essentials of geriatric psychiatry
TRANSCRIPT
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Essentials of Geriatric
Psychopharmacology
Helen Lavretsky, M. D., M. S.
ProfessorUCLA Semel Institute
2012
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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
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Sociodemographic Characteristics
of the Elderly
Population Growth 12.6% of US pop. in 1990 to 12.4% in 2000 to 20% by2030
Oldest-old age group is growing fastest
Gender More women than men
Age is a risk factor for many conditions, acute andchronic, in later life
Function, housing, economic interactions Psychiatric disorders
Dementia
Depression
Delirium
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US Population Growth
1940-2010
0
2
4
6
8
10
12
14
1940 1960 1980 1990 2010
>85 Y.O.
>65 Y.O.
%
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Estimated Number of
U.S. Persons Age 65 and Over
0
10
20
30
40
50
60
70
Millions ofPersons over
65
1900 1920 1940 1960 1980 2000 2020 2030
Year
US Census Bureau, Washington, DC
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Projected USA Demographic
Changes, 2000-2025
-2
-1.5
-1
-0.5
0
0.5
1
1.5
2
30-
34
35-
39
40-44
45-4
9
50-
54
55-
59
60-
64
65-
69
70-
74
75-
79
80-
84
85-
89
Age
Percentchange
Male
Female
US Census Bureau, Washington, DC
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Projected Increase of
Mentally ill Elderly Population
0
10
20
30
40
50
60
70
Millions
ofPersons
over 65
1980 2020
Year
By 2030, more than 15
million elderly, mentally
ill Americans Mentally ill elderly
increasing because of :
standard of living
treatment of physical
and mental disorders
Cohort effect
1. Jeste et al. 1999
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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 ageto 63% of the elderly
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Mental Disorders in Older Persons:
The Silent Epidemic
Alzheimers 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+
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Prevalence of Depressive Disorders in
Various Patient Populations
9
6
3336
33
42
47 45
39
0
510
15
20
25
30
35
40
45
50
Disorder
Prevalence%
*
General Population
Chronically ill
Hospitalized
Geriatric Inpatients
Cancer Outpatients
Cancer Inpatients
Stroke
MIParkinson's disease
*Range depends on the study
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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
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Estimates of Prevalence of Mental
Illness in Older Adults DEPRESSION
MAJOR 1-2 %
CLINICALLY SIGNIFICANT 15%
SUICIDAL BEHAVIOR 0.7-1.2%
SUICIDAL THOUGHTS men 9.6% women 18.7%
ANXIETY d/o 5%
ADin 80-84 yo-11%; 85-89 yo-21%; 90-94 yo-39%
ALCOHOL USE 10-20%
MISUSE OF PRESCRIPTION MEDICATIONS 7%
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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 willincreased by 275% from 4 MLN IN 1970
to 15 mln in 2030
Only 67% increase will occur in those30-44 Y.O.
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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
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Are Older Patients More Sensitive to
Side-effects?
High medical burden
Polypharmacy- 13% of population accountfor 25-39% of prescription cost in the US
Adverse events
High use of psychotropic medications
Changes in pharmacokinetcs and
pharmacodynamics with aging
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Adverse Drug Reactions (ADRs)
as a Function of Increasing Age
010
20
30
40
50
60
1 20-29 40-49 60-69 80+
Age (y)
ADRs per
10,000
Population
Ghose K. Drugs Aging. 1991; 1:25.
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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 medsField TS 2004, Gurwitz JH 2003, Simon SR 2003
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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 alltissues or organ systems
c. Chronological and physiologic age are
poorly correlated
Field TS 2004, Gurwitz JH 2003, Simon SR 2003
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Defining the Problems and Issues of
Medication Use in the Elderly
3. Increasing numbers of medical problems, bothacute and chronic, make patients:
a. Less responsive to treatment
i. Comorbid medical burden is a predictor of poorer
response to acute treatmentii. Fewer choices to use
iii. Even if tolerated, suboptimal response withresidual symptoms and increased functional
impairmentiv. Conditions may be chronic or progressive,
implying a high risk of intercurrent illnesses,interruptions in treatment, and need for review andadjustments
Field TS 2004, Gurwitz JH 2003, Simon SR 2003
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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 medicationsa. Medication errors
b. Inappropriate drug prescribing
c. Drug-drug interactions: both meds and
OTCd. Medication noncompliance
i. Drug schedule/complexity
ii. Drug interruption
iii. Cost Field TS 2004, Gurwitz JH 2003, Simon SR 2003
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Overview of Basic Pharmacology 1
Pharmacokinetics: What the body does to the
drug.Absorption
Distribution
Metabolism
Phase I
Oxidative pathway
CYP450 isoenzymes: 2D6, 1A2, 3A3/4, 2C19;phenotyping?
Phase II: x group is conjugated with y
Glucoronidation
N-Acetylation
ExcretionField TS 2004, Gurwitz JH 2003, Simon SR 2003
T = 0.693 VdClearance
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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
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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 absorbedand enters bloodstream (ESRD, antiacid use diminishabsorption)
Volume of distribution=effects of dilution or concentration inthe body (adipose tissue/lean body mass)
Metabolism= chemical reduction; hydrolysis; microsomaloxidation (Phase 1); Conjugation (Phase 2) or glucuronidation;sulfate conjugation (liver disease; polypharmacy)
Protein binding(malnutrition, ESRD)= free drug%
Excretion- bile, urine (ESRD;ESLD) ClearanceVolume of blood per unit of time, from which thedrug is removed from systemic circulation by hepatic or renalclearance
Concentration at steady state= dosing rate/clearance
Half-life=(0.693 x volume of distribution)/clearnace
Ph i l i l Ch ith A i d
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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-1glycoprotein
Increased / decreased
free drug % in plasma
Kidney Decreased glomerular
filtration rate
Decreased renal
clearance
Muscle Decreased lean body massand increased adipose tissue
Increased Vd,increased T 1/2
Liver Decreased liver size and
hepatic blood decreased
CYP450 activity
Decreased hepatic
clearance
Ph ki i I i h Eld l
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Pharmacokinetic Issues in the Elderly:
Absorption
Changes Effects Implications
Decreased swallowing
Increased gastric pH
Decreased gastric
emptying
Decreased intestinalmotility
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
Ph ki ti I i th Eld l
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Pharmacokinetic Issues in the Elderly:
Distribution
Changes Effects Implications
Decreased muscle
mass
Decreased total
body water
Increased totalbody fat
1. Increased total body fat
leads to increased Vd of
most lipophilic drugs,
resulting in greater half-life
without change in S.S.
[plasma]
2. Effect of decreased total
body H2O in decreasing
half-life of Li+ is offset by
age-associated reduction
in renal Cl
Longer treatment
interval is needed to
reach S.S. [plasma]
of drugs.
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
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Pharmacokinetic Issues in the Elderly: Protein
BindingChanges Effects Implications
Decreasedalbumin
Increased 1-acidglycoprotein
1. Effects of [free drug] varyon whether drug is
protein-bound, binds
preferentially to albumin
or 1-acid glycoprotein,
or whether hepaticclearance is restricted to
unbound drug or not
2. Competition for protein-
binding site by drugs
may cause increases in[free drug]plasma
1. Predict morepotency/toxicity for
neuroleptics; predict
modest decrease in
potency/toxicity for
heterocyclic Ads.2. Greater effects may
occur in malnourished
pts or those with
comorbid medical
problems3. Increase surveillance
for Aes when new
meds added to
regimen
Adapted from Zubenko 2000 and Salzman 1998
Ph ki i I i th Eld l
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Pharmacokineic Issues in the Elderly:
Hepatic Metabolism / Clearance
Changes Effects Implications
Decreased liver
volume
Decreased hepatic
blood flow
Decreasedoxidative
metabolism
Decreased N-
demethylation
Decreased metabolism
results in increased peak
and S.S. plasma levels
Increased ratios of
parent drug todemethylated (active)
metabolites may occur
Age has a modest effect
on biotransformation by
glucoronide, sulfate, oracetyl conjugation
Reductions in CYP450
enzymes may result from
genetic polymorphisms, age-
related diseases, or inhibition
from other meds.
Reduced dosages of drugsmay be needed, especially
upon initiation to avoid peak
concentrations
Proceed with caution when
increasing dosages andadding more meds
Adapted from Zubenko 2000 and Salzman 1998
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Pharmacokinetic Issues in the Elderly:
Renal Clearance
Changes Effects Implications
Decreased
Renal blood flow
Decreased GFR
Decreased renal Cl
leads to longer half-life
and greater S.S.
[plasma] for Li+ and
active H2O-solublemetabolites
Diuretics and NSAIDs
may further increase
half-life andS.S.[Li+]plasma
Evaluate renal function
before initiation of Li= or
other drugs dependent upon
renal excretion.
Common illnesses mayworsen 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
Adapted from Zubenko 2000 and Salzman 1998
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Factor Contributing to Individual Variation
in Clearance of Drugs Age
Gender
Ethnicity
Diet Illness
Environment
Smoking
Alcohol
Other drugs
Heredity (extensive or slow metabolizers)
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Neurochemistry of Aging
Stress Toxic factors
Deficiency in essential nutrients
Neuroendocrine disturbances
Autoimmune process
Genetic factors
Trauma
Vascular disorder Neurodegenerative disease
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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
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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
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Aging and Pharmacodynamics
CNS:sedation, confusion, disorientation, memory
impairment, delirium CV:hypotension, orthostasis, cardiac conduction
abnormalities (arrhythmias, QTc prolongation)
Peripheral anticholinergic effects:constipation, drymouth, blurred vision, urinary retention
Motor effects:EPS, tremor, impaired gait, increasedbody sway, falling
Other:agitation; mood and perceptual disturbances;headache; sexual dysfunction; GI (N/V, anorexia,appetite changes, bowel habits); metabolic,endocrinologic, and electrolyte changes
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Neurochemical Changes in Aging BrainCortex Hippocam Caudate Thalamus
AChE
CAT
M-recept
N-recept
5 HT
NAa/b-recep
DA
MAO-B
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Age-Related Changes in Dopamine System
DA Markers Location Findings
DA neurons
Tyrosine
hydroxylase
MAO
D1
D2
DA transporter
Substantia nigra
Basal ganglia
Caudate nucleus
Cortical, subcorticalareas
Striatum
Basal ganglia
Basal ganglia, striatum
Decreased
Decreased
Unchanged
MAOa(-) MAOb (+)
Unchanged
Decreased
Decreased
Zubenko 2000; Salzman 1998
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Age-Related Changes in the Cholinergic System
Cholinergic
Markers
Location Findings
Cholinergic neurons
Choline uptake
Choline
acetyltransferase
Acetylcholinesterase
M1, M2
G-protein coupling
Nicotinic receptors
Basal forebrain
Brain
Cortex,
hippocampus
CSF
Cortex, thalamus
Basal ganglia
Cortex
Decreased
Decreased
Decreased
Increased
Decreased
M1, decreased
M2, increasedDecreased
Decreased
Zubenko 2000; Salzman 1998
Age-Related Changes in the NA
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Age Related Changes in the NA
System
NA Markers Location Findings
Noradrenergicneurons
Tyrosine hydroxylase
MAO
A2 receptor
B receptors
G-protein coupling
Locus coeruleus
Basal ganglia
Cortical, subcortical
Cortex
Cortex
Animal Cortex
Decreased
Decreased
MAOa unchanged
MAOb increased
Decreased
Unchanged
Decreased
Zubenko 2000; Salzman 1998
A R l t d Ch i th 5 HT S t
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Age-Related Changes in the 5-HT SystemSerotonergic Markers Location Findings
5-HT transporter
Tryptophan
hydroxylase
MAO
5-HT1A receptor
5-HT2A receptor
5-HIAA
Cortex
Selected brain
areas
Cortical,subcortical
Hippocampus
Frontal cortex
Cortex, frontal
CSF
Decreased
Decreased
MAOa, unchanged
MAOb, increased
Increased
Decreased
Decreased
Unchanged or
increased
Zubenko 2000; Salzman 1998
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Adverse Drug Reactions in the
Nursing Home
Psychoactive medications (antipsychotics,
antidepressants, anticonvulsants, and
sedatives/hypnotics) and anticoagulants were
the medications most often associated withpreventable ADRs
Gurwitz JH, et al. Am J Med. 2000;109:87-94.
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Clinical Dilemma
Number of possible drug interactions too large to
memorize
Difficult to determine which interactions are
important Conflicting promotional claims
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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
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Cytochrome P-450 Enzyme
Subtypes
CYP2E1
CYP3A4
CYP2D6
CYP2C
CYP1A2
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CYP3A
High abundance
Present in G.I Tract
High individual variability
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Warfarin Metabolism
S-warfarin CYP2C9 Fluoxetine
Fluvoxamine
(Sertraline)
(Paroxetine)
R-warfarin CYP1A2 Fluvoxamine
(major pathway) (Fluoxetine)
(Sertraline)(Paroxetine)
R-warfarin CYP2C19
(minor pathway) & CYP3A4
Anticholinergic Medications Commonly
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Anticholinergic Medications Commonly
Perscribed in the Elderly
Furosemide
Digoxin
Theophylline
Warfarin
Prednisolone
Triamterene and
hydrochlorothiazine
Nifedipine
Isosorbide
Codeine
Cimetidine
Captopril
Ranitidine
Dipyridamole
Commonly Prescribed in the Elderly
Tune L, et. al. Am J Psychiatry. 1992;149:1393-1394
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When To Worry About Drug Interaction
Narrow therapeutic index of victim
Highly potent inducer or inhibitor
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Coping With Drug Interactions
Anticipation and prevention
Highly potent inducer/inhibitor
Narrow therapeutic index of victim
Victims dependent on one metabolicenzyme/transport protein
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Coping With Drug Interactions
Recognize interaction potential of nondrugs
(herbals)
Keep knowledge base current
Consider interactions whenever the clinicalpicture unexpectedly changes
Psychopharmacologic Therapy
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Psychopharmacologic TherapyDrug Category Target Symptoms
Antipsychotics Psychosis (delusions, hallucinations),
aggression, agitation
Antidepressants Depressive symptoms, anxiety, sleep-
wake cycle disturbances; agitation?
Benzodiazepines Situational anxiety or agitation, sleep
disturbances
Anticonvulsants
(divalproex,
carbamazepine)
Agitation, aggression; impulsivity?
AChEIs and memantinePossibly 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.
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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 (?) Cholinergics (?) Stimulants (?) Melatonin (?)
Cholinergics (?)
Memantine (?)
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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, TCAs, 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? SRIs + opiates?
C
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Concerns About Pharmacologic
Management of Behavioral Problems
Greater adverse
events in elderly
Slower metabolism of
drugs
Risk of falls
Greater risk of
extrapyramidal
symptoms/tardive
dyskinesia (EPS/TD)
Duration of treatment is
unknown
Attempt Monotherapy
Start low, but go slow
Titrate dose until
therapeutic effect is achieved
Continue for weeks to months
Reevaluate
Taper or augment
Reevaluate
Consider alternative agent
If effective If ineffective
G i t i P h h l
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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
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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 at60 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 placeboIM = 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
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Hypnotics/Anxiolytics In The Elderly
Population
Sleep disorders are highly prevalent but not well studiedin the elderly.
Different types of insomnia require different treatments.
Anxiety disorders are the most common psychiatic
disorder in the elderly but few RCTs specifically addressthis 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:
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Geriatric Psychopharmacology:
Antidepressants
SRIs
1stgeneration
2nd
generation Dual (Multi) Action
Venlafaxine (IR,
XR)
Mirtazapine
Duloxetine
Other
Bupropion (IR, SR,XL)
Nefazodone Trazodone
TCAs: 2amines
MAOIs
Isocarboxazid
Phenelzine
Tranylcypromine
Antidepressant Dosages for Depressive
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Disorders in Elderly PatientsTherapeutic 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
Fluoxetine 10-20 10-40 10-20Venlafaxine
(extended release)
37.5-75 75-300 37.5-150
Mirtazapine 7.5-15 15-30 ?
Bupropion 75-150 150-300 75-150
* Includes patients with dementia.
Questions about Antidepressants in
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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 suicidaldepression
Separate analyses for early onset vs. late onset vs.recurrent or chronic depression and subsyndromaldepression
Patients with significant medical comorbidity orconcomitantly taking multiple medications
Limited data on safety in heart disease, liver disease, renaldisease
Very few RCTs in dementia with depression and psychosis
Newer medications (SRIs & Dual action agents) may be bettertolerated because of fewer and different SEs, but do not workfaster
Geriatric Psychopharmacology: 1st
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Geriatric Psychopharmacology: 1 ,
2nd, and 3rdGeneration Antipsychotics
Typical Antipsychotics
Low, medium, high potency agents
Limited use, best avoided
As efficacious but less tolerated, more SEs
Atypical Antipsychotics 2ndgeneration, 3rdgeneration,.
Schizophrenia & Bipolar disorder, not Dementia perse
As efficacious and better tolerated with fewer EPSconcerns, but more expensive and with metabolicderangements
Lower risk for TD, NMS?
Cardiac safety: QTc effects?
Antipsychotic Dosages Recommended
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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
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Newer Antipsychotics: Pharmacologic
Properties
Receptor Binding PropertiesAgent D1 D2 5-HT2 1 2 H1 M1
Haloperidol +++ ++++ + + - - -
Clozapine ++ ++ ++++ +++ +++ ++++ ++++Risperidone - +++ ++++ +++ +++ + ?
Olanzapine +++ +++ ++++ +++ - ++++ ++++
Quetiapine + ++ +++ ++++ + ++++ +++
Ziprasidone + +++ ++ ++ - + -
Aripiprazole ++ ++++ ++ - ? + -
Newer Antipsychotics: Pharmacologic
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Newer Antipsychotics: Pharmacologic
Properties
Side Effect ProfileAgent EPS Prolactin QTc Weight
gain
Abnl
GTT
Lipid
Haloperidol ++++ ++++ + + + -
Clozapine +/- - +++ ++++ +++ +++
Risperidone ++ +++ + ++ + ?
Olanzapine + + + +++ +++ +++
Quetiapine +/- +/- + ++ ++ ++Ziprasidone + + ++ +/- ? ?
Aripiprazole +/- - -/+ +/- ? ?
Cumulative Annual Incidence
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Cumulative Annual Incidence
of TD with Conventional Antipsychotics
60%
52%
26%
10%15%
5%
0
10
20
30
40
50
60
70
0 12 24 36
Months
CumulativeIncidenceofTD
(%o
fSub
jects)
Older Adults
Younger Adults
Jeste DV et al.Arch Gen Psychiatry. 1995;52:756-765.
Adverse Events with Antipsychotic
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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
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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 gainZiprasidone 20-80 mg bid Increased QTc interval
Aripiprazole 5-15 mg qd Blurred vision, headache,
insomnia, nausea
Recommended Uses for Antipsychotic MedicationsDi d Fi t li h i ( ) S d li D ti
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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, Bristol-
Myers 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:
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Cerebrovascular Adverse Events:
Pooled Analyses for Atypicals
NNH (number needed to harm) = 100
Schneider L. Poster presented at: 9th International Conference on Alzheimers Disease andRelated Disorders; July 17-22, 2004; Philadelphia, Pa.
This information concerns a use that has not been approved by the US Food and Drug Administration.
Treated Control Effect PValue
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
ADA/APA Consensus on Antipsychotic
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ADA/APA Consensus on Antipsychotic
Drugs: Metabolic Syndrome
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.
Drug Weight GainRisk for
DiabetesWorseningLipid Profile
Clozapine +++ + +
Olanzapine +++ + +
Risperidone ++ D D
Quetiapine ++ D D
Aripiprazole* +/
Ziprasidone* +/
Screening and Monitoring for Psychiatric
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Patients at Risk for Metabolic ChangesBaseline 4 wks 8 wks 12 wks 3 mos Annual q5yrs
Personal/family
history
x x
Wt (BMI) x x x x x
Waist
circum x x x
BP x x x
Fasting
glucosex x x
Fasting
lipidsx x x x
Consensus Development Conf., Diabetes Care 2004; 27 (2):596-601.
FDA Advisory for Antipsychotic Drugs Used
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for Treatment of Behavioral Disorders in
Elderly Patients (April 11, 2005)
Clinical studies of atypical antipsychotic drugs used off-label 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 bipolardisorder. All antipsychotics may be affected
Death causes variedmost heart-related (heart failure,
sudden death) or infections (pneumonia)
Geriatric Psychopharmacology:
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Geriatric Psychopharmacology:
Mood Stabilizers
Lithium
Anticonvulsants
Carbamazepine Oxcarbazepine
Valproic acid
Lamotrigine
Gabapentin (not used in bipolar disorder)
Mood Stabilizers In The Elderly
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Mood Stabilizers In The Elderly
Side-Effects
Agent GI CNS Motor Skin Other
Lithium ++ +++ +/++ +/++ Renal
thyroid
Valproic Acid ++ ++ +/++ + liver
Carbamazepine + ++/++
+
+/++ +/- Na, liver
Oxcarbazepine +/- + + Na
Lamotrigine +/- + +/- +++ liver
Gabapentin +/- ++ ++
Topiramate - ++ + liver
G i t i P h h l
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Geriatric Psychopharmacology:
Cognitive Enhancers
Cholinesterase Inhibitors
Donepezil
Rivastigmine
Galantamine
NMDA receptor modulator
Memantine
Profile of Anti-Dementia Drugs I
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Donepezil
(Aricept)
Rivastigmine
(Exelon)
Galantamine
(Reminyl)
Memantine
(Namenda)
FDA approved 1996 2000 2001 2003
Chemical
classPiperidine Carbamate Phenanthren
e alkaloid
Cyclic amine
Mechanism of
actionAchEI
(reversible)
AchEI/BchEI
(pseudoirrev.)
AchEI
(reversible)
NMDA-receptor
antagonismOther actions Nicotinic
modulator?
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
Available
formsTablet Capsule, elixir Tablet, elixir Tablet
Profile of Anti-Dementia Drugs II
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Donepezil
(Aricept)
Rivastigmine
(Exelon)
Galantamine
(Reminyl)
Memantine
(Namenda)
Absorptionaffected 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%
Metabolism
(CYP450)2D6, 3A4 Cholinesterase
mediated
hydrolysis
2D6, 3A4;
Renal (25%)
Nonhepatic
Excretion > 50% urine;
15% feces
97% urine;
50% urine
unchanged)
Common Side-Effects of Anti-Dementia
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DrugsAdverse
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
C
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Combined TherapiesCombination Caution
Clozapine + Carbamazepine Contraindicated
Ziprasidone (Geodon Pfizer) + tricyclic
antidepressant
Contraindicated
Low-potency conventional antipsychotic +
fluoxetine
Contraindicated
Antidepressants + antipsychotics Recommend caution with selectiveserotonin 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
valproate sodium (except aripiprazole,
risperidone, or a high-potency conventional
antipsychotic plus valproate or with
codeine, phenyton or tramadol)
Recommended extra monitoring
DRUG INTERACTION IN MANAGEMENT OF
BEHAVIORAL DISTURBANCES
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BEHAVIORAL DISTURBANCES
Other Agents Carbamazepine Gabapentin Lamotrigine Topiramate Valproic
Acid
Selective
Serotonin
Reuptake
Inhibitors
3 0 3 0 2
Tricyclic
Antidepressants 2 0 0 0 2
AntipsychoticAgents
2 0 0 5 3
Cholinesterase
Inhibitors
4 0 0 0 0
Warfarin 1 0 0 0 0
0 No Interaction information is available to date
1 Action is usually needed on the part of the clinician.
2 Action may need to be taken in some cases.
3 An interaction has been reported, but action is usually not necessary.
4 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
Combining MedicationsExtra monitoring for side effects needed when combining a dementia drug with:
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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
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Therapeutic Synergies
Atypical
Antipsychotics
Cholinesterase
Inhibitors
Improvement in Memory and Thinking
Improvement in Psychosis, Apathy,
Anxiety, Depression
Interactive
facilitation
Mutual
Facilitation
Increase Cortical DA Increase Cortical AChEI Action
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
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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
schizophreniaNahas 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
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Basic pharmacologic principles inform psychotropicmanagement in the elderly.
An older person may be more susceptible to drugeffects or adverse reactions based upon a complexinterplay among normal but varying physiologicalchanges of aging, effects of acute and chronicillness, and concurrent use of multiple agents.
Many drugs have not been specifically studied forefficacy or effectiveness in real world elderly,especially the oldest-old, or in all settings andsituations.
Cautious introduction of new agents and frequentassessment for effect, benefit, and tolerance ofdrug is the best approach to avoid poor outcomes.
S t d R di
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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 inpsychotropic 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