Alzheimer dementia: Starting, stopping drug therapy
ABSTRACT
Alzheimer disease is the most common type of dementia. Two classes of cognition-enhancing drugs are approved to treat the symptoms, and both have provided modest benefit in clinical trials. Psychotropic drugs are sometimes used off-label to treat behavioral symptoms of Alzheimer disease. All these medications should be continuously evaluated for clinical efficacy and, when appropriate, discontinued if the primary benefit—preservation of cognitive and functional status and a reduction in behaviors associated with dementia—is no longer being achieved.
KEY POINTS
- In 2016, an estimated 5.2 million Americans age 65 and older had Alzheimer disease; by 2050, the prevalence is expected to be 13.8 million.
- Cognitive enhancers (cholinesterase inhibitors and an N-methyl-d-aspartate receptor antagonist) have shown modest efficacy in preserving cognitive function.
- When evaluating therapy with a cognitive enhancer, practitioners need to consider the potential adverse effects, especially gastrointestinal effects with cholinesterase inhibitors.
- Discontinuation should be considered when the dementia reaches the advanced stage and the initial intended purpose of these drugs is no longer achievable.
Dosing. The cholinesterase inhibitors should be slowly titrated to minimize side effects. Starting at the lowest dose and maintaining it for 4 weeks allows sufficient time for transient side effects to abate. Some patients may require a longer titration period.
As the dose is escalated, the probability of side effects may increase. If they do not subside, dose reduction with maintenance at the next lower dose is appropriate.
Gastrointestinal effects. Given the adverse gastrointestinal effects associated with this class of medications, patients experiencing significant anorexia and weight loss should generally avoid cholinesterase inhibitors. However, the rivastigmine patch, a transdermal formulation, is an alternative for patients who experience gastrointestinal side effects.
Bradycardia risk. Patients with significant bradycardia or who are taking medications that lower the heart rate may experience a worsening of their bradycardia or associated symptoms if they take a cholinesterase inhibitor. Syncope from bradycardia is a significant concern, especially in patients already at risk of falls or fracture due to osteoporosis.
NMDA receptor antagonist
The side-effect profile of memantine is generally more favorable than that of cholinesterase inhibitors. In clinical trials, it has been better tolerated with fewer adverse effects than placebo, with the exception of an increased incidence of dizziness, confusion, and delusions.16,17
Caution is required when treating patients with renal impairment. In patients with a creatinine clearance of 5 to 29 mL/min, the recommended maximum total daily dose is 10 mg (twice-daily formulation) or 14 mg (once-daily formulation).
Off-label use to treat behavioral problems
These medications have been used off-label to treat behavioral problems associated with dementia. A systematic review and meta-analysis showed cholinesterase inhibitor therapy had a statistically significant effect in reducing the severity of behavioral problems.18 Unfortunately, the number of dropouts increased in the active-treatment groups.
Patients with behavioral problems associated with dementia with Lewy bodies may experience a greater response to cholinesterase inhibitors than those with Alzheimer disease.19 Published post hoc analyses suggest that patients with moderate to severe Alzheimer disease receiving memantine therapy have less severe agitation, aggression, irritability, and other behavioral disturbances compared with those on placebo.20,21 However, systematic reviews have not found that memantine has a clinically significant effect on neuropsychiatric symptoms of dementia.18,22,23
Combination therapy
In early randomized controlled trials, adding memantine to a cholinesterase inhibitor provided additional cognitive benefit in patients with Alzheimer disease.15,24 However, a more recent randomized controlled trial did not show significant benefits for combined memantine and donepezil vs donepezil alone in moderate to severe dementia.25
In patients who had mild to moderate Alzheimer disease at 14 Veterans Affairs medical centers who were already on cholinesterase inhibitor treatment, adding memantine did not show benefit. However, the group receiving alpha-tocopherol (vitamin E) showed slower functional decline than those on placebo.26 Cognition and function are not expected to improve with memantine.
CONSIDERATIONS WHEN STOPPING COGNITIVE ENHANCERS
The cholinesterase inhibitors are usually prescribed early in the course of dementia, and some patients take these drugs for years, although no studies have investigated benefit or risk beyond 1 year. It is generally recommended that cholinesterase inhibitor therapy be assessed periodically, eg, every 3 to 6 months, for perceived cognitive benefits and adverse gastrointestinal effects.
These medications should be stopped if the desired effects—stabilizing cognitive and functional status—are not perceived within a reasonable time, such as 12 weeks. In some cases, stopping cholinesterase inhibitor therapy may cause negative effects on cognition and neuropsychiatric symptoms.27
Deciding whether benefit has occurred during a trial of cholinesterase inhibitors often requires input and observations from the family and caregivers. Soliciting this information is key for practitioners to determine the correct treatment approach for each patient.
Although some patients with moderately severe disease experience clinical benefits from cholinesterase inhibitor therapy, it is reasonable to consider discontinuing therapy when a patient has progressed to advanced dementia with loss of functional independence, thus making the use of the therapy—ie, to preserve functional status—less relevant. Results from a randomized discontinuation trial of cholinesterase inhibitors in institutionalized patients with moderate to severe dementia suggest that discontinuation is safe and well tolerated in most of these patients.28
Abruptly stopping high-dose cholinesterase inhibitors is not recommended. Most clinical trials tapered these medications over 2 to 4 weeks. Patients taking the maximum dose of a cholinesterase inhibitor should have the dose reduced to the next lowest dose for 2 weeks before the dose is reduced further or stopped completely.
