J Neural Transm (2006) [Suppl] 71: 27–30
# Springer-Verlag 2006
The DONPAD-study – Treatment of dementia in patients with Parkinson’s disease with donepezil
T. Mu¨ller 1 , J. Welnic 1 , G. Fuchs 3 , H. Baas 4 , G. Ebersbach 5 , H. Reichmann 2
1
Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany
2
Department of Neurology, Medical Faculty of the Technical University, Dresden, Germany
3
Parkinson – Clinic, Wolfach, Germany
4
Department of Neurology, City Hospital Hanau, Germany
5
Movement Disorder Clinic, Beelitz – Heilst €aatten, Germany
Summary Inhibition of acetylcholinesterase improves symptoms of de- mentia in patients with Parkinson’s disease (PD). Dementia in PD has a cumulative incidence of up to 80% and is mainly caused by a distinct cholinergic deficit. Objectives of this investigator initiated multicenter open label trial were to confirm the efficacy of donepezil in the treatment of dementia in PD patients and to investigate the tolerability and safety of donepezil. The Mini Mental State Examination (MMSE)-score significantly increased in patients, who finished the trial. A detailed analysis of the va- rious items of the MMSE revealed, that only task performance of orientation and recall significantly improved. Scores of the short syndrome test and the Clinical Global Impression Scale improved, motor impairment did not increase. Only 14 out of 24 PD patients finished the trial due to predominant onset of vomiting, nausea, dizziness and confusion. This may result from the titration regime of donepezil, that allows only 5 and 10 mg dosages.
Participants with premature study termination had a significant longer dura- tion of PD, less motivation and sleep disturbances at night. Treatment with donepezil was only effective in PD patients with dementia, who experience nearly no side effects from the drug.
Introduction
There is increasing evidence, that inhibitors of acetylcho- linesterase also improve symptoms of dementia in patients with Parkinson’s disease (PD) and allied conditions (Emre, 2004). Clinical symptoms of dementia are deficits of at- tention, cognitive slowing and impairment of executive, visualspatial and memory function with a cumulative inci- dence of up to 80% particularly in PD patients of older age (Aarsland et al., 1996). A distinct cholinergic deficit in PD patients is looked upon as the main cause for this non- dopaminergic feature of the disease in particular from the
neurochemical point of view (Tiraboschi et al., 2000).
Accordingly, predominant open label smaller trials with donepezil and rivastigmine demonstrated an improvement of cognitive function in various kinds of patients with impairment of motor and cognitive function (Werber and Rabey, 2001; Giladi et al., 2003; Leroi et al., 2004). Then the multicenter EXPRESS study compared the efficacy of rivastigmine, an inhibitor of both acetylcholinesterase and butyrylcholinesterase, with placebo. In this trial, rivastig- mine produced a moderate but significant improvement in global ratings of dementia, cognition with measurements of executive functions and attention, and neuropsychiatric behavioural symptoms among patients with dementia asso- ciated with PD. The mean rivastigmine dosage was 8.6 mg at the end of the dose-escalation phase and remained stable throughout the maintenance phase. Predominant choliner- gic adverse effects, i.e. nausea or vomiting, occurred. The rivastigmine treated participants mostly characterised these side effects as mild to moderate and accordingly the rate of premature withdrawal was relatively low (Emre et al., 2004). In contrast to rivastigmine with its selective inhibi- tion of the G 1 cholinesterase isoform in predominant cor- tical and hippocampal regions is donepezil less selective (Weinstock, 1999). Whereas rivastigmine administration allows a slow, more complex, but individually adapted titration within a dose range between 3 and 12 mg accord- ing to the patient’s tolerability of the drug, is the treatment with donepezil more simple with the administration of a 5 mg or a 10 mg oral dosage. However this drug regimen may hypothetically result in a higher incidence of the onset typical adverse effects of central acetylcholinesterase inhi-
Correspondence: T. Mu¨ller, MD, Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Gudrunstrasse 56, 44791 Bochum, Germany
e-mail: thomas.mueller@ruhr-uni-bochum.de
bition. Therefore we conducted an investigator initiated multicenter open label trial in Germany with the objectives to confirm the efficacy of donepezil in the treatment of dementia in PD patients and to investigate the tolerability and safety of donepezil.
Methods
Patients
We enrolled men or women with a diagnosis of PD according to the clinical diagnostic criteria of the United Kingdom Parkinson’s Disease Society Brain Bank (Hughes et al., 1992) and a diagnosis of dementia according to the fourth edition of the Diagnostic and Statistical manual of mental Disorders (ICD 294.1) (for clinical characteristics see Table 1). Further inclusion criteria were a score within the range of 10 to 26 in the Mini Mental State Examination (MMSE) with an onset of symptoms occurring at least two years after the diagnosis of PD and a regular contact with a caregiver. Exclusion criteria were a history of major depressive episodes, presence of any other primary neurodegenerative disorders or other causes of dementia, seizures, prior long term intake of anticholinergic compounds.
The patients had to be on a stable dopaminergic drug regime (N ¼ 2, bromocriptine [5 mg t.i.d., 5,5,7.5 mg]; N ¼ 3, cabergoline [6 mg o.i.d., 4 mg o.i.d., 5 mg o.i.d.]; N ¼ 1, dihydroergocriptine [20 mg o.i.d.]; N ¼ 4, pergolide [0.5 mg o.i.d., 0.5 mg o.i.d., 0.75 mg t.i.d., 0.75 mg t.i.d.]; N ¼ 3, pramipexole [0.18 mg t.i.d., 0.7 mg t.i.d., 0.7 mg t.i.d. þ 0.35 mg]; N ¼ 1, selegiline [5, 2.5 mg]; N ¼ 5, amantadine [150 mg o.i.d., 100 mg o.i.d., 300 mg daily dosage {d.d.}, 200 mg d.d., 450 mg d.d.] for at least four weeks before study participation. The inclusion criteria allowed change of the antiparkinsonian drug regime in case of increase of motor symptoms and intake of atypical neuroleptics in low dosages on a regular basis. Institu- tional ethical boards at each center reviewed the protocol, the informed- consent form and other all information provided to patients and caregivers.
Both, participants (or the legally authorised representative) and the caregiver gave written informed consent. We conducted all procedures in accordance with the ethical standards of the responsible committee on human experi- mentation and with the Helsinki Declaration of 1983.
Design
This was a 12-week open label out patient trial. Treatment started with 5 mg Donepezil once daily, an increase of dosage to 10 mg was performed after the second visit. Assessments were performed at baseline (I), after six weeks
(II) and after 12 weeks (III). There were standardised visits via phone with the patients respectively their caregivers one week after I and II in order to check compliance of the patients, onset of side effects, change of concomi- tant medication and tolerability of the drug. The Clinical Global Impression Scale of severity respectively improvement (CGI), MMSE (Koch et al., 2005), Unified Parkinson’s Disease Rating Scale (UPDRS) (Goetz et al., 2003) and Nurses Observation scale for geriatric patients, Version II (NOS) (Wahle et al., 1996) were performed at visits I, II, III, the Short Syndrome Test (SKT) (Overall and Schaltenbrand, 1992) only at visits I and III.
Investigators were trained for diagnostic and rating procedures under stan- dardized conditions.
Safety measures
At each visit, patients and caregivers were asked for adverse events in an interview with open questions. Efficacy ratings, adverse events, concomitant treatments and drug accountability (pill counting) were assessed, detailed physical examinations, clinical laboratory and vital signs were performed at visits I, II, III.
Study medications
Donepezil was provided by EISAI
+, Germany.
Statistics
Data showed a normal distribution according to the Kolmogorow-Smirnow test. We used ANOVA with repeated measures design and as post hoc test the Tukeys HSD test for comparisons against baseline. Comparisons be- tween baseline data of patients, who finished the trial, and those, who did not, was performed with the t-test of independent samples.
Results
Efficacy of donepezil
The MMSE-score significantly increased in patients, who finished the trial. The detailed analysis of the various items of the MMSE revealed, that only the performance of the tasks orientation and recall significantly improved. The SKT and the CGI significantly reduced. The UPDRS nearly remained unchanged, the daily levodopa dosage was not
Table 1. Clinical characteristics at baseline
All participants Regular finish Drop out
age 71.08 6.1; 57–79 71.14 7.41 71.00 3.97
size (cm) 168.5 8.87; 143–183 170.14 8.60 166.20 9.16
weight (kg) 71.48 11.17; 53–98 73.86 11.23 68.15 10.74
duration of PD (years) 5.06 3.92; 0.5–16 3.29 2.03 7.55 4.65
duration of dementia (years) 1.19 1.18 1.11 1.1 1.30 1.34
levodopa dosage (mg) 423.33 227.84 394.64 178.18 463.50 289.37
UPDRS I, item 4 (motivation) 1.17 1.03 1.57 1.02 0.56 0.73
SKT item 1 (naming of objects) 1.82 1.22 2.21 1.12 1.13 1.13
NOS item 4 (disturbed behaviour at night) 3.68 1.21 4.14 0.95 2.88 1.25
NOS item 5 (interest) 2.17 0.98 2.50 1.02 1.67 0.71
NOS item 14 (clean and tidy) 1.39 0.50 1.21 0.43 1.67 0.50
CGI clinical global impression scale of severity respectively improvement, UPDRS unified Parkinson’s disease rating scale, NOS nurses observation scale for geriatric patients, Version II, SKT short syndrome test, MMSE mini mental state examination;
þp <0.05,
þþp <0.01,
þþþp <0.001; comparisons versus baseline in the post hoc analysis p <0.05, p<0.01, p<0.001
28 T. Mu¨ller et al.
significantly altered (results not shown). There was no effect on the outcomes of the NOS (see Table 2).
Drop out rate
Only 14 out of 24 PD patients finished the trial. Causes for premature withdrawals and early study termination were nausea and dizziness (N ¼ 3, before visit II), hallucinations, anxiety and panic attacks (N ¼ 1, before visit II), confusion (N ¼ 3, before visit II), increase of bradykinesia (N ¼ l, before visit II), onset of pankreatitis (N ¼ 1, before visit II), withdrawal of consent (N ¼ 1, before visit II). This rel- ative high rate of early study terminations allows a com- parison of baseline characteristics of both patient groups.
Participants with premature withdrawal from the study had a longer duration of PD, a higher score of UPDRS I item 4, which indicates increasing loss of initiative and a deterio- rated performance of the SKT task of naming of objects.
Patients, who finished the trial, showed a better sleep beha- viour at night, were more clean and tidy and had more interest in their daily surroundings according to the corre- sponding items of the NOS (see Table 1). There was no change of the concomitant drug regime of participants, who finished the trial. The analysis of the concomitantly applied drugs did not reveal, that a specific kind of agent predis- posed for early study termination.
Discussion
We show, that donepezil administration provided a mod- erate but significant improvement of cognition only in pa- tients with PD associated with dementia, who tolerated treatment with donepezil. In particular, orientation and
word recall became significant better in the MMSE, which reflects brain function and short term memory. The magni- tude of the effect is similar to the one observed in patients with Alzheimer’s disease in placebo controlled trials. There was no significant change of daily levodopa intake in our study participants during the trial (results not shown) and their UPDRS-scores, respectively the various subscores, did not significantly worsen. This is of interest, since there is a controversial debate on onset or aggravation of extra- pyramidal symptoms during cholinesterase inhibition in AD patients or patients with parkinsonism in dementia with lewy bodies (Richard et al., 2002; Heinze et al., 2002;
Hegerl et al., 2003; Di Lazzaro et al., 2004). In particular, there are reports on deterioration of fine motor behaviour during treatment with cholinesterase inhibitors, but conco- mitant application of typical and atypical neuroleptics may have confounded study outcomes or case reports in AD- or PD patients with dementia (Werber et al., 2001; Richard et al., 2002; Heinze et al., 2002; Bohnen et al., 2004). We show, that PD patients do not experience an essential impairment of motor function due to additional intake of donepezil. States of confusion, nausea, dizziness and vomit- ing were the main common causes for premature study withdrawal. This drop out rate with 10 out of 24 partici- pants was relative high compared to other trials with rivastigmine (Emre et al., 2004). This may result from the titration regimen, that allows only 5 and 10 mg dosages in the case of donepezil. In contrast, rivastigmine with its oral treatment dosage range between 3 to 12 mg may be titrated in a more slow, continuous and smooth fashion. A further, still hypothetical reason may be an increased affi- nity of donepezil to the area postrema, which may result in onset of cholinergic side effects, i.e. nausea and vomiting,
Table 2. Clinical outcomes
I II III F
MMSE 21.57 4.43 25.57 4.18 24.71 5.05 18.25
þþþorientation 7.5 2.50 8.79 1.76 8.71 1.73 9.18
þþþmemory 3 3 3 n.s.
attention 2.43 1.16 3.36 1.69 3 1.88 2.36
recall 1.14 0.95 2.21 0.89 2.07 1 8.89
þþspeech 7.5 1.29 8.21 0.97 7.93 1.14 2.66
SKT 14.27 6.65 12.27 6.15 5.83
þCGI 4.29 0.92 3.14 0.77 3.21 0.80 7.27
þþþNOS 92.86 8.46 87.93 16.18 90.86 8.83 1.59
UPDRS total 34.79 10.18 32.29 12.24 34 12.69 1.17
UPDRS I 4.79 2.42 4.07 2.59 4.43 2.31 0.82
UPDRS II 13.64 5.54 12.36 5.47 12.79 5.92 0.94
UPDRS III 15.43 5.27 14.93 6.38 15.29 5.98 0.16
UPDRS IV 0.93 1.27 1.07 1.14 0.79 0.70 0.61
CGI Clinical global impression score, MMSE mini mental state examination, SKT short syndrome test, I, II, III Visits 1, 2, 3; F F-value of ANOVA,
þ
