Download Differentiating Depression, delirium and Dementia

Differentiating Depression,
Delirium and Dementia
Megg Wheeldon RN, BSN, A/GNP-C
Geriatric Educator and Advanced
Practice Nurse
Why Differentiate ?

Depression - most commonly missed diagnosis
in the elderly.
 Delirium - when missed can be fatal
 Dementia - symptoms confused with depression
and delirium
DSM-IV FOR A MAJOR
DEPRESSIVE EPISODE: 1

> 5 symptoms present during the same 2 weeks
 A change from previous functioning
 Functional impairment and/or distress
 Symptoms not due to another cause
DSM-IV. Washington, DC: American Psychiatric Association, 1994
DSM-IV CRITERIA FOR A MAJOR
DEPRESSIVE EPISODE: 2

The total of five symptoms must include:
 Depressed mood and/or
 Loss of interest or pleasure
 Plus…

DSM-IV, Washington DC: American Psychiatric Association,
1994
DSM-IV CRITERIA FOR A MAJOR
DEPRESSIVE EPISODE: 3





Physical Symptoms
Appetite or weight change
Insomnia or hypersomnia
Psychomotor agitation or
psychomotor retardation
Fatigue






Psychological Symptoms
Depressed mood
Loss of interest or pleasure
Feelings of worthlessness or
guilt
Diminished ability to think,
concentrate, or make
decisions
Recurrent thoughts of death
or suicide
DIAGNOSIS OF DEPRESSION
Special Concerns in Older Patients






Recognizing depression may be more difficult in
elderly patients
Depressive symptoms may be incorrectly attributed
simply to aging
Patients may report somatic symptoms rather than
depressed mood
Coexisting physical conditions and medications
complicate diagnosis
Coexisting dementia may complicate diagnosis
If depression is suspected, all relevant symptoms can
be considered related to depression
SELECTED DRUGS ASSOCITED WITH
DEPRESSION





Anticonvulsants
Antihypertensives
Antineoplastic agents
Antiparkinsonian drugs
Antipsychotics





CNS Depressants
Corticosteroids
Digitalis preparation
Histamine (H2)antagonists
Tuberculostatics
RISKS OF NOT TREATING
DEPRESSION IN LATER LIFE

Chronic depression
 Cognitive impairment
 Medical illness
 Poor compliance with medical treatment
 Social dysfunction
 Suicide
TREATMENT OF DEPRESSION IN ELDERLY
PATIENTS WITH ALZHEIMER’S DEMENTIA

20-40% of cognitively impaired elderly persons exhibit
depression or depressive symptoms
 Patients with dementia are more susceptible to
anticholinergic adverse effects on memory and
attention
 Antidepressants with lower anticholinergic activity are
preferable
– Norpramin (Desipramine)
– Wellbutrin (Bupropion)
Trazadone (Desyrel)
PROFILE OF THE IDEAL ANTIDEPRESSANT
Rapid onset
of action
Efficacy
in a range
of disorders
Once0daily
dosing
Ideal
Antidepressant
Cost-effective
Safety in
Overdose
Minimal
Side effects
No drug/food
interactions
THE IMPORTANCE OF
PHARMACOKINETICS IN
DRUG-DRUG INTERACTIONS

The pharmacologic action of a drug may be altered by
the coadministration of a second drug.
 This coadministration may:
– Increase or decrease a known effect
– Create an adverse effect
– Result in a new effect not seen with either drug alone

Use of multiple drugs by the elderly increases the
probability of drug-drug interactions.
RISK FACTORS FOR
DRUG-DRUG INTERACTIONS

Drugs that interfere with the cytochrome P450 system
– Quinidine
– Ketoconazole

Drugs with a low therapeutic index
 Multiple drug regimens
 Patient-specific factors
–
–
–
–
Older age
Substance abuse
Medical illness
Individual factors
Eleanor’s most recent complaint

Tightness in her throat
last night. No SOB or
pain. Thinks her CHF
is acting up.
 SHX: husband has
SDAT, wanders out at
night, yells at her, and
frightens her.
Distinguishing Delirium From Dementia
Delirium
 Marked psychomotor


changes (hyperactive or
hypoactive)
Altered and changing level
of consciousness
Strikingly short attention
span
Dementia
 Psychomotor changes
occur late in the illness
unless depression or
apathy develops
 Consciousness not clouded
until terminal stage
 Attention span not
characteristically reduced
Source: Adapted with permission from Guttman R et al, eds. Diagnosis, Management and Treatment of Dementia: A Practical Guide
for Primary Care Physicians. Chicago, Ill: American Medical Association; 1999.
Distinguishing Delirium From Dementia
Delirium
• Acute illness
• Usually reversible,
often completely
Dementia
• Chronic illness
• Generally irreversible,
often chronically
progressive
Source: Adapted with permission from Guttman R, et al, eds. Diagnosis, Management and Treatment of Dementia: A Practical
Guide for Primary Care Physicians. Chicago, Ill: American Medical Association; 1999.
Possible Contributors to Delirium
 UTI
 Respiratory
infection
 Undiagnosed pain
• Renal insufficiency
• Anemia
• Hypoperfusion states
• Recent surgery
• Sensory impairment
• Cataract, hearing loss
 CHF
 COPD
causing hypoxia
Sources: Lipowski ZJ. JAMA. 1987;258:1789-1792. Lipowski ZJ. Psychiatr Clin North Am. 1992;15:335-346.
Possible Contributors to Delirium
Iatrogenic
 Medications with anticholinergic effects
– Effects may be additive
 Medication
change
 Need to rule out withdrawal syndrome (eg, from
alcohol or short-acting benzodiazepine)
Sources: Lipowski ZJ. JAMA. 1987;258:1789-1792. Lipowski ZJ. Psychiatr Clin North Am. 1992;15:335-346.
Medication with Anticholinergic Effects
• 14 of 25 most commonly prescribed
•
medications in the elderly have detectable
anticholinergic effects
– Many cannot be avoided
– Most have modest effects
However, anticholinergic effects are
cumulative and may be clinically relevant
Source: Tune L et al. Am J Psychiatry. 1992;149:1393-1394.
Medication with Anticholinergic Effects
Commonly prescribed in the elderly

Cimetidine
 Ranitidine
 Prednisolone
 Theophylline
 Warfarin
 Dipyridamole
 Codeine
Source: Tune L et al. Am J Psychiatry. 1992;149:1393-1394.

Nifedipine
 Isosorbide
 Digoxin
 Furosemide
 Triamterene and
hydrochlorothiazide
 Captopril
Psychotropic Medications With
Anticholinergic Effects
 Tricyclic antidepressants
– Amitriptyline
– Doxepin
 Antipsychotics
– Thioridazine
– Chlorpromazine
 Diphenhydramine
– Imipramine
– Clozapine
– Olanzapine
Conventional (Typical) vs Atypical
Antipsychotics
Conventional
Atypical


Introduced in 1950s and 1960s
 Dopamine-receptor blockade
 Examples
– Haloperidol
Introduced in the 1990s
 Dopamine and serotonin
receptor blockade
 Examples
– Thioridazine
– Clozapine
– Chlorpromazine
– Risperidone
– Olanzapine
– Quetiapine
Source: Jeste DV et al. Am J Geriatr Psychiatry. 1999;7:70-76.
Conventional Antipsychotics in Dementia
Meta-Analysis of Controlled Trials



Reviewed 33 controlled studies
No individual study demonstrated efficacy
Modest efficacy demonstrated only when data
combined in meta-analysis
Source: Schneider LS et al. J Am Geriatr Soc. 1990;38:553-563.
Conventional Antipsychotics
Consequences of Acute Side Effects
Side Effect
 Extrapyramidal symptoms: parkinsonism
 Cognitive toxicity: delirium
 Sedation: increased falls

Orthostatic hypotension: increased falls

Anticholinergic Effects: constipation
Source: Tune LE et al. In Davidson M, ed. Psychiatric Clinics of North America. Philadelphia, Pa:
WB Saunders Co; 1991;14:353-373.
Conventional Antipsychotics
Consequences of Acute Side Effects
Side Effect

Anticholinergic effects
Consquences

Constipation, urinary retention, tachycardia, blurred
vision, dry mouth, confusion, delirium
Source: Richelson E. J Clin Psychiatry. 1996;57(suppl 11):4-11.
Atypical Antipsychotics

Clozapine
 Risperidone
 Olanzapine
 Quetiapine
 Others in development
Risperidone in the Elderly


Most prescribed atypical agent
2 double-blind placebo-controlled trials in elderly
patients with dementia (N=969)
 Better side-effect profile than conventional
antipsychotics
 Recommended dosing regimen in dementia
– Starting dose: 0.25 mg to 0.5 mg hs
– Target dose: 0.5 mg to 1.5 mg hs
Sources: Aronson SM. Mental Disorders in the Elderly: New Therapeutic Approaches. 1998;13:150-158. De Deyn PP
et al. Neurology. 1999;53:946-955. Falsetti AE. Am J Health-Syst Pharm. 2000;57:862-870. Jeste DV et al. J Clin
Psychiatry. 1996;57(suppl 3):39-45. IMS NPA data 6/00.
Risperidone in Dementia
Psychosis Subscale—BEHAVE-AD
Mean Improvement
From Baseline*
3.0
2.5
†
2.5
2.2
‡
2.0
1.5
*At end point.
†P=.005 vs placebo.
‡P=.01 vs placebo.
1.6
1.5
1.0
0.5
0.0
Placebo
n=161
0.5 mg
n=146
1.0 mg
n=148
Dose of Risperidone
Source: Katz IR et al. J Clin Psychiatry. 1999;60:107-115.
2.0 mg
n=162
Risperidone in Dementia
Mean Improvement From Baseline*
Mini–Mental State Examination (MMSE)
1.0
†
†
0.5
0.0
-0.5
Placebo
*Least squares mean.
†Not significant vs placebo.
†
0.5 mg
1.0 mg
2.0 mg
Dose of Risperidone
Sources: Katz IR et al. J Clin Psychiatry. 1999;60:107-115. Data on file, Janssen Pharmaceutica.
Quetiapine in the Elderly
151 patients ~65 years of age with psychosis





Multicenter, open-label, 52-week safety study; interim
analysis at week 12
Population: organic psychotic disorders (n=106),
schizophrenia/schizoaffective (n=34), delusional
disorder (n=7), bipolar disorder (n=4)
Quetiapine median dose, 100 mg/d
Improvement noted in BPRS and CGI-S scores
Adverse events: somnolence (32%), dizziness (14%),
postural hypotension (13%), agitation (11%),
constipation (8%)
Source: McManus et al. J Clin Psychiatry. 1999;60:292-298.
Quetiapine in the Elderly

Adverse events
–
–
–
–
–

Somnolence (32%)
Dizziness (14%)
Postural hypotension (13%)
Agitation (11%)
Constipation (8%)
No placebo-controlled studies available yet
Source: McManus DQ et al. J Clin Psychiatry. 1999;60:292-298.
Olanzapine in Dementia
238 patients with Alzheimer’s disease and
psychosis

8-week, double-blind, placebo-controlled trial

Mean dose = 2.4 mg/d (1 to 8 mg/d)

There was no difference in efficacy between olanzapine and
placebo

No differences vs placebo for discontinuation
due to adverse effects
Source: Satterlee WG et al. Psychopharmacol Bull. 1995;31:534.
Olanzapine in Dementia
Study Design

N=206 patients with dementia

Mean age 82.8 years; 61% female

Mean MMSE 6.9/30

6-week multicenter, placebo-controlled study

Randomized to (6 weeks)
– Olanzapine fixed dose (5 mg/d, 10 mg/d, 15 mg/d)
– Placebo
Source: Street J et al. Arch Gen Psychiatry. 2000;57:968-976.
Olanzapine in Dementia
Efficacy Results

Significant improvement in the combined agitation,
delusions, and hallucinations items of the NPI/NH for
5 mg/d and 10 mg/d doses compared to placebo

15 mg/d of olanzapine showed no difference vs placebo
on any measure

Trend for better response at lower dose
Source: Street J et al. Arch Gen Psychiatry. 2000;57:968-976.
Olanzapine in Dementia
Safety Results

EPS rate similar to placebo

Significantly higher incidence of somnolence and gait
disturbance vs placebo

Higher incidence of abnormal gait in olanzapinetreated patients with somnolence vs those without
somnolence

Gait disturbance may be linked to increased falls
Source: Street J et al. Arch Gen Psychiatry. 2000;57:968-976. Rubenstein. Ann Long-Term Care. 2000;8:61-64
Ziprasidone

No studies in elderly patients with dementia
 Efficacy shown in patients with schizophrenia
– Symptoms associated with schizophrenia or schizoaffective
disorder improved

Safety
– Prolonged QTc interval


Potential risk for ventricular arrhythmias/sudden death
Psychopharmacologic Drugs Advisory Committee
recommended approval with caveats
Sources: Reuters Health. July 20, 2000. Available at www.reutershealth.com. Minutes of the meeting of the Psychopharmacologic
Drugs Advisory Committee to the FDA, July 19, 2000. Available at www.fda.gov. Accessed September 20, 2000.
Atypical Antipsychotics
Development of Diabetes
Are independent pathways used?
Increased adiposity
Diabetes
Elevated triglycerides
Abnormal glucose
metabolism
Sources: Wirshing DA et al. Biol Psychiatry. 1998;44:778-783. Meyer JM. Presented at: 38th Annual Meeting of the American College of
Neuropsychopharmacology; December 12-16, 1999; Acapulco, Mexico. Newcomer JW et al. Presented at: 38th Annual Meeting of the American College of
Neuropsychopharmacology; December 12-16, 1999; Acapulco, Mexico. Wilson DR et al. Presented at: 38th Annual Meeting of the American College of
Neuropsychopharmacology; December 12-16, 1999; Acapulco, Mexico.
Atypical Antipsychotic Agents
New Onset Diabetes Risk

Case studies show a correlation between the use of atypical
antipsychotics and diabetes onset, as well as glucose
dysregulation including ketoacidosis in people with diabetes
Clozapine Olanzapine Quetiapine
Hagg et al, 1998
Wirshing et al, 1998
Gatta et al, 1999
Sobel et al, 1999
Iqbal et al, 2000
X
X
Risperidone
X
X
X
X
X
Multiple mechanisms may induce diabetes
Aberrant glucose metabolism
Weight gain
Hypertriglyceridemia
Divalproex: Clinically Attractive for
Behavioral Disturbance in Dementia

Preliminary animal and human data suggest
antiagitation effects

Antiagitation effects often apparent within 1 to 3 weeks

May be effective as monotherapy or combination therapy
– May be effective in agitation nonresponsive to or
worsened by antipsychotics or benzodiazepines
 OBRA Guidelines do not require monitoring forms
Divalproex Sodium
Possible Mechanism of Action





Enhancement of central GABA transmission
Augmentation of 5HT function
Inhibition of limbic kindling
Neuroprotection (Hussini Manji, M.D.)
No Anticholinergic/ Dopaminergic Effects
Summary of Efficacy in
Agitation and Aggression
Data From Trials Using Sodium Valproate or Divalproex Sodium
N
Mellow et al. 1993
4
Design Outcome (No. improved)
Open
Decreased agitation (3)
Sival et al. 1994
23
Chart review
Decreased aggression (6)
Lott et al. 1995
10
Open
Decreased agitation (9)
Horne & Lindley, 1995
1
Open
Decreased agitation (1)
Sandborne et al. 1995
4
Open
Decreased partial agitation (2)
Decreased partial aggression (2)
Narayan et al. 1997
25
Chart review
Decreased agitation (13)
Porsteinsson et al. 1997
12
Open
Decreased aggression (10)
Summary of Efficacy in
Agitation and Aggression (cont.)
Data From Trials Using Valproate
N
Design
Haas et al. 1997
12
Open
Kaskow et al. 1997 10
Open
Kunick et al. 1998
13
Chart review
Decreased agitation (9)
Herrmann. 1998
16
Open
Decreased agitation (8)
Gardner et al. 1998 13
Open
Gupta et al. 1998
Outcome
Decreased aggression (12)
Decreased agitation (5)
Decreased aggression(8)
4
Chart review
Decreased agitation (4)
Goldberg. 1999
22
Chart review
Decreased agitation (16)
Porsteinsson et al. 1999
56
Placebo
controlled
Decreased agitation (38)
Rochester Divalproex Study

N=56 agitated dementia patients in nursing homes
 Randomized, double-blind, placebo-controlled
 Best dose (mean 826 mg/d) vs. placebo for 6 weeks
Target Symptoms
Verbal agitation
Physical agitation
Aggression
Socially inappropriate
%
93
93
93
5
Porsteinsson & Tariot, 2001
Clinical Global Impression
Therapeutic Effect
Marked
Improvement
Unchanged/
Worse
Divalproex (n=28)
40%
32%
Placebo (n=28)
11%
50%
Overall Improvement with Divalproex was 68%
P = 0.07
Porsteinsson AP, et al. Presented at the International Psychogeriatrics
Association annual meeting. August 1999. Vancouver, British Columbia.
Goldberg Study

The Use of Adjunctive Divalproex for Neuroleptic
Unresponsive Behavioral Disturbances in Nursing Home
Residents with Dementia, by Richard Goldberg, MD;
Annals of Long-Term Care,Vol. 7,#2, 2/99

22 residents, unacceptable response to 2 to 4mg of
Risperdal for at least 8 wk.

Divalproex (Depakote®) 375mg - 1500 mg/day, serum
level mean 67.2 g/ml, 6 to 12 wk., Global Rating Scale
Goldberg - Residents receiving
Psychoactive Medications
Med.
# at start
Trazodone
8
Antidepressant
5
Anticonvulsant
2
Lithium
0
Benzodiazepine
4
Neuroleptic (typ.) 0
Atypical
22
# at end
4
4
0
0
1
0
10
Results - Goldberg Study

Divalproex well tolerated  6 pts (27%) much improved; 6 (27%) more
improved; 4 pts (18%) minimally improved; 4 pts
(18%) not improved; 2 pts(9%) worse
 Neuroleptic dose was reduced in 3 of 10 residents
Lorazepam and Divalproex in Nursing
Facilities
Methods
 Retrospective chart review
 Documented dementia and behavioral disturbance
 Improvement defined by reduced frequency of
behavior, and observations recorded by nursing
staff.
Frenchman IB et al. Curr Ther Res Clin Exp 2000;61:621-9.
Lorazepam and Divalproex in
Nursing Facilities

146 patient charts reviewed
 81 patients (55.5%) received lorazepam; 65
patients (44.5%) received divalproex
 37 patients (56.9%) treated with divalproex
showed improvement
 25 patients (30.9%) treated with lorazepam
showed improvement
Frenchman IB et al. Curr Ther Res Clin Exp 2000;61:621-9.
NH Residents: Experiencing Falls
Percent of residents
50%
40%
30%
20%
10%
0%
Lorazepam
Frenchman IB et al. Curr Ther Res Clin Exp 2000;61:621-9.
Divalproex
Residents Experiencing Weight Gain/ Loss
Percent of Residents
60%
50.6%
49.2%
50%
34.6%
40%
30%
23.1%
20%
10%
0%
weight loss
weight gain
Lorazepam
Divalproex
Frenchman IB et al. Curr Ther Res Clin Exp 2000;61:621-9.
Initiating Divalproex

Initiate 125-250 mg q hs or 125 mg BID

Increase by 125-250 mg every 3-7 days or until desired
clinical response

Usual range 375-2000 mg/day
– Usual total level 40-100 g/mL

Divalproex is an enteric-coated formulation to minimize
gastrointestinal side effects

Sprinkle capsules for patients who have difficulty
swallowing pills

Consider Extended Release tablets once stable dosing,
reduces frequency of dosing. 500mg ER now available.
250mg ER available in one month.
Divalproex Sodium
Adverse Effects

Over-dosed patients
– Sedation
– Gait disturbance
– Tremors

Common bothersome
– Alopecia
– Weight gain
– GI distress (less with divalproex)
 Platelets (usually mild)
Grosssman F, Pharmacotherapy. 1998;18:600-606.

Rare
– Hepatotoxicity
– Pancreatitis
Benzodiazepines

Minimal efficacy data

Highly sedating and may increase risk of falls

Further inhibit learning and memory

Paradoxical disinhibition

Commonly used
– Lorazepam
– Oxazepam
Source: Coccaro EF et al. Am J Psychiatry. 1990;147:1640-1645.
Carbamazepine
Dementia-Related Agitation

Three controlled studies
– Two showed efficacy
– One showed no efficacy

Autoinduction of P450 enzymes
 Need for CBC monitoring for hematologic risks
 Blood levels of drug may be irrelevant
 Recommended starting dose in the elderly: 100 to 200
mg given at bedtime
Sources: Chambers CA et al. IRCS Med Sci. 1982;10:505-506. Tariot PN et al. J Am Geriatr Soc. 1994;42:1160-1166.
Tariot PN et al. Am J Psychiatry. 1998;155:54-61. Tariot PN et al. J Clin Psychiatry. 1999;60:684-689.
Antidepressant Agents
 Agitation
in a patient with dementia may be a
“masked depression”
 Carefully selected antidepressant may have a
role
 Caveat: Avoid agents with anticholinergic or
sedating effects
Citalopram
98 patients with moderate AD/SDAT or VD
 Combined double-blind and open-label trial with
placebo and citalopram
 Analysis conducted after 4 weeks of double-blind
treatment
 Citalopram resulted in significant improvement in
emotional bluntness, confusion, irritability, anxiety,
fear/panic, depressed mood, and restlessness
compared to baseline
 Incidence of side effects similar to placebo
Source: Nyth AL et al. Br J Psychiatry. 1990;157:894-901.
Projected Prevalence of AD
4 Million AD Cases Today—
Over 14 Million Projected Within a Generation
16
14.3
14
11.3
12
10
8.7
8
6
4
5.8
6.8
4
2
0
2000
2010
2020
2030
Year
2040
2050
Evans DA et al. Milbank Quarterly. 1990;68:267-289.
Cholinergic Changes in AD

The most prominent neurotransmitter abnormalities are
cholinergic
– Reduced activity of choline acetyltransferase
(synthesis of acetylcholine)1

Reduced number of cholinergic neurons in late AD
(particularly in basal forebrain)2
 Selective loss of nicotinic receptor subtypes in
hippocampus and cortex1,3
1. Bartus RT et al. Science. 1982;217:408-414.
2. Whitehouse PJ et al. Science. 1982;215:1237-1239.
3. Guan ZZ et al. J Neurochem. 2000;74:237-243.
Indications for Evaluation of AD







Difficulty in learning and retaining new information
Difficulty in performing complex tasks
Impaired reasoning ability
Problems with orientation and spatial abilities
Language difficulties
Depression
Behavioral changes
Costa PT et al. 1997. AHCPR Pub. # 19.
Risk Factors for AD

Advanced age
 Genetic factors
– Family history of dementia
– APOE-epsilon4 genotype

Female gender
Small GW et al. JAMA. 1997;278:1363-1371.
Flier JS et al. N Engl J Med. 1991;325:1849-1857.
AD Is Often Misdiagnosed
Patient initially diagnosed
with AD
Patient’s first diagnosis other
than AD
35%
14%
No
72%
Yes
28%
Source: Consumer Health Sciences,
LLC. Alzheimer’s Caregiver Project. 1999.
14%
9%
7%
21%
Dementia (not AD)
Stroke
Depression
No diagnosis
Normal aging
Other
Standard Medical Evaluation of AD
• Patient history and complete physical
examination
• Neurologic evaluation
• Psychologic evaluation
• Laboratory tests
• Brain imaging
Identifying Causes of Dementia:
Laboratory Tests

Complete blood count
 Serum electrolytes (including calcium)
 Liver function tests
 Blood urea nitrogen and creatinine
 Thyroid-stimulating hormone
 Serum vitamin B12 level
Fillit H, Cummings J. Manag Care Interface. 2000;13:51-56.
Geldmacher DS, Whitehouse PJ. Neurology. 1997;48(suppl 6):S2-S9.
Summary of AD Diagnosis

AD can be mistaken for normal aging,
depression, and other conditions
 Early diagnosis and treatment of AD will
benefit both the patient and the caregivers
 The established criteria* provide a high
degree of certainty of diagnosis
* NINCDS/ADRDA criteria.
Current Medications Used to
Treat AD
*Paxil 3%
*Zyprexa 3%
Other
25%
*Zoloft 3%
Vitamin E 3%
*Ativan 4%
*Haldol 6%
Aricept
44%
*Risperdal 9%
*These uses are investigational.
Source: National Disease and Therapeutic Index, 1998.
Current Treatment Summary

Cholinergic agents initially improve and
transiently maintain cognitive abilities in
patients with mild-to-moderate AD
 Cognitive abilities worsen over time,
indicating treatment does not stop (but may
delay) the progression of AD
 New treatments that maintain cognitive ability
and stop the progression of AD are needed
Tacrine (Cognex®)

Half-life of 3–5 hours (variable, affected
by food intake)
 4-times-daily dosing of 10 to 40 mg
(40 to 160 mg/day)
 Metabolized by the cytochrome P450 isoenzyme
CYP1A2
 Associated with hepatotoxicity
(monthly liver testing suggested)
Davis KL, Powchik P. Lancet. 1995;345:625-630.
Crimson ML. Pharmacotherapy 1998;18(2 pt 2):47S-54S.
Tacrine Safety

Adverse gastrointestinal effects (somewhat
alleviated by concomitant food intake)
 Elevated liver transaminase levels (ALT)
– 25%–30% of patients with ALT > 3 times the
upper limit of normal

Monitoring of liver function required
Farlow M et al. JAMA. 1992;268:2523-2529.
Knapp MJ et al. JAMA. 1994;271:985-991.
Donepezil (Aricept®)





The first second-generation cholinesterase inhibitor
Half-life of 70 hours
Once-a-day dosing of 5 to 10 mg
Metabolized by cytochrome P450 isoenzymes
CYP3A and CYP2D6
Higher doses associated with cholinergic side effects,
but generally well tolerated
Bryson HM, Benfield P. Drugs Aging. 1997;10:234-239.
Aricept® package insert.
Donepezil Summary

Donepezil (5* and 10 mg) improves cognition
and global function in patients with
mild-to-moderate AD
 Long-term efficacy is maintained for up
to 38 weeks
 ADL may be partially maintained by donepezil
 Donepezil is generally safe and well tolerated
* In the largest trial, donepezil 5 mg was significantly better
than placebo using the ADAS-cog scale, but scores
worsened from baseline.
Rivastigmine (Exelon®)

Newer second-generation cholinesterase
inhibitor
 Half-life of 1.5 hours
 Dosing (bid) of 3 to 12 mg/day
 Metabolism is almost totally independent
of the hepatic cytochrome P450 system
 Gastrointestinal adverse events are common,
including weight loss
Exelon® package insert.
Rivastigmine Safety (cont)

Rivastigmine was generally safe and
well tolerated
 There was no evidence of hepatotoxicity
 Fewer adverse events were observed with
concomitant food administration versus
administration without food
 In addition to nausea and vomiting,
rivastigmine was associated with significant
weight loss
Exelon [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2000.
Rivastigmine Summary

Rivastigmine (6–12 mg) improves cognition
and global function in patients with
mild-to-moderate AD
 Positive effects on ADL have been observed
in some studies
 Rivastigmine is generally safe and well
tolerated, although cholinergic side effects
occur at high doses
Galantamine (Reminyl®)

Galantamine has a dual mechanism of action
– Competitive inhibition of acetylcholinesterase1
– Allosteric modulation of presynaptic and postsynaptic
nicotinic receptors2

Galantamine improves major aspects of AD
(eg, cognition, behavior, function)1
 Galantamine is generally safe and well tolerated1
1. Tariot PN et al. Neurology. 2000;54:2269-2276.
2. Maelicke A, Albuquerque EX. Eur J Pharmacol. 2000;393:165-170.
Outcome Scales Used in
Galantamine Phase III Trials
Cognition
Cognitive subscales of the Alzheimer’s Disease
Assessment Scale (ADAS-cog)
Global change
Clinician Interview-Based Impression of Change
plus Caregiver Input (CIBIC-plus)
Activities of
daily living
Alzheimer’s Disease Cooperative StudyActivities of Daily Living Inventory (ADCS-ADL)
Disability Assessment for Dementia (DAD)
Behavioral
disturbances
Neuropsychiatric Inventory (NPI)
Comedication

Minimal potential for clinically relevant drug
interactions
– No effect on kinetics of digoxin or warfarin

As with other cholinergics, galantamine should
be used with caution in patients with heart
block or sick sinus syndrome
Do Cholinesterase Inhibitors Treat
More Than Just Symptoms?

Cholinesterase inhibitors are effective for
treating the symptoms of AD
 Even with therapy, the symptoms of AD will
eventually progress
 Cholinergic therapy may slow the progression
of symptoms
 Possible special relevance of nicotinic receptor
modulation
Maelicke A, Albuquerque EX. Eur J Pharmacol. 2000;393:165-170.
Discrimination Between Disease
Modification and Symptomatic Benefit
Withdrawal design
Randomized
phase
Placebo
phase
Active
Disease-modifying
effect
Placebo
Performance
Performance
Randomized
phase
Staggered-start design
Placebo
phase
Active
Placebo
Symptomatic
effect
Symptomatic
effect
Disease-modifying
effect
Time
Time
Leber P. Alzheimer Dis Assoc Disord. 1997;11(suppl 5):S10-S39.
Max

Max comes in for his CPE. Dx are SDAT, HTN,
DM. His wife complains that he has anxiety and
mood changes. He is angry most of the time.
His wife denies he has any psychotic episodes. Pt
is on ACI.
 What would you do?
Treatment

CPE and psych/social exam
 Treat any physical findings
 Add Depakote 125mg at night, increase to
BID if needed.
Mary

85 yr old NH pt with Dx dementia, OP,OA and
Depression. Pt is on Zoloft, ACI, and Ca.
 Nurses complain that she won’t leave her room
and that she is increasingly hostile with care.
 What would you do and what would you
recommend to the nursing staff?
Mary

CPE and psych/social exam - reassess depressive
symptoms
 Evaluate for pain from vertebral fractures.
 Add Fosamax or Miacalcin