Essentials of Geriatric
Psychopharmacology
Helen Lavretsky, M. D., M. S.
Professor
UCLA Semel Institute
2012
Educational Objectives
• To learn about the problems and issues of
medication use and management in the
elderly
• To review pharmacodynamic and
pharmacokinetic considerations relevant to
the use of psychotropics in the older adult
• To review medication management concerns
and controversies in late-life psychiatric
disorders
Sociodemographic Characteristics
of the Elderly
• Population Growth
– 12.6% of US pop. in 1990 to 12.4% in 2000 to 20% by
2030
– Oldest-old age group is growing fastest
• Gender
– More women than men
• Age is a risk factor for many conditions, acute and
chronic, in later life
• Function, housing, economic interactions
• Psychiatric disorders
– Dementia
– Depression
– Delirium
US Population Growth
1940-2010
%
14
12
10
8
>85 Y.O.
>65 Y.O.
6
4
2
0
1940
1960
1980
1990
2010
Estimated Number of
U.S. Persons Age 65 and Over
70
60
50
Millions of 40
Persons over
30
65
20
10
0
1900 1920 1940 1960 1980 2000 2020 2030
Year
US Census Bureau, Washington, DC
Projected USA Demographic
Changes, 2000-2025
2
1
0.5
0
85-89
US Census Bureau, Washington, DC
80-84
Age
75-79
-2
70-74
-1.5
65-69
60-64
55-59
50-54
45-49
40-44
-1
35-39
-0.5
30-34
Percent change
1.5
Male
Female
Projected Increase of
Mentally ill Elderly Population
• By 2030, more than 15
million elderly, mentally
ill Americans¹
• Mentally ill elderly
increasing because of :
70
Millions 60
of
50
Persons
40
over 65
30
20
10
0
1980
2020
Year
1. Jeste et al. 1999
– ↑standard of living
– ↑treatment of physical
and mental disorders
– Cohort effect
Upcoming Crisis in Geriatric
Mental Health
•
•
•
•
•
•
•
Upcoming baby boomers BOOM
Exponential growth in number of older Americans
1900- 3 mln or 4% TO 1997 -34 mln or 13%
In 2011, those born in 1946-1964 will start turning 65
Increasing lifespan to 75
Increasing prevalence of late-onset disorders
Unmet mental health care needs increases with age
to 63% of the elderly
Mental Disorders in Older Persons:
The Silent Epidemic
• Alzheimer‟s and other Memory Disorders
• Depression, Anxiety Disorders, Severe Mental
illness, Alcohol Abuse
• Suicide: Highest Rate: Among Age 75+
• Mental Disorders: 1 in 5 age 65+
Prevalence % *
Prevalence of Depressive Disorders in
Various Patient Populations
50
45
40
35
30
25
20
15
10
5
0
42
33
36
33
9
6
47 45
39
General Population
Chronically ill
Hospitalized
Geriatric Inpatients
Cancer Outpatients
Cancer Inpatients
Stroke
MI
Parkinson's disease
Disorder
*Range depends on the study
Epidemiology of Mental Illness
in Older Adults
•
•
•
•
•
•
•
•
•
•
•
•
DSM-III
Younger adults
MDD
3.9
men
2.7
women
7.9
Bipolar I
1.2
Schizophrenia
1.5
Panic
men
0.7
women
1.9
OCD
2.1
Cognitive disorder
3.4
(mild to severe)
•
•
•
•
•
•
Older adults
0.9
0.6
0.9
0.1
0.2
•
•
•
•
0.04
0.4
0.9
35
Estimates of Prevalence of Mental
Illness in Older Adults
• DEPRESSION
•
•
•
•
MAJOR
CLINICALLY SIGNIFICANT
SUICIDAL BEHAVIOR
SUICIDAL THOUGHTS
• men
• women
1-2 %
15%
0.7-1.2%
9.6%
18.7%
• ANXIETY d/o
5%
• AD
in 80-84 yo-11%; 85-89 yo -21%; 90-94 yo -39%
• ALCOHOL USE
10-20%
• MISUSE OF PRESCRIPTION MEDICATIONS 7%
Projected Prevalence of
Mental Illness in Older
• 10% increase in the next 30 years
• By year 2030 reaching 21.6%
• Number of mentally ill older adults will
increased by 275% from 4 MLN IN 1970
to 15 mln in 2030
• Only 67% increase will occur in those
30-44 Y.O.
Elderly Are More Difficult
to Treat Safely
• Pharmacokinetic changes result in
higher and more variable drug
concentrations
• The elderly often take multiple
medications
• Greater sensitivity exists to a given
drug concentration
• Homeostatic reserve may be impaired
Are Older Patients More Sensitive to
Side-effects?
• High medical burden
• Polypharmacy- 13% of population account
for 25-39% of prescription cost in the US
• Adverse events
• High use of psychotropic medications
• Changes in pharmacokinetcs and
pharmacodynamics with aging
Adverse Drug Reactions (ADRs)
as a Function of Increasing Age
60
50
40
ADRs per
10,000 30
Population
20
10
0
1
20-29
40-49
Age (y)
Ghose K. Drugs Aging. 1991; 1:25.
60-69
80+
Defining the Problems and Issues of
Medication use in the Elderly
1. Increasing numbers of elderly
a. Elderly patients use more medications compared
to younger groups
b. Americans > 65 y.o. fill an average of 13
scripts/yr.
i. 2x the national average
ii. 3x average for individuals < 65 y.o.
c. Number of prescribed meds  with age
d. Non-Rx use also  with age: 2/3 use OTC meds
e. Older Americans
i. Average 6 active medical problems
ii. On average, take 3-4 non psychotropic prescribed meds
Field TS 2004, Gurwitz JH 2003, Simon SR 2003
Defining the Problems and Issues of
Medication use in the Elderly
2. Heterogeneity of population
a. Aging is not synonymous with disease
b. Decrements in physiologic function do not
develop at same rate or extent across all
tissues or organ systems
c. Chronological and physiologic age are
poorly correlated
Field TS 2004, Gurwitz JH 2003, Simon SR 2003
Defining the Problems and Issues of
Medication Use in the Elderly
3. Increasing numbers of medical problems, both
acute and chronic, make patients:
a. Less responsive to treatment
i. Comorbid medical burden is a predictor of poorer
response to acute treatment
ii. Fewer choices to use
iii. Even if tolerated, suboptimal response with
residual symptoms and increased functional
impairment
iv. Conditions may be chronic or progressive,
implying a high risk of intercurrent illnesses,
interruptions in treatment, and need for review and
adjustments
Field TS 2004, Gurwitz JH 2003, Simon SR 2003
Defining the Problems and Issues
b.
Less tolerant to treatment
i. Less physiological reserve
ii. Less functional capacity
iii. Lower threshold
4. Increasing number of medications
a. Medication errors
b. Inappropriate drug prescribing
c. Drug-drug interactions: both meds and
OTC
d. Medication noncompliance
i. Drug schedule/complexity
ii. Drug interruption
iii. Cost
Field TS 2004, Gurwitz JH 2003, Simon SR 2003
Overview of Basic Pharmacology 1
• Pharmacokinetics: What the body does to the
drug.
– Absorption
– Distribution
– Metabolism
• Phase I
T ½ = 0.693 Vd
Clearance
– Oxidative pathway
– CYP450 isoenzymes: 2D6, 1A2, 3A3/4, 2C19;
phenotyping?
• Phase II: “x” group is conjugated with “y”
– Glucoronidation
– N-Acetylation
– Excretion
Field TS 2004, Gurwitz JH 2003, Simon SR 2003
Overview of Basic Pharmacology 2
• Pharmacodynamics: What the drug does to the
body.
• Side-effects
• Toxicity
• Withdrawal reactions
– Changes in aging due to
• Receptor sensitivity
• Receptor availability
Pharmacokinetics of Drugs
• Pharmacokinetics= progress and the time course of drugs as
they are metabolized by the body
• Bioavailability = the amount of medication that is absorbed
and enters bloodstream (ESRD, antiacid use diminish
absorption)
• Volume of distribution=effects of dilution or concentration in
the body (adipose tissue/lean body mass)
• Metabolism= chemical reduction; hydrolysis; microsomal
oxidation (Phase 1); Conjugation (Phase 2) or glucuronidation;
sulfate conjugation (liver disease; polypharmacy)
• Protein binding (malnutrition, ESRD)= free drug%
• Excretion- bile, urine (ESRD;ESLD)
• Clearance – Volume of blood per unit of time, from which the
drug is removed from systemic circulation by hepatic or renal
clearance
• Concentration at steady state= dosing rate/clearance
• Half-life=(0.693 x volume of distribution)/clearnace
Physiological Changes with Aging and
Altered Pharmacokinetics
Organ
system
Change
Pharmacokinetic
Changes
GI
Decreased intestinal and
splanchnic blood flow
Decreased rate of
absorption
Circulation
Decreased plasma albumin
And increased
a-1 glycoprotein
Increased / decreased
free drug % in plasma
Kidney
Decreased glomerular
filtration rate
Decreased renal
clearance
Muscle
Decreased lean body mass
and increased adipose tissue
Increased Vd,
increased T 1/2
Liver
Decreased liver size and
hepatic blood decreased
CYP450 activity
Decreased hepatic
clearance
Pharmacokinetic Issues in the Elderly:
Absorption
Changes
Effects
Implications
Decreased swallowing
Increased gastric pH
Decreased gastric
emptying
Decreased intestinal
motility
Increased transit time
Decreased absorptive
Surface
Decreased mesenteric
blood flow
Rate of absorption is
decreased, effect
worsened by
anticholinergic drugs,
antacids, or
coadministration with food;
bioavailability may be
reduced in some cases
Onset of action is
delayed; clinical
effect is reduced if
absorption is
incomplete.
Factors that reduce
absorption should be
minimized.
Adapted from Zubenko 2000 and Salzman 1998
Pharmacokinetic Issues in the Elderly:
Distribution
Changes
Effects
Implications
Decreased muscle
mass
Decreased total
body water
Increased total
body fat
1.
Longer treatment
interval is needed to
reach S.S. [plasma]
of drugs.
2.
Increased total body fat
leads to increased Vd of
most lipophilic drugs,
resulting in greater half-life
without change in S.S.
[plasma]
Effect of decreased total
body H2O in decreasing
half-life of Li+ is offset by
age-associated reduction
in renal Cl
Single doses of
agents have a
decreased duration
of action due to
redistribution into fat
stores.
Adapted from Zubenko 2000 and Salzman 1998
Pharmacokinetic Issues in the Elderly: Protein
Binding
Changes
Effects
Implications
Decreased
1. Effects of [free drug] vary 1. Predict more
albumin
on whether drug is
potency/toxicity for
protein-bound, binds
neuroleptics; predict
Increased α1-acid
preferentially to albumin
modest decrease in
glycoprotein
or α1-acid glycoprotein,
potency/toxicity for
or whether hepatic
heterocyclic Ads.
clearance is restricted to 2. Greater effects may
unbound drug or not
occur in malnourished
2. Competition for proteinpts or those with
binding site by drugs
comorbid medical
may cause increases in
problems
[free drug]plasma
3. Increase surveillance
for Aes when new
meds added to
regimen
Adapted from Zubenko 2000 and Salzman 1998
Pharmacokineic Issues in the Elderly:
Hepatic Metabolism / Clearance
Changes
Effects
Implications
Decreased liver
volume
Decreased hepatic
blood flow
Decreased
oxidative
metabolism
Decreased Ndemethylation
Decreased metabolism
results in increased peak
and S.S. plasma levels
Increased ratios of
parent drug to
demethylated (active)
metabolites may occur
Age has a modest effect
on biotransformation by
glucoronide, sulfate, or
acetyl conjugation
Reductions in CYP450
enzymes may result from
genetic polymorphisms, agerelated diseases, or inhibition
from other meds.
Reduced dosages of drugs
may be needed, especially
upon initiation to avoid peak
concentrations
Proceed with caution when
increasing dosages and
adding more meds
Adapted from Zubenko 2000 and Salzman 1998
Pharmacokinetic Issues in the Elderly:
Renal Clearance
Changes
Effects
Decreased
Decreased renal Cl
Renal blood flow leads to longer half-life
and greater S.S.
Decreased GFR [plasma] for Li+ and
active H2O-soluble
metabolites
Diuretics and NSAIDs
may further increase
half-life and
S.S.[Li+]plasma
Adapted from Zubenko 2000 and Salzman 1998
Implications
Evaluate renal function
before initiation of Li= or
other drugs dependent upon
renal excretion.
Common illnesses may
worsen renal Cl.
Li+ dosages should be
reduced in elderly.
Toxicity should be monitored
in pts with renal failure who
may retain H2O-soluble
active metabolites
Factor Contributing to Individual Variation
in Clearance of Drugs
•
•
•
•
•
•
•
•
•
•
Age
Gender
Ethnicity
Diet
Illness
Environment
Smoking
Alcohol
Other drugs
Heredity (extensive or slow metabolizers)
Neurochemistry of Aging
•
•
•
•
•
•
•
•
•
Stress
Toxic factors
Deficiency in essential nutrients
Neuroendocrine disturbances
Autoimmune process
Genetic factors
Trauma
Vascular disorder
Neurodegenerative disease
Neurochemical Changes in
Normal Aging Brain
• Pharmacodynamics: drug-receptor interface and
receptor occupancy determine efficacy and AE
• Reduced reserve predisposes to imbalance of
neurotransmitters
• Increased sensitivity to drugs and adverse
effects at a lower plasma concentration
• Anticholinergic drugs cause delirium
• Neuroleptics cause TD/ EPS
Morphologcial Changes in Normal
Aging Brain
• Decreased brain volume
• Decreased number and volume of neurons
• Changes in glia and loss of dendrites and
synapses
• Senile plaques and neurofibrillary tangles
• Granulovascular degeneration
• White matter changes
• More often in neocortex, hippocampus,
amygdala, locus coeruleus, substantia nigra
Aging and Pharmacodynamics
• CNS: sedation, confusion, disorientation, memory
impairment, delirium
• CV: hypotension, orthostasis, cardiac conduction
abnormalities (arrhythmias, QTc prolongation)
• Peripheral anticholinergic effects: constipation, dry
mouth, blurred vision, urinary 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 habits); metabolic,
endocrinologic, and electrolyte changes
Neurochemical Changes in Aging Brain
Cortex
AChE
CAT
M-recept
N-recept
5 HT
NA
a/b-recep
DA
MAO-B
Hippocam
Caudate Thalamus
Age-Related Changes in Dopamine System
DA Markers
Location
Findings
DA neurons
Substantia nigra
Decreased
Tyrosine
hydroxylase
Basal ganglia
Caudate nucleus
Cortical, subcortical
areas
Decreased
Unchanged
MAOa (-) MAOb (+)
MAO
Unchanged
D1
Striatum
Decreased
D2
Basal ganglia
Decreased
DA transporter
Basal ganglia, striatum
Zubenko 2000; Salzman 1998
Age-Related Changes in the Cholinergic System
Cholinergic
Markers
Location
Findings
Cholinergic neurons
Choline uptake
Choline
acetyltransferase
Acetylcholinesterase
M1, M2
Basal forebrain
Brain
Cortex,
hippocampus
CSF
Cortex, thalamus
G-protein coupling
Nicotinic receptors
Basal ganglia
Cortex
Decreased
Decreased
Decreased
Increased
Decreased
M1, decreased
M2, increased
Decreased
Decreased
Zubenko 2000; Salzman 1998
Age-Related Changes in the NA
System
NA Markers
Location
Findings
Noradrenergic
neurons
Locus coeruleus
Decreased
Basal ganglia
Decreased
Tyrosine hydroxylase
MAO
Cortical, subcortical MAOa unchanged
MAOb increased
Cortex
Decreased
A2 receptor
Cortex
Unchanged
Animal Cortex
Decreased
B receptors
G-protein coupling
Zubenko 2000; Salzman 1998
Age-Related Changes in the 5-HT System
Serotonergic Markers
Location
Findings
5-HT transporter
Cortex
Decreased
Tryptophan
hydroxylase
Selected brain
areas
Decreased
MAO
Cortical,
subcortical
5-HT1A receptor
5-HT2A receptor
Hippocampus
Frontal cortex
Cortex, frontal
5-HIAA
CSF
Zubenko 2000; Salzman 1998
MAOa, unchanged
MAOb, increased
Increased
Decreased
Decreased
Unchanged or
increased
Adverse Drug Reactions in the
Nursing Home
• Psychoactive medications (antipsychotics,
antidepressants, anticonvulsants, and
sedatives/hypnotics) and anticoagulants were
the medications most often associated with
preventable ADRs
Gurwitz JH, et al. Am J Med. 2000;109:87-94.
Clinical Dilemma
• Number of possible drug interactions too large to
memorize
• Difficult to determine which interactions are
important
• Conflicting promotional claims
Inhibition of Cytochrome P450 by
Antidepressants Can Cause
Drug Interaction
• >70 distinct P450 enzymes
• Different antidepressants have different
inhibitory effects
• Patterns of inhibition are currently being
researched
• Genetic polymorphism for 2D6 and 2C19,
and 3A4
• Always consider potential drug interaction
Cytochrome P-450 Enzyme
Subtypes
CYP1A2
CYP2E1
CYP2C
CYP2D6
CYP3A4
CYP3A
• High abundance
• Present in G.I Tract
• High individual variability
Cytochrome P-450:
Enzymes and Selected Substrates
1A2
2C
2D6
3A4
Theophylline
Warfarin
Phenytoin
Warfarin
Codeine
Venlafaxine
Antihistamines
Calcium channel
Blockers
Carbamazepine
Cisapride
Corticosteroids
Cyclosporine
Fentanyl
Protease
inhibitors
Statins
Triazolobenzodiazepine
Antipsychotics
Amitriptyline
Benzodiazepines Clomipramine
Fluvoxamine
Omeprazole
Trazodone
Risperidone
Haloperidol
Tamoxifen
Tramadol
β-Blockers
Michaels EL. Pharmacotherapy. 1998;18:84-112. http://medicine.iupui.edu/flockhart/table.htm
Cupp MJ, Tracy TS. Am Fam Physician. 1998;57:107-116
American Medical Directors
Association “Top 10” Drug
Interactions
• Warfarin with:
NSAIDs
Macrolides
Phenytoin
Sulfa Drugs
Quinolones
SSRIs
Warfarin Metabolism
• S-warfarin
CYP2C9
Fluoxetine
Fluvoxamine
(Sertraline)
(Paroxetine)
• R-warfarin
CYP1A2
Fluvoxamine
(Fluoxetine)
(Sertraline)
(Paroxetine)
(major pathway)
• R-warfarin
(minor pathway)
CYP2C19
& CYP3A4
Anticholinergic Medications Commonly
Perscribed in the Elderly
Commonly Prescribed in the Elderly
•
•
•
•
•
•
Furosemide
Digoxin
Theophylline
Warfarin
Prednisolone
Triamterene and
hydrochlorothiazine
•
•
•
•
•
•
•
Tune L, et. al. Am J Psychiatry. 1992;149:1393-1394
Nifedipine
Isosorbide
Codeine
Cimetidine
Captopril
Ranitidine
Dipyridamole
When To Worry About Drug Interaction
• Narrow therapeutic index of victim
• Highly potent inducer or inhibitor
Coping With Drug Interactions
• Anticipation and prevention
– Highly potent inducer/inhibitor
– Narrow therapeutic index of victim
– Victims dependent on one metabolic
enzyme/transport protein
Coping With Drug Interactions
• Recognize interaction potential of “nondrugs”
(herbals)
• Keep knowledge base current
• Consider interactions whenever the clinical
picture unexpectedly changes
Psychopharmacologic Therapy
Drug Category
Target Symptoms
Antipsychotics
Psychosis (delusions, hallucinations),
aggression, agitation
Antidepressants
Depressive symptoms, anxiety, sleepwake cycle disturbances; agitation?
Benzodiazepines
Situational anxiety or agitation, sleep
disturbances
Anticonvulsants
(divalproex,
carbamazepine)
Agitation, aggression; impulsivity?
AChEIs and memantine
Possibly agitation, aggression, apathy,
psychosis, depression, withdrawal
AChEI = acetylcholinesterase inhibitor.
Lavretsky H. Psychiatr Times. Dec 2004;(suppl 1):1-8; Sultzer D, Lavretsky H. In: Kaplan H, Sadock B,
eds. Comprehensive Textbook of Psychiatry. 8th ed. Philadelphia, Pa: Lippincott, Williams and Wilkins;
2005:3728-3733.
This information concerns a use that has not been approved by the US Food and Drug Administration.
Target Behaviors
Agitation/
Aggression
Anxiety
Apathy
Depression
Psychosis
Insomnia
Anorexia
Antipsychotics
Antidepressant
Antidepressant
Antidepressant
Antipsychotics
Antidepressant
Anticonvulsants
Anxiolytics
Cholinergics (?)
Cholinergics
(?)
Cholinergics
(?)
Anxiolytics
Antidepressants
Cholinergics (?) Stimulants (?)
Memantine (?)
Somniforics
Anxiolytics
Memantine (?)
Stimulants (?)
Melatonin (?)
Cholinergics (?)
Memantine (?)
Cholinergics (?)
Toxicity Syndromes In The Elderly
• Antidepressant Withdrawal Syndrome
• Central Anticholinergic Syndrome
– Mad as a hatter, red as a beet, dry as a bone
• Hyperadrenergic Crisis
– MAOI + sympthomimetics, TCA‟s, opiates
• Lithium Intoxication
– Tremors, confusion, myoclonus, seizure, coma
• Long QTc Interval: HR, EKG monitoring
• Neuroleptic Malignant Syndrome
– Same presentation? Value of CPK? Same risk?
• Serotonin Syndrome
– Overlooked? Same Presentation? SRI‟s + opiates?
Concerns About Pharmacologic
Management of Behavioral Problems
• Greater adverse
events in elderly
Attempt Monotherapy
Start low, but go slow
– Slower metabolism of
drugs
Titrate dose until
– Risk of falls
therapeutic effect is achieved
– Greater risk of
extrapyramidal
If ineffective
symptoms/tardive
If effective
dyskinesia (EPS/TD)
Taper or augment
• Duration of treatment is
Reevaluate
unknown
Continue for weeks to months
Reevaluate
Consider alternative agent
Geriatric Psychopharmacology:
Sedative-hypnotics and Anxiolytics
• Benzodiazepines
– Short-acting, high potency
– Long-acting, active metabolites
– Intermediate-acting, no metabolites
• Lorazepam
• Oxazepam
• Temazepam
• Non-benzodiazepines
– Buspirone
– Hypnotics: zolpidem and zaleplon
Benzodiazepines
•
•
•
•
Often used as rescue medication
Adverse events: falls, confusion
Little evidence supporting use or true safety
Lorazepam IM vs olanzapine IM in acute agitation
– Lorazepam 1 mg IM in AD
– Significantly more effective than placebo at
60 minutes (P = .01) and maintained through
2 hours
– Not significantly more effective at 30 minutes
– Effect not consistently maintained at 24 hours
– No significant difference in treatment-emergent
adverse events between lorazepam and placebo
IM = intramuscular.
Meehan KM et al. Neuropsychopharmacology. 2002;26:494-504.
This information concerns a use that has not been approved by the US Food and Drug Administration.
Questions About
Hypnotics/Anxiolytics In The Elderly
Population
• Sleep disorders are highly prevalent but not well studied
in the elderly.
• Different types of insomnia require different treatments.
• Anxiety disorders are the most common psychiatic
disorder in the elderly but few RCTs specifically address
this population
• Long-term use and misuse of BZDs remains a
significant problem in the elderly
– Associated with higher risk for falls, mental confusion,
depression
– Used to treat depression with insomnia, grief
– Long-acting, active metabolite BZDs should not be used
Geriatric Psychopharmacology:
Antidepressants
• SRI‟s
– 1st generation
– 2nd generation
• Dual (Multi) Action
– Venlafaxine (IR,
XR)
– Mirtazapine
– Duloxetine
• Other
– Bupropion (IR, SR,
XL)
– Nefazodone
– Trazodone
• TCA‟s: 2˚amines
• MAOI‟s
– Isocarboxazid
– Phenelzine
– Tranylcypromine
Antidepressant Dosages for Depressive
Disorders in Elderly Patients
Therapeutic dose range
Drug
Starting dose
(mg/day)
Healthy elderly
(mg/day)
Frail elderly*
(mg/day)
Nortriptyline
10-25
Therapeutic level
Lower therapeutic
level
Desipramine
10-25
Therapeutic level
Lower therapeutic
level
Citalopram
10-20
20-40
10-20
Sertraline
25-50
50-150
25-50
Paroxetine
10
10-30
10-20
Escitalopram
5
10-20
5-10
10-20
10-40
10-20
Venlafaxine
(extended release)
37.5-75
75-300
37.5-150
Mirtazapine
7.5-15
15-30
?
Bupropion
75-150
150-300
75-150
Fluoxetine
* Includes patients with dementia.
Questions about Antidepressants in
the Elderly Population
• All are reported to show equal efficacy in late life
depression , however, few studies included
– Patients > 75 y.o. (RCTs in oldest old > 90?)
– Older patients with severe, psychotic and suicidal
depression
– Separate analyses for early onset vs. late onset vs.
recurrent or chronic depression and subsyndromal
depression
– Patients with significant medical comorbidity or
concomitantly taking multiple medications
• Limited data on safety in heart disease, liver disease, renal
disease
• Very few RCTs in dementia with depression and psychosis
• Newer medications (SRIs & Dual action agents) may be better
tolerated because of fewer and different SE‟s, but do not work
faster
Geriatric Psychopharmacology: 1st,
2nd, and 3rd Generation Antipsychotics
• Typical Antipsychotics
– Low, medium, high potency agents
– Limited use, best avoided
– As efficacious but less tolerated, more SE‟s
• Atypical Antipsychotics
– 2nd generation, 3rd generation,….
– Schizophrenia & Bipolar disorder, not Dementia per
se
– As efficacious and better tolerated with fewer EPS
concerns, but more expensive and with metabolic
derangements
– Lower risk for TD, NMS?
– Cardiac safety: QTc effects?
Antipsychotic Dosages Recommended
for Elderly Patients
Therapeutic dose range
Drug
Starting dose
(mg/day)
Healthy
elderly
(mg/day)
Frail elderly*
(mg/day)
Clozapine†
6.25-25
50-400
6.25-50
Risperidone
0.25-0.5
1-3
0.25-1
Olanzapine†
2.5-5
5-20
2.5-5
Quetiapine
25-50
100-750
25-100
Ziprasidone
20-40
40-160
20-80
Aripiprazole
5-10
10-30
5-15
*Includes patients with dementia.
† Higher dose especially in chronic smokers.
Newer Antipsychotics: Pharmacologic
Properties
Receptor Binding Properties
Agent
D1
D2
5-HT2
α1
α2
H1
M1
Haloperidol
+++
++++
+
+
-
-
-
Clozapine
++
Risperidone
Olanzapine +++
Quetiapine
+
Ziprasidone
+
Aripiprazole ++
++
+++
+++
++
+++
++++
++++
++++
++++
+++
++
++
+++
+++
+++
++++
++
-
+++
+++
+
?
++++
+
++++
++++
+
+
++++
?
++++
+++
-
Newer Antipsychotics: Pharmacologic
Properties
Side Effect Profile
Agent
Haloperidol
EPS Prolactin QTc Weight
gain
++++
++++
+
+
Abnl
GTT
+
Lipid ↑
-
Clozapine
+/-
-
+++
++++
+++
+++
Risperidone
Olanzapine
Quetiapine
++
+
+/-
+++
+
+/-
+
+
+
++
+++
++
+
+++
++
?
+++
++
Ziprasidone
Aripiprazole
+
+/-
+
-
++
-/+
+/+/-
?
?
?
?
Cumulative Incidence of TD
(% of Subjects)
Cumulative Annual Incidence
of TD with Conventional Antipsychotics
70
Older Adults
Younger Adults
60
60%
52%
50
40
26%
30
15%
20
10%
5%
10
0
0
12
24
Months
Jeste DV et al. Arch Gen Psychiatry. 1995;52:756-765.
36
Adverse Events with Antipsychotic
Administration
Anticholinergic effects
Cognitive impairment*, delirium*, dry mouth, blurred
vision, constipation*, urinary retention*, tachycardia*,
excerbation of narrow angle glaucoma
Acute extrapyramidal
effects
Rigidity*, bradykinesia*, tremor*, dystonia, akathisia
Tardive movement
disorders
Tardive dyskinesia*, tardive dystonia, tardive akathisia
Cardiovascular effects Hypotension*, tachycardia*, ECG changes
(nonspecific T-wave changes, increased QT interval)
Other adverse effects
Sedation*, falls*, cognitive impairment*, elevated
prolactin level, sexual dysfunction, weight gain,
neuroleptic malignant syndrome, elevated hepatic
enzyme values, jaundice, hyponatremia, seizure, skin
photosensitivity, retinopathy, agranulocytosis, nasal
congestion
* Effects that are particularly common or severe among older patients, even
with treatment at low dosages.
Atypical Antipsychotic Medications for Treating
Agitation in Dementia
Medications
Dosage Range
Adverse Events
Risperidone
0.5-1 mg bid
Constipation,
extrapyramidal symptoms,
insomnia, somnolence
Quetiapine
25 mg bid-400 mg qd
(dosed bid or tid)
Dizziness, headache,
somnolence
Olanzapine
5-15 mg qd
Constipation, dizziness,
dry mouth, somnolence,
weight gain
Ziprasidone
20-80 mg bid
Increased QTc interval
Aripiprazole
5-15 mg qd
Blurred vision, headache,
insomnia, nausea
Recommended Uses for Antipsychotic Medications
Disorder
First-line choice(s) Second-line
Choice(s)
Duration
If
inadequate
response
After
response
Delirium
None
Risperidone 0.75-1.75
mg/day
1 day
1 week
Agitated dementia
(with delusions)
Risperidone (Risperdal,
Janssen) 0.5-2.0 mg/day
Quetiapine (Seroquel,
AstraZeneca 50-150
mg/day; Olanzapine
(Zyprexa, Lily) 5.0-7.6
mg/day
5 days
3 months
Schizophrenia
Risperidone 1.25-3.5
mg/day
Quetiapine 100-300 mg/day;
Olanzapine 7.5-15 mg/day;
Aripiprazole (Abilify, BristolMyers Squibb) 15-30
mg/day
2 weeks
Indefinitely at
lowest
effective dose
Delusional disorder
Risperidone 0.75-2.5
mg/day
Olanzapine 5-10 mg/day
Quetiapine 50-200 mg/day
2 weeks
6 months to
indefinitely at
lowest
effective dose
Psychotic major
depressive disorder
Risperidone 0.75-2.25
mg/day
Olanzapine 5-10 mg/day
Quetiapine 50-200 mg/day
1 week
6 months
Mania with
psychosis
Risperidone 1.25-3.0
mg/day
Olanzapine 5-15 mg/day
5 days
3 months
Cerebrovascular Adverse Events:
Pooled Analyses for Atypicals
Treated
Control
Effect
P Value
Aripiprazole
1/237
2/227
0.45
0.54
Olanzapine
15/1178
2/478
3.04
0.12
Quetiapine
1/355
4/213
0.5
0.05
Risperidone
41/1817
10/1009
2.28
0.02
Ziprasidone
No clinical trials data in dementia patients
NNH (number needed to harm) = 100
Schneider L. Poster presented at: 9th International Conference on Alzheimer‟s Disease and
Related Disorders; July 17-22, 2004; Philadelphia, Pa.
This information concerns a use that has not been approved by the US Food and Drug Administration.
ADA/APA Consensus on Antipsychotic
Drugs: Metabolic Syndrome
Drug
Weight Gain
Clozapine
+++
Olanzapine
+++
Risperidone
++
Quetiapine
++
Aripiprazole*
+/–
Ziprasidone*
+/–
Risk for
Diabetes
+
+
D
D
―
―
Worsening
Lipid Profile
+
+
D
D
―
―
ADA = American Diabetes Association; APA = American Psychiatric Association;
+ = increased effect; – = no effect; D = discrepant results.
*Newer drugs with limited long-term data.
American Diabetes Association et al. Diabetes Care. 2004;27:596-601, also
published in J Clin Psychiatry. 2004;65:267-272.
Screening and Monitoring for Psychiatric
Patients at Risk for Metabolic Changes
Baseline
4 wks
8 wks
12 wks
3 mos Annual q5yrs
Personal/
family
history
x
Wt (BMI)
x
Waist
circum
x
x
x
BP
x
x
x
x
x
x
x
x
x
Fasting
glucose
Fasting
lipids
x
x
x
x
x
x
Consensus Development Conf., Diabetes Care 2004; 27 (2):596-601.
FDA Advisory for Antipsychotic Drugs Used
for Treatment of Behavioral Disorders in
Elderly Patients (April 11, 2005)
• “Clinical studies of „atypical antipsychotic drugs‟ used „offlabel‟ to treat behavioral disorders in elderly patients with
dementia have shown a 1.6-1.7 times higher death rate
associated with their use compared to patients receiving a
placebo.” Absolute risks not reported
• Abilify® (aripiprazole), Zyprexa® (olanzapine), Seroquel®
(quetiapine), Risperdal® (risperidone), Clozaril®
(clozapine), Geodon® (ziprasidone), and Symbyax® –
drugs approved for use in schizophrenia and bipolar
disorder. All antipsychotics may be affected
• Death causes varied – most heart-related (heart failure,
sudden death) or infections (pneumonia)
Geriatric Psychopharmacology:
Mood Stabilizers
• Lithium
• Anticonvulsants
–
–
–
–
–
Carbamazepine
Oxcarbazepine
Valproic acid
Lamotrigine
Gabapentin (not used in bipolar disorder)
Mood Stabilizers In The Elderly
Side-Effects
Agent
GI
CNS
Motor
Skin
Other
Lithium
++
+++
+/++
+/++
Renal
thyroid
Valproic Acid
++
++
+/++
+
liver
Carbamazepine
+
+/++
+/-
Na, liver
Oxcarbazepine
+/-
++/++
+
+
Lamotrigine
+/-
+
+/-
Gabapentin
+/-
++
++
Topiramate
-
++
+
+
Na
+++
liver
liver
Geriatric Psychopharmacology:
Cognitive Enhancers
• Cholinesterase Inhibitors
– Donepezil
– Rivastigmine
– Galantamine
• NMDA receptor modulator
– Memantine
Profile of Anti-Dementia Drugs I
Donepezil
(Aricept®)
FDA approved
Rivastigmine Galantamine Memantine
(Exelon®)
(Reminyl®)
(Namenda®)
1996
2000
2001
2003
Piperidine
Carbamate
Phenanthren
e alkaloid
Cyclic amine
Mechanism of
action
AchEI
(reversible)
AchEI/BchEI
(pseudoirrev.)
AchEI
(reversible)
NMDA-receptor
antagonism
Other actions
Nicotinic
modulator?
Dosing
qAM or qHS
BID
BID
BID
Dosing range
(min-max)
5-10mg/day
3-12mg/day
8-24mg/day
5-20mg/day
Tablet
Capsule, elixir
Tablet, elixir
Tablet
Chemical
class
Available
forms
Nicotinic
modulator
Profile of Anti-Dementia Drugs II
Donepezil
(Aricept®)
Rivastigmine
(Exelon®)
Galantamine Memantine
(Reminyl®)
(Namenda®)
Absorption
affected by food
No
Yes
Yes
No
Time to max.
concentration (hr)
3-5
0.5-2
0.5-2
3-7
Serum half-life
(hr)
50-70
0.5-2
8-10
60-90
Time to s.s.
(days)
14-22
-
2
11
Protein binding
> 90%
40-45%
< 20%
45%
2D6, 3A4
Cholinesterase
mediated
hydrolysis
2D6, 3A4;
Renal (25%)
Nonhepatic
> 50% urine;
15% feces
97% urine;
<1% feces
95% urine;
5% feces
(>50% urine
unchanged)
Metabolism
(CYP450)
Excretion
Common Side-Effects of Anti-Dementia
Drugs
Adverse
Event
Donepezil
(Aricept®)
Rivastigmin
e (Exelon®)
Galantamine
(Reminyle®)
Memantine
(Namenda®)
GI: N/V,
anorexia,
cramps, diarrhea
+++
+++
+++
+/++
(Less nausea,
anorexia)
CV: bradycardia,
syncope
+/++
+/++
+/++
(↑BP, ↑HR)
Sleep: Insomnia
sedation
bad dreams
+
+
+
++
+/-
+/++
+/-
+/-
+
+
+
?
+
+
+
-/+
-/+
-/+
+/++
-/+
-/+
-/+
++
Np: Depression
Psychosis
Agitation
Special Considerations for
Combined Therapies
Combination
Caution
Clozapine + Carbamazepine
Contraindicated
Ziprasidone (Geodon Pfizer) + tricyclic
antidepressant
Contraindicated
Low-potency conventional antipsychotic +
fluoxetine
Contraindicated
Antidepressants + antipsychotics
Recommend caution with selective
serotonin reuptake inhibitors that are
more potent inhibitors of the CYP
450 enzymes (fluoxetine,
fluvoxamine, paroxetine) and with
nefazodone, TCAs and MAOI
Antipsychotic + lithium, carbamazepine,
lamotrigine (Lamictal, GlaxoSmithKline) or Recommended extra monitoring
valproate sodium (except aripiprazole,
risperidone, or a high-potency conventional
antipsychotic plus valproate or with
codeine, phenyton or tramadol)
DRUG INTERACTION IN MANAGEMENT OF
BEHAVIORAL DISTURBANCES
0
1
2
3
4
No Interaction information is available to date
Action is usually needed on the part of the clinician.
Action may need to be taken in some cases.
An interaction has been reported, but action is usually not necessary.
While no clinical studies are available, an interaction appears likely on the basis of in vitro data or clinical
studies with other drugs. Until further data are available, careful monitoring is warranted.
5 Studies suggest minimal or no interaction
Other Agents
Carbamazepine
Gabapentin
Lamotrigine
Topiramate
Valproic
Acid
Selective
Serotonin
Reuptake
Inhibitors
3
0
3
0
2
2
0
0
0
2
Antipsychotic
Agents
2
0
0
5
3
Cholinesterase
Inhibitors
4
0
0
0
0
Warfarin
1
0
0
0
0
Tricyclic
Antidepressants
Combining Medications
Extra monitoring for side effects needed when combining a dementia drug with:
Antidepressant
Another
Psychotropic
Other Drug
Donepezil
Fluoxetine
Fluvoxamine
MAOI
Nefazodone
Paroxetine
TCA
Carbamazepine
Ketoconazole
Tramadol
Galantamine
Fluoxetine
Fluvoxetine
MAOI
Nefazodone
Paroxetine
TCA
Carbamazepine
Codeine
Ketoconazole
Tramadol
Memantine
MAOI
TCA
Rivastigmine
Nefazodone
TCA
-
Carbamazepine
-
-
Therapeutic Synergies
Improvement in Memory and Thinking
Increase Cortical DA
Atypical
Antipsychotics
Increase Cortical AChEI Action
Interactive
Mutual
facilitation
Facilitation
Cholinesterase
Inhibitors
Improvement in Psychosis, Apathy,
Anxiety, Depression
Enhanced Frontal Inhibitory Control of Limbic Circuits?
Direct Inhibition of DA by AChEI?
DA = dopamine.
This information concerns a use that has not been approved by the US Food and Drug Administration.
Therapeutic Synergies
for Behavioral Disturbances
• Cholinergic deficit and loss of neurons in the limbic system
can be partly corrected by AChEIs
• Stabilization and delay of onset of signs and symptoms in
mild to moderate AD (donepezil and galantamine)
• Rivastigmine showed benefits and reduction in need for
other psychotropic agents in NH patients with severe AD
• All AChEIs improve apathy, depression, and anxiety, and
rivastigmine also improves delusions and hallucinations
• Atypical antipsychotic agents in combination with AChEIs
are likely to further improve negative symptoms (eg,
apathy) and psychosis in patients with AD or
schizophrenia
Nahas Z et al. Neurocase. 2003;9:274-282; Robert P. Curr Med Res Opin. 2002;18:156-171;
van Reekum et al. J Neuropsychiatr Clin Neurosci. 2005;17:7-19.
This information concerns a use that has not been approved by the US Food and Drug Administration.
Summary
• Basic pharmacologic principles inform psychotropic
management in the elderly.
• An older person may be more susceptible to drug
effects or adverse reactions based upon a complex
interplay among normal but varying physiological
changes of aging, effects of acute and chronic
illness, and concurrent use of multiple agents.
• Many drugs have not been specifically studied for
efficacy or effectiveness in “real world” elderly,
especially the oldest-old, or in all settings and
situations.
• Cautious introduction of new agents and frequent
assessment for effect, benefit, and tolerance of
drug is the best approach to avoid poor outcomes.
Suggested Readings
• Pollock BG: Geriatric Psychiatry: Psychopharmacology:
General Principles. In: Saddock BJ, Saddock VA, eds.
Comprehensive Textbook of Psychiatry/VII. Baltimore:
Williams & Wilkins 2000 pp 3086-3090.
• Murphy GM Jr. Application of microarray technology in
psychotropic drug trials. J Psychopharmacol. 2006
Jul;20(4 Suppl):72-8.
• Chew ML, Mulsant BH, Pollock BG, Lehman ME,
Greenspan A, Mahmoud RA, Kirshner MA, Sorisio DA,
Bies RR, Gharabawi G. Anticholinergic activity of 107
medications commonly used by older adults. J Am
Geriatr Soc. 2008 Jul;56(7):1333-41