Objective: To discuss the appropriate use of antipsychotic drugs in residents with dementia in long-term care facilities. Data Sources: English-language articles pertinent to treatment of psychoses and behavioral disorders in residents with dementia. Data Synthesis: Appropriate use of antipsychotic drugs for residents of long-term care facilities is regulated by the Health Care Financing Administration through the 1987 Omnibus Budget Reconciliation Act. For residents with dementia, antipsychotic therapy is appropriate only to treat behaviors that might be harmful to the resident or others. If a careful evaluation indicates the need for treatment, non-pharmacologic approaches should be tried before antipsychotic drugs are prescribed. Antipsychotic drugs include both the conventional neuroleptic agents and the newer atypical agents. Side effects, particularly extrapyramidal symptoms and tardive dyskinesia, are important drawbacks to the use of conventional agents, particularly in the elderly. The atypical agents, which block both dopamine and serotonin receptors, appear to have more consistent side effect profiles. Conclusion: Appropriate use of antipsychotic medications in residents with dementia can help in the management of hallucinations, delusions, and severe aggression. The conventional antipsychotic agents have side effects that can be devastating to elderly patients, even when the drugs are used correctly. The newer atypical antipsychotic drugs appear to be more effective and to have a more benign safety profile, a particular advantage for elderly residents. Key Words: Antipsychotic, dementia, extrapyramidal symptoms, long-term care, nursing facility. Abbreviations: EPS = extrapyramidal symptoms; HCFA = Health Care Financing Administration; OBRA '87 = 1987 Omnibus Budget Reconciliation Act; LTC = long-term care. Consult Pharm 1999;14:179-88.

In the description by Alois Alzheimer¹ of the case that bears his name, he wrote of a dementia characterized by "unfounded jealousy, paranoid delusions, hallucination, hiding objects inappropriately, and screaming . . . accompanied by jealousy, agitation. . . ." Alzheimer's disease is characterized by progressive cognitive decrements and is considered to be a disorder that primarily affects memory; however, the behavioral features of Alzheimer's disease are extensive. Patients with this disorder exhibit behavioral disturbances as well as cognitive impairments that must be addressed. The need for safe and effective treatment strategies is recognized. This article reviews the use of antipsychotic agents, particularly the newer atypical antipsychotics, in the management of the behavioral disturbances of dementia and other psychotic illnesses.

Historical Perspective

OBRA '87 regulations specify the conditions and circumstances in which antipsychotic drugs can be used to treat psychiatric illness and the behavioral symptoms accompanying dementia. Most of these regulations were implemented October 1, 1990, resulting in a significant decline in the use of antipsychotic drugs. A review⁴ of the effect of OBRA '87 in one facility showed that antipsychotics were stopped in 45% of residents with a dementia-only diagnosis, demonstrating that OBRA '87 decreased antipsychotic use.

The HCFA guidelines for appropriate indications for use of antipsychotics are presented in Table 1. Organic mental syndromes (including dementia) are listed below the various psychoses and neurologic conditions. For residents with "associated psychotic and/or agitated features" of the organic mental syndromes, clinicians must establish that the behavior in question is detrimental to the resident or interferes with the staff's ability to provide care. Otherwise, residents of LTC facilities might be given antipsychotic agents inappropriately when exhibiting behaviors that are neither frightening nor harmful to the resident. The spirit of the HCFA guidelines is that such persons have the right not to be exposed to these drugs. Other HCFA regulations specify that administration of a drug may be inappropriate if it is given in excessive doses, for excessive periods of time, without adequate monitoring, without a diagnosis or reason, or when monitoring data or undue adverse consequences indicate that the dose should be reduced or the drug discontinued. A drug may also be considered unnecessary if its use does not relieve the condition or behavior for which it is prescribed.

Antipsychotics are commonly used to treat behaviors associated with dementia. HCFA guidelines specify that the behaviors must present a danger to the resident or others before any drug intervention is considered appropriate. Resident yelling, wandering, or running away from the facility may distress staff members, family members, or even other residents, but these behaviors do not harm the person exhibiting the behavior, and thus drug therapy might be considered inappropriate. A drug that impedes a resident from activities or behaviors that are not harmful to self or others is considered a chemical restraint. Behaviors that should not be treated with antipsychotic medication are listed in Table 1.

When antipsychotic drugs are used to treat behaviors associated with dementia, an evaluation must be conducted to determine whether the drug has effectively reduced the frequency or the intensity of the target behavior. These behaviors must be quantitatively assessed to determine that the drug is effective. HCFA guidelines also specify that gradual dose reductions should be made every six months after therapy has begun, unless the dose has already been reduced to the lowest possible dose that will control symptoms. It is generally accepted that a drug reduction should be between 10% and 25% of the original daily dose. However, individual resident factors should be considered before making any changes in dose. Some residents are particularly sensitive to changes in dosing. For example, residents with head injuries, dementia, or developmental disorders, or those who have had a stroke show significant differences in their responses to such changes and the time needed for restabilization after each adjustment. Dose reductions need to be monitored closely for breakthrough symptoms of the disorder being treated as well as for withdrawal reactions. Conversely, practitioners should monitor for dose-related adverse effects and toxicity when doses are being increased. In the past, many practitioners associated the sedation caused by conventional antipsychotics with onset of antipsychotic effect, since residents appeared calmer and less agitated. However, sedation is not correlated with antipsychotic effect. In addition, the atypical antipsychotics do not generally cause as much sedation as the typical antipsychotics.

Once the decision has been made to initiate antipsychotic drug therapy, the most effective drug with the best side-effect profile should be selected.  

Non-pharmacologic Approaches

Evaluation

If problem behaviors do emerge, four steps should be taken: (1) define the actual behavior and frequency, (2) determine whether the behavior is harmful to the resident or others or interferes with function or delivery of care, (3) determine possible causes of the behavior, and (4) review and discuss interventions attempted in the past. In this evaluation, it is important to recognize that the behavior may not be a problem for the resident but rather one for the caregiver or the facility. Common causes of behavioral problems are shown in Table 2.

Characteristics of the identified problem behavior should be assessed by monitoring the resident and collecting baseline data on where and when the behavior occurs. The time of day, circumstances surrounding the behavior, possible causes, and duration and intensity of the behavior should be elicited. It is important to describe what was actually seen or heard without "labeling" the resident. Sufficient time should be devoted to observing and monitoring the behavior to ensure that it does not represent a transitory outburst or the temporary effects of a medical illness or environmental change.

This assessment and intervention should neutralize the impact of the identified behavior. The assessment process should be interdisciplinary and systematic to allow a variety of therapeutic approaches to be used. Regardless of the ultimate approach, attempts at resolving the identified problem should proceed, beginning with those that promise the greatest benefit and least risk to the resident.

Interventions

Staff members may need education to improve their skills in communication, flexibility, anticipation, validation, reorientation, and redirection of residents in the intervention of problem behaviors. Basic techniques that the staff can use to become more effective are shown in Table 3.

The type of non-pharmacologic approach is determined by the behavior and its causes. Improving comfort level, correcting reversible medical causes, modifying the environment, and removing the resident from the source of the problem can be successful. The approaches chosen must be consistent and used by all members of the caregiving staff and interdisciplinary team at all times.

It is important to understand that non-pharmacologic interventions must precede the use of medications. These techniques should continue to be used while medication is instituted. An innovative dementia care program in one nursing facility demonstrated that activities, education, and guidelines for psychotropic medication reduced the use of antipsychotic drugs by more than half.⁵  

Use of Antipsychotic Medications

It is important to distinguish the issue of diagnosis from the target symptoms to ensure that the optimum treatment is chosen. For example, because a resident has a diagnosis of schizophrenia does not mean that his or her anxious or depressive symptoms should be treated with an antipsychotic, unless the anxiety or depression is judged to be the result of psychotic symptoms. Although antipsychotics have a broad range of effects on a variety of behavioral symptoms, they should be used only when the benefits outweigh the risks.

A related issue is that a great degree of care should go into carefully defining target symptoms that are the object of treatment. General terms such as "confusion" and "agitation" mean different things to different individuals. Cohen-Mansfield and colleagues,²³ for example, listed more than 20 behaviors under the general rubric of agitation (Table 4). The more specifically the target behavior can be identified, the more successful the intervention is likely to be. The painstaking elicitation and description of target behaviors is also a safeguard against using these agents for conditions either unlikely to respond or for which more specific or safer treatment exists (Table 1).

The best approach for each resident should involve the dual consideration of diagnosis and current symptoms. Particular attention should also be paid to residents whose existing diagnoses do not explain their current symptoms. For example, it may not be unusual for a person with a lifelong history of schizophrenia to exhibit delusions, but such psychotic symptoms in a person with a diagnosis of panic disorder should prompt a thorough examination before treatment is initiated. As-needed (p.r.n.) dosing of conventional antipsychotics to treat behavioral manifestations of dementia should be avoided except in cases of infrequent agitation without a known precipitating cause.²⁴  

Conventional Antipsychotics

Despite their shortcomings, conventional antipsychotics have been used more than any other single class of psychotropic drugs to treat behavioral disturbances with or without psychosis.^25,26 Although many agitated patients improve with treatment, the response is usually modest, and some patients actually become worse. In the best-designed studies, about a third of the patients with unspecified agitation or aggression had a good response to antipsychotics.²⁵ The specific symptoms that consistently improve with conventional antipsychotics include delusions, hallucinations, and severe or aggressive agitation. Behaviors that respond poorly are repetitive, non-aggressive behaviors such as the inappropriate indications listed in Table 1. Clinicians seem to prefer using the low-dose, high-potency antipsychotics in geriatric patients because the elderly are less likely to have multiple anticholinergic, histaminergic, and alpha-adrenergic side effects. However, these patients are at a higher risk for EPS and need frequent assessments for these effects.^27-30  

Side Effects of Conventional Antipsychotics

Side effects of conventional antipsychotics in the elderly include acute EPS such as parkinsonism and akathisia as well as the more insidious tardive dyskinesia.^33-38 Jeste and Caligiuri³⁹ have estimated that older patients exposed to these agents develop tardive dyskinesia at alarming rates: 26% of their elderly patients developed this disorder after one year of exposure, 52% after two years, and 60% after three years. These drug-induced movement disorders can compound the declining praxis, mobility, and functional abilities of a demented patient. Anticholinergic (e.g., benztropine) or dopaminergic (e.g., amantadine) medications are used to combat drug-induced parkinsonism in younger adults, but in older adults they can contribute to confusion, declining cognition, and increased delirium or psychosis and should therefore be avoided. Residents most at risk for tardive dyskinesia appear to be elderly women with dementia and prominent affective symptoms.

Antipsychotic drugs used to treat agitation in residents with dementia may also impair cognition. Residents with Alzheimer's disease not only have an age-related decline in dopamine receptors, making them susceptible to EPS, but they also have a profound loss of acetylcholine-producing neurons in various brain regions, particularly in the nucleus basalis of Meynert. The latter deficit serves as the basis for all current Food and Drug Administration (FDA) approved treatments for Alzheimer's disease. Thus the use of antipsychotic agents with significant anticholinergic effects may further impair cognition in residents with Alzheimer's disease.^40,41

Orthostatic hypotension is a serious side effect associated with low-potency conventional antipsychotics. This drop in blood pressure is attributed to an alpha1-adrenergic receptor blockade and can result in falls, fractures, and increased morbidity and mortality. With elderly residents particularly sensitive to the side effects of antipsychotics, it is critical that the indications for use and the dose be carefully regulated.^19,28

Dosing Conventional Agents

Because many elderly are highly sensitive to side effects, individual dose adjustment may be the best method to achieve a reasonable balance between efficacy and adverse effects. If this is not feasible, then a change to a different class of antipsychotic or an alternate type of medication may be in order.9 Rational pharmacotherapy for elderly residents requires an attempt to reduce polypharmacy and the use of the lowest appropriate doses of antipsychotics to avoid the subsequent need for concomitant medications. It is also best to avoid giving certain conventional antipsychotics in inconvenient and unnecessary divided doses.⁴² At times, however, rational co-prescribing of different classes of medications (e.g., buspirone, trazodone, selective serotonin re-uptake inhibitors, divalproex) may be necessary until agitation is adequately reduced.

Atypical Antipsychotics

Theoretically, the atypical agents' mechanism of action should be useful for residents with dementia who are cognitively impaired and who often have both behavioral disturbances and flattened affect. Clozapine has demonstrated pharmacotherapeutic efficacy for treatment-resistant schizophrenia⁴⁵ and a reduced propensity for EPS and the development of tardive dyskinesia.⁴⁶ These benefits may be the result of a higher affinity ratio of dopamine Dl to D₂ receptors. Clozapine, however, is not without its liabilities. Its use is associated with significant anticholinergic, histaminergic, and alpha-adrenergic adverse effects. Elderly residents are often unable to tolerate clozapine dose titration because of significant orthostatic hypotension, sedation, confusion, and sialorrhea.⁴⁷ However, it is the increased risk of seizures and 1% incident of agranulocytosis with subsequent need for blood monitoring, that generally limit its use in the elderly.⁴⁸ Starting doses of clozapine in the elderly are typically low (6.25-12.5 mg/day) and are increased to a maximum of 400 mg/day. Case reports involving geriatric patients have described improvements in schizophrenia, psychosis secondary to organic mental syndrome, psychosis secondary to Parkinson's disease, and movement disorders.^45,46,49,50

Risperidone has a much more favorable pattern of receptor blockade than clozapine for use in older adults. While it has potent D₂ and 5-HT₂ blocking properties, it has weak anticholinergic properties.⁵¹ The latter feature should prove useful in treating residents with dementia of the Alzheimer's type. Moreover, owing to its strong serotonin-blocking activity, risperidone ameliorates both positive and negative symptoms and has a relatively benign side-effect profile.

Comparative trials of risperidone and haloperidol in patients with schizophrenia showed that risperidone was as effective as haloperidol and was associated with a lower risk of EPS.^52-55 The emergence of EPS is dose dependent with risperidone;⁵⁵ thus doses should be slowly increased to clinical effect. Risperidone has been used to treat a variety of disorders in the elderly,⁵⁰ including schizophrenia and other psychoses,^56-59 psychosis associated with Parkinson's disease,^60,61 and psychotic and behavioral disturbances associated with dementia.^62-65 Risperidone has also been shown to improve cognitive functioning in elderly patients with psychosis.^63,64 The efficacious and well-tolerated dose of risperidone has been reported to be <3 mg/day in most elderly patients with schizophrenia⁵⁸ and 1-2.5 mg/day in demented patients.^62,64,65 Risperidone has shown promise in the treatment of psychosis and behavioral disturbances in elderly patients with dementia.^62-65 In a recent placebo-controlled, randomized study of risperidone in more than 600 elderly demented patients,⁶⁵ it was found to be significantly more effective than placebo in controlling psychotic symptoms and in reducing both the severity and frequency of aggressive behavior. The optimal dose of risperidone, in terms of both efficacy and tolerability, was 1 mg/day. In an analysis of data from 27 trials of risperidone, only four cases of tardive dyskinesia were identified among 3,298 patients treated with risperidone (probability of tardive dyskinesia = 0.0034 per treatment year).⁶⁶

Olanzapine is structurally similar to clozapine and, like clozapine, blocks a broad spectrum of receptors⁶⁷ and may have a side-effect profile that is difficult for elderly residents to tolerate (i.e., anticholinergic symptoms, sedation, dizziness, and orthostatic hypotension). This must be explored in upcoming clinical trials. When compared with haloperidol, olanzapine was associated with fewer EPS, but its propensity to cause EPS appears to be dose related and EPS may be seen with higher doses.^68,69 Olanzapine is not associated with persistent increased plasma prolactin levels or agranulocytosis. The efficacy of this novel antipsychotic in the treatment of schizophrenia has been demonstrated in double-blind trials that compared doses of 2.5-17.5 mg/day versus haloperidol and placebo.^68-70 Olanzapine has also been used successfully in patients with Parkinson's disease.⁷¹ However, in a study of patients with psychotic and behavioral symptoms secondary to Alzheimer's dementia, no improvement was seen with olanzapine compared with placebo.⁷²

Quetiapine, the most recently introduced atypical antipsychotic, has moderate 5-HT₂ receptor and weak D₂ blockade and reportedly lacks D₁ receptor activity.⁷³ In pre-clinical trials,⁷⁴ quetiapine was found to cause minimal EPS, anticholinergic effects, and orthostatic hypotension. There was no increase in prolactin levels and no apparent risk of agranulocytosis, but sedation was reported and judged to be due to an antihistaminic effect. A transient asymptomatic increase in liver enzymes of more than three times the upper limit of normal requires monitoring during therapy.⁷⁴ The half-life of quetiapine (approximately 6.5 hours) necessitates twice-daily dosing. Results of controlled clinical trials demonstrate that quetiapine at doses of 150-750 mg/day was efficacious and safe in the treatment of schizophrenia.^75,76 Its efficacy was not significantly better than that of haloperidol, but the severity of EPS was significantly less with quetiapine than with haloperidol. The efficacy, safety, and tolerability of quetiapine were studied in 151 elderly patients diagnosed with idiopathic (schizophrenia, bipolar disorder) and organic (psychoses associated with Alzheimer's disease and vascular dementia) psychoses.⁷⁷ Patients were treated with 25-800 mg/day of quetiapine for one year. Overall psychotic symptoms and positive and negative symptoms improved, with no difference between the two groups. Patients exhibited negligible EPS, and the drug was generally well-tolerated.

Investigational Atypical Antipsychotics

Pharmacoeconomics

A similar situation exists when economic considerations prohibit clinicians from using the high-priced atypical antipsychotic agents instead of the less expensive conventional agents. It is important to realize that the cheaper drug is not necessarily the most cost-effective. Drug expenditures constitute only a minuscule part (~1%) of the cost of treating mental illness.⁷⁸ Considered in the context of their impact on the total costs of mental health care, the atypical agents actually may be substantially more cost-effective than the conventional antipsychotic agents. This has been demonstrated for risperidone,^80-83 clozapine,^84-86 and olanzapine⁸⁷ in residents with schizophrenia.

Pharmacoeconomic studies of the atypical antipsychotic drugs in residents with dementia have not yet been published. Nonetheless, the potential for reduced health care costs exists for this population. A parallel might be found in a study in institutionalized adults with mental retardation and behavioral disorders. The expense of caring for such residents increases when aggressive behavior leads to assaults on staff members. Medical costs for the assaulted employee and overtime pay for other employees who must cover for the injured staff member add considerably to health care costs. In the study by Lott et al,⁸⁸ treatment with risperidone greatly reduced aggressive/assaultive, self-injurious, and property-destructive behaviors. In the six months after risperidone was begun, the number of workdays lost because of assault dropped 93% (444 to 29 days) compared with the previous six months. Additional savings were realized when residents whose maladaptive behaviors required one-on-one staffing no longer required such staffing. Based on the savings achieved by risperidone therapy in the first six months, the authors estimated that the first-year acquisition cost of risperidone would be completely offset by the savings.

Formal pharmacoeconomic studies are needed to confirm the expected cost benefit of atypical antipsychotics in reducing aggressive behavior in residents with dementia.

Conclusions

Unfortunately, antipsychotic medications have been used as "too much of a good thing." In the past, these medications were used for inappropriate indications and at inappropriate doses. Even when they are used optimally, older adults can suffer devastating complications from side effects.

It appears that the efficacy of the atypical antipsychotic agents, compared with that of the conventional agents, is better separated from their side effects, suggesting that they may be beneficial in residents with dementia. However, much remains to be learned about these agents and their distinctions from each other as well as from conventional antipsychotics, particularly in various patient populations. As clinical experience with the newer agents grows, clinicians will better understand the place of each of these drugs in the management of residents with dementia. This is an exciting and promising time for residents with dementia, their families, and their caregivers as we move toward improving the care and the quality of life for these residents.

Appendix

Joseph Belanga, RPh, Evergreen Pharmaceutical, Inc., Edmonds, Washington; William Burke, MD, University of Nebraska Medical Center, Omaha, Nebraska; Lawrence J. Cohen, PharmD, BCPP, FASHP, FCCP, FASCP, University of Oklahoma College of Pharmacy, Oklahoma City, Oklahoma; Kerry Cranmer, M.D, Oklahoma City, Oklahoma; Kari Franson, PharmD, Western University, Pomona, California; Donald Hay, MD, St. Louis University, St. Louis, Missouri; Kelly Hollenack, RPh., FASCP, NCS HealthCare, Inc., Dublin, Ohio; Michael Jann, PharmD, FCP, FCCP, Mercer University Southern School of Pharmacy, Atlanta, Georgia; Harlan Martin, RPh, CCP, FASCP, Pharma-Care, Inc., Clark, New Jersey; Alan Mason, RPh, Omnicare, Oklahoma City, Oklahoma.

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