Background and aim: Rivastigmine is now widely approved for the treatment of mild to moderately severe dementia in Parkinson’s disease (PDD). However, since anticholinergic drugs have a role in the management of tremor in patients with Parkinson’s disease (PD), concerns have been raised that the use of cholinergic drugs might worsen PD. The current analyses were performed to examine the potential of rivastigmine to affect tremor and other motor symptoms in patients with PDD.
Methods: The safety profile of rivastigmine was evaluated using a database from a 24-week, randomized, double-blind, placebo-controlled trial in 541 PDD patients (362 randomized to rivastigmine, 179 to placebo), and 334 PDD patients who subsequently entered an open-label 24-week extension on rivastigmine.
Results: During the double-blind trial, the adverse event (AE) of emerging or worsening tremor was reported in 10.2% of patients in the rivastigmine group, compared with 3.9% in the placebo group (p = 0.012). Tremor was most frequently reported during the titration phase of rivastigmine treatment, although this was not reflected in total motor Unified Parkinson’s Disease Rating Scale (UPDRS) part III scores. Dose dependence of this AE was not observed. At the end of the double-blind phase, six (1.7%) rivastigmine-treated patients had discontinued the study because of tremor. In the open-label extension in which all patients received rivastigmine, tremor was reported by 6.9% of patients: 3.8% and 12.2% of whom had previously received double-blind rivastigmine and placebo, respectively (p = 0.006), suggesting that first exposure to rivastigmine leads to a transient increase in tremor. Three (0.9%) of the 334 patients who entered the open-label extension phase discontinued because of tremor. Incidences of worse ning parkinsonism, bradykinesia and rigidity were all <5% in both treatment groups (all p-values not statistically significant, rivastigmine vs placebo). In the 48-week observation of rivastigmine treatment, there was no evidence of adverse long-term motor outcomes. Posthoc analysis showed that similar improvements in the symptoms of dementia, including the ability to perform activities of daily living, were seen regardless of whether exacerbation of tremor was reported during the study.
Conclusion: Rivastigmine did not induce clinically significant exacerbation of motor dysfunction in patients with PDD. Rest tremor incidence as an AE was a transient phenomenon during dose titration of rivastigmine. There was no indication that exposure to long-term rivastigmine was associated with a worsening of PD.
Dementia With Lewy Body Rivastigmine Dopaminergic Medication Rivastigmine Treatment Rivastigmine Group
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This research was funded by Novartis Pharmaceuticals. The sponsor has provided Professors Oertel and Emre with grant support, and personal honoraria. Professors Wolters, De Deyn and Poewe have received personal honoraria from the sponsor during their careers. Dr Kirsch was an employee of the sponsor during the development of the manuscript. Dr Hsu is an employee of the sponsor. Drs Tekin and Lane are employees of the sponsor and have equity or ownership interest.
Perry EK, Curtis M, Dick DJ, et al. Cholinergic correlates of cognitive impairment in Parkinson’s disease: comparison with Alzheimer’s disease. J Neurol Neurosurg Psychiatry 1985; 48: 413–21PubMedCrossRefGoogle Scholar
Tiraboschi P, Hansen LA, Alford M, et al. Cholinergic dysfunction in diseases with Lewy bodies. Neurology 2000; 54: 407–11PubMedCrossRefGoogle Scholar
Bohnen NI, Kaufer DI, Ivanco LS, et al. Cortical cholinergic function is more severely affected in parkinsonian dementia than in Alzheimer disease: an in vivo positron emission tomographic study. Arch Neurol 2003; 60: 1745–8PubMedCrossRefGoogle Scholar
Hutchinson M, Fazzini E. Cholinesterase inhibition in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1996; 61: 324–6PubMedCrossRefGoogle Scholar
Bullock R, Cameron A. Rivastigmine for the treatment of dementia and visual hallucinations associated with Parkinson’s disease. Curr Med Res Opin 2002; 18: 258–64PubMedCrossRefGoogle Scholar
Reading PJ, Luce AK, McKeith IG. Rivastigmine in the treatment of parkinsonian psychosis and cognitive impairment: preliminary findings from an open trial. Mov Disord 2001; 16: 1171–95PubMedCrossRefGoogle Scholar
Fogelson N, Kogan E, Korczyn AD, et al. Effects of rivastigmine on the quantitative EEG in demented parkinsonian patients. Acta Neurol Scand 2003; 107: 252–5PubMedCrossRefGoogle Scholar
Romrell J, Fernandez HH, Okun MS. Rationale for current therapies in Parkinson’s disease. Expert Opin Pharmacother 2003; 4: 1747–61PubMedCrossRefGoogle Scholar
Grady SR, Salminen O, Laverty DC, et al. The subtypes of nicotinic acetylcholine receptors on dopaminergic terminals of mouse striatum. Biochem Pharmacol 2007; 74: 1235–46PubMedCrossRefGoogle Scholar
Millan MJ, DiCara B, Dekeyne A, et al. Selective blockade of dopamine D(3) versus D(2) receptors enhances frontocortical cholinergic transmission and social memory in rats: a parallel neurochemical and behavioural analysis. J Neurochem 2007; 100: 1047–61PubMedCrossRefGoogle Scholar
Zarow C, Lyness SA, Mortimer JA, et al. Neuronal loss is greater in the locus coeruleus than nucleus basalis and substantia nigra in Alzheimer and Parkinson diseases. Arch Neurol 2003; 60: 337–41PubMedCrossRefGoogle Scholar
Jellinger K. The pedunculopontine nucleus in Parkinson’s disease, progressive supranuclear palsy and Alzheimer’s disease. J Neurol Neurosurg Psychiatry 1988; 51: 540–3PubMedCrossRefGoogle Scholar
Rub U, Del Tredici K, Schultz C, et al. Parkinson’s disease: the thalamic components of the limbic loop are severely impaired by alpha-synuclein immunopositive inclusion body pathology. Neurobiol Aging 2002; 23: 245–54PubMedCrossRefGoogle Scholar
Glowinski J. Recent finding on dopaminergic transmission in the basal ganglia. Adv Neurol 1990; 53: 67–73PubMedGoogle Scholar
Liang YQ, Tang XC. Comparative studies of huperzine A, donepezil, and rivastigmine on brain acetylcholine, dopamine, norepinephrine, and 5-hydroxytryptamine levels in freely-moving rats. Acta Pharmacol Sin 2006; 27: 1127–36PubMedCrossRefGoogle Scholar
Emre M, Aarsland D, Albanese A, et al. Rivastigmine for the dementia associated with Parkinson’s disease. N Engl J Med 2004; 351: 29–38CrossRefGoogle Scholar
Poewe W, Wolters E, Emre M, et al. Long-term benefits of rivastigmine in dementia associated with Parkinson’s disease: an active treatment extension study. Mov Disord 2006; 21: 456–61PubMedCrossRefGoogle Scholar
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association, 1994Google Scholar
Fahn S, Elton RL and Members of the UPDRS development committee. Unified Parkinson’s disease rating scale. In: Fahn S, Marsden CD, Calne DB, et al., editors. Recent developments in Parkinson’s disease. Florham Park (NJ): MacMillan Healthcare Information, 1987: 153–64Google Scholar
Galasko D, Bennett D, Sano M, et al. An inventory to assess activities of daily living for clinical trials in Alzheimer’s disease. The Alzheimer’s Disease Cooperative Study. Alzheimer Dis Assoc Disord 1997; 11 Suppl. 2: S33–9PubMedCrossRefGoogle Scholar
Brønnick K, Ehrt U, Emre M, et al. Attentional deficits affect activities of daily living in dementia associated with PD. J Neurol Neurosurg Psychiatry 2006; 77: 1136–42PubMedCrossRefGoogle Scholar
Burn D, Emre M, McKeith I, et al. Effects of rivastigmine in patients with and without visual hallucinations in dementia associated with Parkinson’s disease. Mov Disord 2006; 21: 1899–907PubMedCrossRefGoogle Scholar
Touchon J, Bergman H, Bullock R, et al. Response to rivastigmine or donepezil in patients with Alzheimer’s disease and symptoms suggestive of concomitant Lewy body pathology. Curr Med Res Opin 2006; 22: 49–59PubMedCrossRefGoogle Scholar
Giladi N, Shabtai H, Gurevich T, et al. Rivastigmine (Exelon) for dementia in patients with Parkinson’s disease. Acta Neuro Scand 2003; 108: 367–73CrossRefGoogle Scholar
McKeith I, Del Ser T, Spano P, et al. Efficacy of rivastigmine in dementia with Lewy bodies: a randomized double-blind, placebo controlled international study. Lancet 2000; 356: 2031–6PubMedCrossRefGoogle Scholar
Gurevich TY, Shabtai H, Korczyn AD, et al. Effect of rivastigmine on tremor in patients with Parkinson’s disease and dementia. Mov Disord 2006; 21: 1663–6PubMedCrossRefGoogle Scholar
Bullock R, Lane R. Executive dyscontrol of dementia, with emphasis on subcortical pathology and the role of butyrylcholinesterase. Curr Alzheimer Res 2007; 4: 277–93 94PubMedCrossRefGoogle Scholar
Dubois B, Tolosa E, Kulisevsky J, et al. Efficacy and safety of donepezil in the treatment of Parkinson’s disease patients with dementia [poster presentation]. 8th International Conference on Alzheimer’s and Parkinson’s Diseases; 2007 Mar 14–18; SalzburgGoogle Scholar
Richards M, Stern Y, Marder K, et al. Relationships between extrapyramidal signs and cognitive function in a community-dwelling cohort of patients with Parkinson’s disease and normal elderly individuals. Ann Neurol 1993; 33: 267–74PubMedCrossRefGoogle Scholar
Wilson RS, Schneider JA, Bienias JL, et al. Parkinsonian like signs and risk of incident Alzheimer disease in older persons. Arch Neurol 2003; 60: 539–44PubMedCrossRefGoogle Scholar
Wilson RS, Bennett DA, Gilley DW, et al. Progression of parkinsonian signs in Alzheimer’s disease. Neurology 2000; 54: 1284–9PubMedCrossRefGoogle Scholar
Fleischman DA, Wilson RS, Bienias JL, et al. Parkinsonian signs and cognitive function in old age. J Int Neuropsychol Soc 2005; 11: 591–7PubMedCrossRefGoogle Scholar
Alves G, Larsen JP, Emre M, et al. Changes in motor subtype and risk for incident dementia in Parkinson’s disease. Mov Disord 2006; 21: 1123–30PubMedCrossRefGoogle Scholar
Deuschl G, Raethjen J, Baron R, et al. The pathophysiology of parkinsonian tremor: a review. J Neurol 2000; 247 Suppl. 5: V33–48PubMedCrossRefGoogle Scholar
Aarsland D, Laake K, Larsen JP, et al. Donepezil for cognitive impairment in Parkinson’s disease: a randomised controlled study. J Neurol Neurosurg Psychiatry 2002; 72: 708–12PubMedCrossRefGoogle Scholar
Ravina B, Putt M, Siderowf A, et al. Donepezil for dementia in Parkinson’s disease: a randomized, double-blind, placebo controlled, crossover study. J Neurol Neurosurg Psychiatry 2005; 76: 934–9PubMedCrossRefGoogle Scholar
Lahti AC, Holcomb HH, Weiler MA, et al. Functional effects of antipsychotic drugs: comparing clozapine with haloperidol. Biol Psychiatry 2003; 53: 601–8PubMedCrossRefGoogle Scholar