Adverse Effects of Donepezil in Treating Alzheimer’s Disease Associated With Down’s Syndrome
To the Editor: Many individuals with Down’s syndrome who are over 40 years of age develop clinical and neuropathological evidence of Alzheimer’s disease. Cholinergic deficits have been linked to neuronal loss in the nucleus basalis of Meynert in patients with Alzheimer’s disease, and the nucleus basalis of Meynert in patients with Down’s syndrome contains fewer neurons than are found in normal comparison subjects (1). This implies that cholinergic deficits are also present in the nucleus basalis of Meynert in patients with Alzheimer’s disease associated with Down’s syndrome. Plasma concentrations of donepezil are related to the percentage of red blood cell acetylcholinesterase inhibition and to improvements in cognitive functioning (2). Patients with Down’s syndrome were excluded from donepezil clinical trials (2), and therefore much fewer data regarding its pharmacological effects are available for this population. We report on three patients with Alzheimer’s disease associated with Down’s syndrome who were treated with donepezil.
Ms. A, a 59-year-old woman with Down’s syndrome, demonstrated evidence of progressive cognitive impairment over 2 years, which was manifested as consistent confusion but without aggressive behavior. She started treatment with donepezil, 5 mg/day, and after 8 weeks, she had improvement in mood and was less confused. Ms. A’s dose of donepezil was increased to 10 mg/day, and 2 weeks later, she became agitated and aggressive. Her donepezil treatment was then discontinued, resulting in decreased agitation and aggression.
Mr. B, a 57-year-old man with Alzheimer’s disease associated with Down’s syndrome, demonstrated poor short-term memory and impulsive behavior for several months. He had difficulty with basic activities such as dressing. He started donepezil treatment, 5 mg/day, and after 4 months, he developed urinary incontinence and became increasingly forgetful. His donepezil treatment was discontinued; his urinary incontinence stopped, and he returned to baseline cognitive functioning.
Ms. C, a 65-year-old woman with Down’s syndrome with depression, apathy, and obsessive-compulsive features that were unresponsive to multiple antidepressants, started treatment with donepezil at 5 mg/day. She developed urinary incontinence that stopped when the treatment with donepezil was discontinued.
Patients with Down’s syndrome may respond to medications used to treat Alzheimer’s-associated psychopathology (3). However, further studies are required to adequately assess the safety and efficacy of donepezil for Alzheimer’s disease associated with Down’s syndrome. In these cases, donepezil treatment resulted in adverse effects related primarily to peripheral cholinergic overstimulation, with symptoms of urinary incontinence in two of three patients. Administration of a peripherally acting cholinergic antagonist or possible use of a lower dose of donepezil may block these side effects, allowing for safe use of this medication in this population. Clinicians should be alert to the possibility of adverse effects when administering donepezil to individuals with Down’s syndrome.
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