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CLINICAL PHARMACOLOGY

Use of Atypical Antipsychotic Drugs


in Patients with Dementia
CHARLES D. MOTSINGER, CAPT, USAF, MC, GREGORY A. PERRON, CAPT, USAF, MC,
and TIMOTHY J. LACY, LTCOL, USAF, MC, Andrews Air Force Base, Maryland

Increasingly, atypical antipsychotic drugs are prescribed for elderly patients with symp-
toms of psychosis and behavioral disturbances. These symptoms often occur in
patients with Alzheimers disease, other dementias, or Parkinsons disease. As the
average age of Americans increases, the prevalence of Alzheimers disease and Parkin-
sons disease will rise accordingly. Although nonpharmacologic treatments for behav-
ioral disturbances should be tried first, medications often are needed to enable the
patient to be adequately cared for. Current guidelines recommend using risperidone
and olanzapine to treat psychosis in patients with Alzheimers dementia. Quetiapine
and clozapine are recommended for treatment of psychosis in patients with Parkin-
sons disease. Additional research is needed for a recently approved agent, ziprasi-
done. To minimize side effects, these medications should be started at low dosages
that are increased incrementally. Drug interactions, especially those involving the
cytochrome P450 system, must be considered. Clozapines potentially lethal side
effects limit its use in the primary care setting. Informed use of atypical antipsychotic
drugs allows family physicians to greatly improve quality of life in elderly patients
with dementia and behavior disturbances. (Am Fam Physician 2003;67:2335-40. Copy-
right 2003 American Academy of Family Physicians)

M
Richard W. Sloan, ost family physicians are Typical antipsychotic drugs, such as halo-
M.D., R.Ph., coordina- comfortable prescribing peridol (Haldol), traditionally have been used
tor of this series, is
antidepressants, but anti- to control psychotic and behavior distur-
chairman and residency
program director of psychotic medications are bances in elderly patients, but these drugs
the Department of less commonly prescribed have troubling side effects. Extrapyramidal
Family Medicine at and therefore less familiar. Antipsychotic drugs symptoms can cause stiffness, immobility, and
York (Pa.) Hospital and effectively treat psychosis caused by a variety of falls and are associated with significant mor-
clinical associate pro-
conditions (Table 1). Psychotic symptoms are
fessor in family and
community medicine at classified as either positive or negative. Positive
the Milton S. Hershey symptoms include hallucinations, delusions,
Medical Center, Penn- thought disorders (manifested by marked TABLE 1
sylvania State Univer- incoherence, derailment, tangentiality), and Some Causes of Psychotic Symptoms
sity, Hershey, Pa. in Elderly Patients
bizarre or disorganized behavior. Negative
symptoms include anhedonia, flattened affect,
apathy, and social withdrawal.1 Primary psychiatric conditions
Schizophrenia
Psychotic symptoms in elderly patients
Mood disorders with psychotic features
always should be investigated thoroughly, and
Substance abuse or intoxication
underlying medical conditions should be Delirium*
identified and treated. Although a family Dementia*
physician is less likely to manage schizophre- Intracranial lesions
nia in elderly patients, it is quite common for Tumor
family physicians to treat patients who have Stroke
Alzheimers disease and Parkinsons disease. Subdural hematoma

See page 2241 for


These patients frequently have psychotic
definitions of strength- symptoms that are treated without a special- *Syndromes with multiple potential etiologies.
of-evidence levels. ists aid.

JUNE 1, 2003 / VOLUME 67, NUMBER 11 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 2335
bidity. The newer atypical antipsychotic drugs States increases, the use of atypical antipsy-
offer distinct advantages over older agents, chotic drugs is expected to increase substan-
including decreased extrapyramidal symp- tially. The National Institutes of Health esti-
toms and improved efficacy in treatment of mates that there will be 8.5 million Americans
the negative symptoms of psychosis. Family with Alzheimers disease by the year 2030.5
physicians should become familiar with the Psychotic symptoms are present in at least
use of atypical antipsychotic drugs in elderly 25 percent of mildly demented patients with
patients (Table 2). Alzheimers disease and in 50 percent of
Atypical antipsychotic drugs are especially patients with advanced Alzheimers disease.6
useful in treating symptoms associated with Among persons older than 65 years, the inci-
common neuropsychiatric disorders, such as dence of Parkinsons disease is 2 percent.7 Hal-
Alzheimers disease and Parkinsons disease.2-4 lucinations occur in up to 20 percent of
As the number of elderly people in the United patients with Parkinsons disease; delusions,

TABLE 2
Summary of Atypical Antipsychotic Drugs Used in Elderly Patients

Evidence for Evidence for


use in patients use in patients
with Alzheimers with Parkinsons Dosage in Common or Cytochrome Cost per
Drug disease? disease? the elderly major side effects* P450 system month

Clozapine Limited Yes 6.5 to 75 mg Agranulocytosis, hypotension, 1A2 $11 to $132


(Clozaril) per day seizures, sialorrhea, weight 2D6
gain, tachycardia,
hyperthermia, hyperglycemia
Olanzapine Yes No 1.25 to 5 mg Weight gain, hypotension, 1A2 $78 to $184
(Zyprexa) per day seizures, hyperglycemia
Quetiapine No Yes 12.5 to 200 mg Hypotension, headache, 3A4ll $22 to $151
(Seroquel) per day weight gain, cataract
formation
Risperidone Yes No 0.25 to 3 mg Extrapyramidal symptoms, 2D6 $84 to $164
(Risperdal) per day hypotension,
hyperprolactinemia,
insomnia, weight gain
Ziprasidone No No Not studied QT prolongation, rash, 3A4ll N/A
(Geodon) hypertension

N/A = not available.


*All of these medications can cause sedation. All atypical antipsychotic agents can cause hyperglycemia (contributing to type II diabetes
mellitus), although this most often occurs with olanzapine and clozapine.
Estimated cost to the pharmacist based on average wholesale prices in Red book. Montvale, N.J.: Medical Economic Data, 2002. Cost
to the patient will be higher, depending on prescription-filling fee.
1A2 inhibitors: cimetidine (Tagamet), fluoroquinolones, fluvoxamine (Luvox); can increase effects of the antipsychotic agent.
2D6 inhibitors: celecoxib (Celebrex), amiodarone (Cordarone), cimetidine, paroxetine (Paxil), fluoxetine (Prozac); can increase effects of
the antipsychotic agent.
ll 3A4 inhibitors: ciprofloxacin (Cipro), fluoxetine, grapefruit juice, erythromycin, ketoconazole (Nizoral), diltiazem (Cardizem); can
increase effects of the antipsychotic agent. 3A4 enhancer: phenytoin (Dilantin); can enhance metabolism of clozapine and quetiapine.

2336 AMERICAN FAMILY PHYSICIAN www.aafp.org/afp VOLUME 67, NUMBER 11 / JUNE 1, 2003
Atypical Antipsychotic Drugs

paranoia, and subcortical dementia also may


occur.8,9 The pharmacodynamic action of atypical antipsychotic drugs
is attributed to their action on both the serotonergic and
Treatment of Behavior Disturbances
dopaminergic systems.
Initial interventions for behavior distur-
bances should include cognitive, environmen-
tal, and social techniques. Many demented
patients with behavior disturbances will not
need psychotropic medication but can be TABLE 3
managed successfully with nonpharmacologic Appropriate Use of Antipsychotic Agents in the Elderly*
techniques, such as the use of familiar objects,
maintenance of sleep-wake cycles, redirection, Use only one antipsychotic agent at a time.
and frequent reorienting (verbally or by post- Use an antipsychotic drug only if the clinical record documents one of the
ing a calendar in their room). following conditions:
There are many differences of opinion Schizophrenia Schizo-affective disorder
about when medications are indicated. There Delusional disorder Psychotic mood disorders
Acute psychotic episodes Brief reactive psychosis
is even conflicting evidence about the efficacy
Schizophreniform disorder Atypical psychosis
of medications in treating behavior symp-
Tourettes syndrome Huntingtons disease
toms in dementia.10,11 Therefore, decisions to
Organic mental syndromes associated with psychotic or agitated features as
use these medications should be made on a
defined by at least one of the following:
case-by-case basis. Most guidelines call for the Specific behaviors (biting, kicking, scratching), quantitatively documented by
use of medications only when other methods the facility, that cause the resident to present a danger to himself/herself or
have failed. The Health Care Financing others (including staff) or that interfere with the staffs ability to provide care
Administration has produced regulations Continuous crying out, screaming, yelling, or pacing, if these behaviors impair
governing the use of psychotropic medica- functional capacity and if they are quantitatively documented by the facility
tions in nursing homes. Several authors have Psychotic symptoms (hallucinations, paranoia, delusions) not exhibited as
specific behaviors in schizophrenia and schizo-affective disorder, if these
adapted these regulations into clinically use- behaviors impair functional capacity
ful guidelines (Table 3).12,13
Gradual dosage reduction should be attempted every six months after therapy
begins. Gradual dosage reductions should be targeted to the lowest possible
Typical Antipsychotic Agents dosage to control symptoms.
Psychotic symptoms traditionally have been Use of a listed antipsychotic drug should be avoided if one or more of the
treated with so-called typical antipsychotic following behaviors is the only indication for its use:
drugsolder agents such as haloperidol and Wandering Poor self-care
thioridazine (Mellaril). These medications Restlessness Impaired memory
have a variety of pharmacologic actions. Their Anxiety Depression
ability to block the dopamine (D2) receptor in Insomnia Unsociability
the mesolimbic system reduces positive symp- Indifference to surroundings Fidgeting
toms of psychosis. The D2 blockade in the Nervousness Uncooperativeness
Unspecified agitation
nigrostriatal pathway causes extrapyramidal
symptoms, which include drug-induced
*Recommendations are based on standards from the Health Care Financing
parkinsonism, akathisia, acute dystonia, and Administration.
tardive dyskinesia. The D2-receptor blockade
Adapted with permission from Ruby CM, Kennedy DH. Psychopharmacologic
in the tuberoinfundibular pathway increases medication use in nursing home care: indicators for surveyor assessment of the
serum levels of prolactin, which may present performance of drug regimen reviews, recommendation for monitoring, and
clinically as breast tenderness, galactorrhea, or non-pharmacologic alternatives. Clin Fam Pract 2001;3:577-98, with information
erectile dysfunction.1 Younger patients may from reference 13.
present with amenorrhea.

JUNE 1, 2003 / VOLUME 67, NUMBER 11 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 2337
movement disorders in patients with Parkin-
Atypical Antipsychotic Agents sons disease and has been shown to be less
The pharmacodynamic action of atypical effective than clozapine (Clozaril) in control-
antipsychotic drugs is attributed to their ling psychosis in these patients.18-20
action on both the serotonergic and dopamin- Initial dosages of 0.25 mg per day are
ergic systems. Some experts argue that this titrated slowly upward to achieve the desired
combination of relative effects on dopamine effect. In two studies10,17 documenting the effi-
and serotonin allows atypical antipsychotic cacy of risperidone in patients with dementia,
drugs to treat both positive and negative the mean dosages were 1.1 mg per day and
symptoms of psychosis while producing fewer 1.2 mg per day. Risperidone causes extrapyra-
extrapyramidal symptoms and decreasing midal symptoms in a dosage-dependent man-
iatrogenic hyperprolactinemia.14 ner, so the lowest effective dosage is used.
There is growing concern over recent Significant side effects of risperidone include
reports of hyperglycemia in patients who are insomnia, hypotension, weight gain, and
taking certain atypical antipsychotic drugs. extrapyramidal symptoms. Extrapyramidal
The increased rate of hyperglycemia appears to symptoms are more likely when the dosage is
be independent of weight gain. These findings more than 6 mg per day.21 Risperidone is
have led some investigators to recommend metabolized by the cytochrome P450 2D6 sys-
screening for diabetes twice a year in patients tem. Any medication that affects this enzyme
who are taking atypical antipsychotic drugs.15 (e.g., celecoxib [Celebrex], amiodarone [Cor-
darone], cimetidine [Tagamet], fluoxetine
RISPERIDONE [Prozac], paroxetine [Paxil]) can alter the effi-
Risperidone (Risperdal) usage in Alzheimers cacy of risperidone. Risperidone causes a sig-
disease and Parkinsons disease has mixed nificant elevation in prolactin levels. Caution
results. Significant evidence demonstrates the should be used when prescribing risperidone
efficacy of risperidone in the treatment of psy- with other medications that cause hypotension.
chotic and behavior symptoms in patients with
dementia.10,16,17 [References 10 and 17Evi- OLANZAPINE
dence level A, randomized controlled trials Studies indicate that olanzapine (Zyprexa)
(RCTs)] However, risperidone exacerbates is an effective treatment for psychotic and
behavior symptoms in patients with Alz-
heimers disease.22,23 [Reference 22Evidence
level A, RCT] However, in patients with
The Authors Parkinsons disease, olanzapine was found to
CHARLES D. MOTSINGER, CAPT, USAF, MC, is a family practice psychiatrist and chief of increase motor symptoms and to be less effec-
the life-skills support center at Osan Air Force Base, South Korea. He received his med- tive than clozapine. Therefore, current recom-
ical degree from the Uniformed Services University of the Health Sciences F. Edward
Hbert School of Medicine, Bethesda, Md., and completed a residency in the combined mendations discourage the use of olanzapine
National Capital Consortium family practice/psychiatry program, also in Bethesda. in patients with Parkinsons disease.24 [Evi-
GREGORY A. PERRON, CAPT, USAF, MC, is a family physician and faculty member in the dence level B, uncontrolled study]
Malcolm Grow Medical Center family practice program at Andrews Air Force Base, Md. In patients with Alzheimers disease and
He received his medical degree from the Washington University School of Medicine, St. psychotic symptoms, dosages should start at
Louis, and completed a family practice residency at Malcolm Grow Medical Center.
1.25 to 2.5 mg per day and increase to 5 mg
TIMOTHY J. LACY, LTCOL, USAF, MC, is assistant professor of psychiatry and family per day, if necessary. Surprisingly, dosages of
practice at the Uniformed Services University of the Health Sciences F. Edward Hbert
School of Medicine. He also is program director for the combined National Capital 10 or 15 mg per day are less effective than
Consortium family practice/psychiatry residency program. dosages of 5 mg per day.22-26 Common side
Address correspondence to Capt. Charles D. Motsinger, 715 West View Terr., Alexandria, VA effects of olanzapine include sedation and
22301 (e-mail: charles.motsinger@osan.af.mil). Reprints are not available from the authors. weight gain. Special considerations in elderly

2338 AMERICAN FAMILY PHYSICIAN www.aafp.org/afp VOLUME 67, NUMBER 11 / JUNE 1, 2003
There is growing concern over recent reports of hyperglycemia
in patients who are taking certain atypical antipsychotic drugs.

patients include the risk of orthostatic its use in patients with either Parkinsons dis-
hypotension and seizures. In pre-marketing ease or Alzheimers disease. Side effects of
testing, olanzapine was associated with a 0.9 ziprasidone include rash, hypertension, and
percent rate of seizures. Seizures occurred in (rarely) nondose-dependent QT-interval
patients with confounding factors; conse- prolongation. Ziprasidone should be avoided
quently, this medication should be used with in patients at risk for significant electrolyte
caution in patients who have a lowered seizure abnormalities and in patients with histories
threshold.21 Olanzapine is metabolized by the of significant cardiovascular illness, recent
cytochrome P450 1A2 system, as well as mul- acute myocardial infarction, uncompensated
tiple other hepatic pathways, and therefore has heart failure, and cardiac arrhythmia. Ziprasi-
a low potential for drug-drug interactions. done is metabolized by the cytochrome P450
3A4 system.21
QUETIAPINE
Quetiapine (Seroquel) has shown promise in CLOZAPINE
the treatment of psychosis in elderly patients Research on clozapine in the geriatric pop-
with Alzheimers disease and Parkinsons disease. ulation has had mixed results. Clozapine is
It improves psychosis in patients with Parkin- highly effective in treating psychosis in
sons disease without exacerbating movement patients with Parkinsons disease.30 [Evidence
disorders. This feature has led some experts to Level A, RCT] The American Academy of
recommend it as the first-line agent for treat- Neurology states that clozapine appears to be
ment of psychosis in patients with Parkinsons the most effective agent in the treatment of
disease.27,28 [Reference 28Evidence level B, drug-induced psychosis in patients with
uncontrolled study] It has been shown to be safe Parkinsons disease.18,30 Clozapine has shown
in patients with Alzheimers disease, but more some efficacy in controlling psychosis and
controlled trials are needed before its use in these behavior disturbances in patients with
patients can be endorsed.29 Alzheimers disease.16,31 Initial dosages can
Quetiapine should be initiated at a dosage start as low as 6.5 mg per day and are titrated
of 12.5 mg at bedtime and titrated every three upward.
to five days until the desired effect is achieved Clozapine is well known for its side effects,
or side effects emerge. Common side effects which include agranulocytosis (with a fatality
include sedation, headache, and orthostatic rate as high as 30 percent), sedation, seizures,
hypotension. Cataract formation was noticed sialorrhea, hypotension, weight gain, tachy-
in pre-marketing studies, but a causal rela- cardia, and hyperthermia.21 A complete blood
tionship has not been found. Screening for count must be checked frequently in patients
cataract formation is recommended at the ini- taking this medication. Because of its serious
tiation of therapy and at six-month intervals and potentially lethal side effects, clozapine
thereafter.21 Quetiapine is metabolized by the generally is used only after other options have
cytochrome P450 3A4 system. Serum levels of failed. Clozapine is metabolized by the
quetiapine can be affected by inducers or cytochrome P450 1A2 and 2D6 systems.
inhibitors of this enzyme system (e.g., keto-
conazole [Nizoral], erythromycin, diltiazem The opinions and assertions contained herein are
[Cardizem], fluoxetine, ciprofloxacin [Cipro], the private views of the authors and are not to be
construed as official or as reflecting the views of the
grapefruit juice, and phenytoin [Dilantin]).21 U.S. Air Force Medical Corps or the U.S. Air Force at
large.
ZIPRASIDONE
Because ziprasidone (Geodon) was recently The authors report that they do not have any con-
released, clinical data are lacking to support flicts of interest. Sources of funding: none reported.

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Atypical Antipsychotic Drugs

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