Use of Donepezil for Vascular Dementia

After Alzheimer's disease (AD), vascular dementia (VaD) is the most common dementing illness among elderly persons.^1,2 In most Western countries, VaD makes up 10% to 20% of dementias, and in some Asian countries it is the most common dementing illness.^1,2 In addition, in the presence of AD, cerebrovascular lesions or ischemia may be synergistic in producing the clinical syndrome of dementia.³ Despite the substantial morbidity from VaD, few therapies have been specifically directed at treating this disorder.

In recent years, acetylcholinesterase inhibitors have attained wide use in the treatment of AD.⁴ Drugs such as tacrine, donepezil, or metrifonate may improve memory and other cognitive measures among AD patients. These drugs also may have beneficial effects on associated behaviors such as apathy and degree of cooperativeness.^5,6

Donepezil, which was approved for use in late 1996, does not have the potential for hepatotoxicity that occurs with tacrine.⁴ We report on our preliminary clinical experience of the effects of donepezil on the cognitive and behavioral symptoms of patients with VaD.

METHODS

All patients presented to neurological clinics for evaluation of a memory disorder and underwent extensive clinical evaluations, including laboratory studies and magnetic resonance imaging (MRI) of the brain. This report includes 8 patients who met criteria for probable VaD established by the National Institute of Neurological Disorders and Stroke and the Association Internationale pour la Recherche et l'Enseignement en Neurosciences International Workshop² and by the DSM-IV.⁷ The patients had cognitive impairment by mental status examination, Mini-Mental State Examination (MMSE) scores of 23 or less,⁸ and moderate to severe subcortical lesions on MRI. The MRI lesions were periventricular or deep white matter hyperintensities on T₂-weighted images and lacunar infarctions, and the extent of the cerebrovascular disease on MRI was sufficient to explain the dementing illness.^2,9 We excluded patients whose clinical course and examination suggested a mixed dementia (VaD/AD), who were taking psychoactive medications, or who had active psychiatric or medical conditions that could account for their cognitive impairments. All participants and their caregivers gave informed consent.

Patients were assessed by use of an extended mental status evaluation, the MMSE, and the Clinical Dementia Rating (CDR) scale.¹⁰ Caregivers were interviewed for their assessment of clinical improvement and response to the medication. The patients were evaluated three times: at baseline before initiating 5 mg/day of donepezil; after 6 to 8 weeks of therapy (whereupon the medication was increased to 10 mg/day); and at 6 months of therapy. No patient was discontinued from the study because of potential side effects such as diarrhea or bradycardia.

RESULTS

The clinical data for the 8 patients are shown in Table 1. The mean age of the patients (±SD) was 74.9±3.6 years, and the mean duration of dementia was 3.4±2.0 years. At initiation of donepezil, the patients' mean baseline MMSE score was 20.0±3.16; at 6 months of treatment, it was 21.4±3.25. At initiation of donepezil, the mean baseline CDR score was 1.56±0.42; at 6 months of treatment, it was 1.25±0.38. Although the increase in MMSE scores was not significant, the improvement in CDR scores reached significance (paired t-test: t=2.38, df=7, P<0.05). In particular, the patients showed more initiative on self-care and other items of the CDR.

All caregivers reported a positive result from the medication. The caregivers felt that the medication was beneficial in activating or alerting the patients so that the patients were more engaged in activities and in their self-care.

DISCUSSION

Among patients with VaD, improvement or stabilization in cognition and behavior occurred after treatment with donepezil. Moreover, the drug was well tolerated. Although this is a preliminary clinical experience, it suggests that acetylcholinesterase inhibitors can be useful in the management of patients with VaD.

The most notable observations came from the patients' families and caregivers. They reported improvement on this medication and described it in terms of greater “alertness,” “initiative,” or “activation.” This behavior change was reflected in greater participation in self-care and in other activities, as reflected on the CDR.

These findings are consistent with decreased psychomotor speed, tonic arousal, and behavioral initiation in VaD patients as compared to those with AD.^11–13 The most common behavioral disturbance in VaD may be a lack of behavioral spontaneity.^11,12 These behaviors may result from deep white matter involvement and frontal-subcortical system disturbances in VaD. Furthermore, the relative abulia in VaD, with blunted affect, low motivation, and emotional withdrawal, may be precisely the behavioral symptoms that are responsive to acetylcholinesterase inhibitors.^5,6,14,15

This report is a limited, preliminary clinical experience on the use of donepezil for VaD. The numbers of patients reported is small, and there is no comparison group. Moreover, we chose primary outcome measures that reflected practical clinical monitoring of dementia patients, rather than the AD Assessment Scale or other AD clinical trials measures.⁴ Nevertheless, these findings indicate that acetylcholinesterase inhibitors could benefit VaD patients by improving behavioral initiative and drive. Further investigations, including clinical drug trials, are indicated on the therapeutic effects of these medications on patients with VaD.

TABLE 1. Clinical measures at baseline and six-month follow-up for vascular dementia patients on donepezil

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