Initiating Dementia Treatment, Pharmacological Interventions

December 14, 2022 - The WHO notes that approximately 55 million people in the world have dementia. Considering the rate of aging and the complications that coincide with aging, Alzheimer's Disease International anticipates that the number of people with dementia will double every 20 years, amounting to 139 million by 2050. Understanding how to effectively treat dementia, when to initiate treatment, and when to discontinue treatment can impact disease prognosis and burdens.

While dementia is an irreversible neurodegenerative disease, there are some available pharmacological approaches to alleviate the symptoms of dementia in some patients. According to the National Health Service (NHS), most medications for dementia are targeted toward Alzheimer’s disease (AD) as it is the most common type of dementia. However, some drugs approved for AD may also be used to manage other types of dementia. Approved treatments for dementia include cholinesterase inhibitors (ChEIs) and NMDA antagonists.

Since dementia is a progressive neurodegenerative disease, none of the currently available medications can cure or eliminate dementia. However, these medications can help reduce the symptoms or delay progression to an extent. According to the Alzheimer’s Association, the FDA divides Alzheimer’s medications into two categories: drugs that change disease progression and drugs that temporarily provide symptom relief.

Preventing Disease Progression

One medication being used to alter disease progression is aducanumab, an anti-amyloid antibody infusion therapy. This medication helps remove beta-amyloid plaques, a hallmark of Alzheimer’s disease.

Despite this treatment's potential benefits and novelty, many healthcare professionals are wary of its use due to its associated side effects. The Alzheimer’s Association notes that amyloid-related imaging abnormalities (ARIA), headaches, and falls may occur in patients using this medication.

According to Alzheimer’s Association, “ARIA is a common side effect that does not usually cause symptoms but can be serious. It is typically a temporary swelling in areas of the brain that usually resolves over time. Some people may also have small spots of bleeding in or on the surface of the brain with the swelling, although most people with swelling in areas of the brain do not have symptoms. Some may have symptoms of ARIA such as headache, dizziness, nausea, confusion, and vision changes.”

According to the Mayo Clinic, lecanemab is also being explored to treat AD. The drug works similarly to aducanumab in that it affects amyloid plaques, preventing them from clumping.

According to the Mayo Clinic, “a phase 3 clinical trial found the medicine slowed cognitive decline in people with early Alzheimer's disease by 27%. Lecanemab works by preventing amyloid plaques in the brain from clumping. This was the largest study so far to look at whether clearing clumps of amyloid plaques from the brain can slow the disease.”

The medication has yet to be approved but may be approved by the FDA as early as 2023.

Providing Symptom Relief

The other class of medications is medications used to manage symptoms of dementia, including cognitive and behavioral symptoms.

Cholinesterase Inhibitors

ChEIs inhibit acetylcholinesterase, an enzyme that turns acetylcholine into acetyl and choline.

The first FDA-approved ChEI was tacrine-huperzine A — called tacrine, approved in 1993 to treat mild-to-moderate Alzheimer’s disease (AD). Tacrine had shown some evidence of reduced cognitive deterioration and improved function. However, these benefits were accompanied by adverse side effects. Due to these side effects, neurologists are no longer prescribing this medication.

ChEIs treat memory, language, judgment, and other cognitive symptoms. Currently recommended ChEIs for AD include donepezil, rivastigmine, and galantamine.

Donepezil is approved for all stages of AD, while rivastigmine and galantamine are only for mild-to-moderate AD. Rivastigmine is also approved for mild-to-moderate Parkinson’s disease (PD). Donepezil is typically taken as a once-daily pill. Galantamine can be taken as a once or twice-daily pill. Rivastigmine is often taken as a pill but is also available as a skin patch.

According to a publication called Mental Health and Illness of the Elderly, studies on ChEIs found that they improved cognitive impairment, with galantamine having the most favorable outcomes, followed by rivastigmine and donepezil. Compared to placebo, rivastigmine and donepezil showed significant clinical improvements in global function.

StatPearls cautions that patient responses to ChEIs can vary dramatically, and some patients may not benefit. They are also associated with side effects such as cardiovascular complications, peptic ulcer disease, and weight loss.

NMDA Agonists

Glutamate regulators — or NMDA agonists, such as memantine, are also used to treat cognitive symptoms, including reasoning and the ability to perform simple tasks. These medications regulate glutamate activity, which can help the brain improve information processing. Memantine, approved for moderate-to-severe AD, belongs to a class of drugs associated with symptoms including headache, constipation, confusion, and dizziness.

Some clinicians may opt for drugs that combine ChEIs and glutamate regulators. A combinatory drug composed of donepezil and memantine is approved for moderate-to-severe AD.

Managing Behavioral and Psychological Symptoms

In addition to changes in cognition, patients with dementia may also develop behavioral and psychological symptoms of dementia (BPSD), including agitation, anxiety, wandering, aggression, delusions, or hallucinations.

These symptoms can be managed in multiple ways, including pharmacological and non-pharmacological interventions. Pharmacological interventions include antipsychotic medications, such as risperidone, haloperidol, or antidepressants.

Patients may also be treated with non-pharmacological interventions such as cognitive stimulation therapy, cognitive rehabilitation, and more.

For treating anxiety, the University of California San Francisco (UCSF) cautions against benzodiazepine anti-anxiety medications such as diazepam and lorazepam, as these medications can cause additional confusion and increase fall risk. Alternative medicines to consider include citalopram, escitalopram, and venlafaxine.

There are limited medications available for treating insomnia in dementia patients. According to the Alzheimer’s Association, “at this time, the FDA has approved one drug to address symptoms of insomnia that has been tested in people living with dementia, but trials testing drugs that address other non-cognitive symptoms are underway.”

Currently, suvorexant is approved for patients with mild-to-moderate AD with insomnia. However, this medication has many side effects, such as impaired alertness and coordination, worsening depression, sleepwalking, other complex sleep behaviors, sleep paralysis, and respiratory issues. 

Managing Comorbidities

For all patients — but especially patients with vascular dementia — treating associated diseases is a necessary part of the treatment regimen. According to the NHS, stroke, heart problems, diabetes, high blood pressure, high cholesterol, chronic kidney disease, and depression can affect symptoms of dementia.

Initiating Pharmacological Treatment

Because symptoms can change at different rates for each patient, knowing when to advise or discontinue AD drugs can be difficult.

UCSF recommends that symptoms first be managed through nonpharmacological interventions. Assuming that they cannot be addressed through nonpharmacological approaches, UCSF provides some best practices for managing medications in dementia patients, including the following:

• starting with a low dose and gradually increasing
• avoiding medications with side effects that worsen cognition
• avoiding drug interactions
• focusing on one medication change at a time