Alzheimer's Disease Part III: Treatment

Cicero told of Damocles who wished the pleasures of a king. Saracen magic placed him at the king’s table eating sumptuous food, drinking the finest wine and enjoying more pleasures than his imagination had conceived. Glancing upward, his eyes transfixed on a sword dangling by a single horsehair just above his head. Damocles turned pale. His hands trembled. His joy vanished as he realized that much pleasure brings much danger.

Perhaps the myth of Damocles over dramatizes the risk of Alzheimer’s. After all over 50% of 90-year-olds never experience the illness. Nonetheless as we grow older we sometimes contemplate the threat of Alzheimer’s dangling by a single horsehair just above our eyes’ imagination.

Scientists still search for a cure.  They’re looking for a little more horsehair for that sword.

The U.S. Food and Drug Administration (FDA) has approved five medications to treat the symptoms of Alzheimer's Disease (AD):

• Aricept (donepezil)—approved in 1996 for all mild to moderate stages of AD
• Can help AD patients do things longer
• Dose: 5 mg daily for one month then 10 mg daily
• Side effects are mild but occasionally consist of nausea, diarrhea, anorexia 
• Useless for severe AD
• Exelon (rivastigmine)—approved in 2000 for all stages
• Dose: Initial dose 1.5 mg twice daily then, if tolerated, 3 mg twice daily and gradually increase to the maximum dose of 6 mg twice daily until maximum benefit is reached.
• 70% of patients who responded poorly to Aricept responded to Exelon.
• As many as 40% of patients may develop intolerable nausea, vomiting, diarrhea and anorexia.
• Razadyne (galantamine)—approved in 2001 for mild to moderate AD
• Initial dose 4 mg twice daily. May gradually increase to 12 mg daily
• GI side effects predominate
• Namenda (memantine)—approved in 2003 for moderate to severe AD
• Dose: 5 mg daily, gradually increase to 10 mg twice daily
• First medication approved to treat severe AD
• Impressively benign side effects
• Namzaric (a combination of donepezil and memantine)—approved in 2014 for moderate to severe AD
• The first and only once-a day capsule that works on two pathways to fight symptoms of moderate to severe AD.
• Initial dose 7mg of memantine and 10 mg of donepezil gradually increase to maximum dose of 28 mg/10mg daily

How Medications for Alzheimer’s Work:

• Brain nerve cells (neurons) connect at the junction of neurons called synapses where tiny bursts of chemicals called neurotransmitters transfer information from one cell to another. AD impairs the function of several neurotransmitters. 
• The neurotransmitters acetylcholine and glutamate seem particularly important in AD.
• Cholinesterase inhibitors—Aricept (donepezil) and Razadyne (galantamine)—block acetylcholinesterase, an enzyme responsible for the normal decomposition of acetylcholine. This inhibition of acetylcholinesterase allows an increase of acetylcholine so that information is passed through the synapse more effectively.
• Exelon (rivastigmine) inhibits two enzymes, acetylcholinesterase and butyrylcholinesterase, increasing the effectiveness of acetylcholine.
• Namenda (memantine) works by regulating the activity of glutamate thus preventing excess calcium to flow into nerve cells that kill neurons. Restoring normal glutamate levels improves learning and memory.

Unfortunately these FDA approved medications fail to treat the underlying disease process or stop cell damage. Instead they merely slow the development of the disease.

Other medications may be useful in treating or preventing the AD. Evaluating the benefit-risk ration is especially important with these meds:

• Premarin(conjugated equine estrogen) improves verbal memory, vigilance and reasoning, and has been associated with decreased dementia risk.
• Contraindicated with blood clots in the calf or lung, infection of leg vessels, severe liver disease and estrogen-dependent cancer.
• 10-20 years of estrogen replacement gives a modest chance for breast cancer.
• Estrace (estradiol) has the same benefits and warnings as Premarin but the tablet is half as expensive.
• Eldepryl (selegiline) inhibits monoamine oxidase that breaks down neurotransmitters
• Serious side effect of a hypertensive crisis when certain foods are eaten
• Non-Steroid Anti-Inflammatory Drugs (NSAIDs) such as Aspiring, Motrin, Naprosyn 
• Clinical research indicates NSAIDs may help prevent AD. 
• Serious side effect: Gastric ulcers
• Statins—Lipitor, Mevacor, Zocor
• May reduce the production of beta-amyloid proteins that cause nerve cell death
• Serious side effect: Liver abnormalities

Medications for symptoms of AD:

• Rexulti is useful for paranoia and agitation. (See my blog entry for info on Rexulti.)
• Seroquel is useful for sedation and sleep in acutely agitated AD patients
• SSRIs, especially Zoloft or Celexa, are useful for AD depression 
• Trintellix, a non-SSRI, is my favorite AD antidepressant because it increases serotonin-7 that has been found to increase cognition.
• Trintellix has yet to catch on as "popular" antidepressant
• Academics would be displeased with Trintellix use in AD depression
• Nausea is a limiting factor
• See my blog entry on Trintellix for more information.
• Trazodone for sleep
• May have some efficacy in treating agitation and aggression associated with AD

Warning: Avoid benzodiazepines such as Valium, Xanax, Ativan and others 

• These medications can act as disinhibitors in the elderly resulting in increased agitation.
• Benzodiazepines often cause confusion in the elderly.
• One longitudinal study involving over 400 AD patients has shown long term use of benzodiazepines to be an associated with AD, not a cause for AD.
• Another longitudinal study of over 400 AD patients refuted these findings.
• Longitudinal studies become extremely complicated because complex statistical analysis is necessary for factoring out multiple variables.

 

Fortunately, 19 AD drugs are in Phase 3 clinical trails (people are taking the drug, not animals) that are on pace to launch in the next five years if proved to be safe and effective and if the FDA does not delay the process. 

Irony: The FDA has delayed many effective drugs that treat life-ending disease because of safety reasons. I guess the members failed college Logic 101. 

The FDA sword cuts off speedy development of AD medications.