Alzheimer's Disease and Dementia

Nicotine Patch in Alzheimer's Disease

In patients with Alzheimer's disease (AD), nicotine patches improved attentional performance, but did not affect cognitive performance or clinical status.

Methods: Study subjects (n=8) were 3 men and 5 women, aged 62–87 years, with probable mild-to-moderate AD diagnosed using standard criteria. All were non-smokers. Patients were treated for 4 weeks with either nicotine transdermal system (Nicotrol) or placebo in randomized, double-blind fashion. During treatment, patients wore a nicotine patch on the back (where it was unlikely to be noticed and removed) for 16 hours each day, from awakening until bedtime. Dosages were 5 mg/day during week 1, 10 mg/day during weeks 2 and 3, and 5 mg/day during week 4. After the initial 4-week phase, and a 2-week washout, patients were crossed over to 4 weeks of the alternate treatment. They were evaluated in the clinic on 8 occasions using multiple clinical, cognitive, behavioral, and neuropsychiatric tests.

Results: During nicotine treatment, patients showed marked improvement in attentional performance as measured by the Connors’ continuous performance test (CPT), a measure of reaction time in response to a stimulus. There was a significant decrease in errors of omission (failure to respond to a stimulus; p<0.025) and no significant increase in errors of commission (responding when no stimulus was present). There was also a significant decrease in reaction time variability (p<0.05). These effects were large and were sustained throughout the active treatment period. No significant changes were observed in any of the other study outcomes, including tests of memory, functional assessments, or assessments with the Clinical Global Impression scale by both physicians and caregivers.

Discussion: These findings are consistent with previous findings on nicotine injection in patients with AD. Similar improvements in attention were shown in patients with schizophrenia, in adults with ADHD, and in normal young adults using the nicotine patch. The patch was well tolerated in the present study; however, the appetite suppressant effects of nicotine may be of concern in this patient population because patients with AD tend to lose weight. More studies are needed before clinical use of nicotine administered through a transdermal patch can be recommended.

White H, Levin E: Four-week nicotine skin patch treatment effects on cognitive performance in Alzheimer's disease. Psychopharmacology 1999;143 (April):158–165. From Duke University Medical Center; and the Veterans Affairs Medical Center, Durham, N.C. Funded by R.J. Reynolds.

Extended-Release Physostigmine in Alzheimer's Disease

A 12-week double-blind controlled trial of 176 patients with Alzheimer’s disease found 24 or 30 mg/day extended-release physostigmine salicylate (Synapton) to be effective for the treatment of cognitive defects.

Patients' scores on the cognitive subscale of the Alzheimer Disease Assessment Scale were significantly improved, compared with placebo (difference between groups, -2.02; p=0.01), and were improved on the Clinician Interview-Based Impression of Change with Caregiver Input measure (0.33 points; p=0.02).

However, the substantial adverse effects (primarily GI) associated with physostigmine may limit the clinical usefulness of this drug. Side effects of nausea and vomiting each occurred in 47% of the physostigmine-treated patients. These rates are higher than those reported in trials of other acetylcholinesterase inhibitors.

van Dyck C, Newhouse P, Falk W, Mattes J: Extended-release physostigmine in alzheimer disease. Archives of General Psychiatry 2000;57 (February):157–164. From Yale University School of Medicine, New Haven, Conn.; and other institutions. Funded by Forest Laboratories, New York, N.Y.

ERT for Alzheimer’s Disease

Estrogen replacement therapy failed to slow disease progression or improve cognitive defects in women with Alzheimer’s Disease (AD).

A randomized controlled trial conducted between 1995 and 1999 at 32 U.S. medical centers enrolled 120 women with mild-to-moderate AD and hysterectomies. Patients were randomly assigned to treatment with either 0.625 mg/day (n=42) or 1.25 mg/day (n=39) estrogen or with placebo (n=39) for 12 months.

Scores on the primary outcome measure, the Clinical Global Impression of Change scale, did not differ from baseline between patients receiving estrogen and controls (5.1 vs 5.0; p=0.43); 80% of the estrogen group worsened, compared with 74% of controls (p=0.48). Results of this largest and longest study of ERT in women with AD do not support the role of estrogen in the treatment of this disease.

Mulnard, R: Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. JAMA 2000;283 (February 23):1007–1015. From the University of California, Irvine; and other institutions. Funded by the National Institute on Aging, Bethesda, Md.; and Wyeth Ayerst Pharmace

Treatment of Dementia-Related Hypersexuality

Cimetidine, alone or with ketoconazole or spironolactone, decreased hypersexuality in 20 patients with dementia and problematic sexual behavior.

Methods: This study was based on chart reviews of 20 inpatients (17 men) who were treated with cimetidine for hypersexuality. Cimetidine has antiandrogenic activity, as do the other 2 agents (ketoconazole and spironolactone ) that some patients received as concomitant therapy. Patients were an average of 73 years old and had hypersexual behavior as a consequence of dementia. Before treatment, the behavior was considered problematic and uncontrollable in all cases. Problem behaviors included preoccupation with sex, genital exposure and public masturbation, inappropriate touching or chasing of staff and other residents, and sexual delusions and hallucinations.

Patients received cimetidine as initial therapy, with the dosage titrated until side effects or a response occurred. Ketoconazole or spironolactone were given if additional therapy was needed. Daily dosages used in these patients were 600–1600 mg for cimetidine, 100–200 mg for ketoconazole, and 75 mg for spironolactone. Antipsychotic and other psychotropic drugs were prescribed for delusions, hallucinations, and irritability.

Results: Fourteen patients responded to cimetidine monotherapy, and the remaining 6 responded to the addition of a second agent. Clinicians reported objective decreases in the frequency and severity of inappropriate sexual behavior. In all patients, the sexual behavior was considered manageable and no longer problematic. Treatment was well tolerated, with reported cimetidine-related side effects of nausea, arthralgia, and headache.

Wiseman S, McAuley J, Freidenberg G, Freidenberg D: Hypersexuality in patients with dementia: possible response to cimetidine (letter). Neurology 2000:54 (May):2024. From Ohio State University, Columbus; and Indiana University, Indianapolis.

Drug Trade Names: cimetidine—Tagamet; ketoconazole—Nizoral; spironolactone—Aldactone

Galantamine for AD

A promising new agent for the treatment of Alzheimer’s disease (AD), galantamine (Reminyl), is currently under review for approval by the FDA.¹ Galantamine is a cholinesterase inhibitor that also modulates nicotinic cholinergic receptors; it is hoped that this dual activity will contribute to its efficacy. A previous trial found galantamine to have beneficial effects on cognition, function, and behavior; however, many patients experienced adverse effects during a 4-week dosage escalation.²

Methods: A 5-month multicenter trial was conducted to assess the efficacy and tolerability of galantamine dose titration (up to 8 weeks).³ Subjects (n=978), in their late 70s with mild-to-moderate AD, were randomly assigned to 1 of 4 treatment arms: placebo; 8 mg/day galantamine (for evaluation of dose-response effect); galantamine increased to 16 mg/day over 4 weeks; or galantamine increased to 24 mg/day over 8 weeks. Treatment response was measured using the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) and the 7-point Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus).

Results: Compared with placebo, galantamine at 16 or 24 mg/day was associated with significantly better outcomes on all assessment measurements (p<0.001 for all comparisons), while galantamine at 8 mg/day was judged subtherapeutic. After 5 months, average ADAS-cog scores improved from 29 points at baseline by 1.5 and 1.8 points in patients receiving 16 or 24 mg/day galantamine, respectively, but decreased by 1.8 points in those receiving placebo (p<0.001). The effects of the 2 galantamine dosages did not differ significantly. CIBIC-plus evaluations showed stable or improved status in 64–68% of patients receiving 16 or 24 mg/day galantamine, compared with 47% in the placebo group.

On the secondary outcome measures, patients receiving 16 or 24 mg/day galantamine had significantly smaller decreases in scores on the Activities of Daily Living inventory than the placebo group (p<0.01). Behavioral symptoms worsened in the placebo and 8-mg/day groups, but not in the groups receiving the 2 effective galantamine dosages (p<0.05).

Discontinuation due to adverse effects did not differ significantly between the 16- or 24-mg dosages and placebo (7% and 10% vs 7%). The incidence of serious adverse events was similar among the groups, occurring in 10–13% of patients. Nausea, vomiting, anorexia, and diarrhea occurred more frequently with galantamine than with placebo.

^{1Drug Facts and
Comparisons; 2000 (July):KU-57.²Raskind M, et al:
Galantamine in AD: a 6-month, randomized, placebo-controlled trial with a
6-month extension. Neurology 2000;54:2261–2268.³Tariot P, et al: A
5-month, randomized, placebo-controlled trial of galantamine in AD. Neurology
2000;54 (June):2269–2276. From the University of Rochester Medical Center,
N.Y.; and other institutions including the Janssen Research Foundation. Funded
by Janssen.

New Agent for Alzheimer’s Disease

The first U.S. Phase III clinical trial of memantine (not available in the
U.S., Akatinol) was described by Barry Reisenberg, MD, of New York
University School of Medicine, at the World Alzheimer Congress 2000, held in
Washington, D.C. The trial was conducted at 32 centers throughout the U.S. and
enrolled 252 patients with the functional deteriorations characteristic of
moderately severe disease (incontinence and loss of self-care abilities such as
bathing and dressing). In the 28-week trial, further decline was slowed in
patients receiving the drug, compared with the placebo group.
Memantine was approved in Germany 10 years ago for treating dementias. In
contrast to the anticholinergic drugs now available for mild-to-moderate
Alzheimer's disease, memantine blocks NMDA receptors, whose overactivity is
believed to cause neuronal damage in the disease.

Marx J: Alzheimer's congress: drug shows promise for advanced disease (news).
Science 2000:289 (July 21):375–387.

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