Overview of Geriatric
Psychopharmacology
Presented by: Ann M. Wheeler, PharmD, BCPP
Date: 4/28/2016
Disclosures and Learning Objectives
• Learning Objectives
–
–
–
Be able to discuss pharmacokinetic and
neurochemical changes with aging
Be able to describe the properties of
cholinesterase inhibitors
Be able to describe treatment principles
of depression and anxiety in the elderly
Disclosures: Dr. Ann Hamer has nothing to disclose.
Adverse Drug Events and the Elderly
• 82% of American adults take at least one medication and 29% take
five or more.
• 700,000 emergency department visits and 120,000 hospitalizations
are due to ADEs annually.
• $3.5 billion is spent on extra medical costs of ADEs annually.
• At least 40% of costs of ambulatory (non-hospital settings) ADEs are
estimated to be preventable.
• Taking multiple drugs for multiple health conditions increases the
risk of ADEs, especially in older adults. Although polypharmacy can
be appropriate in cases of multiple comorbidities, prescribers must
consider older adults' physiologic changes in organ function due to
aging and disease.
www.cdc.gov
ADRs with Increasing Age
Pharmacokinetic Changes with Aging
System
Change
PK Impact
GI
↓ Blood flow
↓Rate of absorption
Circulation
↓ Plasma albumin, ↑ α-1
glycoprotein
↑ / ↓ % of free drug in
circulation
Kidney
↓ GFR
↓ Renal clearance
Muscle
↓ Lean body mass;
↑ Adipose tissue
Increased Vd, t1/2
Liver
↓ Size, blood flow and
enzymatic activity
↓ Hepatic clearance
Absorption
Changes
•
•
•
•
•
•
•
↓ swallowing;
↓ gastric emptying;
↑ gastric pH;
↓ intestinal motility;
↑ transit time;
↓ absorptive surface;
↓ mesenteric blood flow
Effects
↓ Rate of absorption*;
Bioavailability may be altered
*Worsened by anticholinergic drugs, antacids, or co-administration with food
Implications
• Onset of actions is delayed
• Clinical effect is reduced if absorption is incomplete
• Factors that reduce absorption should be minimized
Distribution
Changes
• ↓ muscle mass;
• ↓ total body water;
• ↑ total body fat
Effects
↑ Total body fat leads to increased Vd of most lipophilic
drugs, resulting in ↑ t1/2 without change in s.s.
Effect of decreased total body H2O increasing half-life of
Li+ is offset by age-associated reduction in renal clearance
Implications
• Longer treatment interval is needed to reach s.s.
• Single doses of agents have a decreased duration of
action due to redistribution into fat stores.
Protein Binding
Changes
• ↓ albumin;
• ↑ α-1 glycoprotein
Effects
Effects of [free drug] vary on whether drug is protein-bound,
binds preferentially to albumin or α-1 glycoprotein, or
whether hepatic clearance is restricted to unbound drug or
not.
Competition for protein-binding sites by drugs may cause
increases in [free drug]plasma
Implications
• Potentially more potency/toxicity for neuroleptics
• Greater effects may occur in malnourished pts or those
with comorbid medical conditions
• Increase surveillance for adverse effects when adding
new medications
Hepatic Metabolism/Clearance
Changes
•
•
•
•
↓ Liver volume;
↓ Hepatic blood flow
↓ Oxidative metabolism
↓ N-demethylation
Effects
• ↓ metabolism results in ↑peak and s.s. plasma levels
• Increased ratio of parent drug to demethylated metabolite(s).
• Age has a modest effect on biotransformation by glucuronide,
sulfate or acetyl conjugation.
Implications
• Reductions in CYP450 enzymes may result from genetic
polymorphisms, age-related diseases, or inhibition from other
medications
• Reduced dosages of drugs may be needed (especially upon
initiation). Proceed with caution when increasing dose and
adding additional medications.
Renal Clearance
Changes
• ↓ Decreased renal blood flow;
• ↓ Decreased GFR
Effects
Decreased renal clearance leads to longer t1/2 and greater
steady state plasma levels
Drug interactions from diuretics and NSAIDs may further
increase half-life and steady state levels. (e.g. with Li+)
Implications
• Evaluate renal function before initiation of drugs dependent
upon renal excretion (e.g. Li+)
• Common illnesses may worsen renal Cl
• Reduce doses when necessary
• Toxicity should be monitored in pts with renal failure
Neurochemical Changes in the Aging Brain
•
Reduced reserves predisposes elderly to an imbalance of
neurotransmitters
Cortex
Hippocampus
Caudate
Thalamus
ACh
↔
↔
↔
CAT
↓
↓
↓
5HT
↓
↔
↓
↔
DA
↔
↓
↓
↓
MAO-B
↑
↑
↑
↑
Musc receptors
↓
↓
↔
↑
α-receptors
↔
↔
↑
↑
Zubenko, 2000
Aging and Pharmacodynamics
CNS
Sedation, confusion, disorientation, memory
impairment, delirium
CV
Hypotension, orthostasis, cardiac conduction
abnormalities (arrhythmias, QTc prolongation)
Peripheral anticholinergic Constipation, dry mouth, blurred vision, urinary
effects
retention
Motor effects
EPS, tremor, impaired gait, increased body sway,
falling
Other
Agitation, mood and perceptual disturbances,
headache, sexual dysfunction, GI (N/V, anorexia,
appetite changes, bowel changes), metabolic,
endocrine, electrolyte changes
Anticholinergics and the Elderly
Red as a beet, dry as a bone, blind as a bat, hot
as a hare, mad as a hatter
Anticholinergic
Property
Problem
Dry mouth
Reduces the ability to communicate, predisposes to malnutrition, promotes
mucosal damage, denture misfit or dental caries, and increases the risk of
serious respiratory infection secondary to loss of antimicrobial activity of saliva
Mydriasis
Impairs near vision and may precipitate narrow angle glaucoma in predisposed
patients; could lead to an increased risk of accidents, including falls
Constipation
Fecal impaction
Urinary hesitancy
Urinary retention
↑Heart rate
May precipitate or worsen angina
Thermoregulatory
impairment
May lead to life threatening hyperthermia
Central effects
Sedation, and problems ranging from mild confusion to inability to concentrate to
delirium
Reduces function
Increases dependency
DECREASES QOL
Common Mental Health Disorders in the Elderly
• Dementia
• Depression
• Anxiety
Cholinesterase Inhibitors (CIs)
•
Treatment trials are recommended for patients with mild to
moderate dementia.
•
Choice between available agents can be based on cost, individual
patient tolerance—efficacy appears to be similar.
•
CIs, on average, produce small improvements in measure of
cognition and ADL. Not all patients benefit.
•
•
The cholinergic deficit in AD implies loss of ACh producing (presynaptic)
neurons, and to the extent that the disease affects neurons that are
cholinergically post synaptic, there can be little expectation of effect. Attempts
to augment cholinergic activity may be too far downstream in the
pathophysiology.
In patients with severe dementia, CIs can be tapered off over a 2 to
4 week period, but should be restarted if the patient worsens
without the medication.
Cholinesterase Inhibitors—Effectiveness
Dementia
Effectiveness
Alzheimer’s Disease
Improvement in mild to moderate disease
Vascular Dementia
Improvement in cognition, behavior, and ADLs
Dementia with Lewy
Bodies
Marked improvements in cognition as well as
improvements in behavioral symptoms and
hallucinations
Parkinson’s Disease
Modest benefits; can alleviate visual hallucinations
Frontotemporal Dementia
Data does not support use
Mild Cognitive Impairment Trials do not support use; increased mortality noted
with galatamine
Huntington Disease
No evidence to support use
Cholinesterase Inhibitors
Drug
Dose
Utility
Adverse Effects
Donepezil
5mg QD for 4
weeks;
increase to
10mg QD X3
mos, then may
increase to
23mg
•
•
Little peripheral anti-ACh activity
1.5mg BID with
titration q2
weeks up to
6mg BID
•
Rivastigmine
•
(IR) 4 mg BID,
incr. 4 mg bid
q4wk to 12 mg
bid as
tolerated; Max:
24 mg/day
Diarrhea, nausea, vomiting (20%
of pts)
Others: syncope, rhabdomyolysis,
NMS
•
•
Galantamine
Available in tablet or ODT
Efficacy in mild to moderate
AD
Most data in advanced
disease
•
•
•
•
Available in tablet and
transdermal patch
Efficacy in mild to moderate
AD
More GI side effects than
donepezil
Significant nausea, vomiting,
anorexia, and headaches
Available in IR and XR forms
Efficacy in mild to moderate
AD
More GI side effects than
donepezil
Benefits have been
sustained for up to 36
months
GI sx most common: nausea,
vomiting, diarrhea, anorexia,
weight loss
Give with food to minimize nausea
Neuropsychiatric Symptoms in Dementia
General
Approach
Agitation and other behavioral abnormalities can arise from a variety of underlying causes in patients
with dementia, and identifying the genesis of the abnormal behavior is critical to effective
management. In many patients, behavioral changes herald a new infection or medication toxicity. In
others, agitation is driven by pain, fear, confusion, or poor sleep. As with physical symptoms such as
shortness of breath, no single approach or medication can be expected to treat the symptom of
agitation without regard to the underlying cause.
Precipitating
Factors
Most behavioral changes have precipitants:
Delirium—A concomitant medical illness (particularly urinary tract infection or pneumonia), medication
toxicity (particularly anticholinergic side effects of drugs used to treat sleep disturbance, bladder
incontinence, or other illnesses), and other causes of delirium must be considered whenever new
behavioral disturbances arise, particularly in the setting of an acute worsening in cognition
Others:

Cognitive, language, or memory deficits

Discomfort or pain

Frightening, paranoid delusions

Depression

Sleep disorders
Drugs to
Avoid
Benzodiazepines have limited value in patients with dementia. They are not recommended for the
management of neuropsychiatric symptoms of dementia. Benzodiazepine side effects include
worsening gait, potential paradoxical agitation, and possible physical dependence. Benzodiazepine
use should be limited to brief stressful episodes and those with shorter half-lives are preferred.
Antihistamines are widely used for mild sleep disturbances but are discouraged because of high rates
of side effects, particularly for drugs with anticholinergic effects, such as diphenhydramine.
Anticholinergic drugs should be avoided.
Neuropsychiatric Symptoms in Dementia
Treatment
Approach








Identify precipitating cause
Rule out and treat medical causes. Treat pain, sleep disturbance and depression.
Environmental, behavioral, and other non-pharmacologic therapies can be effective in this
population and, when appropriate, are preferred over medications
Antipsychotic agents have limited efficacy and are associated with increased mortality in
patients with dementia. Low doses of olanzapine or risperidone in patients with severe,
disabling symptoms are preferred over other APs after informing families of the mortality
risk. Short term use when possible, with regular reassessments of risks and benefits, is
advised.
Patients with dementia with Lewy bodies are at especially high risk of severe side effects
with neuroleptic medications.
A trial of selective serotonin reuptake inhibitors (SSRIs) is suggested for the treatment of
depression in Alzheimer disease. Citalopram is often used because of its possible
additional benefits for other neuropsychiatric symptoms; the dose of citalopram should
not exceed 20 mg daily in elderly patients. Sertraline is a well-studied alternative to
citalopram. TCAs should be avoided because of side effects and drug interactions
Sleep disturbances are common in patients with dementia. Non-pharmacologic
strategies, including maintenance of good sleep hygiene, avoidance of daytime naps, and
daily exercise, are generally preferred to pharmacotherapy. Small doses of melatonin or
trazodone can be considered if insomnia is refractory to non-pharmacologic strategies.
Because of the risk of side effects with long-term use, we suggest reserving
benzodiazepines for acute stressful episodes
Common Causes of Delirium
Drugs and
Toxins
Prescription Medications: opioids, sedative/hypnotics, antipsychotics, lithium, skeletal
muscle relaxants, benzodiazepines, anticholinergics, polypharmacy
OTC: antihistamines
Drugs of Abuse: ethanol, heroin, hallucinogens
Withdrawal: ethanol, benzodiazepines
Adverse effects: e.g. hyperammonemia from valproic acid, confusion from quinolones,
serotonin syndrome
Poisons: atypical alcohols (e.g. ethylene glycol), inhaled toxins, plant-derived (e.g. Salvia)
Infections
Sepsis; systemic infections; fever related delirium
Common Causes of Delirium
Metabolic
Derangements
Electrolyte disturbance (elevated or depressed); Endocrine disturbance (depressed or
increased); Hypercarbia; Hyper- or hypoglycemia; Hyper- or hypoosmolar state;
Hypoxemia; Inborn errors of metabolism; Nutritional deficiency
Brain Disorders
CNS Infections: encephalitis, meningitis, brain or epidural abscess
Epileptic seizures
Head injury
Hypertensive encephalopathy
Psychiatric Disorders
System Organ
Failure
Cardiac failure; Hematologic (thrombocytosis, hypereosinophilia, leukemic blast cell crisis,
polycythemia); Liver failure; Pulmonary disease; Renal failure
Physical
Disorders
Burns; Electrocution; Hyperthermia; Hypothermia; Trauma
Omega 3 Fatty Acids
Mixed results—some studies have shown improvement in mild cognitive
decline, while others have not. Likely not effective in patients with
dementia.
Sources:
•
Foods: dark meat fin-fish (tuna, salmon, mackerel, herring, sardines),
algae
•
Supplements: DHA and/or EPA from fish oil or algae. No evidence
showing that different supplements are more or less effective.
•
FDA-Approved Drugs: Lovaza (DHA/EPA), Vascepa (EPA), Epanova
(DHA/EPA) are reliable high-dose sources. No evidence that theses drugs
are more or less likely to be effective than other common sources.
Omega 3 Fatty Acids
Dosing
•
The dose of DHA that is most likely to benefit the mild cognitive impairment
is not known
•
The dose likely falls within 180 to 2000 milligrams (mg) per day. Unknown
whether higher doses provide extra benefit to the brain.
•
Across the many observational studies that have tracked dementia risk with
fish and/or DHA intake, no specific ideal dose has emerged and, the intake
of DHA and EPA in general has been less often linked to brain health than
the intake of fish itself. In clinical trials, DHA supplements of 400 to 2000
milligrams per day have been tested with varying but very limited success at
improving cognitive function in older people, with no specific dose yielding a
greater chance of success.
Omega 3 Fatty Acids
Other uses
•
Anti-inflammatory properties
•
These compounds may improve aspects of health ranging from
cardiovascular disease, risk of death from cancer, age-related macular
degeneration, RA, Crohn’s disease, depression, and ADHD.
Safety
• Long-chain omega-3 fatty acids are well-tolerated and generally recognized
as safe at doses below 3 grams per day.
Depression in the Elderly—Risk Factors
•Changes in physical health
•Presence of a new or chronic physical
disorder (e.g. diabetes), or development of
multiple chronic physical disorders
•Stroke, bypass operation, or hip fracture
•Poor health, physical or functional disability,
and sensory impairment
•Severe and chronic pain
•Changes in circumstances/ social
support
•Income changes, such as retirement or
financial difficulties
•Social changes
•Recent loss of a loved one
•Living alone or social isolation
•Diminished social network
•Changes in mental health
•Prior episode of depression
•Family history of major depression
•Cognitive impairment
•At-risk drinking, alcohol abuse, or illicit
substance abuse
•Medication misuse or abuse
•Side effects of some medications
•Changes in medications or newly
prescribed medications for other disorders
•Changes in circumstances
Depression in the Elderly—Prevalence
•
Depression, particularly
minor depression, is underrecognized and undertreated in the elderly.
•
Prevalence of major
depression doubles over
the age of 80 years.
•
Tends to be higher in
female patients (gender
stereotyping?)
•
AA and Latino older adults
less likely than Caucasians
to receive treatment.
Depressive symptoms can mimic the symptoms
of dementia—its victims withdraw, cannot
concentrate, and appear confused. Some experts
estimate that as many as 10% of those diagnosed
with dementia actually suffer from depression
that, if treated, is reversible.
https://store.samhsa.gov/shin/content/SMA11-4631CD-DVD/SMA11-4631CD-DVD-KeyIssues.pdf
Depression in the Elderly—Impact
•
Depression in the elderly is associated with decreased levels of
functioning, worse health status, and reduced quality of life.
•
Older adults with depression are more disabled with respect to self
care and daily community living skills, compared to older adults
without depression.
•
They also tend to recover more slowly from physical disorders,
such as stroke or hip fractures.
•
Older adults with depression are more likely to die, either because
of worsening of physical disorders or by suicide.
https://store.samhsa.gov/shin/content/SMA11-4631CD-DVD/SMA11-4631CD-DVD-KeyIssues.pdf
Depression in the Elderly—Treatment
• Treatment selection based on:
•
The severity and duration of depression;
•
The older adult’s clinical presentation;
•
The older adult’s prior history of response to treatments;
•
The presence of other health conditions or medications;
•
The tolerability of the treatments with respect to side
effects or required effort; and
•
The older adult’s treatment preferences (including cost).
50 – 80% of older adults who receive appropriate treatment achieve a
reduction in their symptoms of depression.
https://store.samhsa.gov/shin/content/SMA11-4631CD-DVD/SMA11-4631CD-DVD-KeyIssues.pdf
Depression in the Elderly—Treatment
•
No single drug class or ATD has been shown to be more effective
in treating geriatric depression than another.
•
Initial doses should be low but “average” adult doses may be
required to achieve adequate response.
•
SSRIs are generally considered first-line.
•
Most commonly reported adverse events in the elderly are: insomnia, anxiety,
nausea, diarrhea, sexual dysfunction, and headaches.
•
SSRIs may increase the risk of GI bleeding (risk is greatest within the 1st month
of treatment and in patients w/ cirrhosis or liver failure)
•
SSRIs have been linked to SIADH in elderly (monitor Na+)
Depression in the Elderly—Treatment
•
Venlafaxine, duloxetine and mirtazapine—good alternatives.
•
Use caution with venlafaxine in renal failure
•
Use caution with duloxetine in hepatic failure
•
Bupropion is recommended as a second-line agent.
•
TCAs, trazodone and nefazodone are generally not recommended.
•
Lower anticholinergic effects with secondary amines (e.g. nortriptyline,
desipramine) compared to tertiary amines
•
Efficacy may be delayed in the elderly. Medication trials generally
need to be longer.
•
Agents with known drug interactions are less desirable
Depression in the Elderly—Treatment
Drug
Average Dose Range in Elderly
SSRIs
Citalopram
10-20mg
Escitalopram
10-20mg
Fluoxetine
10-30mg
Fluvoxamine
50-150mg
Paroxetine
10-30mg
Sertraline
25-100mg
SNRIs
Desvenlafaxine
50mg
Duloxetine
10-30mg
Venlafaxine
37.5-150mg
Others
Bupropion
100-250mg
Mirtazapine
7.5-10mg
Vilazodone
10-20mg
Anxiety in the Elderly
•
•
Risk Factors
•
Increasing frailty, medical illness, and losses can contribute to feelings of
vulnerability and fear, and can reactivate anxiety disorders.
•
A lack of social supports, a recent traumatic event, medical illnesses and
medications, poor self-rated health, the presence of another psychiatric illness
(particularly another anxiety disorder or depression), an early-onset anxiety
disorder, and female gender are all risk factors for late-life anxiety disorders.
Prevalence
•
Community prevalence rates vary from 3.5 – 10.2% in the geriatric population,
however only 1.3% are diagnosed with anxiety
•
Over 45% of patients in LTC facilities have the diagnosis of depression and
anxiety
•
GAD is the most common anxiety disorder in the elderly
•
Over 90% of individuals with GAD also had at least one other psychiatric
disorder during their lifetime
Anxiety in the Elderly
•
Clinical Course
•
Anxiety and GAD rarely starts in the elderly, rather is a continuation of
symptoms
•
Anxiety disorders in the elderly are associated with:
•
•
Decreased physical activities and functional status
•
Poorer self-perceptions of health
•
Decreased life satisfaction
•
Increased loneliness
•
More severe chronic diseases
Anxiety in elderly men has been associated with an increase in
mortality
Anxiety in the Elderly
•
Anxiety disorders are linked with increased morbidity and mortality
among individuals who have medical illness, and the presence of
medical illness increases the risk of anxiety disorders.
•
Individuals with dementia who have anxiety often show their
emotions indirectly through physical signs (tension, restlessness,
fidgeting, agitation, sleep disturbance, wringing hands) and through
their countenance (anxious or worried appearance).
Anxiety in the Elderly
System
Medical Condition
Cardiovascular
Angina, arrhythmia, MI, mitral valve prolapse, stroke
Endocrine
Diabetes, hypocalcemia, hyperthyroidism,
pheochromocytoma
GI/GU
PUD, pancreatic cancer, UTI
Metabolic
Anemia, hypoglycemia, hyponatremia, hyperkalemia
Pulmonary
COPD, pneumonia, PE, hypoxemia
Neurological
Delirium, dementia, hearing or visual impairment, Parkinson’s
Disease, seizure disorders, brain cancer, strategic strokes
Drugs Associated with Late Life Anxiety: stimulants, sedative/benzo withdrawal,
antidepressants, levodopa, neuroleptics, CCBs, alpha- and beta-blockers, digitalis,
estrogen, thyroid medications, bronchodilators, steroids, theophylline, antihistamines,
pseudoephedrine, analgesics, muscle relaxants, NSAIDs
Anxiety in the Elderly
•
Pharmacologic Treatment
•
SSRIs are considered to be the drugs of choice
•
Drugs with fewer DDIs and favorable PK profiles are preferred (e.g. escitalopram,
sertraline)
•
May take 4 to 6 weeks before effective
•
Efficacy with venlafaxine XR has been shown, however caution should
be used when treating patients with renal insufficiency and
hypertension
•
Duloxetine—not much data
•
TCAs—generally avoided
•
Buspirone has demonstrated efficacy, multiple daily dosing may make
it less desirable in the elderly
Anxiety in the Elderly
•
Benzodiazepines
•
Frequently used (despite significant adverse effects) due to fast onset
•
If used, lorazepam and oxazepam are preferred because of short halflives, no active metabolites, and lack of oxidative metabolism.
•
Problems:
•
•
Cognitive impairment
•
Negative effect on gait
•
Rebound agitation
Elderly patients are more vulnerable to the cognitive and psychomotor
effects of benzodiazepines and eliminate long-acting drugs more
slowly than younger patients, and are predisposed to an increased risk
of falls.
The End
Next Week:
Management of
Agitation in
Dementia