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Antioxidant treatment of tardive dyskinesia
Prostaglandins, Leukotrienes and Essential Fatty Acids (1996)55(1 & 2), 77-81
© Pearson ProfesSionalLtd 1996
Antioxidant t r e a t m e n t of tardive dyskinesia John Rotrosen 1,2, Lenard Adler 1,2, James Lohr 3,4, Robert Edson 6, Philip LavorP ,6 1New York Department of Veterans Affairs Medical Center, 423 East 23rd Street, New York, NY 10010, USA. 2New York University School of Medicine, NY, USA. 3San Diego Department of Veterans Affairs Medical Center, CA, USA. 4University of California at San Diego, CA, USA. SPaloAlto Cooperative Studies Coordinating Center, CA, USA. 6Stanford University, CA, USA.
Summary Tardive dyskinesia (TD) is a frequently occurring side effect of treatment with neuroleptic antipsychotic drugs. TD is a persistent and often irreversible syndrome characterized by abnormal movements, including lingual and orofacial dyskinesia, grimacing, tics, choreic movements of the limbs and trunk, and athetosis and dystonia. In some patients the muscles of respiration and speech may also be involved. There is no established treatment for TD.
PREVALENCE OF TD
Among individuals treated with neuroleptics the prevalence of TD is on the order of 10-15% in young populations, 12-25% in more chronic patients, and 25-45% in very chronic patients. 1,2A mean prevalence of 24.2% was found in a meta-analysis of 76 studies including 39 187 patients with a history of neuroleptic exposure? Estimates of severity have generally identified severe impairment in about 4-5%, moderate impairment in about 4 5 0 and mild impairment in about 50% of TD patients. Van Putten estimates that between 400 000 and a million Americans have TD, and that 4-6% of these have severe pathology? With aging there is increased risk; for example, 50-70% of patients over 55 years old may develop TD during their first year of neuroleptic treatment. 5,6
TD also increases the global severity of mental illness and its associated costs. Schizophrenic patients with TD have a shorter time to relapse, a higher relapse rate, leading to more frequent hospitalizations, and longer hospital lengths of stay than those without TD.Z8 TD is associated with increased morbidity related to respiratory tract infections and cardiovascular disorders, and TD may cause death in a small percentage of patients, especially those with respiratory dyskinesias.9-a2 In spite of the development of new 'atypical' antipsychotic agents TD will remain a problem for the foreseeable future. Except for clozapine, there is no evidence that TD is associated more with one neuroleptic than with others; and for those patients with existing TD there is no established treatment. PATHOPHYSlOLOGY AND TREATMENT
IMPACT OF TD
TD is a social handicap that leads to social isolation and compromises dignity and quality of life. Patients with TD are often uncomfortable in public because of their abnormal movements. They are less likely to be accepted into rehabilitation or resocialization programs, and they are less likely to be employable, particularly in jobs with public exposure. These restrictions often prevent placement and prevent independent life in the community. Correspondence to: John Rotrosen, Tel. 212 263 6802; Fax. 212 951 3356.
The pathophysiology of TD is unknown, although several models have been put forth, and from these derivative treatment approaches have been proposed and evaluated. Traditionally the pathophysiology of TD has been attributed to 'denervation supersensitivity' resulting from longterm neuroleptic exposure, i.e., blockade of dopamine neurotransmission leads to compensatory postsynaptic dopamine receptor proliferation or 'supersensitivity' accounting for dyskinetic movements. This construct was originally proposed by Klawans who posited a 'supersensitivity of striatal dopamine receptors, similar to 77
78
Rotrosen et al
denervation-induced supersensitivity seen in peripheral muscles'Y Limited support for this comes both from animal models showing increased receptor density and behavioral supersensitivity to dopamine agonists following neuroleptic treatment, and from analogous receptor findings in humansY Dyskinetic movements are also suppressed by neuroleptics, and 'withdrawal' or 'emergent' dyskinesias are often seen with neuroleptic reduction or discontinuation? 4 However, denervation supersensitivity now appears to be an overly simplistic model for TD. For example, dyskinetic movements do not usually occur until after chronic neuroleptic treatment in humans, while dopamine supersensitivity occurs within weeks of initiation of neuroleptic treatment in rats.~5,~6 Postmortem studies in humans treated with neuroleptics have found consistent increases in dopamine receptors, while only a portion of these patients develop TDY Also, rats which develop dyskinesia-like movements continue to demonstrate these movements after the resolution of dopamine supersensitivityY Finally, the failure of treatment approaches targeted to exploit a 'supersensitivity' hypothesis raises questions about the validity and utility of the hypothesis. Increasing neuroleptic dosage may suppress dyskinetic movements initially, but will likely exacerbate underlying pathology leading to worsening and possible irreversibility. The APA Task Force on Tardive Dyskinesia 12 recommends reduction or discontinuation of neuroleptics when possible since this may result in improvement in up to 50% of patients where TD is recognized in its early stages. Unfortunately, where neuroleptics were appropriately indicated initially, reduction or discontinuation is rarely possible because of the quality of life costs and risks associated with the underlying psychopathology. A second category of hypotheses invokes neurotransmitter interaction imbalances and/or disrupted modulatory and regulatory pathways. Treatment approaches addressing these potential imbalances have included efforts with drugs and nutritional supplements to increase or decrease activity at noradrenergic, cholinergic, GABAergic, serotonergic, and opioid synapses. Nearly every agent for which an hypothesis can be generated has been investigated for its effect on TD. Unfortunately none of these 'neurotransmitter balancing' approaches has been found to be consistently effective. Studies conducted in over a thousand patients between 1979 and 1987 identified such inconsistencies in treatment effect that no practical treatment recommendations could be madeY ,19 OXYGEN
FREE RADICALS AND TD
In 1986 Cadet, Lohr and Jeste 2° put forth a 'free radical hypothesis' purporting to explain the pathophysiology
of TD and suggesting novel therapeutic approaches for TD. In brief, this hypothesis points out that neuroleptic treatment activates oxidative processes in the brain. These, in turn increase free radical formation and may cause oxidative membrane and subcellular damage. For a number of reasons the basal ganglia are particularly vulnerable to this effect, leading to the development of dyskinetic movements. Treatment with antioxidants might then prevent or reverse both the pathology and symptomatology. This hypothesis was elaborated in a number of subsequent papers, 21-2~ and tested in over ten clinical trials, which are described below. The brain is particularly susceptible to free radical damage because of its high oxygen use, 26its high concentration of transition metals such as iron, manganese and copper, (which act as catalysts for free radical formation), its low concentrations of antioxidants (e.g., vitamins C and E) and low levels of the enzymes of the antioxidant defense system (e.g., catalase, superoxide dismutase, glutathione peroxidase), 2z28 and because of its high concentrations of polyunsaturated fatty acids which are targets for free radical attack. While free radicals can damage most cellular constituents (e.g., DNA, protein, membrane lipids) their effects on functional neurophysiology are most likely a consequence of their ability to initiate an oxidative chain reaction known as the lipid peroxidation cascade. Consequences of lipid peroxidation can include alterations in membrane fluidity, 29,~° disruption of receptor-second messenger coupling, dysregulation of ion transport, shifts in transmembrane electrical potential, 31,32and formation of peroxide pores 3a which can permit leakage of calcium24 All of these membrane effects can transiently or permanently affect biological signal transmission and calcium leakage can cause swelling and functional cell shutdown and ultimately cell death. Vitamin E is the major exogenous lipid-soluble antioxidant, and as it resides within the lipid membrane it can effectively disrupt the lipid peroxidation cascade, aS,a6 becoming itself, a less toxic free radical. Cells can also repair early membrane changes possibly through mechanisms involving phospholipase A2 which may preferentially remove oxidized fatty acids from membrane phospholipidsY ,3z There are several (independent) mechanisms by which chronic treatment with neuroleptics may increase free radical formation and cause tissue damage. Catecholamine metabolism via monoamine oxidase produces hydrogen peroxide, 3s,39 and catecholamines themselves can be oxidized to quinones and semiquinones, which can generate free radicals (semiquinones are free radicals themselves). Further, in animals chronic neuroleptic treatment increases the accumulation of iron and manganese in brain, particularly the basal ganglia structures asso-
Prostaglandins, Leukotrienes and Essential Fatty Acids (1996) 55(1 & 2), 77-81
© Pearson Professional Ltd 1996
Antioxidant treatment of tardive dyskinesia 79
ciated with movement disorders. 4°,41 These transition metals can increase free radical formation both by catalyzing the Haber-Weiss reaction and by catalyzing oxidation of catecholamines.42 In humans increased iron has been measured in postmortem brains from patients with TD,43,44 and in the caudates of live patients with TD on the basis of decreased T2 relaxation times in magnetic resonance imaging studies. 45 Alterations in both plasma fatty acids and erythrocyte membrane fatty acids have been reported in schizophrenia, 46,47with consistently greater reductions in patients with TD. In keeping with this, Vaddadi et al4s describe limited improvement in TD following EFA supplementation. Patients treated with neuroleptics have elevated CSF indices of lipid peroxidation and copper compared to untreated controls, 49 and amongst patients treated with neuroleptics those with TD have increased CSF indices of lipid peroxidation compared to control patients without TD.24,5°
recruited over one year to compare vitamin E to placebo over a minimum of one year of treatment (maximum of two years). Randomization will be stratified by VAMC, age, and severity of TD. Outcome assessments include a well-validated movement disorders scale (the Abnormal Involuntary Movement Scale [AIMS]) and electromechanical measures of force instability. Data analyses will primarily use longitudinal marginal models for the repeated measures design to test specific hypotheses about the difference in longitudinal profiles of scores between treatment groups. This study should be completed in mid 199Z
A C K N O W L E D G EM E N T S
This work is supported in part by the Department of Veterans Affairs.
REFERENCES C L I N I C A L S T U D I E S OF A N T I O X l D A N T S IN T D
Over ten controlled and open therapeutic trials with vitamin E have been conducted in patients with existing TD. 2z,51-62 Of these, nearly all reported some efficacy for vitamin E, with better treatment response seen in patients with recent onset TD. Many of these studies used random assignment, double-blind, placebo-controlled methodology, and used validated outcome measures. However, most were relatively small studies (8 to 35 patients) and were of relatively short duration (four to eight weeks). A longer term extension of the original Adler et al. study showed r,ontinued efficacy out to 36 weeks in a sample of 25 patients. 63 Taken together these studies support the hypothesis that vitamin E produces a clinically meaningful improvement in TD over the course of two to three months of treatment, and suggest that this effect is largest in recent onset TD patients.
VA C O O P E R A T I V E S T U D Y 3 9 4
The Department of Veterans Affairs recently funded "CA Cooperative Study 394. The primary goal of this study is to establish whether vitamin E is a safe and efficacious treatment for widespread and long-term use in TD by conducting a large multi-site study with a sufficiently long treatment and follow-up period. Secondary goals are (1) to investigate which clinical features (e.g. duration of TD) predict good therapeutic response, and (2) to identify clinical aspects of the TD syndrome that are more and less responsive to vitamin E therapy. The study is a double-blind, randomized, parallel-group study of up to 180 TD patients from 9 VAMCs who will be © Pearson Professional Ltd 1996
1. Smith J. M., Kucharski L. T., Oswald W., Waterman L. J. A systematic investigation of tardive dyskinesia in inpatients. Am J Psychiatry 1979; 136: 918-922. 2. Woerner M., Kane J., Lieberman J. et al. The prevalence of tardive dyskinesia. J Clin Psychopharmaco11991; 11: 34-42. 3. Yassa R., Jeste D. V. Gender differences in tardive dyskinesia: a critical review of the literature. Schizophrenia Bull 1992; 18: 701-715. 4. Lund D. S. Tardive dyskinesia lawsuits on the increase. The
Psychiatric Times. 1993. 5. Saltz B. L., Woerner M. G., Katie J. M. Prospective study of tardive dyskinesia incidence in the elderly. JAMA 1991; 226: 2402-2406. 6. Lieberman J., Kane J., Woerner M. et al. Prospective study of tardive dyskinesia incidence in the elderly. Psychopharm Bull 1984; 20: 382-386. 7. Kucharski T., Smith J., Dunn D. Tardive dyskinesia and hospital discharge ]Nervous Mental Dis 1980; 168. 8. Lieberman J., Kane J., Sarantakos S. Prediction of relapse in schizophrenia Arch Gen Psychiatry 1987; 44: 597-603. 9. Mehta D., Mallya A., Volavka J. Mortality of patients with tardive dyskinesia. Am J Psychiatry 1978; 135: 371-372. 10. Yassa R., Mohelsky H., Dimitry R., Schwartz G. Mortality rate in tardive dyskinesia. Am J Psychiatry 1984; 141:1018-1019 11. Youssef H. A., Waddington J. L. Morbidity and mortality in tardive dyskinesia: associations in chronic shizophrenia. ACTA Psychiatr Scand 1987; 75: 74-77. 12. APA Task Force on Tardive Dyskinesia. APA Press, Inc., Washington, D.C., 1992. 13. Khot V., Egan M. F., Hyde T M., Wyatt R. J. Neuroleptics and classical tardive dyskinesia. In: Lang A. E., Weiner W. J., eds. Drug-induced Movement Disorders, Mount Kisco, NY: Futura Publishing Co., 1992; pp 121-166. 14. Gerlach J., Reisby N., Randrup A. Dopamine hypersensitivity and
cholinergic hypofunction in the pathophysiologyof TD. Psychopharrnacologia 1974; 46: 363-369. 15. Jenner P., Maarsden C. D. Adaptive changes in brain dopamine function as a result of neuroleptic treatment. Adv Neuro11988; 49:417-431. 16. Burt D. R., Creese I., Snyder S. H. Antischizophrenic drugs:
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chronic treatment elevates dopamine receptor binding in the brain. Science 1977; 196: 326-328. 17. Cross A. J., Crow T. J., Ferrier I. N. et al. Dopamine receptor changes in schizophrenia in relation to the disease process and movement disorders. J Neurol Transmission 1983; 18 (suppl.): 265-272. 18. Waddington J. L., Cross A. J., Ganlble S. J., Bourne R. L. Spontaneous orofacial dyskinesia and dopaminergic function in rates after 6 months of neuroleptic treatment. Science 1983; 220: 530-532. 19. Jeste D. V., Wyatt R. J. Therapeutic stegies against tardive dyskinesia: two decades of experience. Arch Gen Psychiatry 1982; 29: 803-815. 20. Cadet J. L., Lohr J. B., Jeste D. V. Free radicals and tardive dyskinesia. Trends NeuroSci 1986; 9: 107-108. 21. Cadet J. L., Lohr J. B. Possible involvement of free radicals in neuroleptic-induced movement disorders. Ann N Y Acad Sci 1989; 570: 176-185. 22. Lohr J. B., Cadet J. L., Lohr M. A., Jeste D. V., Wyatt R. J. Alphatocopherol in tardive dyskinesia. Lancet 1987; 1: 913-934. 23. Lohr J. B., Cadet J. L., Lohr M. A. et al. Vitamin E in the treatment of tardive dyskinesia: The possible involvement of free radical mechanisms. Schizophrenia Bull 1988; 14: 291-296. 24. Lohr J. B., Kuczenski R., Bracha S., Moir M., Jeste D. V. Increased indices of free radical activity in the cerebrospinal fluid of patients with tardive dyskinesia. Biol Psychialry 1990; 28: 535-539. 25. Lohr J. B. Oxygen radicals and neuropsychiatric illness: Arch Gen Psychialry 1992; 48:1097-1106. 26. Lambertsen C. J. In: Mountcastle V. B., ed. Medical Physiology Vol. 2. Saint Louis: Mosby; 1980; 1722. 27. Halliweil B., Gutteridge J. M. C. Oxygen free radicals and iron in relation to biology and medicine: Some problems and concepts. Arch Biochem Biophyst 1986; 246: 501-514. 28. Halliwell B., Oxidants and the central nervous system: Some fundamental questions. Acta Neuroi Scand 1989; 126: 23-33. 29. Dobretsov G. E., Borschevskaya T. A., Petrov V. A., Vladimirov Y. A. The increase of phospholipid bilayer rigidity after lipid peroxidation. FEBS Lett 1977; 84: 125-128. 30. Bruch R. C., Thayer W. S. Differential effect of lipid peroxidation on membrane fluidity as determined by electron spin resonance probes. Biochem Biophys Acta 1983; 733: 216-222. 31. Marshansky V. N., Novgorodov S. A., Yaguzhinsky L. S. The role of lipid peroxidation in the induction of cation transport in rat liver mitochondria: The antioxidant effect of oligomycin and dicyclohexylcarbodimide. FEBS Lett 1983; 158: 27-30. 32. Scott J. A., Rabito C. A. Oxygen radicals and plasma membrane potential. Free Rad Biol Med 1988; 5: 237-246. 33. Bindoli A. Lipid peroxidation in mitochondria. Free Rad Biol Med 1988; 5: 247-261. 34. Franceschi D., Graham D., Sarasua M., Zoilinger R. M. Jr. Mechanisms of oxygen free radical-induced calcium overload in endothelial cells. Surgery 1990; 108: 292-29Z 35. Scott J. A. Phospholipase activity and plasma membrane homeostasis. J Theoret Biol 1984; 111: 659-665. 36. Diplock A. T., Machlin L.J., Packer L., Pryor W. A. Vitamin E: biochemistry and health implications. Ann NY Acacl Sci 1989; 570. 3Z Van Kujik E J. G. M., Sevanian A., Handelman G. J., Dratz E. A. A new role for phospholipase A2: Protection of membranes from lipid peroxidation damage. Trends Biochem Sci 1987; 1 2 : 3 1 - 3 4 . 38. Cohen G. Oxy-radical toxicity in catecholamine neurons. Neuro toxicology 1984; 5: 77-82. 39. Cohen G., Spina M. B. Hydrogen peroxide production in dopamine neurons: Implications for understanding Parkinson's
disease. ProgParkinson Res 1988; 119-126. 40. Weiner W. J., Nausieda P. A., Klawans H. L. Effects of chlorpromazine on central nervous system concentrations of manganese, iron, and copper. L/~ Sc/1977; 20:1181-1186 41. Bird E. D., Collins G. H., Dodson M. H., Grant L. H. The effect of phenothiazine on the manganese conccentration in the basal ganglia of sub-human primates. In: Barbeau A, Bumette J-R, eds. Progress in Neuro-Genetics. Amsterdam: Excerpta Medica, 1967; 600-605. 42. Miller D. M., Buettner G. R., Aust S. D. Transition metals as catalysts of "autoxidation" reactions. Free Rad Biol Med 1990; 8: 9 5 - 1 0 8 .
43. Hunter R., BlacAc~oodW., SUlith M. C., Cumings J. N. Neuropathological fmdings in three cases of persistent dyskinesia following phenothiazine medication. J Neurol Sci 1968; 7: 263-273. 44. Campbell W. G., Raskind M. A., Gordon T., Shaw C. M. Iron pigment in the brain of a man with tardive dyskinesia. AmJ Psychiatry 1985; 142: 364-365. 45. Bartzolds G., Garber J., Oldendorf W. H., Marder S. R., Goldstein M. J. Shortened T2 of caudate in MRI study of tardive dyskinesia. Abstr Am Coil Neuropsychopharmacol 1989; 10Z 46. Horrobin D. E, Manku M. S., Morse-Fisher N. et al. Essential fatty acids in plasma phospholipids in schizophrenics. Biol Psychiatry 1989; 25: 562-568. 4Z Glen A. I. M., Glen E. M. T, Horrobin D. F. et al. A red cell membrane abnormality in a subgroup of schizophrenic patients: evidencce for two diseases. Schizophrenia Res 1994; 12:53-61.
48. Vaddadi K. S., Courtney P., Giilard C. J., Manku M. S., Horrobin D. F. A double-blind trial of essential fatty acids supplementation in patients with tardive dyskinesia. Psychia~O] Res 1989; 27:313-323 49. Pall H. S., Williams A. C., Blake D. R., Lunec J. Evidence of enhanced lipid peroxidation in the cerebrospinal fluid of patients taking phenothiazines. Lancet 1989; 2: 596-599. 50. Sram R. J., Billkova B., Kocisova J. et al. Antioxidants effect on alcohol, drugs and aging. In: Mendelsohn M. L., Albertini R. J., eds. Mutation and the Environment. New York: Wfley-Liss; 1990; pp 327-337. 51. Lohr, J. L., Caligniri, M. P. A double-blind placebo-controlled study of vitamin E treatment of tardive dyskinesia. J Clin Psychiatry In press. 52. Elkashef A. M., Ruskin P. E., Bacher N., Barrett D. Vitamin E in the treatment of tardive dyskinesia. Am J Psychiatry 1990; 147: 505-506. 53. Egan M. T, Hyde T., Albers G. et al. Treatment of tardive dyskinesia with vitamin E. Am J Psychiatry 1992; 149: 773-77Z .... 54. Shriqui C. L, Bradwejn J., Annabel L., Jones B. D. Vitamin E in the treatment of tardive dyskinesia: a double-blind placebo controlled study. AmJPsychiaPey 1992; 149: 391-393. 55. Adler L, Peselow E., Rotrosen J. et al. Vitamin E treatment of tardive dyskinesia. Am J Psychiatry In Press. 56. Schmidt M., Meister P., Baumann P. Treatment of tardive dysldnesia with vitamin E. EurPsychiatry 1991; 6: 201-207. 5Z Spivak B., Schwartz B., Radwan M. et al. Alpha-tocopherol treatment for tardive dyskinesia. J Nerv &lent Dis 1992; 180:400-401.
58. Junker D., Steigleider P., Gattaz W. E Alpha-tocopherol in the treatment of tardive dyskinesia. Clin Neuropharm 1992; 15 (supp 1, pt b): 639B. 59. Akhtar S., Jajor T. R., Kumar S. Vitamin E in the treatment of tardive dyskinesia. J Postgrad Med 1993; 29:124-126.
Prostaglandins, Leukotrienes and Essential Fatty Acids (1996) 55(1 & 2), 77-81
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Antioxidant treatment of tardive dyskinesia
60. Peet M., Laugharne J., Rangarajan N., et al. Tardive dyskinesia, lipid peroxidation and sustained amelioration with vitamin E treatment. Int CIin Psychopharm 1993; 8:151-153. 61. Lain L. C. W., Chiu H. F. K., Hung S. F. Vitamin E in the treatment of tardive dyskinesia: A replication study. J Nerv Merit Dis 1994; 182:113-114.
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62. Dabiri L. M., Pasta D., Darby J. K. et al. Effectiveness of vitamin E for treatment of long-term tardive dyskinesia. Am J Psychiatry 1994; 151: 925-926. 63. Adler L., Peslow E., Angrist B. Vitamin E in tardive dyskinesia: Effects of longer term treatment. Am Coll Neuropsychopharmacol Abstr 1992; p. 213.
Prostaglandins, Leukotrienes and Essential Fatty Acids (1996) 55(1 & 2), 77-81
© Pearson ProfesSionalLtd 1996
Antioxidant t r e a t m e n t of tardive dyskinesia John Rotrosen 1,2, Lenard Adler 1,2, James Lohr 3,4, Robert Edson 6, Philip LavorP ,6 1New York Department of Veterans Affairs Medical Center, 423 East 23rd Street, New York, NY 10010, USA. 2New York University School of Medicine, NY, USA. 3San Diego Department of Veterans Affairs Medical Center, CA, USA. 4University of California at San Diego, CA, USA. SPaloAlto Cooperative Studies Coordinating Center, CA, USA. 6Stanford University, CA, USA.
Summary Tardive dyskinesia (TD) is a frequently occurring side effect of treatment with neuroleptic antipsychotic drugs. TD is a persistent and often irreversible syndrome characterized by abnormal movements, including lingual and orofacial dyskinesia, grimacing, tics, choreic movements of the limbs and trunk, and athetosis and dystonia. In some patients the muscles of respiration and speech may also be involved. There is no established treatment for TD.
PREVALENCE OF TD
Among individuals treated with neuroleptics the prevalence of TD is on the order of 10-15% in young populations, 12-25% in more chronic patients, and 25-45% in very chronic patients. 1,2A mean prevalence of 24.2% was found in a meta-analysis of 76 studies including 39 187 patients with a history of neuroleptic exposure? Estimates of severity have generally identified severe impairment in about 4-5%, moderate impairment in about 4 5 0 and mild impairment in about 50% of TD patients. Van Putten estimates that between 400 000 and a million Americans have TD, and that 4-6% of these have severe pathology? With aging there is increased risk; for example, 50-70% of patients over 55 years old may develop TD during their first year of neuroleptic treatment. 5,6
TD also increases the global severity of mental illness and its associated costs. Schizophrenic patients with TD have a shorter time to relapse, a higher relapse rate, leading to more frequent hospitalizations, and longer hospital lengths of stay than those without TD.Z8 TD is associated with increased morbidity related to respiratory tract infections and cardiovascular disorders, and TD may cause death in a small percentage of patients, especially those with respiratory dyskinesias.9-a2 In spite of the development of new 'atypical' antipsychotic agents TD will remain a problem for the foreseeable future. Except for clozapine, there is no evidence that TD is associated more with one neuroleptic than with others; and for those patients with existing TD there is no established treatment. PATHOPHYSlOLOGY AND TREATMENT
IMPACT OF TD
TD is a social handicap that leads to social isolation and compromises dignity and quality of life. Patients with TD are often uncomfortable in public because of their abnormal movements. They are less likely to be accepted into rehabilitation or resocialization programs, and they are less likely to be employable, particularly in jobs with public exposure. These restrictions often prevent placement and prevent independent life in the community. Correspondence to: John Rotrosen, Tel. 212 263 6802; Fax. 212 951 3356.
The pathophysiology of TD is unknown, although several models have been put forth, and from these derivative treatment approaches have been proposed and evaluated. Traditionally the pathophysiology of TD has been attributed to 'denervation supersensitivity' resulting from longterm neuroleptic exposure, i.e., blockade of dopamine neurotransmission leads to compensatory postsynaptic dopamine receptor proliferation or 'supersensitivity' accounting for dyskinetic movements. This construct was originally proposed by Klawans who posited a 'supersensitivity of striatal dopamine receptors, similar to 77
78
Rotrosen et al
denervation-induced supersensitivity seen in peripheral muscles'Y Limited support for this comes both from animal models showing increased receptor density and behavioral supersensitivity to dopamine agonists following neuroleptic treatment, and from analogous receptor findings in humansY Dyskinetic movements are also suppressed by neuroleptics, and 'withdrawal' or 'emergent' dyskinesias are often seen with neuroleptic reduction or discontinuation? 4 However, denervation supersensitivity now appears to be an overly simplistic model for TD. For example, dyskinetic movements do not usually occur until after chronic neuroleptic treatment in humans, while dopamine supersensitivity occurs within weeks of initiation of neuroleptic treatment in rats.~5,~6 Postmortem studies in humans treated with neuroleptics have found consistent increases in dopamine receptors, while only a portion of these patients develop TDY Also, rats which develop dyskinesia-like movements continue to demonstrate these movements after the resolution of dopamine supersensitivityY Finally, the failure of treatment approaches targeted to exploit a 'supersensitivity' hypothesis raises questions about the validity and utility of the hypothesis. Increasing neuroleptic dosage may suppress dyskinetic movements initially, but will likely exacerbate underlying pathology leading to worsening and possible irreversibility. The APA Task Force on Tardive Dyskinesia 12 recommends reduction or discontinuation of neuroleptics when possible since this may result in improvement in up to 50% of patients where TD is recognized in its early stages. Unfortunately, where neuroleptics were appropriately indicated initially, reduction or discontinuation is rarely possible because of the quality of life costs and risks associated with the underlying psychopathology. A second category of hypotheses invokes neurotransmitter interaction imbalances and/or disrupted modulatory and regulatory pathways. Treatment approaches addressing these potential imbalances have included efforts with drugs and nutritional supplements to increase or decrease activity at noradrenergic, cholinergic, GABAergic, serotonergic, and opioid synapses. Nearly every agent for which an hypothesis can be generated has been investigated for its effect on TD. Unfortunately none of these 'neurotransmitter balancing' approaches has been found to be consistently effective. Studies conducted in over a thousand patients between 1979 and 1987 identified such inconsistencies in treatment effect that no practical treatment recommendations could be madeY ,19 OXYGEN
FREE RADICALS AND TD
In 1986 Cadet, Lohr and Jeste 2° put forth a 'free radical hypothesis' purporting to explain the pathophysiology
of TD and suggesting novel therapeutic approaches for TD. In brief, this hypothesis points out that neuroleptic treatment activates oxidative processes in the brain. These, in turn increase free radical formation and may cause oxidative membrane and subcellular damage. For a number of reasons the basal ganglia are particularly vulnerable to this effect, leading to the development of dyskinetic movements. Treatment with antioxidants might then prevent or reverse both the pathology and symptomatology. This hypothesis was elaborated in a number of subsequent papers, 21-2~ and tested in over ten clinical trials, which are described below. The brain is particularly susceptible to free radical damage because of its high oxygen use, 26its high concentration of transition metals such as iron, manganese and copper, (which act as catalysts for free radical formation), its low concentrations of antioxidants (e.g., vitamins C and E) and low levels of the enzymes of the antioxidant defense system (e.g., catalase, superoxide dismutase, glutathione peroxidase), 2z28 and because of its high concentrations of polyunsaturated fatty acids which are targets for free radical attack. While free radicals can damage most cellular constituents (e.g., DNA, protein, membrane lipids) their effects on functional neurophysiology are most likely a consequence of their ability to initiate an oxidative chain reaction known as the lipid peroxidation cascade. Consequences of lipid peroxidation can include alterations in membrane fluidity, 29,~° disruption of receptor-second messenger coupling, dysregulation of ion transport, shifts in transmembrane electrical potential, 31,32and formation of peroxide pores 3a which can permit leakage of calcium24 All of these membrane effects can transiently or permanently affect biological signal transmission and calcium leakage can cause swelling and functional cell shutdown and ultimately cell death. Vitamin E is the major exogenous lipid-soluble antioxidant, and as it resides within the lipid membrane it can effectively disrupt the lipid peroxidation cascade, aS,a6 becoming itself, a less toxic free radical. Cells can also repair early membrane changes possibly through mechanisms involving phospholipase A2 which may preferentially remove oxidized fatty acids from membrane phospholipidsY ,3z There are several (independent) mechanisms by which chronic treatment with neuroleptics may increase free radical formation and cause tissue damage. Catecholamine metabolism via monoamine oxidase produces hydrogen peroxide, 3s,39 and catecholamines themselves can be oxidized to quinones and semiquinones, which can generate free radicals (semiquinones are free radicals themselves). Further, in animals chronic neuroleptic treatment increases the accumulation of iron and manganese in brain, particularly the basal ganglia structures asso-
Prostaglandins, Leukotrienes and Essential Fatty Acids (1996) 55(1 & 2), 77-81
© Pearson Professional Ltd 1996
Antioxidant treatment of tardive dyskinesia 79
ciated with movement disorders. 4°,41 These transition metals can increase free radical formation both by catalyzing the Haber-Weiss reaction and by catalyzing oxidation of catecholamines.42 In humans increased iron has been measured in postmortem brains from patients with TD,43,44 and in the caudates of live patients with TD on the basis of decreased T2 relaxation times in magnetic resonance imaging studies. 45 Alterations in both plasma fatty acids and erythrocyte membrane fatty acids have been reported in schizophrenia, 46,47with consistently greater reductions in patients with TD. In keeping with this, Vaddadi et al4s describe limited improvement in TD following EFA supplementation. Patients treated with neuroleptics have elevated CSF indices of lipid peroxidation and copper compared to untreated controls, 49 and amongst patients treated with neuroleptics those with TD have increased CSF indices of lipid peroxidation compared to control patients without TD.24,5°
recruited over one year to compare vitamin E to placebo over a minimum of one year of treatment (maximum of two years). Randomization will be stratified by VAMC, age, and severity of TD. Outcome assessments include a well-validated movement disorders scale (the Abnormal Involuntary Movement Scale [AIMS]) and electromechanical measures of force instability. Data analyses will primarily use longitudinal marginal models for the repeated measures design to test specific hypotheses about the difference in longitudinal profiles of scores between treatment groups. This study should be completed in mid 199Z
A C K N O W L E D G EM E N T S
This work is supported in part by the Department of Veterans Affairs.
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Over ten controlled and open therapeutic trials with vitamin E have been conducted in patients with existing TD. 2z,51-62 Of these, nearly all reported some efficacy for vitamin E, with better treatment response seen in patients with recent onset TD. Many of these studies used random assignment, double-blind, placebo-controlled methodology, and used validated outcome measures. However, most were relatively small studies (8 to 35 patients) and were of relatively short duration (four to eight weeks). A longer term extension of the original Adler et al. study showed r,ontinued efficacy out to 36 weeks in a sample of 25 patients. 63 Taken together these studies support the hypothesis that vitamin E produces a clinically meaningful improvement in TD over the course of two to three months of treatment, and suggest that this effect is largest in recent onset TD patients.
VA C O O P E R A T I V E S T U D Y 3 9 4
The Department of Veterans Affairs recently funded "CA Cooperative Study 394. The primary goal of this study is to establish whether vitamin E is a safe and efficacious treatment for widespread and long-term use in TD by conducting a large multi-site study with a sufficiently long treatment and follow-up period. Secondary goals are (1) to investigate which clinical features (e.g. duration of TD) predict good therapeutic response, and (2) to identify clinical aspects of the TD syndrome that are more and less responsive to vitamin E therapy. The study is a double-blind, randomized, parallel-group study of up to 180 TD patients from 9 VAMCs who will be © Pearson Professional Ltd 1996
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