0
Get Alert
Please Wait... Processing your request... Please Wait.
You must sign in to sign-up for alerts.

Please confirm that your email address is correct, so you can successfully receive this alert.

1
Letter to the Editor   |    
Donepezil for Down’s Syndrome
PRIYA S. KISHNANI, M.D.; GAIL A. SPIRIDIGLIOZZI, PH.D.; JAMES H. HELLER, M.A., M.S.; JENNIFER A. SULLIVAN, M.S.; P. MURALI DORAISWAMY, M.D.; K. RANGA RAMA KRISHNAN, M.D.
Am J Psychiatry 2001;158:143-143. doi:10.1176/appi.ajp.158.1.143

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.

Kishnani PS, Sullivan JA, Walter BK, Spiridigliozzi G, Doraiswamy PM, Krishnan KRR: Cholinergic therapy for Down’s syndrome. Lancet 1999; 353:1064–  1065
 
Hemingway-Eltomey JM, Lerner AJ: Adverse effects of donepezil in treating Alzheimer’s disease associated with Down’s syndrome (letter). Am J Psychiatry  1999; 156:1470
[PubMed]
 
McLendon B, Doraiswamy P: Defining meaningful change in Alzheimer’s disease trials: the donepezil experience. J Geriatr Psychiatry Neurol  1999; 12:39–48
[PubMed]
[CrossRef]
 
+

References

Kishnani PS, Sullivan JA, Walter BK, Spiridigliozzi G, Doraiswamy PM, Krishnan KRR: Cholinergic therapy for Down’s syndrome. Lancet 1999; 353:1064–  1065
 
Hemingway-Eltomey JM, Lerner AJ: Adverse effects of donepezil in treating Alzheimer’s disease associated with Down’s syndrome (letter). Am J Psychiatry  1999; 156:1470
[PubMed]
 
McLendon B, Doraiswamy P: Defining meaningful change in Alzheimer’s disease trials: the donepezil experience. J Geriatr Psychiatry Neurol  1999; 12:39–48
[PubMed]
[CrossRef]
 
+
+

CME Activity

There is currently no quiz available for this resource. Please click here to go to the CME page to find another.
Submit a Comments
Please read the other comments before you post yours. Contributors must reveal any conflict of interest.
Comments are moderated and will appear on the site at the discertion of APA editorial staff.

* = Required Field
(if multiple authors, separate names by comma)
Example: John Doe



Related Content
Books
Manual of Clinical Psychopharmacology, 7th Edition > Chapter 12.  >
Manual of Clinical Psychopharmacology, 7th Edition > Chapter 12.  >
What Your Patients Need to Know About Psychiatric Medications, 2nd Edition > Chapter 73.  >
APA Practice Guidelines > Chapter 16.  >
Topic Collections
Psychiatric News
PubMed Articles