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1/2007
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Cholinesterase inhibitors for Parkinson’s disease-related visual hallucinations unresponsive to atypical antipsychotics

Tomasz Sobow

Arch Med Sci 2007; 3, 1: 69-72
Online publish date: 2007/03/23
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Introduction
Psychotic symptoms in Parkinson’s disease (PD) are relatively frequent and their treatment is problematic. A recommended partial discontinuation of anti-parkinsonian drugs is commonly ineffective while the use of antipsychotics (including atypicals) bears substantial risk of motor functions worsening. Moreover, many psychotic PD patients are also cognitively impaired, which makes drug interventions even more challenging [1]. Cholinergic deficiency in PD-dementia (PDD), as well as in pathologically related dementia with Lewy bodies (DLB), has been shown to be even greater than in Alzheimer’s disease, for which cholinesterase inhibitors (ChEI) are standard first-line treatment [2]. In several controlled studies, ChEI have been successfully used in PDD patients [3, 4] and there is some preliminary evidence that patients with psychotic symptoms (particularly visual hallucinations) might respond even better than those without [5]. Finally, there are several case reports showing that psychotic symptoms in PD (with or without dementia) as well as in DLB may be ameliorated with donepezil or rivastigmine [6-9]. Despite these encouraging reports the use of cholinesterase inhibitors for neuropsychiatric complications in PD (and PDD) remains controversial and it is not clear whether a clear clinically significant effect in addition to statistically significant differences really exists. Here we report the successful use of rivastigmine or donepezil in 5 patients with visual hallucinations in PD clinically unresponsive to atypical antipsychotics.
Material and methods
Five patients (4 men, mean age 79±2.2 years) evaluated at the Outpatient Unit of the Department of Old Age Psychiatry and Psychotic Disorders with long-standing Parkinson’s disease (with or without dementia) accompanied by visual hallucinations (VH) previously unresponsive to atypical antipsychotics were offered a trial of cholinesterase inhibitor, rivastigmine (4 patients) or donepezil (1 patient). All patients were diagnosed clinically by at least one consultant neurologist and in accordance with the Parkinson’s Disease Society Brain Bank criteria for Parkinson’s disease. Motor dysfunction was assessed with a motor subscale of the Unified Parkinson’s Disease Rating Scale (UPDRS, maximum of 64 points, the more points the worse the patient’s status) and global disease severity with Hoehn-Yahr staging system (range of score 1 to 5, 5 being the most advanced stage). Cognitive status was screened with the Mini Mental State Examination (MMSE, maximum of 30 points, the fewer points the worse the patient’s status) and dementia was diagnosed according to the ICD-10 criteria for dementia in Parkinson’s disease. Delirium was excluded as a possible cause of hallucinations in all subjects. VH were evaluated using item 2 (hallucinations) of the Neuropsychiatric Inventory (NPI); both severity (0 to 3 points scale) and frequency (0 to 4 points scale) were assessed and the arithmetic product (severity times frequency scores; VH-NPI) calculated. Patients were considered unresponsive to antipsychotic treatments when either they experienced intolerable side effects (most notably worsening of parkinsonism in the case of haloperidol, sulpiride, risperidon and olanzapine; sedation and falls in the case of olanzapine, haloperidol, thioridazine and quetiapine) or no clinically meaningful improvement was observed despite at least 4 weeks of well-tolerable dose (all cases treated with clozapine or quetiapine). Detailed clinical characteristics of patients are provided in the Table I. Rivastigmine was prescribed at an initial dose of 3 mg per day (in two doses) and donepezil of 5 mg per day (bedtime). Dose escalation (after at least two weeks of treatment) was possible after phone or personal contact with patients and/or their caregivers to, respectively, 6 and 10 mg per day. Patients were clinically evaluated after 6 and 12 weeks for the presence of hallucinations and, additionally, changes in UPDRS, MMSE and VH-NPI as well as any adverse events (including their possible relationship to ChEI treatment) emerging during the trial.
Results
All subjects completed the trial and no adverse events-related discontinuations occurred. General tolerability of ChEI treatment in our patients was good and there were no discontinuations due to adverse events. One patient (treated with rivastigmine) experienced nausea and appetite loss that resolved after 2 weeks without intervention. The patient on donepezil experienced headaches that responded to low doses of paracetamol and ceased after 3-4 weeks of treatment. Interestingly, doses of ChEI used were low in comparison to those used in Alzheimer’s disease treatment (5 mg/day in the case of donepezil and 3 (3 patients) to 6 (1 patient) mg/day in the case of rivastigmine). After 6 weeks of treatment VH resolved completely in 2 subjects (1 on rivastigmine and 1 on donepezil), usually within the first 2 weeks of trial, and in 3 patients (on rivastigmine) VH persisted but their frequency and/or severity were markedly diminished as measured by change in VH-NPI (mean VH-NPI score 2.0±0.9 versus 9.2±0.7 at baseline, Wilcoxon matched-pairs sign rank test, p=0.06). After an additional 6 weeks VH resolved in two further subjects while in one patient they persisted but were transient and appeared only at dawn (mean VH-NPI score at 12 weeks 0.8±0.5 versus 9.2±0.7 at baseline, Wilcoxon matched-pairs sign rank test, p=0.06; for individual changes in VH-NPI scores over time see chart). In 3 subjects complete discontinuation of antipsychotics was possible, while in two others (patients 1 and 4) 6.25 and 12.5 mg of clozapine daily was enough to control symptoms. Neither changes in UPDRS scores nor exaggeration of subjective complaints about extrapyramidal symptoms were noted during treatment (mean score at 12 weeks 22.4±2.1 as compared to 23.2±1.9 at baseline, not significant, Wilcoxon matched-pairs sign rank test, p=0.25). MMSE scores tended to be higher at the end of the trial than at baseline (23.8±1.4 versus 22.8±1.9, not significant, Wilcoxon matched-pairs sign rank test, p=0.2).
Discussion
Previous studies, including randomized trials in demented patients with DLB and PD, have rather consistently shown that cholinesterase inhibitors are effective in alleviating psychotic symptoms (mainly visual hallucinations) in those problematic subjects [3, 10]. Here, we have shown that ChEI might also be helpful in hallucinating PD subjects even in the absence of dementia. Not only did patients respond clinically but also antipsychotic drugs could be discontinued or their doses markedly reduced. Moreover, no extrapyramidal symptoms exaggeration was observed and general tolerability of ChEI, as measured by treatment-emergent adverse effects profile, was good. Interestingly, very low to low doses of ChEI were sufficient in all cases, which quite naturally might have resulted in a very good tolerability. It must be noted, however, that no worsening in movement could have also been observed due to discontinuation of previous antipsychotic treatments. However, this seems to be rather unlikely since in all cases the last neuroleptic used (quetiapine or clozapine) has itself very low EPS risk. These observations then seem to be clinically important since antipsychotics (both classical neuroleptics and atypicals) are often badly tolerated in patients with PD and might be hazardous (due to putatively increased risk of stroke) in demented elderly patients. ChEI might be an interesting alternative or, particularly taking into account a possible pathogenesis of visual hallucinations in PD, even drugs of choice in both demented and non-demented PD subjects with VH [1, 2]. The use of low doses of ChEI and waiting patiently for their clinical effectiveness might be helpful in avoiding non-tolerance, including gastrointestinal symptoms (in the study of Emre et al. [3] nearly 1 in 7 patients vomited) and extrapyramidal symptoms worsening.
Conclusions
Cautious use of ChEI in cases of VH in the course of PD unresponsive to antipsychotics (including atypicals) might be an interesting alternative treatment of these patients, even in the absence of dementia.
References
1. Weintraub D, Stern MB. Psychiatric complications in Parkinson disease. Am J Geriatr Psychiatry 2005; 13: 844-51. 2. 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: 1745-8. 3. Emre M, Aarsland D, Albanese A, et al. Rivastigmine for dementia associated with Parkinson’s disease. N Engl J Med 2004; 351: 2509-18. 4. Maidment I, Fox C, Boustani M. Cholinesterase inhibitors for Parkinson’s disease dementia. Cochrane Database Syst Rev 2006; (1): CD004747. 5. 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: 1171-4. 6. Bergman J, Lerner V. Successful use of donepezil for the treatment of psychotic symptoms in patients with Parkinson’s disease. Clin Neuropharmacol 2002; 25: 107-10. 7. Bullock R, Cameron A. Rivastigmine for the treatment of dementia and visual hallucinations associated with Parkinson’s disease: a case series. Curr Med Res Opin 2002; 18: 258-64. 8. Kurita A, Ochiai Y, Kono Y, Suzuki M, Inoue K. The beneficial effect of donepezil on visual hallucinations in three patients with Parkinson’s disease. J Geriatr Psychiatry Neurol 2003; 16: 184-8. 9. Rovers JM, Dautzenberg PL, ter Bruggen JP. Rivastigmine als ondersteuning bij het dilemma van de behandeling van hallucinaties optredend bij ziekte van Parkinson. Tijdschr Gerontol Geriatr. 2006; 37: 117-20. 10. Simard M, van Reekum R. The acetylcholinesterase inhibitors for treatment of cognitive and behavioral symptoms in dementia with Lewy bodies. J Neuropsychiatry Clin Neurosci 2004; 16(4): 409-25.
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