Essentials of Geriatric Psychiatry

8/12/2019 Essentials of Geriatric Psychiatry

1/87

Essentials of Geriatric

Psychopharmacology

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

ProfessorUCLA Semel Institute

2012


2/87

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


3/87

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


4/87

US Population Growth

1940-2010

0

2

4

6

8

10

12

14

1940 1960 1980 1990 2010

>85 Y.O.

>65 Y.O.

%


5/87

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


6/87

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


7/87

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


8/87

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


9/87

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+


10/87

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


11/87

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


12/87

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%


13/87

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.


14/87

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


15/87

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


16/87

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.


17/87

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


18/87


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


19/87


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


20/87

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


21/87

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


22/87

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


23/87

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


24/87

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


25/87

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


26/87


Distribution


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.


Pharmacokinetic Issues in the Elderly: Protein


27/87

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


Ph ki i I i th Eld l


28/87

Pharmacokineic Issues in the Elderly:

Hepatic Metabolism / Clearance


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



29/87


Renal Clearance


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



30/87

Factor Contributing to Individual Variation

in Clearance of Drugs Age

Gender

Ethnicity

Diet Illness

Environment

Smoking

Alcohol

Other drugs

Heredity (extensive or slow metabolizers)


31/87

Neurochemistry of Aging

Stress Toxic factors

Deficiency in essential nutrients

Neuroendocrine disturbances

Autoimmune process

Genetic factors

Trauma

Vascular disorder Neurodegenerative disease


32/87

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


33/87

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


34/87


35/87

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


36/87

Neurochemical Changes in Aging BrainCortex Hippocam Caudate Thalamus

AChE

CAT

M-recept

N-recept

5 HT

NAa/b-recep

DA

MAO-B


37/87

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


38/87

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


Age-Related Changes in the NA


39/87

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


A R l t d Ch i th 5 HT S t


40/87

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



41/87

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.


42/87

Clinical Dilemma

Number of possible drug interactions too large to

memorize

Difficult to determine which interactions are

important Conflicting promotional claims


43/87

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


44/87

Cytochrome P-450 Enzyme

Subtypes

CYP2E1

CYP3A4

CYP2D6

CYP2C

CYP1A2


45/87

CYP3A

High abundance

Present in G.I Tract

High individual variability


46/87


47/87


48/87

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


49/87

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


50/87

When To Worry About Drug Interaction

Narrow therapeutic index of victim

Highly potent inducer or inhibitor


51/87

Coping With Drug Interactions

Anticipation and prevention

Highly potent inducer/inhibitor

Narrow therapeutic index of victim

Victims dependent on one metabolicenzyme/transport protein


52/87

Coping With Drug Interactions

Recognize interaction potential of nondrugs

(herbals)

Keep knowledge base current

Consider interactions whenever the clinicalpicture unexpectedly changes

Psychopharmacologic Therapy


53/87

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.


54/87

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 (?)


55/87

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


56/87

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


57/87

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


58/87

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.


Questions About


59/87

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



60/87


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


61/87

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


62/87

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


63/87

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


64/87

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


65/87


Properties

Receptor Binding PropertiesAgent D1 D2 5-HT2 1 2 H1 M1

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

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

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

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

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

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



66/87


Properties

Side Effect ProfileAgent EPS Prolactin QTc Weight

gain

Abnl

GTT

Lipid

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

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

Risperidone ++ +++ + ++ + ?

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

Quetiapine +/- +/- + ++ ++ ++Ziprasidone + + ++ +/- ? ?

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

Cumulative Annual Incidence


67/87

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


68/87

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


69/87

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


70/87

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:


71/87

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.


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


72/87

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


73/87

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


74/87

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)



75/87


Mood Stabilizers

Lithium

Anticonvulsants

Carbamazepine Oxcarbazepine

Valproic acid

Lamotrigine

Gabapentin (not used in bipolar disorder)

Mood Stabilizers In The Elderly


76/87

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


77/87


Cognitive Enhancers

Cholinesterase Inhibitors

Donepezil

Rivastigmine

Galantamine

NMDA receptor modulator

Memantine

Profile of Anti-Dementia Drugs I


78/87

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


79/87

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


80/87

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


81/87

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


82/87

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:


83/87

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


84/87


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.




85/87

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.


Summary


86/87

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


87/87

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

Documents

Essentials of Geriatric Psychiatry