Pharmacy Medication Update: DementiaMegan J. Ehret, PharmD, MS, BCPPAssociate Professor University of Connecticut

Objectives • Describe the clinical presentation and diagnostic criteria for

dementia and mild cognitive impairment.• Describe the treatment guidelines and landmark clinical trials

for the treatment of dementia.• Select an evidenced-based drug therapy regimen for

stabilizing symptoms of dementia.• Identify essential information to discuss during patient

education about the drug therapy of dementia.

Prevalence/Clinical Course• 2-4% of population over 65 years old • Increases with age • AD accounts for 60% of all dementias in the elderly

• Gradual onset and is slowly progressive• Cognition is affected early on with impairment in motor,

behavioral, and sensory functioning occurring later• Time to onset to death: 8-10 years• Loss of 3-4 points/year on MMSE

Risk Factors • Degeneration of cholinergic neurons• Cortical atrophy• Presence of neurofibrillary tangles• Accumulation of neuritic plaques• Increasing age• Down Syndrome• Head trauma• Depression• Lower educational level

DSM 5 Diagnostic Criteria- Alzheimer’s Disease• Must meet criteria for major or mild neurocognitive disorder• Cognitive decline from baseline in 1/5: Attention, Executive

Function, Learning and Memory, Language, Perceptual-Motor, or Social Cognition)

• Cognitive impairment is slow and gradual

DSM 5 2013

Signs and Symptoms of AD• Loss of early memory- progresses to loss of long-term

memory• Final stages: gait abnormalities, motor disturbances, decline in

communication abilities, dependent on others

Objective Signs of AD

• Amyloid Beta Peptide-• Imagining is appropriate in pts. with persistent mild cognitive

impairment, pts. with core AD with atypical or unusual course, and progressive dementia with early age onset (<65)

• MRI- Cortical atrophy• MMSE- 3-4 point loss• MoCA- Rapid screening instrument for mild cognitive

dysfunction • Total score is 30; >26 is normal

• Genetic Testing- APOE4, presenilins 1 and 2• Controversial

Alzheimer’s Association/Society of Nuclear Medicine and Molecular Imagining 2013

MINI-MENTAL STATE EXAM (MMSE)

Other Rating Scales • Alzheimer’s Disease Assessment Scale (ADAS)• Evaluate the severity of dysfunction in cognition, and non-

cognitive behaviors over time• Severe Impairment Battery• Used to detect cognitive function in severe dementia

• Neuropsychiatric Inventory• Assesses behavioral problems in dementia

• Behavioral Pathology in Alzheimer’s Disease (BEHAVE-AD)• Assess behavioral symptoms and measure outcomes in

treatment studies

TREATMENT GUIDELINES

NON-PHARMACOLOGICAL TREATMENT

Therapies and Plans• Increase enjoyable activities• Redirect and refocus• Increase social activities for the patient• Eliminate sources of conflict and frustration• Assess the pt.'s caregiver for signs and symptoms of

depression

PHARMACOLOGICAL TREATMENT

General Approach • First line treatment: Cholinesterase Inhibitors, memantine can

also be used in moderate to severe dementia

• Second line treatment: addition of memantine to cholinesterase inhibitors

• Medications have been shown to only temporarily slow the progression of the disease

• Switching between cholinesterase inhibitors is well tolerated and provides therapeutic benefit if previous agent lacked efficacy or tolerability

Cholinesterase Inhibitors • Inhibit the cholinesterase (AChE) • Enzyme responsible for hydrolysis of acetylcholine • Elevates concentrations of acetylcholine for synaptic

transmission in the CNS• Thought to improve memory and cognition

Donepezil (Aricept)®• Treatment of mild to severe AD

• Mild to moderate: 5mg daily; may increase to 10mg daily after 4-6 weeks, may increase to 23mg daily after >3 months

• Moderate to severe: same as above

• 23mg greater benefit in cognition, but not global functioning; higher rates of GI adverse events

Donepezil• Warnings/Precautions• Peptic ulcer disease and GI bleeding: monitor for GI bleeding

especially in those who are higher risk • Weight Loss

• Adverse Events• Nausea, vomiting, and diarrhea: administer medication with

food; reduce dose• Vagotonic effects: slows conduction through SA and AV nodes

resulting in bradycardia • Insomnia: Give medication in morning

Rivastigmine (Exelon)®• Treatment of mild, moderate, and severe AD, treatment of

Parkinson’s Disease Dementia

• 1.5mg twice daily, may increase by 3mg daily every 2 weeks based on tolerability; max dose: 6mg twice daily

• Patch: 4.6mg/24hrs daily, may titrate to 9.5mg/24hrs, then to 13.3mg/24hrs (verify that old patch has been removed prior to applying a new patch)

• If dosing is interrupted for more than 3 days, pt. needs to be restarted on initial dose

• Same warnings/precautions

Galantamine (Razadyne)®• Mild to moderate AD

• IR or solution: 4mg twice daily for 4 weeks, then 8mg twice daily for >4 weeks, if tolerated than 12mg twice daily

• ER: 8mg once daily for 4 weeks, then 16mg daily for >4 weeks, if tolerated than 24mg daily

• Same warnings/precautions

Memantine (Namenda)®• Treatment of moderate to severe AD

• Low to moderate, uncompetitive, N-methyl-D-aspartate (NMDA) receptor antagonist• Glutamate is an amino acid which may contribute to the

pathogenesis of AD by over-stimulating the NMDA receptor

• Short acting: 5mg/day for 1 week, 5 mg twice daily for 1 week, 5 mg in the AM and 10mg in the PM for one week, then 10mg twice daily

• Long acting: 7mg/day for 1 week, 14mg/day for 1 week, 21mg/day for 1 week, then 28mg/day

Memantine • Use with caution in patients with seizure disorders, hepatic

impairment, or mild-moderate renal impairment

• Most common adverse effects: dizziness, headache, hallucinations, insomnia, confusion, and constipation

Duration of Therapy • Controversial• If no efficacy seen within 3 months of therapy at maximum

dose, switching should be attempted• Both immediate switching and a 7-14 day wash our has been

done: good tolerability and efficacy

DIETARY SUPPLEMENTS

Vitamin E• Late 1990’s: recommended due to it’s antioxidant effect• Decrease the accumulation of free radicals

• Evidence on prevention is mixed

• Adverse effects: impaired hemostatis, fatigue, nausea, diarrhea, abdominal pains, falls

• Meta-analysis: high-dose can increase mortality

• Not recommended

Nutraceuticals/Supplements• Ginkgo Biloba: increase blood flow, decrease blood viscosity,

antagonize platelet-activating factor receptors, increase anoxia tolerance, inhibit monoamine oxidase, antioxidant

• Side effects: nausea, vomiting, diarrhea, headaches, dizziness, palpitations, restlessness, weakness

Nutraceuticals/Supplements• Omega-3: large, prospective, placebo-controlled trial in AD

subjects• Primary study endpoints: negative

Medical Food• Axona

• Modification of medium-chain triglyceride formulation• Contains mixtures of C5-C12 fatty acids • Converted to betahydroxybutyrate: oxidative phosphorylation

substrate by neuron mitochondria; supports brain bioenergetics

• Supported by trials of 40 mg /day for 45 days

Behavioral and Psychological Symptoms in Dementia

Diagnostic Criteria• No specific diagnostic criteria

• Could be met for impulse control disorders, obsessive-control disorder, and bipolar disorder

Signs and Symptoms • Physically aggressive agitation: pushing, biting, kicking, spitting• Physically nonaggressive behavior: pacing, wondering,

inappropriate voiding, undressing• Verbally aggressive behavior: screaming, yelling, cursing• Verbally nonaggressive behavior: requesting attention,

repetitively calling out

• Most common: apathy, delusions, aggression/agitation, anxiety, psychomotor disturbance, irritability, sleep/wake disturbance, depression, disinhibition, hallucinations

Risk Factors/ Prevalence• Can occur in up to 60% of demented patients in community

dwelling and 80% in long term care facilities • 1/3 of mildly-impaired dementia pts., 2/3 of moderate

impairment pts. • After 5 yrs. w/dementia: 90% with have one BPSD

• Risk of developing varies• Fronto-temporal dementias, LBD, vascular dementia,

Huntington’s disease more likely to experience BPSD symptoms

Clinical Course • Depression, apathy, social withdrawal: can be noticed several

years before diagnosis of dementia

• As dementia progresses: frequency and intensity of agitation and aggression worsen

• At end stages of dementia, episodes of agitation and aggression may diminish

Treatment Guidelines • Rule out psychological and psychosocial causes for change in

behavior• Elimination of causative factors and psychosocial intervention

are treatments of choice• Medication therapy can be recommended• Hyperactivity syndrome and psychosis: risperidone,

olanzapine, quetiapine, aripiprazole, citalopram, trazodone, and carbamazepine

• Valproic acid and lithium should be avoided: lack of evidence

World Federation of Societies of Biological Psychiatry 2011

Non-Pharmacological Treatment • Treatment of choice• Recognizing, redirecting, and diffusing the neuropsychiatric

behavior• Intervene early• Stay calm- avoid arguing or trying to reason with the patient • Wondering:• Environmental modifications• Providing activities• Electronic alarms• Safety Plans

Non-Pharmacological Treatment• Sleep disturbances• Strive for consistent bedtimes• Limit daytime napping• Restrict use of alcohol and caffeinated beverages• Reduce light levels, changes in temperature, and nighttime noises• Avoid changes in daily routines

• Other therapies:• Music therapy• Light therapy• Massage therapy• Multisensory Stimulation

PHARMACOLOGICAL TREATMENT

Antipsychotics • Evidence is high to support the use of antipsychotics for BPSD

• Second Generation Antipsychotics• Over 37 trials; risperidone, olanzapine, quetiapine, aripiprazole• Limited to no data: clozapine, ziprasidone, paliperidone,

iloperidone, asenapine, lurasidone• Range: 2 days to 1 year; endpoints were not standardized

Dementia Psychosis Agitation

Aripiprazole ++ + +

Olanzapine + +/- ++

Quetiapine + +/- +/-

Risperidone ++ ++ ++

Past Areas of Concern

Current Medical Realities

SHIFT IN RISK PERCEPTION OF ANTIPSYCHOTICS

SedationWeight

GainInsulin

Resistance

CHD

Hyper-lipidemia

Weight Gain

Diabetes

Prolactin

Insulin Resistance

Sedation

Hyperlipidemia

Coronary HeartDisease

Tardive Dyskinesia

TD

Prolactin

SIDE EFFECTS OF ATYPICAL ANTIPSYCHOTICS

CLOZ = clozapine; RIS = risperidone; OLZ = olanzapine; QUET = quetiapine; ZIP = ziprasidone; ARIP = aripiprazole; Adapted from: Nasrallah HA, Mulvihill T. Ann Clin Psychiatry. 2001(Dec);13(4):215-227

00+++++++++Blood sugar

00 +++++++++Lipids

-/+-/++++++++++++Weight gain

00++++++/-+++Sedation

0+/000/++/++0Tremors, stiffness, endocrine problems

000+/++0+++Dry mouth, constipation

0/+0/++++/0++++Low Blood Pressure

CLOZ RIS OLZ QUE ZIP ARIP

WEIGHT GAIN ATYPICAL ANTIPSYCHOTICS

Data for Package Labels

LIPID ABNORMALITIES

Data from product labels

Drug Weight Gain

Risk for Diabetes

Worsening Lipid Profile

Clozapine (Clozaril) +++ ++ ++

Olanzapine (Zyprexa)

+++ ++ ++

Risperidone (Risperdal)Paliperidone (Invega)

++ +/- +/-

Quetiapine (Seroquel)

++ +/- +

Aripiprazole* (Abilify) +/- - -

Ziprasidone* (Geodon)

+/- - -

ADA/APA CONSENSUS CONFERENCE ON ANTIPSYCHOTIC DRUGS AND OBESITY AND DIABETES SUMMARY

+ = increase effect; - = no effect; D = discrepant results. *Newer drugs with limited long-term data.

ADA/APA CONSENSUS CONFERENCE ON ANTIPSYCHOTIC DRUGS AND OBESITY AND DIABETES SUMMARY

Baseline

4 wk

8 wk

12 wk

Quarterly Annually

Q5yr

Weight X X X X X X

BP X X X

Fasting Glucose

X X X

Waist Circumference

X X

Fasting Lipid

X X X

Antipsychotics• Typical Antipsychotics• 5 clinical trials comparing the efficacy of haloperidol to a SGA• Average haloperidol dose per day: 2-4 mg• No difference in efficacy with haloperidol versus a SGA

Adverse Events- Black Box Warning

WARNINGS: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS and SUICIDALITY AND ANTIDEPRESSANT DRUGS

Black Box Warning: Cerebrovascular Accidents • Cerebrovascular Adverse Events, Including Stroke, in Elderly

Patients with Dementia-Related Psychosis

• In placebo-controlled trials with risperidone, aripiprazole and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse events (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects

Risk Factors for Stroke• Beyond Control• Advancing age, risk

doubles after age 55 years

• Male gender• African-American• Family history of

diabetes• Family history of stroke

or • TIA

• May be altered• • Medical• Hypertension• Atrial fibrillation• Elevated cholesterol• Coronary Heart Disease• Sleep Apnea

• • Lifestyle• Smoking• Obesity• Excessive Alcohol

Source: National Stroke Association

Antidepressants• Mixed studies• Trazodone > haloperidol• Fluoxetine = haloperidol• Sertraline > placebo; agitation• Citalopram- mixed studies• Fluvoxamine + perphenazine > perphenazine alone

• All studies showed similar adverse event profiles; studies were relatively short in duration, lacked randomization, and small number of pts.

Mood Stabilizers• One meta-analysis and 5 RTCs: did not support efficacy of

valproic acid in treating aggression, agitation, or psychosis

• Carbamazepine: one meta-analysis and 3 trials: efficacy in treatment of agitation and aggression compared to placebo; placebo was better tolerated

• Oxcarbazepine: failed trial

• Lamotrigine, gabapentin, topiramate: case reports or case series

Cholinesterase Inhibitors• AChE inhibitors can improve BPSD

• If AChE inhibitors are tapered: Worsening of BPSD symptoms can occur

Memantine• Naturalistic, small, open-labeled studies

• Modest improvement in BPSD and overall good tolerability

General Recommendations• Do not discontinue or change the dose of treatment without

discussion with health care provider

• Reduce/eliminate risk for strokes and diabetes

• What matters most:• Symptom relief• Reduced care giver burden• Increase quality of life• Avoidance of unacceptable risks• Improved functional status• Risk reduction and cost of care

CONCLUSION

Key Concepts• Etiology is unknown• Current pharmacotherapy neither cures or arrests the

pathology• Pharmacotherapy focuses on 3 areas: • Cognition• Behavioral and psychiatric symptoms• Functional ability

• Pharmacotherapy may reduce the total cost of treating AD by delaying cognitive decline and time to nursing home placement