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To the Editor: Down’s syndrome is the most common genetic disorder; it is recognizable at birth because of its associated cognitive and adaptive impairments. The neuropathological and neurochemical similarities between Down’s syndrome and Alzheimer’s disease and the role of cholinergic agents such as donepezil hydrochloride as proven symptomatic therapies for Alzheimer’s disease led our group to publish what we believe to be the first report on the use of donepezil therapy in Down’s syndrome (1).
A subsequent study was performed by Hemingway-Eltomey and Lerner (2). We commend these authors for drawing attention to the needs of patients with Down’s syndrome and agree with their rationale for the use of cholinesterase inhibitor therapy (e.g., donepezil) to treat this syndrome. The authors reported on three patients with comorbid adult Down’s syndrome and Alzheimer’s disease, aged 57, 59, and 65, respectively, who developed adverse effects when treated with donepezil (2). Two patients were reported to develop urinary incontinence during donepezil therapy (one after 4 months; the other after an unspecified period). The third patient did well taking 5 mg/day, but the patient’s behavior worsened when the dose was increased to 10 mg/day. At this point, the investigators discontinued the patient’s therapy.
Our experience with the use of donepezil in adult patients with Down’s syndrome has been different. In our initial pilot study (1), four patients (mean age=38 years, range=24–64) were treated for an average of 40.5 weeks (one individual was treated for 80 weeks). There were no reports of urinary incontinence or sustained worsening of behavior. Two of the four patients also met DSM-IV criteria for dementia. All of the patients had begun treatment with 5 mg/day of donepezil, which was increased to 10 mg/day after a minimum of 6 weeks. Transient diarrhea in one patient and agitation lasting 2 weeks in another patient at the time of the dose increase were the only side effects we observed (1). We have since treated five additional patients (mean age=42 years and 8 months, range=23–42) for an average duration of 18.2 weeks (range=5–27 weeks) and found tolerability to be good (unpublished data).
These data highlight the difficulties encountered in extrapolating tolerability and causality of adverse events from small case studies. In addition, elderly patients with Alzheimer’s disease and Down’s syndrome often have multiple comorbidities and are taking concomitant medications that can confound the attribution of causality for adverse events in uncontrolled studies. For example, in patients with Alzheimer’s disease, agitation can result from the natural progression of dementia, from environmental or social triggers, from worsening of medical illnesses, and/or as a side effect of their medications. Clinical experience with more than 1 million elderly patients with Alzheimer’s disease worldwide has suggested that donepezil is generally well tolerated.
In data from the U.S. phase II and III pivotal Alzheimer’s disease clinical trials, which ranged from 3 to 6 months’ duration (donepezil-treated group: N=747, placebo-treated group: N=355), 3% of the individuals in the placebo group reported urinary incontinence, compared to 1% of the donepezil group. Agitation was reported in 7% of the patients taking placebo compared to 4% of those taking donepezil. The dose of donepezil in the phase II trial ranged from 1 to 5 mg/day, whereas in the phase III trial, it was either 5 or 10 mg/day after 1 week at a dose of 5 mg/day (data available from Eisai, Inc.). In general, cholinergic side effects can be minimized by increasing the dose from 5 to 10 mg/day more slowly (e.g., after 6 weeks, rather than 1 week) (from donepezil package insert), by instituting temporary drug holidays, and/or by decreasing the dose from 10 to 5 mg/day if side effects occur at the higher dose (3). However, readers must bear in mind that donepezil has not been systematically investigated for use in patients with Down’s syndrome. Randomized controlled clinical trials of cholinergic therapy are warranted in adult and pediatric patients with Down’s syndrome; both are currently underway at our center.
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