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Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012
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Page 1: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

Essentials of Geriatric

Psychopharmacology

Helen Lavretsky, M. D., M. S.

Professor

UCLA Semel Institute

2012

Page 2: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · 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

Page 3: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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

Page 4: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

US Population Growth

1940-2010

0

2

4

6

8

10

12

14

1940 1960 1980 1990 2010

>85 Y.O.

>65 Y.O.

%

Page 5: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

Estimated Number of

U.S. Persons Age 65 and Over

0

10

20

30

40

50

60

70

Millions of

Persons over

65

1900 1920 1940 1960 1980 2000 2020 2030

Year

US Census Bureau, Washington, DC

Page 6: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

Projected USA Demographic

Changes, 2000-2025

-2

-1.5

-1

-0.5

0

0.5

1

1.5

2

30-3

4

35-3

9

40-4

4

45-4

9

50-5

4

55-5

9

60-6

4

65-6

9

70-7

4

75-7

9

80-8

4

85-8

9

Age

Percen

t ch

an

ge

Male

Female

US Census Bureau, Washington, DC

Page 7: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

Projected Increase of

Mentally ill Elderly Population

0

10

20

30

40

50

60

70

Millions

of

Persons

over 65

1980 2020

Year

• By 2030, more than 15

million elderly, mentally

ill Americans¹

• Mentally ill elderly

increasing because of :

– ↑standard of living

– ↑treatment of physical

and mental disorders

– Cohort effect

1. Jeste et al. 1999

Page 8: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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

Page 9: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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+

Page 10: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

Prevalence of Depressive Disorders in

Various Patient Populations

96

3336

33

42

47 45

39

0

5

10

15

20

25

30

35

40

45

50

Disorder

Prev

ale

nce %

*

General Population

Chronically ill

Hospitalized

Geriatric Inpatients

Cancer Outpatients

Cancer Inpatients

Stroke

MI

Parkinson's disease

*Range depends on the study

Page 11: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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

Page 12: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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%

• AD in 80-84 yo-11%; 85-89 yo -21%; 90-94 yo -39%

• ALCOHOL USE 10-20%

• MISUSE OF PRESCRIPTION MEDICATIONS 7%

Page 13: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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.

Page 14: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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

Page 15: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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

Page 16: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

Adverse Drug Reactions (ADRs)

as a Function of Increasing Age

0

10

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.

Page 17: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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

Page 18: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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

Page 19: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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

Page 20: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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

Page 21: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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

– Excretion Field TS 2004, Gurwitz JH 2003, Simon SR 2003

T ½ = 0.693 Vd

Clearance

Page 22: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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

Page 23: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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

Page 24: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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

Page 25: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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

Page 26: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

Pharmacokinetic Issues in the Elderly:

Distribution

Changes Effects Implications

Decreased muscle

mass

Decreased total

body water

Increased total

body 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

Page 27: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

Pharmacokinetic Issues in the Elderly: Protein

Binding Changes Effects Implications

Decreased

albumin

Increased α1-acid

glycoprotein

1. Effects of [free drug] vary

on whether drug is

protein-bound, binds

preferentially to albumin

or α1-acid glycoprotein,

or whether hepatic

clearance is restricted to

unbound drug or not

2. Competition for protein-

binding site by drugs

may cause increases in

[free drug]plasma

1. Predict more

potency/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

problems

3. Increase surveillance

for Aes when new

meds added to

regimen

Adapted from Zubenko 2000 and Salzman 1998

Page 28: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

Pharmacokineic Issues in the Elderly:

Hepatic Metabolism / Clearance

Changes Effects Implications

Decreased liver

volume

Decreased hepatic

blood flow

Decreased

oxidative

metabolism

Decreased N-

demethylation

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, age-

related 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

Page 29: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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-soluble

metabolites

Diuretics and NSAIDs

may further increase

half-life and

S.S.[Li+]plasma

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

Adapted from Zubenko 2000 and Salzman 1998

Page 30: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

Factor Contributing to Individual Variation

in Clearance of Drugs • Age

• Gender

• Ethnicity

• Diet

• Illness

• Environment

• Smoking

• Alcohol

• Other drugs

• Heredity (extensive or slow metabolizers)

Page 31: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

Neurochemistry of Aging

• Stress

• Toxic factors

• Deficiency in essential nutrients

• Neuroendocrine disturbances

• Autoimmune process

• Genetic factors

• Trauma

• Vascular disorder

• Neurodegenerative disease

Page 32: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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

Page 33: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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

Page 34: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012
Page 35: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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

Page 36: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

Neurochemical Changes in Aging Brain Cortex Hippocam Caudate Thalamus

AChE

CAT

M-recept

N-recept

5 HT

NA

a/b-recep

DA

MAO-B

Page 37: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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, subcortical

areas

Striatum

Basal ganglia

Basal ganglia, striatum

Decreased

Decreased

Unchanged

MAOa (-) MAOb (+)

Unchanged

Decreased

Decreased

Zubenko 2000; Salzman 1998

Page 38: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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, increased

Decreased

Decreased

Zubenko 2000; Salzman 1998

Page 39: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

Age-Related Changes in the NA

System

NA Markers Location Findings

Noradrenergic

neurons

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

Page 40: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

Age-Related Changes in the 5-HT System Serotonergic 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

Page 41: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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.

Page 42: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

Clinical Dilemma

• Number of possible drug interactions too large to

memorize

• Difficult to determine which interactions are

important

• Conflicting promotional claims

Page 43: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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

Page 44: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

Cytochrome P-450 Enzyme

Subtypes

CYP2E1

CYP3A4

CYP2D6

CYP2C

CYP1A2

Page 45: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

CYP3A

• High abundance

• Present in G.I Tract

• High individual variability

Page 46: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

Cytochrome P-450:

Enzymes and Selected Substrates

1A2 2C 2D6 3A4

Theophylline

Warfarin

Antipsychotics

Benzodiazepines

Fluvoxamine

Phenytoin

Warfarin

Amitriptyline

Clomipramine

Omeprazole

Codeine

Venlafaxine

Trazodone

Risperidone

Haloperidol

Tamoxifen

Tramadol

β-Blockers

Antihistamines

Calcium channel

Blockers

Carbamazepine

Cisapride

Corticosteroids

Cyclosporine

Fentanyl

Protease

inhibitors

Statins

Triazolo-

benzodiazepine 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

Page 47: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

American Medical Directors

Association “Top 10” Drug

Interactions

• Warfarin with: NSAIDs

Macrolides

Phenytoin

Sulfa Drugs

Quinolones

SSRIs

Page 48: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

Warfarin Metabolism

• S-warfarin CYP2C9 Fluoxetine

Fluvoxamine

(Sertraline)

(Paroxetine)

• R-warfarin CYP1A2 Fluvoxamine

(major pathway) (Fluoxetine)

(Sertraline)

(Paroxetine)

• R-warfarin CYP2C19

(minor pathway) & CYP3A4

Page 49: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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

Page 50: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

When To Worry About Drug Interaction

• Narrow therapeutic index of victim

• Highly potent inducer or inhibitor

Page 51: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

Coping With Drug Interactions

• Anticipation and prevention

– Highly potent inducer/inhibitor

– Narrow therapeutic index of victim

– Victims dependent on one metabolic

enzyme/transport protein

Page 52: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

Coping With Drug Interactions

• Recognize interaction potential of “nondrugs”

(herbals)

• Keep knowledge base current

• Consider interactions whenever the clinical

picture unexpectedly changes

Page 53: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

Psychopharmacologic Therapy Drug 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 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.

Page 54: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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 (?)

Page 55: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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?

Page 56: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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

Page 57: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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

Page 58: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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.

Page 59: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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

Page 60: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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

Page 61: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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

Fluoxetine 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

* Includes patients with dementia.

Page 62: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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

Page 63: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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?

Page 64: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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.

Page 65: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

Newer Antipsychotics: Pharmacologic

Properties

Receptor Binding Properties

Agent D1 D2 5-HT2 α1 α2 H1 M1

Haloperidol +++ ++++ + + - - -

Clozapine ++ ++ ++++ +++ +++ ++++ ++++

Risperidone - +++ ++++ +++ +++ + ?

Olanzapine +++ +++ ++++ +++ - ++++ ++++

Quetiapine + ++ +++ ++++ + ++++ +++

Ziprasidone + +++ ++ ++ - + -

Aripiprazole ++ ++++ ++ - ? + -

Page 66: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

Newer Antipsychotics: Pharmacologic

Properties

Side Effect Profile

Agent EPS Prolactin QTc Weight

gain

Abnl

GTT

Lipid ↑

Haloperidol ++++ ++++ + + + -

Clozapine +/- - +++ ++++ +++ +++

Risperidone ++ +++ + ++ + ?

Olanzapine + + + +++ +++ +++

Quetiapine +/- +/- + ++ ++ ++

Ziprasidone + + ++ +/- ? ?

Aripiprazole +/- - -/+ +/- ? ?

Page 67: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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

Cu

mu

lati

ve I

ncid

en

ce o

f T

D

(% o

f S

ub

jects

)

Older Adults

Younger Adults

Jeste DV et al. Arch Gen Psychiatry. 1995;52:756-765.

Page 68: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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.

Page 69: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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

Page 70: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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, 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

Quetiapine 50-250 mg/d

Olanzapine 5-15 mg/day

5 days 3 months

Page 71: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

Cerebrovascular Adverse Events:

Pooled Analyses for Atypicals

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.

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

Page 72: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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 Gain

Risk for

Diabetes

Worsening

Lipid Profile

Clozapine +++ + +

Olanzapine +++ + +

Risperidone ++ D D

Quetiapine ++ D D

Aripiprazole* +/– ― ―

Ziprasidone* +/– ― ―

Page 73: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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 x

Wt (BMI) x x x x x

Waist

circum x x x

BP x x x

Fasting

glucose x x x

Fasting

lipids x x x x

Consensus Development Conf., Diabetes Care 2004; 27 (2):596-601.

Page 74: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

FDA Advisory for Antipsychotic Drugs Used

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 bipolar

disorder. All antipsychotics may be affected

• Death causes varied – most heart-related (heart failure,

sudden death) or infections (pneumonia)

Page 75: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

Geriatric Psychopharmacology:

Mood Stabilizers

• Lithium

• Anticonvulsants

– Carbamazepine

– Oxcarbazepine

– Valproic acid

– Lamotrigine

– Gabapentin (not used in bipolar disorder)

Page 76: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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

Page 77: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

Geriatric Psychopharmacology:

Cognitive Enhancers

• Cholinesterase Inhibitors

– Donepezil

– Rivastigmine

– Galantamine

• NMDA receptor modulator

– Memantine

Page 78: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

Profile of Anti-Dementia Drugs I

Donepezil

(Aricept®)

Rivastigmine

(Exelon®)

Galantamine

(Reminyl®)

Memantine

(Namenda®)

FDA approved 1996 2000 2001 2003

Chemical

class Piperidine Carbamate Phenanthren

e alkaloid

Cyclic amine

Mechanism of

action AchEI

(reversible)

AchEI/BchEI

(pseudoirrev.)

AchEI

(reversible)

NMDA-receptor

antagonism

Other 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

forms Tablet Capsule, elixir Tablet, elixir Tablet

Page 79: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

Profile of Anti-Dementia Drugs II

Donepezil

(Aricept®)

Rivastigmine

(Exelon®)

Galantamine

(Reminyl®)

Memantine

(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%

Metabolism

(CYP450) 2D6, 3A4 Cholinesterase

mediated

hydrolysis

2D6, 3A4;

Renal (25%)

Nonhepatic

Excretion > 50% urine;

15% feces

97% urine;

<1% feces

95% urine;

5% feces

(>50% urine

unchanged)

Page 80: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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

+ + +

-/+ -/+ -/+ +/++

-/+ -/+ -/+ ++

Page 81: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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

valproate sodium (except aripiprazole,

risperidone, or a high-potency conventional

antipsychotic plus valproate or with

codeine, phenyton or tramadol)

Recommended extra monitoring

Page 82: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

DRUG INTERACTION IN MANAGEMENT OF

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

Antipsychotic

Agents

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

Page 83: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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 -

Page 84: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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.

Page 85: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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.

Page 86: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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.

Page 87: Essentials of Geriatric Psychopharmacology - ctsi.ucla.edu · Essentials of Geriatric Psychopharmacology Helen Lavretsky, M. D., M. S. Professor UCLA Semel Institute 2012

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