Vol. 4, No. 8 / August 2005

Managing dementia:
Risks of using vs. not using atypical antipsychotics

• Take everyone off atypicals? • Investigating other treatments • When to try medication • Educating patients, families • Dosing atypicals in older patients

Don’t let medicolegal concerns dictate dementia treatment, these five experts advise. Here’s what they recommend to protect patients and yourself.

Senior editor 

Assistant editor 

A typical antipsychotics may increase mortality in older patients, as the FDA warns. Yet no proven alternatives exist to manage dementia’s behavior problems, say geriatricians interviewed by Current Psychiatry.

“I’ve had calls from psychiatrists in nursing home practices and primary care physicians,” says Sumer Verma, MD, associate professor of psychiatry, Boston University School of Medicine. “They ask, ‘Should I take everyone off atypicals?’ ‘Should I try benzodiazepines or cholinesterase inhibitors?’”

To answer these and other questions, we interviewed Dr. Verma and:

• Murray Raskind, MD, director, Alzheimer’s Disease Research Center, University of Washington, Seattle

• Pierre Tariot, MD, professor of psychiatry, University of Rochester (NY) Medical Center

• Bruce Pollock, MD, head of the division of geriatric psychiatry, University of Toronto

• Patricia Recupero, JD, MD, clinical professor of psychiatry, Brown University, Providence, RI.

This report summarizes their insights on whether to change atypical antipsychotic prescribing patterns, when to use medication to control dementia-related behaviors, and how to balance the medical risks against the benefits of controlling or preventing violent behavior.

To address prescribers’ fears about possible malpractice claims, these experts also offer advice on explaining antipsychotics’ risks to patients’ families and documenting these discussions.

Take everyone off atypicals?

In April, the Food and Drug Administration (FDA) ordered a black box on the labels of atypical antipsychotics and olanzapine-fluoxetine combination tablets stating that these agents may increase the risk of death from stroke, heart attack, or other causes in older patients (Box 1).

The warning does not prohibit off-label use of atypicals, and Dr. Verma says if the dementia patient’s behavioral symptoms are well-controlled, stay the course. The other psychiatrists we interviewed agree but differ about how long to continue antipsychotic therapy.

Nothing works as well. Little or no evidence supports using other psychotropics for short-term management of severe dementia-related behaviors.

“Right now, atypical antipsychotics remain the drugs of choice,” Dr. Pollock says. “It seems perverse that a clinician, acting out of medicolegal fears, would use a medication for which there is no evidence of efficacy—simply because it doesn’t have a black-box warning.”

But atypicals are not silver bullets, Dr. Tariot adds. Aripiprazole,¹ olanzapine,^2,3 and risperidone^4-6 have shown efficacy for treating agitation in dementia but with differing levels of tolerability. Trials of quetiapine in dementia have been more positive.^7,8

Balancing risks. Data reviewed by FDA showed increased incidence of deaths from cardiac, cardiovascular, and cardiopulmonary causes (Table 1).⁹ These risk factors, however, are prevalent in elderly persons independent of medication.

“If you’re 85 and you don’t have underlying heart disease, you’re a very unusual person,” Dr. Raskind says. “So, there’s no evidence of a substantial risk for acute cardiac events from the atypicals.”

On the other hand, consider the risk of a patient becoming agitated or violent. Dr. Recupero recommends weighing acute risks against the potential for long-term cardiac complications.

“Harm to others and harm to the patient from getting into an altercation and injuring himself is a current, acute, and severe risk,” says Dr. Recupero, adding that these risks could lead to hospitalization in a state facility—a more-restrictive and isolated environment than most long-term care facilities.

Dr. Verma notes that drug-drug interactions are less prevalent with atypicals than with other psychotropics—no minor consideration for a population in which polypharmacy is prevalent.

Dr. Raskind acknowledges that some atypicals increase the risk of weight gain and diabetes but adds, “Metabolic problems are a bigger concern in younger people. Vascular disease can develop over 10 or 20 years, but worrying about that in a person who’s age 85 is probably being overly cautious.”

“Almost all drugs have some down side, but that doesn’t mean that they shouldn’t be used,” Dr. Raskind adds. “They just have to be used appropriately. And the rationale for accepting the risk-benefit ratio has to be clearly documented” (Box 2).

Investigating other treatments

Mood stabilizers have reduced aggressive dementia-related behaviors in some small studies:

• Divalproex, 250 to 1,500 mg/d, showed efficacy in treating aggressive behaviors across 6 weeks in a placebo-controlled study of 56 patients.¹⁰

• Valproate, 250 to 1,500 mg/d, decreased the baseline mean Brief Psychiatric Rating Scale (BPRS) Agitation Factor score by 3.1 points in a 6-week, open-label extension involving 56 patients.¹¹

• Carbamazepine, 300 mg/d, also showed short-term efficacy against agitation in dementia in a trial of 51 nursing home patients. Across 6 weeks, the mean total BPRS score decreased by 7.7 points among the treatment group, compared with a 0.9-point decrease among those taking placebo.¹²

Dr. Raskind, however, says more research is needed before mood stabilizers can be considered a treatment option for aggression in dementia.

The glutamate inhibitor memantine, 10 mg bid, was shown to improve behavioral symptoms in patients with moderate to severe Alzheimer’s disease, based on Neuropsychiatric Inventory scores.¹³

The cholinesterase inhibitor galantamine, 8 to 24 mg/d, also helped control mild to moderate agitation or psychosis in retrospective, placebo-controlled studies.^14,15 Dr. Raskind, however, says patients with more-severe behavioral symptoms were excluded from these trials. Dr. Verma says cholinesterase inhibitors have shown benefit in long-term dementia treatment, but not for acute short-term use.

Benzodiazepines may provide short-term relief from agitation in dementia, but Dr. Raskind warns these sedating agents increase the risk of unsteadiness and falls in older patients.^16,17

Newer nonhypnotic sleep medications—zolpidem, eszopiclone, and zaleplon—may help manage dementia-related behaviors by improving sleep, but Dr. Pollock says these agents have not been studied for this purpose.

Dr. Pollock adds that selective serotonin reuptake inhibitors (SSRIs) have shown some effectiveness in controlling dementia-related behaviors, but evidence is limited.^18,19 He prescribes citalopram when comorbid anxiety symptoms fuel agitation or if depressive symptoms are present. Because SSRIs have been associated with increased risk of internal bleeding, Dr. Pollock says not to use them in stroke patients who are receiving anticoagulant therapy.

“To devise better pharmacologic approaches, we need more research to define what’s causing these behaviors at a biologic level,” Dr. Raskind says. “Perhaps this controversy will stimulate us to develop better and safer treatments.”

When to try medication

Dr. Raskind says he considers medication when a patient with dementia:

• experiences delusions and/or hallucinations

• shows irritability or pressured motor activity, suggesting emotional distress

• is aggressive, assaultive, or highly disruptive and endangers others.

Dr. Tariot adds that he would also consider medication if the patient is not eating.

Before starting an antipsychotic, make sure that an environmental or psychosocial stressor or medical condition is not fueling the aggression. “This behavior has a meaning,” Dr. Tariot says. “It’s up to us to discover that meaning and find out what we can do to help.”

Watch for medical causes. Dr. Pollock advises examining for medical causes of agitation, such as a urinary tract infection or respiratory disorder. “A change in behavior is often the first sign of a medical problem,” he notes. [See “When ‘agitation’ spells a medical problem,” Current Psychiatry, February 2005.]

Also check whether a drug the patient is taking for a medical condition—such as warfarin or digoxin—is causing anticholinergic effects. To justify using an atypical antipsychotic, “you need to be clear that behavior is a direct result of the psychosis, that the patient is acting on delusions or hallucinations,” Dr. Pollock adds.

Eliminate environmental stressors. An older patient’s difficulties with vision, hearing, and/or speech can increase his or her frustration and trigger behavior problems, Dr. Verma says.

“If I cannot hear or see well and I vaguely see lips moving but hear no sound, I assume that you are whispering about me,” Dr. Verma says. “That’s where paranoia begins. It is treated with a hearing aid, not an antipsychotic.”

Dr. Verma warns against prescribing a psychotropic to eliminate behaviors that are problematic but not dangerous. “Inappropriate voiding, being foul-mouthed, etc., can be controlled a lot of other ways than using medication.” He suggests, for example, posting large signs to help incontinent patients find the bathroom.

More-frequent visits from family members and increased attention from staff can help the patient adjust to a nursing home and decrease the risk of inappropriate behaviors, Dr. Pollock notes.

Dr. Verma urges clinicians to continue environmental manipulation after medication is started: “You still must make sure that there are no cords or rugs to trip over, the patient’s surroundings are brightly colored, and sound is appropriately modulated because of the patient’s poor hearing.”

Educating patients, families

Family members—who often make treatment decisions on an older patient’s behalf—need to understand atypical antipsychotics’ risks and benefits. Dr. Recupero recommends giving them handouts describing the medication’s action, side effects, and contraindications during the risk/benefit discussion. Document the family’s comments and apprehensions in the chart.

“A signed consent form is not a substitute for an informed consent discussion,” Dr. Recupero warns. “It is better to record that you had a comprehensive discussion and top it off with a signed consent.”

If the patient or proxy agrees to an atypical antipsychotic after the risk/benefit discussion, Dr. Recupero suggests keeping the patient on the atypical if anticipated clinical gains are realized.

If new evidence arises about risks of medications the patient is taking, be sure to discuss these risks with the patient or proxy as appropriate. “Informed consent is a process, not an event,” Dr. Recupero says.

Dosing atypicals in older patients

When prescribing antipsychotics to older patients, Dr. Verma says the adage “start low and go slow” cannot be overemphasized.

“I could be a lot more aggressive when treating a 30-year-old person with schizophrenia who is in much better metabolic health,” Dr. Verma says. “By contrast, an older person’s adaptive reserve is diminished.” Table 2 lists suggested first-line dosing strategies for managing dementia’s behavioral and psychotic symptoms, based on Dr. Verma’s clinical experience.

Dr. Verma recommends titrating more quickly for patients who are significantly distressed but more gradually for someone who is moderately stressed or agitated. “You’ve got to monitor the situation,” he says “There’s no formula for titration.” If the patient still does not respond or cannot tolerate the medication, he says, “I might switch to another atypical antipsychotic.”

Before switching, Dr. Raskind says, find out if an underlying medical condition or other medication is thwarting the antipsychotic’s efficacy. Again, check for and modify environmental triggers.

Dr. Pollock would avoid giving an atypical to a patient who recently had a heart attack or stroke but would not rule out “a small dose of an atypical” if the behavior were life-threatening.

Reassessing need. Dr. Pollock suggests re-evaluating the prescription every 4 months. Assess response to the medication, risk factors, and consequences of recurrent behavior problems. Consider reducing the dosage or discontinuing the atypical if the patient is stable, then monitor for relapse.

Dr. Verma, however, advocates continuing the atypical at the lowest possible dosage to maintain therapeutic effect and prevent recurrence of problem behaviors. After prescribing the atypical, he suggests waiting at least 4 weeks before reducing the dosage in patients with a history of rapid decompensation, unpredictable behavior, and extremely aggressive and dangerous episodes. Wait 1 to 3 weeks before reducing the dosage for patients who were stable before the episode. Bring the dosage back up if behavior problems resurface.

Related resources

• Sink KM, Holden KF, Yaffe K. Pharmacological treatment of neuropsychiatric symptoms of dementia. A review of the evidence. JAMA 2005;293:596-608.

• Straus SM, Bleumink GS, Dieleman JP, et al. Antipsychotics and the risk of sudden cardiac death. Arch Intern Med 2004;164:1293-7.

• U.S. Food and Drug Administration, Center for Drug Evaluation and Research. Atypical antipsychotic drugs information. www.fda.gov/cder/drug/infopage/antipsychotics/default.htm.

Drug Brand Names

Aripiprazole • Abilify
Carbamazepine • Tegretol
Citalopram • Celexa
Divalproex • Depakote
Eszopiclone • Lunesta
Galantamine • Reminyl, Razadyne
Haloperidol • Haldol
Memantine • Namenda
Olanzapine • Zyprexa
Olanzapine-fluoxetine • Symbyax
Quetiapine • Seroquel
Risperidone • Risperdal
Valproate • Depakene
Zaleplon • Sonata
Ziprasidone • Geodon
Zolpidem • Ambien

References

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15. Cummings JL, Schneider L, Tariot PN, et al. Reduction of behavioral disturbances and caregiver distress by galantamine in patients with Alzheimer’s disease. Am J Psychiatry 2004;161:532–8.
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