High Donepezil Doses And Parkinsonian Symptoms
- LucaRozzini, Clinica Neurologica, University of Brescia Italy, Geriatric Research Group, Brescia, P.zzle Spedali Civili 1, Brescia, Italy [email protected]
- Diego Ghianda, Marco Trabucchi, Alessandro Padovani
In order to discuss the topic raised by Onofrj et al. in the recent paper in Neurology, we present a case of parkinsonism after administration of high Donepezil dosage in patient with Lewy Body Dementia .
A 70 year-old woman was admitted to the Rehabilitation Unit for Dementia in September 2003 for a progressive deambulation worsening. In 1997 the patient developed insomnia ad agitation followed by an occasional episode of spatial disorientation. In 1999 she developed apathy, social isolation and anxiety, nocturnal hallucinations and loss of interests for the activities of daily living.In 2000 the patient, after a diagnosis of LBD, was treated by a neurologist with Donepezil 20 mg/day for the cognitive impairment and with Trazodone .
Onofrj et al. suggest that parkinsonism due to high dose of Donepezil might be secondary to accumulation of the drug we hypothesize that the parkinsonism might be also present after chronic treatment through the same mechanism of accumulation. In LBD, as well as in PD , there is an extensive degeneration of nigrostriatal dopaminergic neurons, but in contrast to what normally occurs in PD, dopaminergic replacement approaches have failed.
References:
What Happens In Pdd
People with PDD may have trouble focusing, remembering things or making sound judgments. They may develop depression, anxiety or irritability. They may also hallucinate and see people, objects or animals that are not there. Sleep disturbances are common in PDD and can include difficulties with sleep/wake cycle or REM behavior disorder, which involves acting out dreams.
PDD is a disease that changes with time. A person with PDD can live many years with the disease. Research suggests that a person with PDD may live an average of 57 years with the disease, although this can vary from person to person.
Comparison Of Cognitive Changes Between The Donepezil Treatment And Non
The initial K-MMSE scores were 26.9±1.9 in the control group and 26.3±2.2 in the treatment group. The K-MMSE scores after 48 weeks were 27.1±2.1 in the control group and 26.0±2.4 in the treatment group. There was no significant effect of treatment on the K-MMSE scores . The MoCA scores at baseline were 23.2±3.9 and 21.4±3.8 in the control and treatment groups, respectively. After 48 weeks, the MoCA scores changed to 24.2±3.5 and 23.0±4.0 in the control and treatment groups, respectively. There was no significant time and group interaction effect of the LMM on the MoCA scores .
The CDR and CGI showed no statistically significant treatment effect in the LMM. No deterioration in the UPDRS part III score associated with the treatment was observed . There were no significant group differences in the changes in the comprehensive neuropsychological test scores between the control and treatment groups .
Table 2 Primary and secondary outcome measures.
One patient from each group converted to dementia. There was no statistically significant treatment effect on dementia conversion .
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Cholinesterase Inhibitors Are Beneficial For People With Parkinson’s Disease And Dementia
The clinical features of dementia with Lewy bodies and Parkinson’s disease with dementia have much in common. As patients with DLB and PDD have particularly severe deficits in cortical levels of the neurotransmitter acetylcholine, blocking its breakdown using a group of chemicals known as cholinesterase inhibitors may lead to clinical improvement. Six trials showed a statistically significant improvement in global assessment, cognitive function, behavioural disturbance and activities of daily living rating scales in PDD and cognitive impairment in Parkinson’s disease patients treated with cholinesterase inhibitors. There was no current disaggregated evidence to support their use in CIND-PD. In a single trial, no statistically significant improvement was observed in patients with DLB who were treated with cholinesterase inhibitors and further trials are necessary to clarify the effect of cholinesterase inhibitors in this patient group.
The currently available evidence supports the use of cholinesterase inhibitors in patients with PDD, with a positive impact on global assessment, cognitive function, behavioural disturbance and activities of daily living rating scales. However, almost half of the trial data, which could potentially change this conclusion, have not been made public. The effect in DLB remains unclear. There is no current disaggregated evidence to support their use in CIND-PD.
Reference lists of relevant studies were searched for additional trials.
How Should I Take Donepezil
Follow all directions on your prescription label and read all medication guides or instruction sheets. Use the medicine exactly as directed.
You may take donepezil with or without food.
Swallow the regular tablet whole and do not crush, chew, or break it.
Remove an orally disintegrating tablet from the package only when you are ready to take the medicine. Place the tablet in your mouth and allow it to dissolve, without chewing. Swallow several times as the tablet dissolves. After the tablet dissolves completely, drink a glass of water.
If you need surgery or dental work, tell the surgeon or dentist ahead of time that you are using donepezil. You may need to stop using the medicine for a short time.
You should not stop using donepezil without your doctor’s advice.
Store at room temperature away from moisture and heat.
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Aricept Helps Cognition In Parkinson’s
This article is a collaboration between MedPage Today and:
SYDNEY — Parkinson’s disease patients who have impaired cognition appeared to benefit from the Alzheimer’s disease medicine donepezil — with no detriment to their motor skills, researchers reported here.
A meta-analysis of four studies showed a mean change in the Mini-Mental State Examination of 1.53 in favor of donepezil compared with placebo , said Leah Shiong Shu, MD, chief resident in adult neurology at Philippine General Hospital in Manila.
Action Points
- Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
- Note that this meta-analysis of four randomized, controlled trials demonstrated that donepezil is efficacious in terms of improving scores on the Mini-Mental State Exam in patients with Parkinson’s disease and cognitive impairment.
- Be aware that more than 90% of the patients in this analysis came from a single large trial, which largely drives these results.
None of the studies scrutinized for the meta-analysis showed any impact of donepezil therapy on the Unified Parkinson’s Disease Rating Scale , Shiong Shu reported at her poster presentation at the International Congress on Parkinson’s Disease and Movement Disorders.
Hence, the researchers undertook the meta-analysis to see if they could determine donepezil’s effectiveness.
Disclosures
Enhancing Healthcare Team Outcomes
Donepezil is most commonly used for the treatment of Alzheimer dementia and is FDA approved for use in mild, moderate, and severe Alzheimer disease. It is crucial to educate the family and caregivers that donepezil does not alter the progression of Alzheimer disease. However, it can alleviate some symptoms by improving cognition and/or behavior. Healthcare professionals, including clinicians, need to be aware of the benefits and limitations of donepezil when prescribing to older adults. After starting treatment, prescribers should follow up for cognition and behavior assessments to assess treatment efficacy, drug tolerance and check cholinergic excess symptoms. A pharmacist consult should include verifying dosing, performing medication reconciliation, looking for drug-drug interactions, and reporting to the prescriber if any issues. Nurses should monitor for adverse effects, evaluate medication compliance and therapeutic effectiveness. Management of dementia needs an interprofessional team approach, including health care professionals such as clinicians, nurse practitioners, physician assistants, nurses, pharmacists, family, and caregivers, all engaged in the collaborative activity and open communication to drive optimal patient outcomes.
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Donepezil May Reduce Parkinson’s
Megan Brooks
The randomized, placebo-controlled trial showed that unsteady subjects with PD fell approximately half as often while taking donepezil than their counterparts in the placebo group, Kathryn A. Chung, MD, Department of Neurology, Oregon Health & Sciences University, Portland, and colleagues report in the October 5 issue of Neurology.
“Cholinesterase inhibitors have been used to treat cognitive decline in subjects with PD and have been tolerated well by the majority. Reduced falls may be another reason to initiate this therapy but further studies are needed,” the investigators write.
Echoing the need for further study, Eric J. Ahlskog, MD, PhD, of the Mayo Clinic, Rochester, Minnesota, who authored a commentary on the study, told Medscape Medical News, “it is too soon to begin prescribing donepezil for patients with falls. We collectively await further confirmation and elucidation of this effect.”
Falls Prevalent in Advanced PD
As PD advances, postural instability becomes a significant cause of morbidity and rarely improves with dopaminergic therapy, Dr. Chung and colleagues point out in their article. Medications with anticholinergic properties may impair balance and increase the risk for falls, they further note.
Because PD itself can be considered an acetylcholine-deficient state, the researchers wondered whether acetylcholine augmentation may improve balance and reduce falls in PD patients.
False-Positive Trial?
Findings Suggestive, Not Definitive
Patient Disposition And Baseline Demographics And Clinical Characteristics
We enrolled 80 patients for this study but 26 of them were lost at follow-up . Total 14 patients withdrew their consents . Ten patients in the treatment group experienced adverse effects and one patient in the treatment group died due to aspiration pneumonia which was not related to the donepezil treatment. We excluded one patient in the treatment group because of poor compliance. In addition, four patients in the control group were excluded for further analysis since they took choline alfoscerate.
Figure 1
The demographics, and clinical characteristics for the two groups are shown in Table . There were no significant differences in the age, sex, education or disease duration between the two groups. The baseline values of the primary and secondary outcome measures were not different between the two groups. There was no significant difference in the levodopa equivalent daily dose.
Table 1 Baseline demographics and clinical characteristics.
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Behavioural And Psychological Symptoms
Psychosis
The psychiatric symptoms of Parkinson’s disease dementia are common, complex and disabling. Their prevalence in patients attending movement disorder clinics is between 21 and 46% . Some symptoms are noteworthy because they are mild, patients may have retained insight and require no specific therapy other than reassurance. These include vivid dreams, visual illusions and ideas of presence .
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Donepezil For Mild Cognitive Impairment In Parkinsons Disease: A 48
K. Baik, S. Kim, S. Kang, Y. Sohn, P. Lee, S. Kang
Category:Parkinsons Disease: Clinical Trials
Objective: To investigate the efficacy of donepezil for mild cognitive impairment in Parkinsons disease .
Background: MCI is common in PD. The mechanism of PD-MCI is unclear, but previous studies implicated that cholinergic deficits might be associated with PD-MCI. Donepezil and rivastigmine, acetylcholinesterase inhibitors , increase acetylcholine level and duration of the neurotransmitter action in the synaptic cleft. They are widely used for symptomatic treatment of Alzheimers disease. Also, AChEIs had showed moderate improvements of cognition in PD dementia. However, there is no approved treatment in PD-MCI with cholinesterase inhibitor.
Results: Of the 80 patients enrolled, 54 completed the study. Differences in the K-MMSE, MoCA, CDR, UPDRS part III, CGI between both groups at the three assessments and comprehensive neuropsychological test between baseline and 48-week were calculated using a linear mixed model. There were no significant time x group interaction effects. However, the treatment group showed a significant decrease of TB2R at bilateral frontotemporoparietal channels compared to the non-treatment group.
Although we could not demonstrate improvement in the cognitive functions, Donepezil treatment could be beneficial in PD patients with MCI by decreasing the slow-wave relative to the fast wave in EEG, which could reflect the enhancement of brain connectivity.
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How To Cope With Side Effects
What to do about:
- diarrhoea â drink lots of fluids, such as water or squash, to avoid dehydration. Signs of dehydration include peeing less than usual or having dark strong-smelling pee. Do not take any other medicines to treat diarrhoea, including rehydration salts, without first speaking to a pharmacist or doctor
- feeling sick â it may help to avoid eating very rich, fatty or spicy food
- headache â make sure you rest and drink plenty of fluids. If it’s bothering you, ask a pharmacist to recommend a painkiller. Talk to a doctor if your headaches last longer than a week or are severe
- feeling sleepy in the daytime or feeling dizzy â try taking your medicine at night. If you feel dizzy or tired do not drive or ride a bike until you feel more alert. Talk to a doctor if these effects bother you, or do not get better
As your body gets used to donepezil, these side effects should wear off. If you are still bothered by them after a week or two, speak to a doctor. They may want to adjust your dose or recommend a different medicine.
How Can We Support The Sleep/wake Cycle Of Pdd
For people with PDD who are confused about the day-night cycle, some daily strategies can be helpful. At night, starting a lights out routine that happens at the same hour every day, where all curtains are closed and lights are turned off, can help the person understand that it is sleep time. During the day, opening the curtains, allowing the person with PDD to spend as much time in the daylight as possible, avoiding naps, and organizing stimulating activities, can be helpful. Having lots of calendars and clocks in every room might also help a person with PDD be less confused about the time of day.
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What If I Forget To Take It
If you forget a dose of donepezil, skip the missed dose and take the next one at the normal time the next day.
Do not take a double dose to make up for a forgotten dose.
If you’ve forgotten to take your donepezil for more than a week, talk to your doctor before you take any more.
If you forget doses often, it may help to set an alarm to remind you. You could also ask a doctor, pharmacist or dementia support group for advice on other ways to help you remember to take your medicine.
Eeg Recording And Data Processing
Participants were relaxed and awake during the recording. Eye-closed, resting state EEG data were recorded for at least five minutes. The international 1020 system was used for electrode placement. 19 channels with referential montage were used: FP1, FP2, F7, F3, Fz, F4, F8, T3, C3, Cz, C4, T4, T5, P3, Pz, P4, T6, O1, and O2. We selected three minutes of eye-closed and artifact-free data based on visual inspection for further analysis.
The EEG data were high pass filtered offline above 1 Hz, low pass filtered below 45.5 Hz and recomputed to obtain the common average reference. Artifacts were removed during visual inspection and using advanced mixture independent component analysis . Sensor level analysis using the spectopo function based on EEGLAB was performed in the following eight spectral bands: Delta , Theta , Alpha1 , Alpha2 , Beta1 , Beta2 , Beta3 , and Gamma .
The imaginary coherence was employed as a measure of functional connectivity. The iCoh is an imaginary part of the coherency which is defined as follows:
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How Is Age Related To Pdd
Both PD and PDD are more common with increasing age. Most people with PD start having movement symptoms between ages 50 and 85, although some people have shown signs earlier. Up to 80% of people with PD eventually develop dementia. The average time from onset of movement problems to the development of dementia is about 10 years.
Design Of The Phase 2 And 3 Studies
This analysis pooled the data from the phase 2 and 3 studies of donepezil for DLB conducted in Japan. The phase 2 studies, consisting of a RCT and a subsequent OLE , were conducted as two sequential protocols. A 12-week randomized, double-blind, placebo-controlled exploratory study was first conducted to investigate the efficacy and safety of donepezil at 3, 5, and 10 mg/day starting in 2007 . In the patients who completed this RCT, the safety and efficacy of long-term administration at 5 mg were further investigated in the following 52-week OLE . The phase 3 study was conducted as a single protocol consisting of an RCT phase and a subsequent OLE phase. A 16-week randomized, double-blind, placebo-controlled comparative study consisting of a 12-week confirmatory phase and a 4-week transition period and a subsequent 36-week OLE phase were conducted starting in 2011 for a total duration of 52 weeks . The aim was to confirm the superiority of donepezil at 5 and 10 mg/day for 12 weeks over placebo with regard to both cognitive function and behavioral symptoms and to evaluate the safety and efficacy of long-term administration of 10 mg/day for 52 weeks. Each study was conducted in accordance with the principles of the Declaration of Helsinki. The protocols were approved by the institutional review board at each participating center.
Fig. 1
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Summary Of The Results Of The Phase 2 And 3 Studies
The results of the phase 2 and 3 studies are reported in detail elsewhere . Briefly, in phase 2, the RCT showed that donepezil significantly improved cognitive, behavioral, and global functions with good tolerability, and the OLE demonstrated that administration was well tolerated even for a long duration and that the effect on cognitive and behavioral impairment was maintained for up to 52 weeks. In phase 3, although the RCT failed to confirm a superiority concerning the behavioral symptoms over placebo, it confirmed the efficacy concerning cognitive function without serious safety concerns. The OLE demonstrated a lasting improvement in cognitive function for up to 52 weeks, without increasing the risk of clinically significant safety events.
How Can We Manage Hallucinations
It may not be necessary to treat all hallucinations of a person with PDD. Hallucinations are often harmless, and it is okay to allow them to happen, as long as they are not disruptive or upsetting to the person or surroundings. Sometimes, recognizing the hallucination and then switching the topic might be an efficient way of handling frustrations that occur because of a hallucination. If hallucinations need medical treatment, your provider may be able to discuss and suggest some options. However, many of the medications used to treat hallucinations may make movement symptoms worse.
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