and the Elderly
• Antipsychotic medications are commonly used to treat elderly
patients with delirium, agitation and psychosis due to Alzheimer’s disease, and
• Starting doses for antipsychotics are much lower in elderly
patients compared to young patients, especially for patients with dementia.
reported side effects of atypical antipsychotics include possible increased
risk of diabetes and stroke.
• Choosing between
antipsychotics for elderly patients can be difficult because there is limited
data available from clinical trials.
There are several
disorders for which primary care physicians use antipsychotic medications in
elderly persons. Such conditions include delirium; psychosis, agitation, and
aggression in patients with dementia; and primary psychotic disorders, such as
schizophrenia and psychotic depression. This article reviews the use of older
typical or conventional antipsychotics as well as newer atypical
antipsychotics, and includes recommended doses for elderly patients and side
effects of these medications that are particularly relevant to elderly
As the population ages and
the first of the baby boomers approach 65 years of age, the primary care
physician (PCP) will need to become more knowledgeable about the use of
antipsychotic medications in elderly patients. Over the past decade there have
been several changes in the use of antipsychotics in older patients. These
changes include the introduction of newer atypical antipsychotics, the use of
lower doses of antipsychotics than in the past, and the emergence of new side
effects of the atypical antipsychotics, including diabetes, hyperlipidemia, and
possible cerebrovascular events.
This article reviews the
most common clinical situations in which a PCP would use an antipsychotic, the
basic prescribing principles for antipsychotics in elderly persons, and the
frequently prescribed antipsychotics. It also discusses important risks and
cautions associated with the use of specific antipsychotics for elderly
For a PCP, there are
several types of patients who would potentially be treated with an
antipsychotic: a hospitalized patient with delirium; a patient with
moderate-to-severe dementia and psychosis or agitated behavior; or a patient
with a primary psychiatric disorder, such as schizophrenia, depression with
psychotic features, or bipolar disorder. For each of these conditions, the PCP
may be the one who initiates treatment, co-manages the patient’s treatment with
a psychiatrist, or assumes the ongoing management of a patient who has been
stable on an antipsychotic for years.
Antipsychotics are approved by the United States Food and Drug
Administration for use only in patients with schizophrenia. The use of these
drugs in other conditions (eg, psychosis or agitation in persons with dementia)
is off-label. At the same time, off-label use of drugs is not prohibited and
may often be necessary for the treatment of severe behavioral disorders for
which there are no approved treatments. Off-label use merely reflects the fact
that there has not been adequate evidence of the efficacy of these drugs in
specific conditions based on randomized controlled trials of a regulatory
Common Psychiatric Disorders in the Elderly
Delirium is a syndrome characterized by confusion, altered mental
status, and waxing and waning levels of consciousness.1 Delirium is
almost always due to an underlying medical condition and is estimated to occur
in up to 15% to 20% of hospitalized patients, with elderly patients being at
especially high risk.1,2 Hospitalized patients with delirium are
often confused, may pull out their intravenous (IV) lines or attempt to get out
of bed and risk falling, and can be combative with hospital staff and family
members. Although the primary treatment for delirium is treating the underlying
medical condition and providing nonpharmacologic interventions, such as
orienting patients, encouraging a normal sleep-wake cycle, and minimizing the
effects of visual and hearing impairments,2 often antipsychotics are
used to help decrease confusion and agitated behavior.
There have been few large studies of antipsychotics for the treatment of
delirium. Haloperidol is probably the most widely used antipsychotic in
patients with delirium. In part, this is because it is available in oral,
intramuscular (IM), and IV forms. Furthermore, long-term side effects, such as
tardive dyskinesia, are probably not relevant during the short-term treatment
of delirium, and it has been successfully used for many years.1
There is one randomized controlled trial comparing haloperidol and olanzapine
in patients in the surgical intensive care unit, which found similar
improvements for both medications.3 Other atypical antipsychotics
have been studied mainly in small open-label trials, but are also used in the
treatment of delirium.4-6
Alzheimer’s Disease and
Antipsychotics are often
used to treat the behavioral disturbances associated with Alzheimer’s disease
(AD) and other dementias.7 A large majority of patients with AD
experience behavioral disturbances at one stage or another. These disturbances
can range from a reversed sleep-wake cycle, in which the patient is awake all
night and sleeps during the day; to a paranoia that is compounded by the memory
problems of dementia (eg, a patient accuses the caregiver of stealing food or
money, when the patient does not remember having just ate the food or misplaced
the money); to severe agitated behavior, such as striking a family member or
screaming loudly.8 These behavioral disturbances can be very
difficult to manage for caregivers and are one of the primary reasons for
nursing home placement among patients with dementia.9
Although treatment for the behavioral disturbances of AD and other
dementias includes psychosocial interventions, such as social contact,
behavioral therapy, and structured environment,10 antipsychotics are
often an important part of managing these behavioral disturbances. All of the
atypical antipsychotics, as well as haloperidol, are used in clinical practice
to treat the behavioral disturbances of dementia, though only haloperidol,
risperidone, olanzapine, quetiapine, and aripiprazole have been studied in
large-scale, double-blind, placebo-controlled, randomized, clinical trials.
Recommended ranges of starting and maintenance doses are shown in the Table.
Primary Psychotic Disorders
Common primary (ie, not due to known neurological or other medical
diseases) psychotic disorders seen in elderly patients include schizophrenia,
bipolar disorder with psychosis, and major depressive disorder (MDD) with
psychotic features. All of these disorders are characterized by psychotic
symptoms that include auditory or visual hallucinations; delusions (fixed false
beliefs); and disorganization of thought processes, behavior, or speech.
A majority of elderly patients with schizophrenia have had the disorder
since their teens or twenties, whereas a minority of patients develop
schizophrenia after 45 years of age.11 Elderly patients with
schizophrenia generally have fewer and less severe psychotic symptoms than
their younger counterparts.
Psychotic symptoms can
also be a feature of bipolar disorder, either in the manic phase or in the
depressed phase. There has been relatively little research done on bipolar
disorder in elderly patients, but some investigators believe that extreme mood
swings of bipolar disorder diminish with age, and that elderly bipolar patients
are more likely to experience mixed states with depression and agitation than
classic manic episodes.12
Finally, elderly patients with MDD can develop psychotic symptoms. In
elderly depressed patients, these psychotic symptoms often include extreme
guilt for relatively minor past events or somatic delusions, such as a
preoccupation with one’s own death or having cancer.12
Basic Principles for Use of Antipsychotic Medications
in Elderly Patients
As with many other types
of medications, the antipsychotics should be used with greater caution in
elderly patients than in younger individuals. Important considerations in the
treatment of elderly patients include comorbid medical illnesses, drug-drug
interactions, and age-related changes in drug metabolism. In addition, all of
the antipsychotics have side effects that are more common or clinically more
important in elderly patients. For example, elderly patients taking haloperidol
(and other older antipsychotics) have a greater incidence of tardive dyskinesia
compared to younger patients taking the same medications or elderly patients
taking newer atypical antipsychotics. Most of the atypical antipsychotics, when
given in higher doses, cause orthostatic hypotension in elderly patients, and
this orthostatic hypotension is often worsened by concomitant antihypertensive
medications. Finally, there are recently recognized side effects of the
atypical antipsychotics that may also pose significant risks for elderly
patients, including diabetes and hyperlipidemia (primarily reported with
olanzapine and clozapine),13 a possible increased risk for stroke
(reported with risperidone and olanzapine),14 and QTc prolongation
(reported with ziprasidone).
Specific Antipsychotic Medications
Haloperidol is the only typical antipsychotic discussed in this article.
Prior to the introduction of the atypical antipsychotics, it was the most
widely used antipsychotic in elderly patients. However, the short-term side
effects of extrapyramidal symptoms (EPS) and the long-term side effect of
tardive dyskinesia are important adverse effects that limit haloperidol’s
usefulness in elderly patients.15 The EPS primarily include
parkinsonism and akathisia (subjective and objective restlessness); acute
dystonias are less common in older than in younger adults. Currently, the one
condition in which haloperidol may still be the preferred antipsychotic is
delirium in hospitalized patients; this is, in part, because it can be given in
IM, IV, or oral forms. In addition, the course of treatment for delirium is
typically short, so the risks of side effects associated with long-term usage,
such as tardive dyskinesia, are lower. On the other hand, haloperidol is not a
drug of choice in elderly patients who require long-term treatment, such as
those with schizophrenia or psychosis of AD, because these patients are at the
highest risk for developing tardive dyskinesia.
Clozapine was the first atypical antipsychotic to be approved by the
FDA. Its use is largely restricted to patients with treatment-resistant
schizophrenia and, to a smaller extent, for psychosis in patients with
Parkinson’s disease. Clozapine is a difficult drug to use in elderly persons
because of the risk of agranulocytosis, anticholinergic delirium, sedation, and
Risperidone was the second atypical antipsychotic to be approved by the
FDA and, therefore, of all the atypical agents, clinicians have had the most
experience with this medication. EPS and tardive dyskinesia are much less
common with risperidone and other atypical antipsychotics compared to
haloperidol.16 The drug is metabolized by the liver to an active
metabolite and this active metabolite is excreted by the kidney, so that severe
liver or kidney disease can result in increased plasma levels of risperidone.
Randomized clinical trials have found risperidone to be effective in treating
elderly patients with schizophrenia17 and for treating the psychosis
and agitation associated with AD.14,18,19 It is also used to treat
agitation in hospitalized elderly patients with delirium.
Common side effects of this medication, especially at higher doses,
include EPS and orthostatic hypotension, which tend to be more pronounced in
elderly patients, especially those taking antihypertensive medications.
Initiating treatment with a low dose and slowly titrating the dose of risperidone
can minimize the risk of these adverse events. A recent study reported a
significantly increased incidence of cerebrovascular events (ie, strokes or
transient ischemic attacks) in elderly patients taking risperidone,14
although a cause-and-effect relationship between risperidone and
cerebrovascular events has not been established.
Olanzapine was the third
atypical antipsychotic to be approved by the FDA, and is also widely used in
elderly patients. Two randomized controlled trials of olanzapine in elderly
patients have shown its efficacy in psychosis and agitation associated with AD
and in schizophrenia.17,20 A recent investigation compared
olanzapine to haloperidol in patients with delirium in the surgical intensive
care unit and found that the two medications resulted in similar clinical
A common side effect of this medication is sedation; therefore,
olanzapine is typically given at night. Weight gain is also a significant side
effect. Similar to risperidone, this medication can cause orthostatic
hypotension and care should be used when it is started in elderly patients,
especially those on concomitant antihypertensive medications. In addition, five
clinical trials in elderly patients with dementia found higher rates of cerebrovascular
accidents. All of these events caused mortality in elderly patients taking
olanzapine compared to those taking placebo, and in February 2004 the
manufacturer, Eli Lilly, issued a warning regarding the increased risk of such
events in patients taking olanzapine. Currently, the absolute risk of new-onset
diabetes, hyperlipidemia, or stroke is unknown; furthermore, a cause-and-effect
relationship between olanzapine and stroke or mortality has not been
Quetiapine was approved by the FDA in 1997. There are limited data from
randomized controlled trials for quetiapine in elderly patients, but it is
commonly used to treat behavioral disturbances of AD and psychotic disorders in
elderly patients. A randomized controlled comparison of quetiapine versus
haloperidol versus placebo in patients with psychosis due to AD found no
difference among the three treatment arms on the primary outcome, psychotic
symptoms.21 However, quetiapine improved everyday functioning to a
greater degree than haloperidol or placebo.
One of the most common side effects of this medication is sedation. In
addition, quetiapine causes orthostatic hypotension in approximately 10% of
patients and syncope in 1% of patients. Similar to risperidone and olanzapine,
orthostatic hypotension is most likely to occur during the initial dose
titration period, is worse in patients who are elderly or taking
antihypertensive medications, and can be decreased by starting with a low dose
and increasing the dose slowly.
Ziprasidone was approved
by the FDA in 2001. To date, there has not been a published double-blind
controlled trial of ziprasidone in elderly patients. One clinically significant
side effect that is particularly relevant for elderly patients is cardiac conduction
delay, specifically QTc prolongation. Therefore, it is recommended that
ziprasidone not be used in patients who have known cardiac conduction defects,
including atrioventricular block, bundle branch blocks, or congenital heart
disease. In addition, it should be avoided in patients with uncompensated heart
failure or recent myocardial infarction. The use of concomitant medications
that cause prolonged QTc, such as antiarrhythmics, should be avoided in
patients taking ziprasidone; similarly, loop and thiazide diuretics can lower
potassium and magnesium, thereby increasing the risk of QTc prolongation.
Additional recommendations for the use of ziprasidone in elderly patients
include periodic electrocardiograms to monitor for new-onset QTc prolongation
and thorough evaluation of symptoms of dizziness, palpitations, or syncope in
patients on this medication. Although ziprasidone can cause orthostatic
hypotension, the incidence of this side effect is much lower than with other
atypical antipsychotics (1% versus 10%, respectively).
Aripiprazole is the newest atypical antipsychotic to be approved by the
FDA. Double-blind, placebo-controlled trials have shown its efficacy in
reducing behavioral disturbances in AD patients with psychosis and agitation.
Its main side effect is sedation at higher doses. It has not yet been reported
to cause weight gain, diabetes, or cardiac conduction defects in elderly
Other Concerns of the
Two of the more recently reported major side effects of the atypical
antipsychotics include diabetes and hyperlipidemia; recently, the FDA issued a
recommendation that all persons receiving atypical antipsychotics should be
screened for new-onset diabetes and hyperlipidemia. To date, a majority of the
case reports linking atypical antipsychotics and diabetes have been in patients
treated with clozapine or olanzapine.13 A recently published
guideline22 from the American Psychiatric Association and the
American Diabetic Association concluded that the atypical antipsychotics
associated with the highest risk of diabetes were clozapine and olanzapine, and
that the risk with risperidone and quetiapine is less clear. Some studies have
shown an increased risk for diabetes with these drugs, while others have not.
Although the two most recently approved atypical antipsychotics, aripiprazole
and ziprasidone, have relatively limited epidemiological data, clinical trial
experience has not shown an increased risk for diabetes with these medications.
PCPs are increasingly using antipsychotic medications to treat their
elderly patients. In elderly persons, the starting doses of antipsychotics are
much lower than those in younger patients. In addition, the effective
maintenance doses are also generally lower in elderly patients. Newer atypical
antipsychotics are more widely used than the older medications, such as
haloperidol, mainly due to a lower incidence of EPS and tardive dyskinesia with
these medications. However, there are several recently recognized side effects
of the atypical antipsychotics that are particularly relevant to elderly
patients, including increased risk of diabetes, and possibly cerebrovascular
1. Meagher DJ.
Delirium: optimizing management. BMJ.
2. Inouye SK, Bogardus ST Jr, Charpentier PA, et al. A multicomponent intervention to prevent delirium in
hospitalized older patients. N
Engl J Med. 1999;340(9):669-676.
3. Skrobik YK,
Bergeron N, Dumont M, Gottfried SB. Olanzapine vs haloperidol: treating
delirium in a critical care setting. Intensive
Care Med. 2004;30(3):444-449.
4. Sasaki Y, Matsuyama T, Inoue S, et al. A prospective, open-label, flexible-dose study of quetiapine
in the treatment of delirium. J
Clin Psychiatry. 2003;64(11):1316-1321.
5. Horikawa N, Yamazaki T, Miyamoto K, et al.
Treatment for delirium with risperidone: results of a prospective open trial
with 10 patients. Gen Hosp Psychiatry. 2003;25(4):289-292.
6. Kim KY, Bader
GM, Kotlyar V, Gropper D. Treatment of delirium in older adults with
quetiapine. J Geriatr
Psychiatry Neurol. 2003;16(1):29-31.
7. Jeste DV, Finkel
SI. Psychosis of Alzheimer’s disease and related dementias. Diagnostic criteria
for a distinct syndrome. Am J
Geriatr Psychiatry. 2000;8(1):29-34.
8. Grossberg GT.
Diagnosis and treatment of Alzheimer’s disease. J Clin Psychiatry. 2003;64(suppl 9):3-6.
9. Lebowitz BD,
Pearson JL. Intervention research in psychosis: prevention trials. Schizophr Bull.
J. Nonpharmacologic interventions for inappropriate behaviors in dementia: a
review, summary, and critique. Am
J Geriatr Psychiatry. 2001;9(4):361-381.
11. Jeste DV, Lacro JP, Gilbert PL, Kline J, Kline N.
Treatment of late-life schizophrenia with neuroleptics. Schizophr Bull. 1993;19(4):817-830.
12. Koenig HG, Blazer DG. Mood disorders. In: Blazer DG,
Steffens DC, Busse EW, eds. The American Psychiatric Publishing Textbook of Geriatric
Psychiatry. 3rd ed. Washington, DC: American Psychiatric Publishing, Inc.; 2004:241-268.
13. Jin H,
Meyer JM, Jeste DV. Phenomenology of and risk factors for new-onset diabetes
mellitus and diabetic ketoacidosis associated with atypical antipsychotics: an
analysis of 45 published cases. Ann
Clin Psychiatry. 2002;14(1):59-64.
14. Brodaty H, Ames D, Snowdon J, et al. A randomized
placebo-controlled trial of risperidone for the treatment of aggression,
agitation, and psychosis of dementia. J Clin Psychiatry. 2003;64(2):134-143.
15. Jeste DV,
Rockwell E, Harris MJ, Lohr JB, Lacro J. Conventional vs. newer antipsychotics
in elderly patients. Am J
Geriatr Psychiatry. 1999;7(1):70-76.
CR, Jeste DV. Incidence of tardive dyskinesia with typical versus atypical
antipsychotics in very high risk patients. Biol
17. Jeste DV, Barak Y, Madhusoodanan S, Grossman F,
Gharabawi G. International multisite double-blind trial of the atypical
antipsychotics risperidone and olanzapine in 175 elderly patients with chronic
schizophrenia. Am J Geriatr Psychiatry. 2003;11(6):638-47. Erratum in: Am J Geriatr
18. De Deyn
PP, Rabheru K, Rasmussen A, et al. A randomized trial of risperidone, placebo,
and haloperidol for behavioral symptoms of dementia. Neurology. 1999;53(5):946-955.
19. Katz IR, Jeste DV, Mintzer JE, Clyde C, Napolitano J,
Brecher M, for the Risperidone Study Group. Comparison of risperidone and
placebo for psychosis and behavioral disturbances associated with dementia: a
randomized, double-blind trial. J Clin Psychiatry. 1999;60(2):107-115.
JS, Clark WS, Gannon KS, et al, for the HGEU Study Group. Olanzapine treatment
of psychotic and behavioral symptoms in patients with Alzheimer disease in
nursing care facilities: a double-blind, randomized, placebo-controlled trial. Arch Gen Psychiatry.
PN, Schneider L, Katz I, Mintzer J, Street J. Quetiapine in nursing home
residents with Alzheimer’s dementia and psychosis. Am J Geriatr Psychiatry. 2002;10(2 suppl 1):93.
22. American Diabetes Association, American
Psychiatric Association, American Association of Clinical Endocrinologists,
North American Association for the Study of Obesity. Consensus development
conference on antipsychotic drugs and obesity and diabetes. Diabetes Care. 2004;27(2):596-601.