Treatment for Alzheimer’s Disease Maenne Okunola June 2011 UGA COP: Pharm D. Candidate Preceptor: Dr. Ali Rahimi

Treatment Goal Currently there is no current therapy to treat Alzheimer’s disease. Current therapy is aimed at prolonging the patient’s cognitive function and secondary goals include symptomatically treating psychiatric and behavioral abnormalities Current therapy has not been shown to prolong life, cure AD, halt or reverse the pathophysiological degradation of the disease

Natural Disease Progression Alzheimer’s Disease Assessment Scale-Cognition (ADAS-cog) scores worsen by an average of 4 points over 6 months and 7 points over 1 year 4 points represents a clinically significant change In clinical practice a Mini Mental Status Examination (MMSE) is used due to time requirements of the ADAS-cog  An untreated patient has an average decline of 2-4 points per year

Brain Comparison

Ideal Treatment Improving symptomatic decline by improving cognitive function, daily activities, and behavior  Current therapy Arrests the neurodegenerative molecular process  Research needed

Treatment Algorithm Cholinesterase Inhibitor NMDA Antagonist Cholinesterase Inhibitor + NMDA antagonist Titrate doses to recommended maintenance therapy as tolerated Symptomatic approach is used to treat behavioral symptoms

Cholinesterase Inhibitors

Donepezil (Aricept)- used in mild to severe disease Galantamine (Razadyne)- used in mild to moderate disease Rivastigmine (Exelon)- used in mild to moderate disease Combination of more than one cholinesterase inhibitor is not recommended Choice of therapy often selected based on ease of use for the patient, cost and safety issues Switching can occur if patients are not tolerating the initial treatment or a treatment failure  If MMSE decline is greater than 2-4 points in one year changing therapy is warranted

Cholinesterase Inhibitors Donepezil, Rivastigmine and Galantamine All show similar efficacy and adverse event profiles with gastrointestinal complaints being the most common symptom Dose titration over several months can help tolerability of urinary incontinence, dizziness, headache, syncope, bradycardia, muscle weakness, salivation and sweating Abrupt discontinuation is discouraged due to worsening of cognition or behavioral problems in some medications Avoid use with anti-cholinergic medications which is especially important when trying to treat behavioral abnormalities.

Cholinesterase Inhibitors Mechanism of Action Donepezil- specifically and reversibly inhibits acetylcholinesterase Rivastigmine- inhibits both butylcholinesterase and acetylcholinesterase Galantamine- selective, competitive, reversible acetylcholinesterasse inhibitor and also enhances the action of acetylcholine on nicotinic receptors Clinical relevance is unknown

NMDA Antagonist

N-methyl-D Aspartate (NMDA) Antagonist Memantine- used in moderate to severe disease  Not recommended in early stages of the disease  Only NMDA-antagonist available  Blocks glutamatergic neurotransmission by antagonizing NMDA receptors Glutamate an excitatory neurotransmitter in the brain  Most common side effects include constipation, confusion, dizziness, headache, hallucinations, coughing, and hypertension

Dosage Forms Galantamine (Razadyne)- capsule, tablet, and solution Donepezil (Aricept)- tablet (oral disintegrating tablet) Rivastigmine (Exelon)- capsule, patch, and solution Memantine (Namenda)- tablet and solution

Treatment for Non-cognitive Symptoms Psychosis Disruptive behavior Depression Environmental interventions then pharmacological therapy Limited clinical data; therefore, treatment is empirical General guidelines: reduced doses, close monitoring closely, slow dose titrations, and careful documentation Cholinesterase inhibitors and memantine should be considered as first line therapy in patients with behavior abnormalities in the beginning stages of AD

Antipsychotics Haloperidol Olanzapine Quetiapine Risperidone Ziprasidone Treatment of psychosis: hallucinations, delusions, suspicions Treatment of disruptive behaviors: Agitation and aggression Not FDA approved

Concern with Antipsychotics Worsening cognitive impairment, oversedation, falls, tardive dyskinesia, neuroleptic malignant syndrome, hyperlipidemia, weight gain, diabetes mellitus, cerebrovascular accidents A dose reduction or discontinuation should be considered periodically in patients Physical restraints should be limited to patients who pose imminent harm to themselves or others.

Antidepressants Citalopram Escitiolopram Fluoxetine Paroxetine Sertraline Venlafaxine Trazadone Treatment of depression: poor appetite, insomnia, hopelessness, anhedonia, withdrawal, suicidal thoughts, agitation, or anxiety As many as 50% of AD patients suffer from depression

Anticonvulsants Carbamazepine Valproic Acid Treatment of agitation or aggression

Standard of treatment None exists Duration of treatment ranges from clinician to clinician. May be months to years No clear standard of care for dosing from clinical trials No clear standard of when to discontinue therapy in very severe stages of AD  Many clinicians do discontinue therapy when the patient becomes bed ridden

Key Non-pharmacological Methods Education Preparation Communication

Educating patient and family at the time of diagnosis  Discussion of the course of illness  Expectations from treatment  Legal and financial planning including a durable power of attorney  Quality of life issues  Re-enforcing the importance of communication between the patient and family members  Decreasing environmental triggers and personal discomfort

Non-Pharmacological Interventions Physical well-being Increased overall well being Stimulation oriented treatments: recreational activity, art therapy, music therapy, pet therapy and aromatherapy may be useful, but lack of sufficient evidence to validate effectiveness but used in clinical practice

Caregivers Find time to rest, relax and tend to personal affairs because stress will impact the health and quality of life of both the patient and the caregiver Help patients to discover a structured level of autonomy using reminders and explanations Be aware of signs and symptoms of decline Knowing when to institutionalize a patient

Interventions Patients should be assessed every 3-6 months Patients may need to stop driving even at mild levels of treatment Sleep disturbances common in people with dementia, proper sleep hygiene should be implemented before beginning pharmacological therapy

Behavioral Management Sleep disturbances Wandering Urinary Incontinence Agitation Aggression May be useful to try this before beginning drug therapy

Epidemiological Correlations Brain Vascular Health Lipid lowering agents Non inflammatory agents Vitamin B 6, B12 and B12 deficiency Hyerhomocysteinemia

Brain Vascular Health New studies have evidence brain vascular disease plays an important role in the progression of dementia Brain vascular disease may accelerate deposition of beta amyloid plaques and increase amyloid toxicity to neurons and the neural synapses Brain vascular health includes managing blood pressure, glucose, cholesterol and homocysteine.  Elevated homocysteine levels correlate with decreased performance on cognitive tests Importance of stating physically, mentally, and socially active

Folate, Vitamin B12, Vitamin B6 Defects in these vitamins are associated with neurological and psychological dysfunction In elderly patients there is increased concern of satiety, atrophic gastritis, and decreased function of the olfactory functions Increased homocysteine has a direct correlation with a deficiency and these vitamins

Estrogen Therapy Epidemiological studies post menopausal women who took estrogen replacement therapy had a lower incidence of AD Studies did not show an improvement in behavioral or functional outcomes when estrogen used to treat cognitive decline Estrogen has a risk of stroke and other cardiovascular events

Anti-inflammatory Agents Epidemiological studies suggest patients on anti-inflammatory agents have a lower incidedence of AD Treatment less than 2 years proved beneficial in some patients Clinical studies does not show evidence of cognitive benefit and tolerability was an issue

Lipid Lowering Agents Epidemiological studies and AD show a correlation between higher midlife total cholesterol rates and AD Correlation between people on lipid lowering therapy and lower incidences' of AD  Pravastatin and lovastatin but not simvastatin were associated with a lower incidence of AD  More trials are needed to address the impact of cognitive benefit, the duration of treatment, class effect, and optimal dosing for its role in AD Role of therapy should remain for people with indications for their use

Therapies in the Pipeline Vitamin E Atomexetine IGIV 10% Thiazolidinediones (anti-inflammatory effects) Over 900 studies occurring now phase 1- 4 and Ginkgo Biloba Huperzine A Semagacestat (LY450139) Coenzyme Q10 Acupuncture Over 100 studies phase 3

Vitamin E Antioxidant- may be useful because of the accumulation of free radicals associated with AD Favorable side effect profile and low cost Impaired hemostasis, fatigue, nausea, diarrhea, abdominal pain, and thinning of the blood Increased mortality in older patients Doses above 400 international units per day should be avoided in patients with AD May be beneficial in combination with Selegeline: Phase III study-PREADVISE- examining anti-oxidant effects of Selegeline

Ginkgo Biloba Increased blood flow, decreased viscosity of the blood, antagonizing platelet activating factor receptors, increased tolerance to anoxia, inhibiting monoamine oxidase, anti-infective properties, preventing damage of membranes caused by free radicals If used for dementia should be used as soon as deterioration of cognitive functioning occurs Side effects are typically mild and rare Herbal products are typically poorly standardized

Huperzine A An alkyloid isolated from the Chinese club moss, Huperzia serrata Reversibly inhibits acetylcholinesterase and is administered orally in doses mcg 2-4 times daily May be more promising for symptomatic treatment of Alzheimer’s disease Promising product from clinical studies, but lack of product purity Concurrent use with other available cholinesterase inhibitors should be avoided

Semagacestat (LY450139) Inhibiting the enzyme gamma-secretase lowers the production of beta amyloid. Semagacestat (LY450139) a functional gamma-secretase inhibitor lowers the beta amyloid in the blood and spinal fluid in humans. Effect of LY a gamma-secretase inhibitor on the progression of Alzheimer’s disease as compared with Placebo- Currently Phase III 60 mg orally titrated up to 140 mg

Immune Globulin Intravenous (Human), 10% (IGIV, 10%) A Randomized, Double-Blind, Placebo-Controlled, Two Dose-Arm, Parallel Study of the Safety and Effectiveness of Immune Globulin Intravenous (Human), 10% (IGIV, 10%) for the Treatment of Mild to Moderate Alzheimer's Disease – Phase III trial The purpose of this study is to determine whether IGIV, 10% treatment, administered at two different doses results in a significantly slower rate of decline of dementia symptoms in subjects with mild to moderate (AD). Approved in 2005 for primary immunodeficiency

Coenzyme Q10 A natural antioxidant in the body Role of therapy currently being explored, but limited clinical trials in humans for AD

Helpful links

Economic Impact US health care cost is greater than $100 billion Annual cost for caring for an individual with advanced AD is approximately $50,000 According to CDC, there is 231,900 patients in nursing homes with AD which accounts for 15.5% of the nursing home population 4 th leading cause of death in adults

Resources gammagard-liquid/dosage-administration.html html cdc.gov

Resources National Guideline Clearinghouse (NGC). Guideline synthesis: Management of Alzheimer's disease and related dementias. In: National Guideline Clearinghouse (NGC). Rockville (MD): 2006 Nov (revised 2010 Sep). [cited 2011 June 13]. Available: Dipiro J,Talbert R, Yee G., Matzke G, Wells B, Posey L. Pharmacotherapy: A Pathophysiologic Approach. 7th. New York: McGraw-Hill, B Vitamins, Homocysteine, and Neurocognitive Function in the Elderly. American Journal of Clinical Nutrition. February 2000;71(2):614s-620s. Accessed June 15, 2011.