Pharmacotherapeutic strategies in the treatment of severe Alzheimer’s disease

ABSTRACT

Introduction: Alzheimer’s disease (AD) is a slowly progressive neurodegenerative disease. Patients with severe AD often require assistance with daily functioning and have a substantially higher probability of admission to nursing homes compared to the general population.

Areas covered: Medications approved by the US Food and Drug Administration for the treatment of severe AD include the cholinesterase inhibitors (ChEIs), donepezil (10 and 23 mg/day) and rivastigmine (transdermal patch, 13.3 mg/24 hours), and the N-methyl-D-aspartate receptor antagonist memantine (immediate- and extended-release formulations). This article will review the efficacy, safety, and tolerability data of these agents in the treatment of severe AD. Issues related to combination therapy, neuropsychiatric symptoms, and treatment discontinuation are also discussed.

Expert opinion: AD therapeutics provide benefits on measures of cognition, functioning, behavior, and global status even in the severe stages of AD. Combination therapy with memantine and ChEIs may provide additive benefits compared with ChEI monotherapy. Decisions regarding discontinuation of these medications should be made on a case-by-case basis, with some evidence suggesting that discontinuation may worsen cognition and functional impairment. It is recommended that patients entering the terminal stages of AD discontinue all medications not necessary for comfort.

KEYWORDS:

• Alzheimer’s disease
• cholinesterase inhibitors
• donepezil
• memantine
• rivastigmine
• severe

Article highlights

• Cholinesterase inhibitors (ChEIs) and memantine continue to provide benefits on multiple domains in the severe stages of AD.

• Therapeutic options in severe AD include donepezil, rivastigmine transdermal patch, and memantine immediate or extended release.

• A high dose 23 mg/day donepezil is available which has additional benefits on cognition over the 10 mg/day dose. Questionable benefits on global clinical impression and issues related to tolerability prominently during up-titration may limit its use in patients vulnerable to side effects of medications.

• The 13.3 mg/24 hour rivastigmine patch provides benefits in excess of lower doses of rivastigmine and may improve patient adherence and decrease caregiver stress compared to administration of capsules.

• While the effects are modest, combination therapy with ChEIs and memantine seems to provide benefits that are additive compared to ChEI monotherapy.

• Discontinuing AD pharmacotherapies may worsen cognition, increase functional impairment, and increase the risk of nursing home placement. However, AD pharmacotherapies should be discontinued in the event of patient preference, intolerable side effects, or when patients enter the ‘terminal’ stages of AD (hospice eligible, bedridden, limited verbal ability, marked limitations in basic ADLs).

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Declaration of interest

G.T Grossberg serves as a consultant/speaker for Acadia, Accera, Actavis/Forest/Allergan, Daiichi Sankyo, GE Pharmaceuticals, Genentech, Lundbeck, Novartis, Otsuka, Roche, and Takeda. G.T. Grossberg’s department has received research support from Accera, Eli Lilly, and Noven. G.T. Grossberg serves on safety monitoring boards for EryDel, Merck and Newron. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.