Antipsychotic Medications and the Elderly

David P. Folsom, MD, Gauri V. Nayak, MA, and Dilip V. Jeste, MD

Dr. Folsom is assistant professor in the Departments of Psychiatry and Family Medicine at the University of California, San Diego.

Ms. Nayak is a predoctoral research fellow in geriatric psychiatry at the University of California, San Diego.

Dr. Jeste is the Estelle and Edgar Levi Chair in Aging and professor of psychiatry and neurosciences at the University of California, San Diego, and chief of the Division of Geriatric Psychiatry at the Veterans Affairs San Diego Healthcare System.

Disclosure: Dr. Folsom has received financial support from the National Institute of Mental Health. Dr. Jeste is a consultant for, has received grant and/or research support from, and has received honorarium and/or expenses from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, and Pfizer.

Funding/support: This work was supported by grants from the National Institute of Mental Health (grants #MH66248, MH59101, MH49671, MH43693, and MH59101) and the Department of Veterans Affairs.

Please direct all correspondence to: David P. Folsom, MD, 3500 La Jolla Village Dr, San Diego, CA 92093; Tel: 858-552-8585; Fax: 858-552-7404; E-mail: [email protected].

Abstract

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 patients.

Introduction

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 patients.

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 nature.

Common Psychiatric Disorders in the Elderly

Delirium

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 Other Dementias

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

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

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 postural hypotension.

Risperidone

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

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 improvements.³

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 demonstrated.

Quetiapine

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

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

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 persons.

Other Concerns of the Atypical Antipsychotics

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.

Conclusion

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 events. PP

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