is possible that a similar mechanism may be involved in neuroleptic-induced parkinsonism. Such an argument implies that patients who showed this side-effect early during their treatment with neuroleptics may be more susceptible to developing TD. Some studies have reported such an occurrence (52,62,63,152). Crane (63) reported that 12.5070 of 180 patients had both neuroleptic-induced parkinsonism and TD. Patients with TD demonstrate more parkinsonian signs (63). Richardson and Craig (151) also reported 26.7070 of 86 patients who suffered from neuroleptic-induced abnormalities had both parkinsonism and tardive dyskinesia. Furthermore, the presence of severe or worsening parkinsonism is associated with the development of TD (52). Another potential risk factor for the development of TD is poor prognosis schizophrenic patients who show poor response to neuroleptic treatment. One confounding factor with this group of patients relates to the observation of spontaneous involuntary movements in chronic schizophrenic patients who have not been treated with neuroleptics (7,15,28,66,138). The free radical hypothesis of dyskinesia may help to explain the occurrence of these movement abnormalities in severe chronic schizophrenics. In essence, in some schizophrenic patients, there may exist, in the course of the illness, a state of excess dopamine in the basal ganglia which causes, with the passage of time, the formation of toxic by-products of catecholamines. These toxic substances may then lead to the destabilization of striatal cell membranes. Thus, related pathogenetic mechanism may be responsible for the development of idiopathic movements in schizophrenia (spontaneous dyskinesia), the progression of the schizophrenic illness, and the appearance of tardive dyskinesia in some patients. The free radical theory of TD predicts that older patients and patients with cognitive deficits or abnormal CT scans should be at greater risk to develop TD. A number of studies support this notion (25,103,104,114,131,177). The association between persistent dyskinesia and brain damage has also been discussed (72). More recently, Richardson and her colleagues (152) reported that there was a positive correlation between increasing age and the development of TD in a mentally retarded population. Waddington et al. (187-189) have also reported that young rats treated long-term with neuroleptics had a higher incidence of abnormal orofacial movements than controls. These abnormal movements were comparable to those observed in older animals. Patients with TD were older and were more cognitively impaired than schizophrenic patients without TD (186). It has been suggested that some patients may develop a condition termed "tardive dysmentia" during chronic treatment with neuroleptics (130,131,195). Thus, when taken together, the reviewed data suggest that chronic use of neuroleptics may be accelerating a mechanism that is common to the development of aging and TD. This process may be the formation of toxic active species during chronic use of neuroleptics. Some animal studies have documented the fact that neuroleptics can cause changes in the oxidative status of the rat brain (41). Furthermore some of the neuroleptic-induced biochemical changes

are attenuated by treatment with the antioxidant vitamin E (reviewed by Cadet, 36; see also ref. 80).

Clinical Implications of the Free Radical Hypothesis The present argument suggests that treatment with antioxidants such as vitamin E and selenium may be beneficial in alleviating or preventing the development of TD. The first reported doubleblind study had revealed that vitamin E can indeed be beneficial in the treatment of TD (39). A number of investigators have replicated these findings (4,16,73,74,141,169) but see Shrigui et al., (163) for a negative study. It will be important to determine whether the use of free radical scavengers such as vitamin E may actually prevent the appearance of TD. It remains to be resolved whether patients who suffer from TD were deficient in free radical scavenging systems before the inception of antipsychotic treatment. Postmortem and cerebrospinal fluid studies in this population of patients may help to characterize the systems that are more affected by chronic use of neuroleptics. For example, is there a depletion of glutathione, superoxide dismutase, or seleniumin the brains of these individuals? Do schizophrenic patients show evidence of neurologic dysfunction have low levels of these antioxidant enzymes, of vitamin E, or of vitamin C? Nevertheless, we have conducted basic studies to test the idea that neuroleptic might cause changes in free radical scavenging systems in rat brain. The chronic use of neuroleptics caused significant decreases in the activity of SOD and catalase but did not significantly affect glutathione or glutathione peroxidase (41). Lohr et al. (117) have also provided evidence for increases in indices of oxidative stress in the cerebrospinal fluid of patients who suffer from tardive dyskinesia. CONCLUSION In conclusion, free radicals may play a hitherto unrecognized role in the development and manifestation of some neuropsychiatric diseases. It is also possible that some of the drugs used in the treatment of these diseases might have deleterious effects on the central nervous system by the production of endogenous toxins or by the suppression of scavenging mechanism on which the organism depends for its survival. Because these issues are very important to the well-being of a large population of patients who need to be treated with these medications, we have sought to determine the role of these reactive substances in the development of these disorders. It is important to point out that, in addition to their action on DA receptors, neuroleptics can affect calmodulin which is important to the action of nitric oxide synthase (29). Decreased levels of NO might lead to increased action of the superoxide radical which is known to react with NO to form peroxynitrite (94). It has recently been suggested that NO may act both as a toxic agent in its own right (68) or as a scavenger of the superoxide radical (136). Thus, the role of NO in TD needs to be evaluated. A multidisciplinary approach to these disorders might help to dissect the cellular and molecular mechanisms involved in the initial appearance and the progression of some of these neuropsychiatric disorders (124). The use of transgenic technology promises to significantly impact this approach (43).

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