Donepezil for dementia with Lewy bodies: A randomized, placebo-controlled trial. - About Medicines for Lewy Body Dementia (LBD)

Objective:

Since cholinergic deficits are prominent in dementia with Lewy bodies (DLB), we investigated the effects of a cholinesterase inhibitor, donepezil, in such patients in a randomized, double-blind, placebo-controlled exploratory phase II trial.

Methods:

One-hundred and forty patients with DLB, recruited from 48 specialty centers in Japan, were randomly assigned to receive placebo, 3, 5, or 10 mg of donepezil hydrochloride daily for 12 weeks (n=35, 35, 33, and 37, respectively). Effects on cognitive function were assessed using the Mini-Mental State Examination (MMSE) and several domain-specific neuropsychological tests. Changes in behavior were evaluated using the Neuropsychiatric Inventory (NPI), caregiver burden using the Zarit Caregiver Burden Interview (ZBI), and global function using the Clinician's Interview-Based Impression of Change-plus Caregiver Input (CIBIC-plus). Safety measures included the Unified Parkinson's Disease Rating Scale (UPDRS) part III.

Results:

Donepezil at 5 and 10 mg/day were significantly superior to placebo on both MMSE (mean difference, 95%CI, p value; 5 mg, 3.8, 2.3 to 5.3, p<0.001; 10 mg, 2.4, 0.9 to 3.9, p=0.001) and CIBIC-plus (p<0.001 for each): 3 mg/day was significantly superior to placebo on CIBIC-plus (p<0.001), but not on MMSE (p=0.017). Significant improvements were found also in behavioral measures (p<0.001) at 5 and 10 mg/day and caregiver burden (p=0.004) at 10 mg/day. The safety results were consistent with the known profile of donepezil and similar among groups.

Interpretation:

Donepezil at 5 and 10 mg/day produces significant cognitive, behavioral, and global improvements that last at least 12 weeks in DLB patients, reducing caregiver burden at the highest dose. Donepezil is safe and well-tolerated.

Etsuro Mori MD, PhD, Manabu Ikeda MD, PhD, Kenji Kosaka MD, PhD, on behalf of the Donepezil-DLB Study Investigators. Donepezil for dementia with Lewy bodies: A randomized, placebo-controlled trial. Annals of Neurology, DOI: 10.1002/ana.23557

For a full copy of the paper, contact the corresponding author: Etsuro Mori MD, PhD (morie@med.tohoku.ac.jp)

Excerpt from Alzheimers Weekly:

The study was a randomized, double-blind, placebo-controlled exploratory phase II trial.

The benefits of donepezil on cognitive function were assessed using a series of well-known tests. These include:

* The Mini-Mental State Examination (MMSE) to test cognition.
* The Neuropsychiatric Inventory (NPI) was used to evaluate changes in behavior.
* The Zarit Caregiver Burden Interview (ZBI) measured caregiver burden.
* The Clinician's Interview-Based Impression of Change-plus Caregiver Input (CIBIC-plus) was used for global function.
* The Unified Parkinson's Disease Rating Scale (UPDRS) part III was included for measuring safety. This is because Lewy Bodies are prominent in Parkinson's as well as DLB, so what applies to Lewy Bodies in Parkinson's seems to apply just as well to people with DLB.

Results:

3 mg/day: Donepezil was significantly superior to placebo on the CIBIC-plus, but not on the MMSE.

5 and 10 mg/day: Donepezil was significantly superior to placebo on both MMSE and CIBIC-plus. Significant improvements were found also in behavioral measures.

10 mg/day: Donepezil showed significant improvement of caregiver burden.

Safety: The safety results were consistent with what is already known about donepezil and other cholinesterase inhibitors.

Bonuses & Downsides

One downside came out in a prior study called, Donepezil Associated Bradyarrhythmia in a Patient with Dementia with Lewy Bodies (DLB). The study warns about the susceptibility of people with LDB to bradyarrhythmia, and hence the added cardiac risk of a medication like donepezil. [AlzLibrary notes: this was a case study, involving a single patient, not a clinical trial]

* "While acetylcholinesterase inhibitors (ChE-Is) have been shown to improve cognitive and behavioral deficits in DLB, these patients may be more susceptible to bradyarrhythmetic side effects from this class of drugs due to the autonomic insufficiency associated with the disease."

On the positive side, donepezil affords Lewy Body dementia a unique opportunity. It can do part of the job of antipsychotic medications. This is a bonus for two reasons:

* DLB (Dementia with Lewy Bodies) is more prone to hallucinations
* DLB often forbids the use of antipsychotics.

The bonus is in the cholinesterase inhibitor donepezil potentially being able to treat behavioral deficits which, until now, had no effective treatment.

Donepezil is not FDA-Approved for DLB. Therefore, if your doctor wants to prescribe it, they will need to do so "off-label."

As with all medications, these and other considerations need to be weighed carefully by your healthcare professionals. Be sure to ask your doctor.