Advances in the Pharmacological Management of Parkinson Disease

  • E. Tolosa
Part of the Journal of Neural Transmission. Supplementa book series (NEURAL SUPPL, volume 64)


Numerous advances have taken place in the pharmacological management of Parkinson disease (PD) in recent years. Some of the more clinically relevant will be discussed in the text that follows. New drugs have been developed to treat or prevent the motor fluctuations and dyskinesias that occur frequently with the continuous use of levodopa. Such drugs include the catechol-O-methyl-transferase (COMT) inhibitors, such as tolcapone and entecapone, and new dopamine (DA) agonists with long half lives such as cabergoline, pramipexole or ropirinole. Also new, atyical, antipsychotics have appeared which have revolutionized the treatment of PD since they allow us to control hallucinations and other psychotic behaviour without worsening of motor function. Finally preliminary reports suggest that Cholinesterase inhibitors, such as rivastigmine, can be usefull in the management of cognitive impairment in PD, one of the most difficult clinical problems encountered in the management of this neurodegenerative disorder.


Parkinson Disease Dementia With Lewy Body Motor Fluctuation Pharmacological Management Motor Complication 
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  1. Aarsland D, Larsen JP, Lim NG, Tandberg E (1999) Olanzapine for psychosis in patients with Parkinson’s disease with and without dementia. J Neuropsychiatry Clin Neurosci 11: 392–394PubMedGoogle Scholar
  2. Aarsland D, Andersen K, Larsen JP, Lolk A, Nielsen H, Kragh-Sorensen (2001) Risk of dementia in Parkinson’s disease. A community-based, prospective study. Neurology 56: 730–736PubMedCrossRefGoogle Scholar
  3. Adler CH, Sethi KD, Hauser RA, et al (1997) Ropinirole for the treatment of early Parkinson’s disease. Neurology 49: 393–399PubMedCrossRefGoogle Scholar
  4. Adler CH, Singer C, O’Brien C, hauser RA, Lew MF, Marek KL, et al (1998) Randomized, placebo-controlled study of tolcapone in patients with fluctuating Parkinson’s disease treated with levodopa-carbidopa. Arch Neurol 55: 421–428CrossRefGoogle Scholar
  5. Agid Y, Ahlskog A, Albanese A, et al (1999) Levodopa in the treatment of Parkinson’s disease: a consensus meeting. Mov Disord 14: 911–913PubMedCrossRefGoogle Scholar
  6. Boiler F, Mizutani T, Roessmann U, Gambetti P (1980) Parkinsons disease, dementia and Alzheimer disease: clinicopathological correlations. Ann Neurol 7: 329–335CrossRefGoogle Scholar
  7. Borison RL (1995) Clinical efficacy of serotonin-dopamine antagonists relative to classic neuroleptics. J Clin Psychopharmacol 15 [Suppl 1]: 24–29CrossRefGoogle Scholar
  8. Borison RL, Rathiraja AP, Bruce I, et al (1992) Risperidone: clinical safety and efficacy in schizophrenia. Psychopharmacol Bull 28: 213–218PubMedGoogle Scholar
  9. Brandstäder D, Oertel WH (2002) Treatment of drug-induced psychosis with quetiapine and clozapine in Parkinson’s disease. Neurology 58: 160–161CrossRefGoogle Scholar
  10. Calopa M, Tolosa E, Ferrer I, et al (2002) In: Tolosa E, Schultz J, McKeith I, Ferrer I (eds) Neurodegenerative disorders asociated with alpha synuclein pathology. Medicina STM Editores, Barcelona, pp 127–135Google Scholar
  11. Cash R, Donnis T, L’Heureux R, Raisman R, Javoy-Agid F, Scatton B (1987) Parkinson’s disease and dementia: norepinephrine and dopamine in locus ceruleus. Neurology 37: 42–46PubMedCrossRefGoogle Scholar
  12. Cotzias GC, Van Woert MH, Schiffer LM (1970) Aromatic amino acids and modification of parkinsonism. N Engl J Med 282: 31–33PubMedCrossRefGoogle Scholar
  13. Dewey RB, O’Suilleabhain PE (2000) Treatment of drug-induced psychosis with quetiapine and clozapine in Parkinson’s disease. Neurology 55: 1753–1754PubMedCrossRefGoogle Scholar
  14. Factor SA, Brown D (1992) Clozapine prevents recurrence of psychosis in Parkinson’s disease. Mov Disord 7: 125–131PubMedCrossRefGoogle Scholar
  15. Factor SA, Friedman JH (1997) The emerging role of clozapine in the treatment of movement disorders. Mov Disord 12: 483–496PubMedCrossRefGoogle Scholar
  16. Factor SA, Brown D, Molho ES, Podskalny GD (1994) Clozapine: a 2-year open trial in PD patients with psychosis. Neurology 44: 544–546PubMedCrossRefGoogle Scholar
  17. Factor SA, Molho ES, Podskalny GD, Brown D (1995) Parkinson’s disease: drug-induced psychiatric states. In: Weiner WJ, Lang AE (eds) Advances in neurology, vol 65. Raven Press, New York, pp 115–138Google Scholar
  18. Fahn S (1974) On-off phenomenon with levodopa therapy in parkinsonism. Neurology 24: 431–441PubMedCrossRefGoogle Scholar
  19. Fern¨¢ndez HH (2000) Quetiapine for 1-dopa induced psychosis in PD. Neurology 55: 899CrossRefGoogle Scholar
  20. Fernandez HH, Durso R (1998) Clozapine for dopaniergic-induced paraphilias in Parkinson’s disease. Mov Disord 13: 597–598PubMedCrossRefGoogle Scholar
  21. Fern¨¢ndez HH, Friedman JH, Jacques C, Rosenfeld M (1999) Quetiapine for the treatment of drug-induced psychosis in Parkinson’s disease. Mov Disord 14: 484–487CrossRefGoogle Scholar
  22. Friedman JH (1998) Olanzapine in the treatment of dopaminomimetic psychosis in patients with Parkinson’s disease. Neurology 50: 1195–1196PubMedCrossRefGoogle Scholar
  23. Friedman JH, Lannon MC (1989) Clozapine in the treatment of psychosis in PD. Neurology 39: 1219–1221PubMedCrossRefGoogle Scholar
  24. Friedman JH, Goldstein S, Jacques C (1998) Substituting clozapine for olanzapine in psychiatrically stable Parkinson’s disease patients: results of an open label pilot study. Clin Neuropharmacol 5: 285–288Google Scholar
  25. Gerlach J, Peacock L (1994) Motor and mental side effects of clozapine. J Clin Psychiatry 55 [Suppl B]: S107–S109Google Scholar
  26. Goetz C (1998) Influence of COMT inhibition on levodopa pharmacology and therapy. Neurology 50 [Suppl 5]: 26–30CrossRefGoogle Scholar
  27. Goetz CG, Stebbins GT (1993) Risk factors for nursing home placement in advanced Parkinson’s disease. Neurology 43: 2227–2229PubMedCrossRefGoogle Scholar
  28. Goetz CG, Vogel C, Tanner CM, Stebbins GT (1998) Early dopaminergic drug-induced hallucinations in parkinsonian patients. Neurology 51: 811–814PubMedCrossRefGoogle Scholar
  29. Goetz CG, Blasucci LM, Leurgans S, Pappert EJ (2000) Olanzapine and clozapine. Comparative effects on motor function in hallucinating PD patients. Neurology 55: 748–749CrossRefGoogle Scholar
  30. Goodwin FK (1971) Psychiatric side effects of 1-dopa in man. JAMA 218: 1915–1920PubMedCrossRefGoogle Scholar
  31. Graham JM, Sussman JD, Ford KS, Sagar HJ (1998) Olanzapine in the treatment of hallucinosis in idiopathic Parkinson’s disease: a cautionary note. J Neurol Neurosurg Pschiatry 65: 774–777CrossRefGoogle Scholar
  32. Hakim A, Mathieson G (1979) Dementia in Parkinson disease: a neuropathologic study. Neurology 29: 1209–1214PubMedCrossRefGoogle Scholar
  33. Halperin JR, Murphy B (1992) Extrapyramidal reaction to ondansetron. Cancer 69:1275PubMedCrossRefGoogle Scholar
  34. Hansen L, Salmon D, Galasko D, Masliah E, Katzman R, De Teresa R, Thal L, Pay MM, Hofstetter R, Klauber M, Rice V, Butters N, Alford M (1990) The Lewy body variant of Alzheimer’s disease: a clinical and pathologic entity. Neurology 40: 1–8PubMedCrossRefGoogle Scholar
  35. Hurtig HI, Trojanowski JQ, Galvin J, Ewbank D, Schmidt ML, Lee VM-Y, Clark CM, Glosser G, Stern MB, Gollomp SM, Arnold SE (2000) ¦Á-synuclein cortical Lewy bodies correlate with dementia in Parkinson’s disease. Neurology 54: 1916–1921PubMedCrossRefGoogle Scholar
  36. Hutchinson M, Fazzini E (1996) Cholinesterase inhibition in Parkinson’s disease. J Neurol Neurosurg Psychiatry 61: 324–325PubMedCrossRefGoogle Scholar
  37. Keränen T, Gordin A, Harjola VP, Karlsson M, Korpela K, y cols (1996) The effect of cathecol-O-methyltransferase inhibition by entacapone on the pharmacokinetics and metabolism of levodopa in healthy volunteers. Clin Neuropharmacol 50: 47–55Google Scholar
  38. Kieburtz K, Shoulson I, McDermontt M, et al (1997) Safety and efficacy of pramipexole, in early Parkinson disease. A randomized dose-ranging study. JAMA 278: 125–130CrossRefGoogle Scholar
  39. Klawans HL (1986) Individual manifestations of Parkinson’s disease after ten or more years of levodopa. Mov Disord 1: 187–192PubMedCrossRefGoogle Scholar
  40. Krupp P, Barnes P (1992) Clozapine-associated agranulocytosis: risk and aetiology. Br J Psychiatry 160 [Suppl 17]: 38–40Google Scholar
  41. Kurth MC, Adler CH (1998) COMT inhibition: a new strategy for Parkinson’s disease. Neurology 50 [Suppl 5]: 3–14CrossRefGoogle Scholar
  42. Kuruma I, Bartholini G, Tissot R, Pletscher A (1971) The metabolism of L-3-Omethyldopa, a precursor in man. Clin Pharmacol Ther 12: 678–682PubMedGoogle Scholar
  43. Lennox G, Lowe J, Morrell K, Landon M, Mayer RJ (1989) Anti-ubiquitin immunocy-tochemistry is more sensitive than conventional techniques in the detection of diffuse Lewy body disease. J Neurol Neusosurg Psychiatry 52: 67–71CrossRefGoogle Scholar
  44. Lew MF, Waters CH (1993) Clozapine treatment of parkinsonism with psychosis. J Am Geriatr Soc 41: 669–671PubMedGoogle Scholar
  45. Livingston MG (1994) Risperidone. Lancet 343: 457–460PubMedCrossRefGoogle Scholar
  46. Männistö PT (1994) Clinical potential of catechol-O-methyltransferase (COMT) inhibitors as adjuvants in Parkinson’s disease. CNS Drugs 1: 172–179CrossRefGoogle Scholar
  47. Männistö PT, Kaakkola S (1989) New selective COMT inhibitors: useful adjuncts for Parkinson’s disease? Trends Pharmacol Sci 10: 47–55CrossRefGoogle Scholar
  48. Männistö PT, Tuomainen P, Tuomainen PK (1992) Different in vivo properties of three new inhibitors of cathechol-O-methyl transferase in rat. Br J Pharmacol 105: 569–574PubMedCrossRefGoogle Scholar
  49. Manson AJ, Schräg A, Lees AJ (2000) Low-dose olanzapine for levodopa induced dyskinesias. Neurology 55: 795–799PubMedCrossRefGoogle Scholar
  50. Marsden CD, Parkes JP, Quinn N (1982) Fluctuations of disability in Parkinson’s disease. In: Marsden CD, Fahn S (eds) Movement disorders. Butterworth, LondonGoogle Scholar
  51. Matheson AJ, Lamb HM (2000) Quetiapine. A review of its clinical potential in the management of psychotic symptoms in Parkinson’s disease. CNS Drugs 14: 157–172CrossRefGoogle Scholar
  52. McKeith I, Del Ser T, Spano P, Emre M, Wesnes K, Anand R, Cicin-Sain A (2000) Efficacy of rivastigmine in dementia with Lewy bodies: a randomized, double-blind, placebo-controlled international study. Lancet 356: 031–2036CrossRefGoogle Scholar
  53. Meco G, Alessandria A, Binfati V, Giustini P (1994) Risperidone for hallucinations in 1-dopa-treated PD patients. Lancet 343: 1370–1371PubMedCrossRefGoogle Scholar
  54. Megens AAHP, Awouters FHL, Schotte A, et al (1994) Survey on the pharmacodynamics of the new antipsychotic risperidone. Psychopharmacol 114: 9–23CrossRefGoogle Scholar
  55. Meltzer HY (1993) New drugs for the treatment of schizophrenia. Psychiatr Clin North Am 16: 365–385PubMedGoogle Scholar
  56. Meltzer HY, Matsubara S, Lee J-C (1989) Classification of typical and atypical antipsychotic drugs on the basis of dopamine Dl, D2 and serotonin-2 pKi values. J Pharmacol Exp Ther 251: 238–246PubMedGoogle Scholar
  57. Moore NA, Tye NC, Axton MS, Risius FC (1992) The behavioural pharmacology of olanzapine, a novel “atypical” antipsychotic agent. J Pharmacol Exp Ther 262: 545–551PubMedGoogle Scholar
  58. Moskovitz C, Moses H, Klawans H (1978) L-dopa induced psychosis: a kindling phenomena. Am J Psychiatry 135: 6–10Google Scholar
  59. Nausieda P, Tanner C, Klawans H (1983) Serotonergically active agents in the treatment of the l-dopa induced psychosis. In: Fahn S, Calne DB, Shoulson I (eds) Experimental therapeutics of movement disorders. Raven Press, New York, pp 23–32 (Adv Neurol 37)Google Scholar
  60. Nutt JG, Fellman JH (1984) Pharmacokinetics of levodopa. Clin Neuropharmacol 7: 35–49PubMedCrossRefGoogle Scholar
  61. Nutt JC (1990) Levodopa induced dyskinesia. Neurology 40: 340–345PubMedCrossRefGoogle Scholar
  62. Ostergaard K, Dupond E (1988) Clozapine treatment of drug-induced psychotic symptoms in late stages of PD. Acta Neurol Scand 78: 349–350PubMedCrossRefGoogle Scholar
  63. Papavasiliou PS, Cotzias GC, Duby SE, et al (1972) Levodopa in parkinsonism: potentiation of central effets with a peripheral inhibitor. N Engl J Med 285: 8–14CrossRefGoogle Scholar
  64. Parkinson Study Group (1997) Entacapone improves motor fluctuations in levodopa-treated Parkinson’s disease patients. Ann Neurol 4 [Suppl 3]: 3–11Google Scholar
  65. Parkinson Study Group (1999) Low-dose clozapine for the treatment of drug-induced psychosis in Parkinson’s disease. N Engl J Med 340: 757–763CrossRefGoogle Scholar
  66. Parkinson Study Group (2000) Pramipexole vs levodopa as initial treatment for Parkinson’s disease. JAMA 284: 1931–1938CrossRefGoogle Scholar
  67. Parsa MA, Bastani B (1998) Quetiapine (Seroquel) in the treatment of psychosis in patients with Parkinson’s disease. J Neuropsychiatry Clin Neurosci 10: 216–219PubMedGoogle Scholar
  68. Perry EK, Curtis M, Dick DJ, Candy JM, Atack JR, Bloxham CA, Blessed G, Fairbairn A, Tomlinson BE, Perry RM (1985) Cholinergic correlates of cognitive impairment in Parkinson’s disease: comparisons with Alzheimer’s disease. J Neurol Neurosurg Psychiatry 48: 413–421PubMedCrossRefGoogle Scholar
  69. Perry RH, Irving D, Blessed G, Perry EK, Fairbairn A (1989) Senile dementia of Lewy body type and spectrum of Lewy body disease Lancet i: 1088Google Scholar
  70. Pfeiffer RF, Kang J, Graber B, Hofman R, Wilson J (1990) Clozapine for psychosis in Parkinson’s disease. Mov Disord 5: 239–242PubMedCrossRefGoogle Scholar
  71. Quinn NP, Rossor MN, Marsden CD (1986) Dementia and Parkinson’s disease: pathological and neurochemical consequences. Br Med Bull 42: 86–90PubMedGoogle Scholar
  72. Rajput AH, Martin W, Saint-Hilaire MH, Dorflinger E, Pedder S (1997) Tolcapone improves motor function in parkinsonian patients with the “wearing-off” phenomenon: a double-blind, placebo-controlled, multicenter trial. Neurology 49:1066–1071PubMedCrossRefGoogle Scholar
  73. Rascol A, Montastruc JL, Guirard-Chaumeil B, Clanet M (1982) Bromocriptine as first treatment of Parkinson’s disease. Long-term results. Rev Neurol 138: 402–408Google Scholar
  74. Rascol O, Brooks DJ, Korczyn AD, et al (2000) A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. N Engl J Med 342: 1484–1491PubMedCrossRefGoogle Scholar
  75. Reading PJ, et al (2001) Rivastigmine in the treatment of parkinsonian psychosis and cognitive impairment: preliminary findings from an open trial. Mov Disord 16:1171 - 1195PubMedCrossRefGoogle Scholar
  76. Rich SS, Friedman JH, Ott BR (1995) Risperidone versus clozapine in the treatment of psychosis in six patients with Parkinson’s disease and other akinetic-rigid syndromes. J Clin Psychiatry 56: 556–559PubMedGoogle Scholar
  77. Rinne JO, Rummukainen J, Paijarvi L, Rinne UK (1989) Dementia in Parkinson’s disease is related to neuronal loss in the medial substantia nigra. Ann Neurol 25:146–151CrossRefGoogle Scholar
  78. Rinne UK (1983) Problems associated with long term levodopa treatment of Parkinson’s disease. Acta Neurol Scand 95: 19–26CrossRefGoogle Scholar
  79. Rinne UK, Bracco F, Chouza C, et al (1997) Cabergoline in the treatment of early Parkinson’s disease: results of the first year of treatment in a double-blind comparison of cabergoline and levodopa. Neurology 48: 363–368PubMedCrossRefGoogle Scholar
  80. Rinne UK, Bracco F, Chouza C, et al (1998) Early treatment of Parkinson’s disease with cabergoline delays the onset of motor complications. Results of a double-blind levodopa controlled trial. The PkDS009 study Group. Drugs 55 [Suppl 1]: 23–30PubMedCrossRefGoogle Scholar
  81. Rinne UK, Larsen JP, Siden A, Worm-Petersen J (1998) The Nomecomt Study Group. Entacapone enhances the response to levodopa in Parkinsonian patients with motor fluctuations. Neurology 51: 1309–1314PubMedCrossRefGoogle Scholar
  82. S¨¢nchez-Ramos JR (1997) High dose pergolide monotherapy for the treatment of severe dyskinesias in Parkinson’s disease. In: Olanow WC, Obeso JA (eds) Beyond the decade of the brain, vol 2. Dopamine agonists in early Parkinson’s disease. Wells Medical Limited, UK, pp 217–232Google Scholar
  83. Sethi KD, O’Brien CF, Hammerstad JP, et al (1998) Ropinirole for the treatment of early Parkinson’s disease-a 12-month experience. Arch Neurol 55: 1211–1216PubMedCrossRefGoogle Scholar
  84. Shannon KM, Bennett JP Jr., Friedman JH (1997) Efficacy of pramipexole, a novel dopamine agonist, as monotherapy in mild to moderate Parkinson’s disease. Neurology 49: 724–728PubMedCrossRefGoogle Scholar
  85. Tagliavini F, Pilleri G, Bouras C, Constantinidis J (1992) The basal nucleus of Meynert in idiopathic Parkinson’s disease. Acta Neurol Scand 69: 20–28Google Scholar
  86. Tolosa E (1998) Current Parkinson’s disease therapy. Levodopa-The Gold Standard. Clin Neuropharmacol 21 [Suppl 1]: S1–S4Google Scholar
  87. Tolosa E (1999) Levodopa-induced dyskinesias and fluctuations in Parkinson disease. PIL, ParisGoogle Scholar
  88. Tolosa E, Marin C (1997) Dopamine agonists in Parkinson’s disease: a clinical review. In: Olanow WC, Obeso JA (eds) Beyond the decade of the brain, vol 2. Dopamine agonists in early Parkinson’s disease. Wells Medical Limited, UK, pp 143–161Google Scholar
  89. Tolosa E, Mart¨ªn W, Cohen H, Jacobson J (1975) Patterns of clinical response and plasma dopa levels in Parkinson’s disease. Neurology 25(2): 177–183PubMedCrossRefGoogle Scholar
  90. Tolosa E, Blesa R, Bayes A, et al (1987) Low-dose bromocriptine in early phases of Parkinson’s disease. Clin Neuropharmacol 10: 169–174CrossRefGoogle Scholar
  91. Tolosa E, Valldeoriola F, Mart¨ª MJ (1994) New and emerging strategies for improving levodopa treatment. Neurology 44: 535–544Google Scholar
  92. Trosch RM, Friedman JH, Lannon MC, Pahwa R, Smith D, Seeberger LC, O’Brien CF, Le Witt PA, Koller WC (1998) Clozapine use in Parkinson’s disease: a retrospective analysis of a large multicentered clinical experience. Mov Disord 13: 377–382PubMedCrossRefGoogle Scholar
  93. Weiner WJ, Minagar A, Shulman LM (2000) Quetiapine for 1-dopa induced psychosis in PD. Neurology 54: 1538PubMedCrossRefGoogle Scholar
  94. White A, Corn TH, Feetham, Faulconbridge C (1991) Ondansetron in treatment of schizophrenia. Lancet 337: 1173PubMedCrossRefGoogle Scholar
  95. Wilson JA, Smith RG (1989) The prevalence and aetiology of long term L-dopa side effects in elderly parkinsonian patients. Age Ageing 18: 11–16PubMedCrossRefGoogle Scholar
  96. Wolters EC, Hurwitz TA, Mak E, et al (1990) Clozapine in the treatment of parkinsonian patients with dopaminomimetic psychosis. Neurology 40: 832–834PubMedCrossRefGoogle Scholar
  97. Wolters EC, Jansen EN, Tuynman-Qua HG, Bergmans PL (1997) Olanzapine in the treatment of dopaminomimetic psychosis in patients with Parkinson’s disease. Neurology 47: 1085–1087CrossRefGoogle Scholar
  98. Workman RH Jr, Orengo CA, Bakey AA, Molinari VA, Kunik ME (1997) The use of risperidone for psychosis and agitation in demented patients with PD. J Neuropsychiatry Clin Neurosci 9: 594–597PubMedGoogle Scholar
  99. Zoldan J, Friedberg G, Goldberg-Stern, Melamed E (1993) Ondansentron for hallucinosis in advanced Parkinson’s disease. Lancet 341: 562–563PubMedCrossRefGoogle Scholar
  100. Zoldan J, Friedberg G, Weizman A, Melamed E (1996) Ondansetron, a 5-HT3 antagonist for visual hallucinations and paranoid delusional disorder associated with chronic L-DOPA therapy in advanced Parkinson’s disease. In: Battistin L, Scarlato G, Caraceni T, Ruggieri S (eds) Parkinson’s disease. Lippincot-Raven, Philadelphia, pp 541–544 (Adv Neurol 69)Google Scholar
  101. Zweig RM, Cardillo JE, Cohen M, Giere S, Hedreen JC (1993) The locus ceruleus and dementia in Parkinson’s disease. Neurology 43: 986–991PubMedCrossRefGoogle Scholar

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© Springer-Verlag/Wien 2003

Authors and Affiliations

  • E. Tolosa
    • 1
  1. 1.Neurology Service, ICMSN, and Banco de Tejidos Neurológicos, Hospital ClinicoUniversity of BarcelonaBarcelonaSpain

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