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Medical Treatments and Medications

Summary

This chapter explains the current medical treatments available for dementia, focusing primarily on medications approved for Alzheimer's disease. You will learn about cholinesterase inhibitors (including donepezil, rivastigmine, and galantamine) and memantine, understanding how these medications work, their potential benefits, and side effects. The chapter also covers symptom management strategies and introduces the concept of clinical trials for those interested in participating in research studies. While these medications cannot cure dementia or stop its progression, understanding treatment options helps families make informed decisions about care and maintain realistic expectations about what medical interventions can achieve.

Concepts Covered

This chapter covers the following 7 concepts from the learning graph:

  1. Cholinesterase Inhibitors
  2. Memantine
  3. Donepezil
  4. Rivastigmine
  5. Galantamine
  6. Symptom Management
  7. Clinical Trials

Prerequisites

This chapter builds on concepts from:

The Landscape of Dementia Treatment: Setting Realistic Expectations

When a loved one receives a dementia diagnosis, families naturally ask, "What treatments are available? What can we do?" These questions reflect hope and the desire to fight back against the disease. Understanding the current state of dementia treatment requires both honesty about limitations and optimism about available options.

The truth about current dementia medications:

They cannot: - Cure dementia - Stop disease progression - Reverse existing damage - Work for everyone - Restore lost abilities

They may: - Temporarily slow cognitive decline in some people - Modestly improve function for a period of time - Help with certain symptoms - Provide a window of better function lasting months to a couple years - Improve quality of life even if cognitive test scores don't dramatically improve

This realistic framework prevents the disappointment that comes from unrealistic expectations while recognizing that even modest benefits matter. A medication that maintains function for an extra 6-12 months gives families more time together, more conversations, more memories—and that has real value.

Currently, the FDA has approved several medications specifically for Alzheimer's disease: - Three cholinesterase inhibitors: donepezil (Aricept), rivastigmine (Exelon), galantamine (Razadyne) - One NMDA receptor antagonist: memantine (Namenda) - Combination medication: donepezil plus memantine (Namzaric) - Newer treatments (2021-2023): aducanumab (Aduhelm) and lecanemab (Leqembi) - anti-amyloid monoclonal antibodies with limited availability and significant controversies

Other dementia types have fewer specific treatments, though some Alzheimer's medications may be used off-label.

This chapter will explain how these medications work, what benefits they may provide, potential side effects, and how they're used in practice.

Cholinesterase Inhibitors: Boosting Acetylcholine

Cholinesterase inhibitors are a class of medications that work by increasing levels of acetylcholine, a neurotransmitter crucial for memory and learning. These medications represent the cornerstone of Alzheimer's disease treatment and are typically the first medications prescribed.

Understanding the Acetylcholine System

To understand how cholinesterase inhibitors work, we need to revisit brain chemistry from Chapter 2:

Acetylcholine is a neurotransmitter that: - Facilitates communication between neurons - Is particularly important in brain regions involved in memory (hippocampus, cortex) - Enables new memory formation and retrieval of existing memories - Supports attention and concentration

In Alzheimer's disease: - Neurons that produce acetylcholine degenerate and die - Acetylcholine levels decline - Memory and cognitive function worsen - This acetylcholine deficit contributes significantly to symptoms

The enzyme cholinesterase breaks down acetylcholine after it's released, ending its action. This is normally a good thing—neurotransmitters need to be cleared away so the signal can stop and the next signal can begin. But when acetylcholine is already in short supply (as in Alzheimer's), this breakdown exacerbates the deficit.

Cholinesterase inhibitors work by blocking the enzyme cholinesterase, preventing it from breaking down acetylcholine. With the breakdown enzyme inhibited, acetylcholine remains in the synapse longer, compensating somewhat for the reduced production. Think of it like this: if your sink is draining too quickly, you can either turn up the faucet (produce more water) or partially close the drain (prevent water from leaving). Since we can't make Alzheimer's neurons produce more acetylcholine, we slow down its removal instead.

The Three FDA-Approved Cholinesterase Inhibitors

Three cholinesterase inhibitors are FDA-approved for Alzheimer's disease. They work through the same basic mechanism but differ in specifics of action, formulations, dosing, and side effect profiles.

Donepezil (Aricept): The Most Widely Used

Donepezil (brand name Aricept) is the most commonly prescribed cholinesterase inhibitor, approved for all stages of Alzheimer's disease from mild to severe.

Key characteristics: - Approval: FDA-approved for mild, moderate, and severe Alzheimer's disease - Dosing: Once daily, taken at bedtime - Starting dose: 5 mg for 4-6 weeks - Standard dose: 10 mg - High dose (moderate-severe): 23 mg (though benefit over 10 mg is debated) - Formulations: - Standard tablets - Orally disintegrating tablets (dissolve on tongue—helpful if swallowing is difficult) - Half-life: Long (about 70 hours), allowing once-daily dosing

Advantages of donepezil: - Once-daily dosing (better adherence) - Long track record (approved since 1996) - Available in generic form (affordable) - Orally disintegrating tablet option - Approved for all Alzheimer's stages - Generally well-tolerated

Common side effects: - Nausea (most common, usually transient) - Diarrhea - Vomiting - Loss of appetite - Muscle cramps - Insomnia or vivid dreams (if these occur, take in morning instead) - Fatigue

Serious but rare side effects: - Slow heart rate (bradycardia) - Fainting - Seizures - Stomach ulcers or bleeding - Urinary obstruction - Worsening of COPD or asthma

Who should avoid or use cautiously: - People with sick sinus syndrome or heart conduction abnormalities - Those with history of ulcers or GI bleeding - People with asthma or COPD - Those with seizure disorders - Men with enlarged prostate

Typical experience:

Month 1-2: Starting at 5 mg, patient may experience mild nausea for 1-2 weeks, then typically adjusts. Some families notice subtle improvement—patient seems more engaged, conversation flows better, or function stabilizes rather than declining.

Month 2-3: Dose increased to 10 mg. Nausea may recur briefly then resolve. Benefit, if present, usually becomes more apparent.

Months 3-12: Function typically plateaus—patient maintains current abilities rather than declining as expected. Some people show measurable improvement on cognitive tests; others show no change on tests but families report functional benefits.

Year 2+: Eventually disease progression overcomes medication benefit. Function begins declining again, but patient may still be better than if they'd never taken medication.

Not everyone responds. Some people show clear benefit; others show none. Generally, medication is continued if there's perceived benefit or if function is stable, and stopped if there's clear progression despite treatment.

Rivastigmine (Exelon): Patch and Oral Options

Rivastigmine (brand name Exelon) is the second most commonly used cholinesterase inhibitor, unique in being available as a transdermal patch in addition to oral formulations.

Key characteristics: - Approval: FDA-approved for mild to moderate Alzheimer's disease and Parkinson's disease dementia - Dosing: - Oral: Twice daily with food - Starting: 1.5 mg twice daily - Gradually increase every 4 weeks: 3 mg → 4.5 mg → 6 mg twice daily - Patch: Once daily - Starting: 4.6 mg/24 hours patch - Increase after 4 weeks: 9.5 mg/24 hours patch - Higher dose (moderate-severe): 13.3 mg/24 hours patch - Formulations: - Capsules - Oral solution - Transdermal patch - Half-life: Short (about 1.5 hours for oral), requiring twice-daily dosing

Advantages of rivastigmine: - Patch formulation reduces GI side effects significantly - Approved for Parkinson's disease dementia (only cholinesterase inhibitor with this indication) - Patch provides steady drug levels (no peaks and troughs) - Patch helpful if swallowing difficulties or medication non-adherence - Oral solution available if neither pills nor patch works

Common side effects: - Oral formulations: Nausea, vomiting, diarrhea, loss of appetite (more common than with donepezil) - Patch: Skin irritation at application site (most common), nausea (much less than oral) - Dizziness - Headache - Weakness

Advantages of the patch: - Dramatically reduced GI side effects compared to oral rivastigmine - Once-daily application (better adherence than twice-daily pills) - Steady medication levels throughout the day - Useful if patient refuses pills or can't swallow - Can verify adherence (see if patch is on)

Patch application tips: - Rotate application sites (upper/lower back, chest, upper arm) - Avoid same site for at least 14 days - Apply to clean, dry, hairless skin - Don't apply to areas with skin irritation - Change patch at same time each day - Remove old patch before applying new one - Wash hands after applying - May continue wearing while bathing/swimming

Skin irritation management: - Occurs in 20-40% of patients - Usually mild redness/itching - Rotating sites helps - Consider anti-itch cream (check with doctor) - If severe, may need to switch to oral or different medication

Typical experience:

For oral rivastigmine: Slower titration than donepezil, with gradual dose increases every 4 weeks. GI side effects more common, so many patients don't tolerate it as well as donepezil. Those who do tolerate it may have similar benefits.

For rivastigmine patch: Much better tolerated than oral. Patient wears patch on back or chest; caregiver changes it daily. Skin irritation common but usually manageable with site rotation. Benefits similar to oral formulation but with fewer GI complaints.

Galantamine (Razadyne): Dual-Action Inhibitor

Galantamine (brand name Razadyne, formerly Reminyl) is the third FDA-approved cholinesterase inhibitor, with a dual mechanism of action that distinguishes it from the other two.

Key characteristics: - Approval: FDA-approved for mild to moderate Alzheimer's disease - Dosing: - Immediate-release: Twice daily with food - Starting: 4 mg twice daily for 4 weeks - Increase to 8 mg twice daily for 4 weeks - Target: 12 mg twice daily - Extended-release: Once daily with food - Starting: 8 mg once daily for 4 weeks - Increase to 16 mg once daily for 4 weeks - Target: 24 mg once daily - Formulations: - Immediate-release tablets - Extended-release capsules - Oral solution - Half-life: 7 hours

Dual mechanism of action:

Unlike donepezil and rivastigmine, which only inhibit cholinesterase, galantamine has two mechanisms:

  1. Cholinesterase inhibition (like the others)
  2. Nicotinic receptor modulation - Enhances the action of acetylcholine on nicotinic receptors, potentially providing additional benefit

Whether this dual action translates to superior clinical benefit remains unclear—studies show similar efficacy across the three cholinesterase inhibitors.

Advantages of galantamine: - Dual mechanism may provide theoretical advantage - Extended-release formulation allows once-daily dosing - Oral solution available - May be worth trying if another cholinesterase inhibitor didn't work or wasn't tolerated

Common side effects: - Nausea (most common, especially if dose increased too quickly) - Vomiting - Diarrhea - Loss of appetite and weight loss - Dizziness - Headache - Decreased heart rate

Important precautions: - Must take with food to minimize GI side effects - Contraindicated in severe liver or kidney disease - Dose reduction needed in moderate liver/kidney impairment - Can slow heart rate—caution in those with heart conduction problems

Typical experience:

Extended-release galantamine: Taken once daily with breakfast. Starting dose of 8 mg for a month, then 16 mg, then 24 mg. Nausea common in first 1-2 weeks after starting or increasing dose, then usually resolves. Taking with food and slow titration minimize side effects. Benefits similar to other cholinesterase inhibitors.

Comparing the Three Cholinesterase Inhibitors

Feature Donepezil Rivastigmine Galantamine
Dosing Once daily Twice daily (oral)
Once daily (patch)		 Twice daily (IR)
Once daily (ER)
FDA Approval Mild, moderate, severe Mild to moderate
Parkinson's dementia		 Mild to moderate
Special Features Orally disintegrating tablet Transdermal patch Dual mechanism
GI Side Effects Moderate High (oral)
Low (patch)		 Moderate-High
Titration Speed Faster Slower Moderate
Generic Available Yes Yes Yes

Which to choose? There's no clear winner—all three have similar efficacy. Choice typically depends on: - Dosing convenience: Donepezil (once daily) or rivastigmine patch - Tolerability: If GI side effects with one, try another (or rivastigmine patch) - Specific indication: Rivastigmine only one approved for Parkinson's dementia - Formulation needs: Patch if swallowing difficulty or adherence concerns - Insurance coverage: Generic versions of all three available, but coverage varies - Physician/patient preference: Some doctors have preferred choices based on experience

What to Expect from Cholinesterase Inhibitors

Realistic expectations about benefits:

Cognitive effects: - Modest improvement or stabilization on cognitive tests - About 2-4 point improvement on MMSE in responders (out of 30 points) - Some people improve, some stabilize, some continue declining - Effect typically lasts 6-18 months before disease progression overcomes benefit - About 40-60% of people show measurable response

Functional benefits: - May maintain ability to perform daily activities longer - Can delay need for higher level of care - Might preserve function for several months longer than without treatment - Even if cognitive tests don't show improvement, families may notice functional benefits

Other potential benefits: - Improved alertness and engagement - Better ability to participate in activities - Reduced apathy in some patients - Possible modest benefit for behavioral symptoms

When benefits are unclear: - Some people show clear benefit (family notices significant difference) - Others show no obvious benefit (function continues declining) - Some show subtle benefit (hard to know if they're better or would have declined more without medication)

Decision to continue or stop: - Usually continued if there's perceived benefit or stable function - May be stopped if clear progression despite treatment - Sometimes tried for 3-6 months then stopped to see if function worsens without it (if it does, restart) - Risk-benefit ratio shifts over time—in very late dementia, side effects may outweigh minimal benefit

Side Effect Management

Gastrointestinal side effects (nausea, vomiting, diarrhea): - Most common side effects - Usually worse in first 2-4 weeks, then improve - Taking with food helps - Slow titration minimizes side effects - Consider switching to rivastigmine patch if GI effects intolerable - Anti-nausea medication (ondansetron, meclizine) can help temporarily

Loss of appetite and weight loss: - Monitor weight regularly - Ensure adequate calorie intake - May need nutritional supplements - If significant weight loss, consider whether benefit justifies continuing

Vivid dreams or insomnia (donepezil): - Take dose in morning instead of evening - Usually resolves with timing change - If persists, may need to switch medications

Slow heart rate: - Check heart rate if dizziness or fainting - Report to doctor if heart rate <50 beats/minute - May need ECG monitoring - Consider different medication if symptomatic bradycardia

Muscle cramps: - Usually mild and transient - Stretching and hydration help - Magnesium supplements may help (check with doctor)

When to call the doctor: - Severe or persistent vomiting - Black or bloody stools (sign of GI bleeding) - Fainting or near-fainting episodes - Seizures - Severe diarrhea with dehydration - Significant weight loss - Difficulty urinating (especially in men) - Severe skin reaction to rivastigmine patch

Memantine: A Different Mechanism

Memantine (brand name Namenda) represents a completely different approach to Alzheimer's treatment compared to cholinesterase inhibitors. Rather than affecting acetylcholine, memantine modulates glutamate, an excitatory neurotransmitter.

Understanding Glutamate and Excitotoxicity

Glutamate is the brain's primary excitatory neurotransmitter: - Enables communication between neurons - Essential for learning and memory - Activates NMDA receptors on neurons

In healthy brains, glutamate is carefully regulated. But in Alzheimer's disease: - Glutamate regulation becomes abnormal - Excessive glutamate accumulates in synapses - Chronic overstimulation of NMDA receptors occurs - This leads to excitotoxicity—neurons are damaged by excessive stimulation - Calcium floods into cells, triggering cell death pathways

Memantine works by partially blocking NMDA receptors, reducing the excessive stimulation that contributes to neuronal damage. Importantly, memantine's blockade is selective and voltage-dependent: - It blocks pathological (excessive, chronic) activation but allows normal (physiological, brief) activation to proceed - This selectivity means memantine doesn't interfere with normal learning and memory while reducing excitotoxic damage

Think of it like a surge protector: it allows normal electrical signals through but blocks dangerous power surges that could damage equipment.

Memantine: Clinical Use

Key characteristics: - Approval: FDA-approved for moderate to severe Alzheimer's disease - Dosing: - Immediate-release: Twice daily - Start: 5 mg once daily for 1 week - Week 2: 5 mg twice daily - Week 3: 10 mg morning, 5 mg evening - Week 4+: 10 mg twice daily (target dose: 20 mg/day) - Extended-release: Once daily - Start: 7 mg once daily - Week 2+: 14 mg once daily - Week 3+: 21 mg once daily - Week 4+: 28 mg once daily (target dose) - Formulations: - Immediate-release tablets - Extended-release capsules - Oral solution - Combination with donepezil (Namzaric) - Half-life: Long (60-80 hours)

When memantine is prescribed:

Memantine is typically added when: - Alzheimer's disease progresses to moderate or severe stage - Patient is already taking a cholinesterase inhibitor and progressing - Used in combination with cholinesterase inhibitor (different mechanisms may provide additive benefit) - Sometimes used alone if cholinesterase inhibitors aren't tolerated

The combination of a cholinesterase inhibitor plus memantine is common in moderate to severe Alzheimer's, as the medications work through different mechanisms.

Benefits of memantine: - Modest slowing of cognitive decline in moderate-severe Alzheimer's - May help maintain daily function longer - Possible benefits for behavioral symptoms (agitation, aggression) - May reduce care burden on caregivers - Generally well-tolerated with fewer side effects than cholinesterase inhibitors - Adding memantine to cholinesterase inhibitor may provide additional benefit beyond either alone

Typical improvement: - 2-3 point benefit on cognitive tests compared to placebo - Modest functional benefit (ability to perform daily activities) - May delay nursing home placement by several months - Not everyone responds; responders show clearer benefit than non-responders

Side Effects of Memantine

Memantine is generally better tolerated than cholinesterase inhibitors, with fewer and milder side effects.

Common side effects: - Dizziness (most common) - Headache - Confusion (ironically, though less common) - Constipation - Drowsiness or fatigue

Less common side effects: - Hallucinations (rare, but if they occur, may need to discontinue) - Agitation or anxiety - High blood pressure - Shortness of breath - Cough

Serious but rare side effects: - Severe confusion or hallucinations - Seizures - Blood clots - Allergic reactions

Who should avoid or use cautiously: - People with severe kidney disease (dose reduction needed if moderate kidney impairment) - Those with history of seizures - People taking other NMDA antagonists

Side effect management: - Slow titration minimizes dizziness and confusion - Taking with food may help with GI effects - Extended-release formulation may reduce side effects - If dizziness occurs, ensure adequate hydration and rise slowly from sitting/lying - Report severe confusion or hallucinations to doctor immediately

Memantine in Practice

Typical course:

A 78-year-old man with Alzheimer's disease has been taking donepezil 10 mg for two years. Initially he improved slightly, then stabilized, but now his MMSE has dropped from 20 to 15 (moderate stage) and he's having more difficulty with daily activities. His doctor adds memantine, starting at 5 mg and gradually increasing to 10 mg twice daily over a month.

Over the next several months, his function stabilizes again. He still has dementia, but the combination of donepezil plus memantine helps maintain his current level longer than would be expected without treatment. He can still dress himself, eat independently, and recognize family members—abilities that might have deteriorated sooner without the medications.

Eventually, disease progression will overcome the medications' benefits, but the treatment has provided months of better function and quality of life.

Combination Therapy: Namzaric

Namzaric is a combination medication containing both donepezil and memantine in a single capsule.

Available doses: - 7 mg memantine / 10 mg donepezil - 14 mg memantine / 10 mg donepezil - 21 mg memantine / 10 mg donepezil - 28 mg memantine / 10 mg donepezil

Advantages of Namzaric: - Convenience: One pill instead of two - Improved adherence - Reduces pill burden - Extended-release formulation (once daily dosing)

Disadvantages: - More expensive than generic donepezil plus generic memantine - Less flexibility (can't independently adjust doses of each medication) - Must already be on stable doses of both medications separately before switching - Extended-release capsules must be swallowed whole (can't open or crush)

When Namzaric is appropriate: - Patient stable on both donepezil and memantine separately - Adherence is an issue (reducing pill count helps) - Family willing to pay extra for convenience - Patient can swallow capsules

Most patients start donepezil and memantine separately, then may switch to Namzaric later if both medications are working well.

Newer Anti-Amyloid Therapies: A Controversial Frontier

In 2021 and 2023, the FDA approved two new medications that directly target amyloid plaques, a hallmark of Alzheimer's pathology. These represent a fundamentally different approach to treatment, but they come with significant controversies, limitations, and practical challenges.

Aducanumab (Aduhelm) and Lecanemab (Leqembi)

Aducanumab (Aduhelm): - FDA-approved June 2021 under accelerated approval pathway - Monoclonal antibody targeting amyloid plaques - Intravenous infusion every 4 weeks - Extremely expensive ($28,000/year) - Controversial approval based on unclear clinical benefit - Many medical centers refuse to prescribe it - Medicare restricts coverage to clinical trial participation

Lecanemab (Leqembi): - FDA-approved January 2023 - Monoclonal antibody targeting amyloid - Intravenous infusion every 2 weeks - Expensive ($26,500/year) - Showed modest slowing of cognitive decline (27% slower decline over 18 months) - More widely accepted than aducanumab, though still controversial - Medicare covers for appropriate patients

How these medications work: - Antibodies that bind to amyloid plaques - Immune system then clears the antibody-amyloid complexes - Reduces amyloid burden in the brain - Theory: Removing amyloid should slow disease progression

The controversy:

These medications generate intense debate because: - Modest benefit: Lecanemab slows decline by about 27%—real but small. Patients still progress, just slightly more slowly. - Unclear clinical significance: Statistical benefit doesn't always translate to noticeable improvement in daily life - Amyloid hypothesis uncertainty: Removing amyloid may not be sufficient to stop Alzheimer's (many people have amyloid without dementia) - Serious side effects: Brain swelling (ARIA-E) and brain microbleeds (ARIA-H) occur in 13-17% of patients, some severe - Cost: $26,000-28,000 per year raises healthcare cost concerns - Limited eligibility: Only for early Alzheimer's with confirmed amyloid, excluding most dementia patients - Practical barriers: Requires biweekly or monthly IV infusions, frequent MRI monitoring, apoE testing

Who might be eligible: - Early (mild cognitive impairment or mild dementia) stage Alzheimer's - Confirmed amyloid pathology (by PET scan or CSF) - No APOE ε4/ε4 genotype (higher risk of side effects) - No contraindications (anticoagulants increase bleeding risk) - Ability to receive regular infusions and monitoring

Current reality (as of 2024): - Very few patients actually receive these medications - Limited availability (specialized infusion centers required) - Insurance barriers (high cost, coverage restrictions) - Many neurologists remain skeptical about benefit-risk ratio - Ongoing research may clarify their role

For most families dealing with dementia today, cholinesterase inhibitors and memantine remain the primary medication options, with anti-amyloid therapies available only to a small subset of carefully selected patients.

Symptom Management: Treating Behavioral and Psychological Symptoms

While cholinesterase inhibitors and memantine target cognitive symptoms, many people with dementia also experience behavioral and psychological symptoms that require management:

  • Depression and anxiety
  • Agitation and aggression
  • Psychosis (hallucinations, delusions)
  • Sleep disturbances
  • Apathy

Non-pharmacological approaches should always be tried first (covered in Chapter 7: Managing Challenging Behaviors). Medications for behavioral symptoms are considered when non-drug approaches are insufficient and symptoms cause significant distress or safety concerns.

Antidepressants for Depression and Anxiety

Depression affects 30-50% of people with dementia. Treating depression improves quality of life even if it doesn't improve cognitive function.

Commonly used antidepressants: - SSRIs (Selective Serotonin Reuptake Inhibitors): Sertraline (Zoloft), citalopram (Celexa), escitalopram (Lexapro) - First-line choice for depression in dementia - Generally well-tolerated - Take 4-6 weeks for full effect - Side effects: Nausea, sexual dysfunction, increased fall risk

  • SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors): Venlafaxine (Effexor), duloxetine (Cymbalta)
  • Alternative if SSRIs ineffective

  • May also help with pain

  • Mirtazapine (Remeron):

  • Helpful if depression with poor appetite or insomnia
  • Sedating (take at bedtime)
  • May increase appetite and cause weight gain

Important considerations: - Takes 4-6 weeks to see full benefit - Continue for at least 6-12 months if effective - Don't stop abruptly (taper slowly) - May slightly increase fall risk - Monitor for worsening confusion

Antipsychotics for Severe Agitation and Psychosis

Antipsychotic medications are sometimes used for severe behavioral symptoms when non-drug approaches have failed and safety is at risk. These medications carry significant risks and should be used cautiously and only when necessary.

Black Box Warning: All antipsychotics carry FDA black box warning for increased risk of death when used in elderly people with dementia. This doesn't mean they can never be used, but decision requires careful risk-benefit assessment.

When antipsychotics might be considered: - Severe, persistent agitation or aggression causing danger - Psychosis causing severe distress - Other interventions have failed - Benefits clearly outweigh risks

Commonly used antipsychotics: - Risperidone (Risperdal): Most studied in dementia; low doses may reduce aggression - Quetiapine (Seroquel): Often used for sleep and agitation; less evidence of benefit - Olanzapine (Zyprexa): Effective but causes weight gain and metabolic problems - Aripiprazole (Abilify): Alternative option with different side effect profile

Major risks: - Increased mortality (stroke, sudden death, infections) - Increased stroke risk - Worsening confusion and sedation - Parkinsonism (stiffness, shuffling gait, tremor) - Falls - Aspiration pneumonia - Metabolic effects (weight gain, diabetes, high cholesterol)

Principles of use: - Start with lowest possible dose - Use for shortest possible time - Target specific symptoms - Monitor closely for side effects - Attempt to taper and discontinue periodically - Document why medication is necessary and benefit achieved

Important: Haloperidol (Haldol) and other older "typical" antipsychotics have even higher risks and are generally avoided except in emergency situations.

Sleep Medications

Sleep disturbances are common in dementia. Non-drug approaches (sleep hygiene, light exposure, reducing daytime napping) should be tried first.

If medication needed: - Melatonin: Natural hormone, generally safe, may help with sleep-wake cycle - Trazodone: Sedating antidepressant, commonly used off-label for insomnia - Mirtazapine: Sedating antidepressant that also helps appetite

Medications to AVOID in dementia: - Benzodiazepines (Valium, Ativan, etc.): Increase confusion, falls, and paradoxical agitation - Anticholinergic sleep aids (Benadryl, Unisom): Worsen cognition and confusion - Ambien, Lunesta: Increase falls and confusion in elderly

Pain Management

Unrecognized pain often causes behavioral symptoms in dementia. People with advanced dementia may be unable to report pain verbally, so caregivers must watch for signs: - Grimacing or facial tension - Guarding or protecting body parts - Resistance to movement or care - Increased agitation or aggression - Changes in sleep or appetite

Pain treatment: - Acetaminophen (Tylenol): Safe, effective for mild-moderate pain; can give regularly - Topical analgesics: Creams or patches for arthritis pain - Opioids: If needed for moderate-severe pain, start low and monitor carefully

Avoid NSAIDs (ibuprofen, naproxen) long-term—increase bleeding, ulcers, kidney problems in elderly.

Clinical Trials: Advancing Research and Access to Experimental Treatments

Clinical trials are research studies that test new treatments to determine if they're safe and effective. Participating in clinical trials offers potential benefits but also involves risks and commitments that families should carefully consider.

Why Clinical Trials Matter

Clinical trials are essential for developing new treatments: - Testing whether new medications slow or stop dementia progression - Evaluating whether lifestyle interventions or combination therapies help - Understanding disease mechanisms - Moving from laboratory discoveries to real-world treatments

Every medication currently available went through clinical trials with participants who volunteered to help advance science.

Types of Clinical Trials

Phase 1 trials: - First testing in humans (usually small numbers) - Primarily assess safety - Often test in healthy volunteers first - Determine appropriate dosing

Phase 2 trials: - Larger groups with the disease - Test whether treatment shows signs of working - Continue safety monitoring - Refine dosing

Phase 3 trials: - Large trials comparing new treatment to placebo or standard treatment - Definitive test of whether treatment works - Extensive safety monitoring - If successful, used for FDA approval

Phase 4 trials: - After FDA approval - Monitor long-term effects - Study in broader populations - Identify rare side effects

Observational studies: - Don't test new treatments - Follow people over time to understand disease progression - Identify risk factors and biomarkers - Contribute to scientific understanding

Benefits of Participating

Potential personal benefits: - Access to experimental treatments before they're available to public - May receive cutting-edge therapy that could help - Close monitoring and medical care from specialists - Free medication and study-related care - Contributing to research that may help future generations

Societal benefits: - Advancing scientific knowledge - Helping develop new treatments - Contributing to hope for future cure - Leaving a legacy of helping others

Risks and Considerations

Potential risks: - Experimental treatment may not work - May receive placebo (in placebo-controlled trials) - Possible side effects from untested treatments - Time commitment for visits and monitoring - Testing procedures (blood draws, scans, cognitive tests) - Travel to research center if not local

Practical considerations: - Time commitment (frequent visits, especially early in trial) - Transportation to study site - Caregiver involvement required - Cognitive and physical demands of participation - Stopping other medications may be required - Eligibility criteria may exclude many people - May not know if receiving active treatment or placebo until trial ends

Eligibility Criteria

Most trials have strict inclusion and exclusion criteria:

Often required: - Specific diagnosis (usually early Alzheimer's, confirmed by biomarkers) - Specific stage (mild cognitive impairment or early dementia) - Age range (typically 50-85) - Study partner/caregiver available - Stable on current medications (or willing to stop them) - Willing and able to undergo study procedures

Often excluded: - Other neurological conditions - Severe medical conditions - Certain medications - Inability to undergo MRI - Advanced dementia (most trials focus on early stages) - Recent participation in other trials

These criteria mean many people with dementia don't qualify for most trials.

Finding Clinical Trials

Resources for finding trials: - ClinicalTrials.gov: U.S. government database of all registered clinical trials - Search by condition, location, and other criteria - Provides contact information for trials - Alzheimer's Association TrialMatch: Matching service connecting participants with trials - Confidential and free - Personalized matching based on profile - Academic medical centers: Many conduct dementia trials - Physician referral: Neurologists and geriatricians may know of local trials - Advocacy organizations: Provide information about research opportunities

Questions to Ask Before Enrolling

  1. What is the purpose of the study? What is being tested and why?

  2. What will I be required to do? Visits, procedures, time commitment?

  3. What are the possible risks and benefits? Both for this individual and for science?

  4. Will I receive placebo or active treatment? Is it randomized? What's the probability?

  5. What happens if the treatment causes problems? Who pays for treatment of side effects?

  6. Can I continue my current medications? What must be stopped?

  7. How long will the trial last? What happens afterward?

  8. What will I learn from participating? Will I get individual results?

  9. Can I stop participating if I want to? Participation is always voluntary.

  10. Who has reviewed and approved the study? Institutional review board oversight?

  11. What costs will be covered? Study medication, visits, tests? What about transportation?

  12. Who can answer questions? 24/7 contact for concerns?

Making the Decision

Consider: - Current disease stage and prognosis - Potential for benefit vs. burden of participation - Individual and family goals and values - Willingness to accept uncertainty - Practical ability to meet requirements - Altruistic motivation to help research

Remember: - Participation is always voluntary - Can withdraw at any time for any reason - No obligation to enroll just because you're eligible - Take time to discuss with family and healthcare providers

For many families, participating in research provides meaning and hope—a way to fight back against dementia by contributing to future treatments, even if individual benefit is uncertain.

Conclusion: A Balanced Approach to Medical Treatment

Medical treatment for dementia represents one important component of comprehensive care, but it's not the whole story. Current medications provide modest benefits for some people, improving or maintaining function for a period of time. They cannot cure dementia, stop its progression, or restore what's been lost—but they can extend the time when a person functions better, and that matters.

Key principles for approaching dementia medications:

  1. Maintain realistic expectations - Medications help some people modestly; they don't perform miracles. Small benefits are still valuable.

  2. Individualize treatment - What works for one person may not work for another. Trial and careful monitoring determine whether medication helps.

  3. Balance benefits and risks - All medications have side effects. Continue treatment only if benefits outweigh risks.

  4. Combine approaches - Medications work best alongside non-pharmacological interventions (cognitive stimulation, physical activity, social engagement, behavioral management).

  5. Reassess over time - What makes sense early may not make sense in very advanced dementia. Regularly evaluate whether continuing treatment serves the person's best interests.

  6. Focus on quality of life - The goal isn't just cognitive test scores but functional abilities, comfort, engagement, and quality of life.

  7. Consider research participation - Clinical trials advance science and may provide access to experimental treatments.

The landscape of dementia treatment continues to evolve. Researchers are testing new medications, combination therapies, and prevention strategies. While progress has been slower than hoped, ongoing research offers reasons for optimism that more effective treatments will emerge. Until then, currently available medications, combined with excellent care and behavioral interventions, represent the best approach to managing dementia.

Key Takeaways

  • Current medications for dementia provide modest, temporary benefits but cannot cure or stop disease progression
  • Cholinesterase inhibitors (donepezil, rivastigmine, galantamine) work by increasing acetylcholine levels in the brain
  • All three cholinesterase inhibitors have similar efficacy; choice depends on dosing convenience, tolerability, and formulation needs
  • Rivastigmine patch reduces GI side effects compared to oral cholinesterase inhibitors
  • Memantine works through a different mechanism (blocking excessive glutamate activity) and is approved for moderate to severe Alzheimer's
  • Combination therapy (cholinesterase inhibitor plus memantine) may provide additional benefit beyond either alone
  • Expected benefits: modest slowing of cognitive decline, possible functional improvements, duration of 6-18 months before disease overcomes medication effect
  • Common side effects: nausea, diarrhea, loss of appetite (cholinesterase inhibitors); dizziness and headache (memantine)
  • Anti-amyloid therapies (aducanumab, lecanemab) represent new approach but have limited availability, high cost, and controversial benefit-risk profile
  • Behavioral symptoms (depression, agitation, psychosis) may require additional medications, but non-drug approaches should be tried first
  • Antipsychotics carry black box warning for increased mortality in dementia and should be used only when necessary with careful monitoring
  • Clinical trials offer access to experimental treatments and advance research, but involve time commitment and potential risks
  • Treatment decisions should consider individual goals, values, and quality of life, not just cognitive test scores
  • Medications work best as part of comprehensive care including behavioral interventions, social engagement, and caregiver support

Review Questions

  1. Explain how cholinesterase inhibitors work and why they might help with Alzheimer's disease symptoms.

  2. Compare and contrast the three cholinesterase inhibitors (donepezil, rivastigmine, galantamine). When might you choose each one?

  3. What are realistic expectations for benefits from cholinesterase inhibitors? What can they do and what can't they do?

  4. Explain memantine's mechanism of action. How is it different from cholinesterase inhibitors?

  5. When is combination therapy (cholinesterase inhibitor plus memantine) typically used, and why?

  6. What are the most common side effects of cholinesterase inhibitors, and how can they be managed?

  7. Why do anti-amyloid therapies (aducanumab, lecanemab) remain controversial despite FDA approval?

  8. Why do antipsychotic medications carry a black box warning for use in dementia, and when might they still be considered?

  9. What are the potential benefits and risks of participating in a clinical trial for dementia?

  10. How should families approach decisions about continuing or stopping dementia medications as the disease progresses?

Additional Resources

Next: Chapter 10: Therapeutic Interventions explores non-pharmacological approaches to dementia care, including cognitive stimulation, physical exercise, music therapy, and other therapeutic interventions that improve quality of life.