Discinesia tardia: I. fisiopatologia e tratamento

Andrade, Luiz Augusto F.; Bertolucci, Paulo Henrique F.; Pereira, João Santos

doi:10.1590/S0004-282X1984000400008

Resumos

A introdução dos neurolépticos foi importante contribuição para o tratamento das doenças mentais. Contudo sua eficácia foi limitada por efeitos colaterais, entre os quais se encontram movimentos anormais da musculatura orofacial, cujo aparecimento parece estar relacionado à desnervação farmacológica crônica de receptores no estriado, com o conseqüente desenvolvimento de hipersensibilidade por desnervação. É feita revisão desta e de outras teorias fisiopatológicas, além do tratamento, que deve basear-se na retirada dos neurolépticos, sempre que possível. São apresentadas várias drogas com ação nos sistemas dopaminérgico, colinérgico e GABA-érgico que podem ser úteis no tratamento.

The major breakthrough in the treatment of mental diseases was the introduction of neuroleptics in the early 50's. Soon after this an increasing number of patients under the use of these drugs presented involuntary abnormal orofacial movements which have been considered directly dependent on the drug action. The term "tardive diskynesia" (TD) was coined for these movements. Many theories have been put forward to explain the pathophysiology of TD. The most proeminent theory concerns with the possibility of denervation hypersensitivity occurring in striatal post-synaptic dopamine neurons. The authors review the most important theories and offer a new possibility based on the assumption that the post-synaptic dopamine receptors under chronic neuroleptic action develop a shift in its affinity towards the direction of agonist action. This means that the post-synaptic receptor increase its affinity, and possibly its number, to agonist drugs and dopamine. The paper includes a review of the main drugs used in this condiction, attempting to explain the specific sites where they act, either in the dopaminergic, cholinergic or GABA-ergic systems.

Discinesia tardia: I. fisiopatologia e tratamento

Tardive diskynesia: pathophysiology and treatment

Luiz Augusto F. Andrade^I; Paulo Henrique F. Bertolucci^II; João Santos Pereira^II

^IProfessor Adjunto e Doutor em Neurologia. Setor de Investigações em Moléstias Extrapiramidais da Disciplina de Neurologia do Departamento de Neurologia e Neurocirurgia da Escola Paulista de Medicina

^IIPós-graduando em Neurologia. Setor de Investigações em Moléstias Extrapiramidais da Disciplina de Neurologia do Departamento de Neurologia e Neurocirurgia da Escola Paulista de Medicina

RESUMO

A introdução dos neurolépticos foi importante contribuição para o tratamento das doenças mentais. Contudo sua eficácia foi limitada por efeitos colaterais, entre os quais se encontram movimentos anormais da musculatura orofacial, cujo aparecimento parece estar relacionado à desnervação farmacológica crônica de receptores no estriado, com o conseqüente desenvolvimento de hipersensibilidade por desnervação. É feita revisão desta e de outras teorias fisiopatológicas, além do tratamento, que deve basear-se na retirada dos neurolépticos, sempre que possível. São apresentadas várias drogas com ação nos sistemas dopaminérgico, colinérgico e GABA-érgico que podem ser úteis no tratamento.

SUMMARY

The major breakthrough in the treatment of mental diseases was the introduction of neuroleptics in the early 50's. Soon after this an increasing number of patients under the use of these drugs presented involuntary abnormal orofacial movements which have been considered directly dependent on the drug action. The term "tardive diskynesia" (TD) was coined for these movements. Many theories have been put forward to explain the pathophysiology of TD. The most proeminent theory concerns with the possibility of denervation hypersensitivity occurring in striatal post-synaptic dopamine neurons. The authors review the most important theories and offer a new possibility based on the assumption that the post-synaptic dopamine receptors under chronic neuroleptic action develop a shift in its affinity towards the direction of agonist action. This means that the post-synaptic receptor increase its affinity, and possibly its number, to agonist drugs and dopamine. The paper includes a review of the main drugs used in this condiction, attempting to explain the specific sites where they act, either in the dopaminergic, cholinergic or GABA-ergic systems.

Texto completo disponível apenas em PDF.

Full text available only in PDF format.

Trabalho realizado no Setor de Investigações em Moléstias Extrapiramidais da Disciplina de Neurologia do Departamento de Neurologia e Neurocirurgia da Escola Paulista de Medicina.

Disciplina de Neurologia, Departamento de Neurologia e Neurocirurgia, Escola Paulista de Medicina - Rua Botucatu, 740 - 04023, São Paulo, SP - Brasil.

1. AMSTERDAM, J. & MENDELS, J. - Treatment-resistant tardive dyskinesia: a new therapeutic approach. Am. J. Psychiat. 136:1197, 1979.
2. AXELSSON, J. & THESLEFF, S. - A study of supersensitivity in denervated mammalian muscle. J. Physiol. 147:178, 1959.
3. BJORNDAL, N.; CASEY, D. & GERLACH, J. - Dopamine antagonits and agonist treatment of tardive dyskinesia. Adv. Biochem. Psychopharmacol. 24:541, 1980.
4. BOURGEOIS, M. & TIGNOL, J. - Les dyskinésia tardives des neuroleptiques. Nouv. Pres. med., 6:3649, 1977.
5. BURT, D.R.; CREESE, I. & SNYDER, S.H. - Antischizophrenic drugs: chronic treatment elevates dopamine receptor binding in brain. Science 196:326, 1977.
6. CHASE, T.N. & TAMMINGA, C.A. - Pharmacologic studies of tardive dyskinesia. Adv. Biochem. Psychopharmacol. 24:457, 1980.
7. CLOW, A.; JENNER, P. & MARSDEN, C.D. - An experimental model of tardive dyskinesia. Life Sci. 23:421, 1978.
8. CLOW, A.: JENNER, P.; THEODOROU, A. & MARSDEN, C.D. - Striatal dopamine receptors become supersensitive while rats are given trifluoperazine for six months. Nature 278:59, 1979.
9. CLOW, A.; JENNER, P. & MARSDEN, C.D. - Change in dopamine behaviour during one year's neuroleptic administration. Eur. J. Pharmacol. 57:365, 1979.
10. CRANE, G.E. - Persistent dyskinesia. Brit. J. Psychiat. 122:395, 1973.
11. CREESE, I.; BURT, D.R. & SNYDER, S.H. - Dopamine receptor binding: differentiation of agonist and antagonits states with 3H-dopamine and 3H-haloperidol. Life Sci. 17:993, 1976.
12. DAVIS, K.L.; HOLLISTER, L.E.; BARCHAS, J.D. & BERGER, P.A. - Choline in tardive dyskinesia and Huntington's disease. Life Sci. 19:1507, 1976.
13. DELAY, J.; DENIKER, P. & HARL, J.M. - Utilisation en thérapeutique psychiatrique d'une phenothiazine d'action centrale elective (4560 RP). Ann. med. psychol. 110:112, 1952.
14. DUVOISIN, R.C - Reserpine for tardive dyskinesia. N. Engl. J. Med. 286:611, 1972.
15. FAHN, S. - Treatment of tardive dyskinesia: use of dopamine-depleting agents. Clin. Neuropharmacol. 6:151, 1983.
16. GERLACH, J.; RYE, T. & KRISTJANSEN, P. - Effect of baclofen on tardive dyskinesia. Psychopharmacology 56:145, 1978.
17. GIANUTSOS, G.; DRAWBAUGH, R.B.; HYNER, M.D. & LAL, H. - Behavioral evidence of dopaminergic supersensitivity after chronic haloperidol. Life Sci. 14:887. 1974.
18. GOETZ, C.G.; WEINER, W.J.; NAUSIEDA, P.A. & KLAWANS, H.L. - Tardive dyskinesia: pharmacology and clinical implications. Clin. Neuropharmacol. 5:3, 1982.
19. GRINSPOON, L.; EWALT, J.R. & SHADER, R. - Psychotherapy and pharmacotherapy in chronic schizophrenia. Am. J. Psychiat. 124:1645, 1968.
20. HITRI, A.; WEINER, W.J.; BORISON, R.L.; DIAMOND, B.I.; NAUSIEDA, P.A. & KLAWANS, H.L. - Dopamine binding following prolonged haloperidol pre-treatment. Ann. Neurol. 3:134, 1978.
21. IVERSEN, L.L. - Dopamine receptors in brain. Science 188:1084, 1975.
22. IVERSEN, S.D.; HOWELLS, R.B. & HUGHES, R.P. - Behavioral consequences of long-term treatment with neuroleptic drugs. Adv. Biochem. Psychopharmacol. 24:305, 1980.
23. JUS, A.; PINEAU, R.; LACHANCE, R.; PELCHAT, G.; JUS, K.; PIRES. P. & VILLENEUVE, R. - Epidemiology of tardive dyskinesia. Part 1. Dis. nerv. System 37:210, 1976.
24. JUS, A.; JUS, K. &FONTAINE, P. - Long-term treatment of tardive dyskinesia. J. clin. Psychiat. 40:72, 1979.
25. KARNIOL, I.G. - Algumas considerações sobre a discinesia tardia e em particular sua incidência e, características num hospital psiquiátrico do nosso meio, seu diagnóstico diferencial e uma aproximação ao estudo dos prováveis mecanismos dopaminérgicos subjacentes. Tese - Faculdade de Ciências Médicas, Universidade Estadual de Campinas. Campinas, 1979.
26. KEBABIAN, J.W. & CALNE, D.B. - Multiple receptors for dopamine. Nature 277:93, 1979.
27. KLAWANS, H.L. - The pharmacology of tardive dyskinesias. Amer. J. Psychiat. 130:82, 1973.
28. KLAWANS, H.L.; GOETZ, C.G.; TANNER, C.M.; WEINER, W.J.; NAUSIEDA, P.A. & ROFFMAN, M. - The effect of baclofen in tardive dyskinesia. Neurology (NY) 31:78, 1981.
29. KOBAYASHI, R.M. - Drug therapy of tardive dyskinesia. N. Engl. J. Med., 296:257, 1977.
30. LEE, T.; SEEMAN, P.; RAJPUT, A.; FARLEY, I.J. & HORNYKIEWICZ, O. - Receptor basis for dopaminergic supersensitivity in Parkinson's disease. Nature 273:59, 1978.
31. MARSDEN, C.D. & JENNER, P. - The pathophysiology of extra-piramidal side-effects of neuroleptic drugs. Psych. Med. 10:55, 1980.
32. MEYER, H.H. - Die Behandung exogener Psychosen mit Phenothiazenderivaten. Encephale 45:524, 1956.
33. NAIR, N.P.V.; YASSA, R.; RUIZ-NAVARRO, J. & SCHWARTZ, G. - Baclofen in the treatment of tardive dyskinesia. Amer. J. Psychiat. 135:1562, 1978.
34. NAIR, N.P.V.; LAL, S.; SCHWARTZ, G. & THAVUNDAYIL, J.X. - Effect of sodium valproate and baclofen in tardive dyskinesia: clinical and neuroendocrine studies. Adv. Biochem. Psychopharmacol. 24:437, 1980.
35. OWEN, F.; CROSS, A. J.; CROW, T.J.; LONGDEN, A.; POULTER, M. & RILEY, G.J. - Increased dopamine-receptor sensitivity in schizophrenia. Lancet 2:223, 1978.
36. POST, R.M. & GOODWIN, F.K. - Time-dependent effects of phenothiazines on dopamine turnover in psychiatric patients. Science 190:488, 1975.
37. RIDDALL, D.R. & LEAVENS, W.J. - Affinities of drugs for the agonist and antagonits states of the dopamine receptor. Eur. J. Pharmacol. 51:187, 1978.
38. STBCK, H. - Le syndrome extrapyramidal et diencéphalique au cours des traitements au Largactil et au Serpasil. Ann. med. psych. 112:737, 1974.
39. STEWART, R.M.; ROLLINS, J.; BECKHAM, B. & ROFFMAN, M. - Baclofen in tardive dyskinesia patients maintened on neuroleptics. Clin. Neuropharmacol. 5:365, 1982.
40. TAMMINGA, C.A.; SMITH, R.C.; ERICKSEN, S.E.; CHANG, S. & DAVIS, J.M. - Cholinergic influences in tardive dyskinesia. Amer. J. Psychiat. 134:769, 1977.
41. TANNER, C.M. - Treatment of tardive dyskinesia: other therapies. Clin. Neuropharmacol. 6:159, 1983.
42. TARSY, D. & BALDESSARINI, R.J. - Pharmacologically induced behavioral supersensitivity to apomorphine. Nature 245:262, 1973.
43. UHRBRAND, L. & FAURBYE, A. - Reversible and irreversible dyskinesia after treatment with perphenazine, chlorpromazine, reserpine and electroconvulsive therapy. Psychopharmocologia 10:408, 1960.

Datas de Publicação

Publicação nesta coleção
13 Ago 2012
Data do Fascículo
Dez 1984

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

[1] 1. AMSTERDAM, J. & MENDELS, J. - Treatment-resistant tardive dyskinesia: a new therapeutic approach. Am. J. Psychiat. 136:1197, 1979.

[2] 2. AXELSSON, J. & THESLEFF, S. - A study of supersensitivity in denervated mammalian muscle. J. Physiol. 147:178, 1959.

[3] 3. BJORNDAL, N.; CASEY, D. & GERLACH, J. - Dopamine antagonits and agonist treatment of tardive dyskinesia. Adv. Biochem. Psychopharmacol. 24:541, 1980.

[4] 4. BOURGEOIS, M. & TIGNOL, J. - Les dyskinésia tardives des neuroleptiques. Nouv. Pres. med., 6:3649, 1977.

[5] 5. BURT, D.R.; CREESE, I. & SNYDER, S.H. - Antischizophrenic drugs: chronic treatment elevates dopamine receptor binding in brain. Science 196:326, 1977.

[6] 6. CHASE, T.N. & TAMMINGA, C.A. - Pharmacologic studies of tardive dyskinesia. Adv. Biochem. Psychopharmacol. 24:457, 1980.

[7] 7. CLOW, A.; JENNER, P. & MARSDEN, C.D. - An experimental model of tardive dyskinesia. Life Sci. 23:421, 1978.

[8] 8. CLOW, A.: JENNER, P.; THEODOROU, A. & MARSDEN, C.D. - Striatal dopamine receptors become supersensitive while rats are given trifluoperazine for six months. Nature 278:59, 1979.

[9] 9. CLOW, A.; JENNER, P. & MARSDEN, C.D. - Change in dopamine behaviour during one year's neuroleptic administration. Eur. J. Pharmacol. 57:365, 1979.

[10] 10. CRANE, G.E. - Persistent dyskinesia. Brit. J. Psychiat. 122:395, 1973.

[11] 11. CREESE, I.; BURT, D.R. & SNYDER, S.H. - Dopamine receptor binding: differentiation of agonist and antagonits states with 3H-dopamine and 3H-haloperidol. Life Sci. 17:993, 1976.

[12] 12. DAVIS, K.L.; HOLLISTER, L.E.; BARCHAS, J.D. & BERGER, P.A. - Choline in tardive dyskinesia and Huntington's disease. Life Sci. 19:1507, 1976.

[13] 13. DELAY, J.; DENIKER, P. & HARL, J.M. - Utilisation en thérapeutique psychiatrique d'une phenothiazine d'action centrale elective (4560 RP). Ann. med. psychol. 110:112, 1952.

[14] 14. DUVOISIN, R.C - Reserpine for tardive dyskinesia. N. Engl. J. Med. 286:611, 1972.

[15] 15. FAHN, S. - Treatment of tardive dyskinesia: use of dopamine-depleting agents. Clin. Neuropharmacol. 6:151, 1983.

[16] 16. GERLACH, J.; RYE, T. & KRISTJANSEN, P. - Effect of baclofen on tardive dyskinesia. Psychopharmacology 56:145, 1978.

[17] 17. GIANUTSOS, G.; DRAWBAUGH, R.B.; HYNER, M.D. & LAL, H. - Behavioral evidence of dopaminergic supersensitivity after chronic haloperidol. Life Sci. 14:887. 1974.

[18] 18. GOETZ, C.G.; WEINER, W.J.; NAUSIEDA, P.A. & KLAWANS, H.L. - Tardive dyskinesia: pharmacology and clinical implications. Clin. Neuropharmacol. 5:3, 1982.

[19] 19. GRINSPOON, L.; EWALT, J.R. & SHADER, R. - Psychotherapy and pharmacotherapy in chronic schizophrenia. Am. J. Psychiat. 124:1645, 1968.

[20] 20. HITRI, A.; WEINER, W.J.; BORISON, R.L.; DIAMOND, B.I.; NAUSIEDA, P.A. & KLAWANS, H.L. - Dopamine binding following prolonged haloperidol pre-treatment. Ann. Neurol. 3:134, 1978.

[21] 21. IVERSEN, L.L. - Dopamine receptors in brain. Science 188:1084, 1975.

[22] 22. IVERSEN, S.D.; HOWELLS, R.B. & HUGHES, R.P. - Behavioral consequences of long-term treatment with neuroleptic drugs. Adv. Biochem. Psychopharmacol. 24:305, 1980.

[23] 23. JUS, A.; PINEAU, R.; LACHANCE, R.; PELCHAT, G.; JUS, K.; PIRES. P. & VILLENEUVE, R. - Epidemiology of tardive dyskinesia. Part 1. Dis. nerv. System 37:210, 1976.

[24] 24. JUS, A.; JUS, K. &FONTAINE, P. - Long-term treatment of tardive dyskinesia. J. clin. Psychiat. 40:72, 1979.

[25] 25. KARNIOL, I.G. - Algumas considerações sobre a discinesia tardia e em particular sua incidência e, características num hospital psiquiátrico do nosso meio, seu diagnóstico diferencial e uma aproximação ao estudo dos prováveis mecanismos dopaminérgicos subjacentes. Tese - Faculdade de Ciências Médicas, Universidade Estadual de Campinas. Campinas, 1979.

[26] 26. KEBABIAN, J.W. & CALNE, D.B. - Multiple receptors for dopamine. Nature 277:93, 1979.

[27] 27. KLAWANS, H.L. - The pharmacology of tardive dyskinesias. Amer. J. Psychiat. 130:82, 1973.

[28] 28. KLAWANS, H.L.; GOETZ, C.G.; TANNER, C.M.; WEINER, W.J.; NAUSIEDA, P.A. & ROFFMAN, M. - The effect of baclofen in tardive dyskinesia. Neurology (NY) 31:78, 1981.

[29] 29. KOBAYASHI, R.M. - Drug therapy of tardive dyskinesia. N. Engl. J. Med., 296:257, 1977.

[30] 30. LEE, T.; SEEMAN, P.; RAJPUT, A.; FARLEY, I.J. & HORNYKIEWICZ, O. - Receptor basis for dopaminergic supersensitivity in Parkinson's disease. Nature 273:59, 1978.

[31] 31. MARSDEN, C.D. & JENNER, P. - The pathophysiology of extra-piramidal side-effects of neuroleptic drugs. Psych. Med. 10:55, 1980.

[32] 32. MEYER, H.H. - Die Behandung exogener Psychosen mit Phenothiazenderivaten. Encephale 45:524, 1956.

[33] 33. NAIR, N.P.V.; YASSA, R.; RUIZ-NAVARRO, J. & SCHWARTZ, G. - Baclofen in the treatment of tardive dyskinesia. Amer. J. Psychiat. 135:1562, 1978.

[34] 34. NAIR, N.P.V.; LAL, S.; SCHWARTZ, G. & THAVUNDAYIL, J.X. - Effect of sodium valproate and baclofen in tardive dyskinesia: clinical and neuroendocrine studies. Adv. Biochem. Psychopharmacol. 24:437, 1980.

[35] 35. OWEN, F.; CROSS, A. J.; CROW, T.J.; LONGDEN, A.; POULTER, M. & RILEY, G.J. - Increased dopamine-receptor sensitivity in schizophrenia. Lancet 2:223, 1978.

[36] 36. POST, R.M. & GOODWIN, F.K. - Time-dependent effects of phenothiazines on dopamine turnover in psychiatric patients. Science 190:488, 1975.

[37] 37. RIDDALL, D.R. & LEAVENS, W.J. - Affinities of drugs for the agonist and antagonits states of the dopamine receptor. Eur. J. Pharmacol. 51:187, 1978.

[38] 38. STBCK, H. - Le syndrome extrapyramidal et diencéphalique au cours des traitements au Largactil et au Serpasil. Ann. med. psych. 112:737, 1974.

[39] 39. STEWART, R.M.; ROLLINS, J.; BECKHAM, B. & ROFFMAN, M. - Baclofen in tardive dyskinesia patients maintened on neuroleptics. Clin. Neuropharmacol. 5:365, 1982.

[40] 40. TAMMINGA, C.A.; SMITH, R.C.; ERICKSEN, S.E.; CHANG, S. & DAVIS, J.M. - Cholinergic influences in tardive dyskinesia. Amer. J. Psychiat. 134:769, 1977.

[41] 41. TANNER, C.M. - Treatment of tardive dyskinesia: other therapies. Clin. Neuropharmacol. 6:159, 1983.

[42] 42. TARSY, D. & BALDESSARINI, R.J. - Pharmacologically induced behavioral supersensitivity to apomorphine. Nature 245:262, 1973.

[43] 43. UHRBRAND, L. & FAURBYE, A. - Reversible and irreversible dyskinesia after treatment with perphenazine, chlorpromazine, reserpine and electroconvulsive therapy. Psychopharmocologia 10:408, 1960.