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Dementia, a syndrome of progressive cognitive deficits that interfere with social and occupational functioning, results from degeneration of the brain of varying causes. The most common types include Alzheimer’s Disease (AD), vascular dementia, and Lewy Body dementia. These debilitating syndromes are becoming more common as America ages, increasingly result in hospice enrollment, and have been the subject of several past Connecticut Hospice blogs.
The drugs used to treat dementia fall into three categories: acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine), the NMDA receptor antagonist memantine, all given by mouth, and the anti-amyloid monoclonal antibodies lecanemab and donanemab, given by infusion. The effectiveness of these drugs and their possible harms are the subject of this blog.
It is important to recognize that dementia is not one illness, and that different drugs have different outcomes depending on dementia type and may even vary between individuals with the same type of dementia. Donepezil and galantamine are only FDA-approved for mild to severe AD, and memantine is approved for moderate to severe AD. Cholinesterase inhibitors may show benefit in dementia with Lewy bodies and mild to moderate Parkinson’s related dementia, but only rivastigmine is FDA-approved for Parkinson’s dementia (rivastigmine is also approved for AD). Memantine may show a small benefit in moderate-to-severe vascular dementia, but, again, it is not FDA-approved for this use. There is no evidence of benefit for any of these agents in frontotemporal dementia. The anti-amyloid monoclonal antibodies are only indicated and FDA-approved for patients with mild dementia due to Alzheimer’s disease with confirmed amyloid pathology (by PET scanning or cerebrospinal fluid testing). There is no evidence supporting their use, nor are they approved or recommended for other types of dementia. Notably, the anti-amyloid antibody lecanemab costs approximately $26,500 per year, not including the substantial additional costs of required infusions, imaging, and monitoring for adverse effects.
Acetylcholinesterase inhibitors should be started at the earlier stages of disease, when they have the greatest benefit. This benefit wanes over time and is minimal in advanced disease or in patients over 85 years old. Memantine should be started in moderate to severe stages. Combination therapy may be considered as dementia progresses.
The studies on these drugs report the “effect size” – the difference between the drug and placebo on outcomes such as cognitive function, overall status, activities of daily living (such as the ability of a patient to independently eat, dress, walk, bath, and groom), institutionalization, caregiver burden, and quality of life.
Overall, the literature demonstrates positive effects for all three categories of drugs when compared to placebo (with exceptions), but is not encouraging as to meaningful real world outcomes for people living with dementia. Large reviews show small though statistically significant improvements in some measures of cognition, though these are generally below the minimum considered clinically important for most patients. There was mixed evidence for delayed institutionalization, some evidence for reduced caregiver burden, but no demonstrated impact on quality of life. The slowing of cognitive decline may not be evident to individual patients or caregivers.
None of these agents have been shown to improve cognition. Rather, the clinical course for most patients is stabilization or a slower rate of cognitive decline, with no actual cognitive improvement. Cognitive decline usually resumes at the pre-treatment rate after several months of treatment.
The side effects of these agents can be significant and even life threatening, and patients using them, who are typically unable to advocate for themselves, should be closely monitored.
The most common side effects of acetylcholinesterase inhibitors are nausea, vomiting, diarrhea, anorexia, insomnia, dizziness, headache, slow heart rate, fainting, and weight loss. These side effects are more frequent at higher doses. Agitation, depression, and appetite disorders (including poor appetite) are more common than with placebo, and may be especially problematic in people with preexisting psychiatric and behavioral complications of dementia. Slow heart rate and fainting are potentially fatal, especially in patients with pre-existing cardiac conditions.
Memantine is better tolerated than acetylcholinesterase inhibitors. The most common side effects are dizziness, headache, confusion, and constipation. Gastrointestinal and psychiatric side effects are less common.
The most common side effects of anti-amyloid monoclonal antibodies are so-called amyloid-related imaging abnormalities (ARIA) – a specific set of abnormalities seen only on MRI scanning -- and infusion-related reactions. ARIA is often asymptomatic but can cause symptoms such as headache, confusion, visual disturbances, dizziness, or neurologic abnormalities. Clinically significant and fatal brain bleeding have been reported. Infusion-related reactions (e.g., chills, fever, nausea, rash) are also common, typically mild to moderate, and most often occur with the first few infusions.
In summary:
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