Drugs, Death, and Disconcerting Dilemmas

Because of pharmacodynamic and pharmacokinetic changes associated with aging, there are many more risks attendant to treating elderly patients with psychotropics. The FDA has recently issued black box warnings for older adults who may be at higher risk for adverse events than their younger counterparts. This article reviews the concerns associated with the use of antipsychotics in older patients.

Dementia

Concern about the inappropriateness of off-label prescribing of antipsychotics for older adults was magnified exponentially by the recent addition of an FDA black box warning for older adults with dementia to the prescribing information. In 2003, a warning was applied to risperidone(Drug information on risperidone) about its increased risk of “cerebrovascular adverse events, including stroke.” Soon thereafter, similar black box warnings for cerebrovascular adverse events were issued for olanzapine and aripiprazole(Drug information on aripiprazole). While the absolute risk difference was 1% to 2% between antipsychotic- and placebo-treated patients, the relative risk was approximately twice as high in the medication group.¹

Subsequently, the severity of the warnings escalated as data emerged of an increased risk of mortality in older persons with dementia treated with atypical antipsychotics. Specifically, the mortality black box warning reads, “Analyses of 17 placebo-controlled trials (modal duration of 10 weeks) in these patients [with dementia-related psychosis/agitation] revealed a risk of death in the drug-treated patients of 1.6 to 1.7 times higher than that of placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared with a rate of about 2.6% in the placebo group.”

Retrospective data analyses later convinced the FDA to extend this warning to typical antipsychotics. Perhaps this was to prevent increased use of typical antipsychotics in the absence of supporting evidence or as a medicolegal safety choice. In fact, in our review of large retrospective data analyses, 4 of 6 studies indicate a higher risk of death with typical antipsychotics than with atypical antipsychotics.²

The next logical question is, “What is the long-term risk, because most older adults with dementia who take antipsychotics do so for more than 10 weeks?” Ballard and colleagues³ conducted a study in the United Kingdom to address this important question. Patients on various long-term regimens of typical antipsychotics or risperidone were randomly assigned to continue treatment with antipsychotics or to convert their regimen to supposedly indistinguishable placebo pills for 12 months of double-blind follow-up. At 12 months, the modified intent-to-treat analysis found cumulative probability of survival 70% for those maintained on antipsychotics versus 77% for those whose regimen was switched to placebo—a 7% absolute risk difference in favor of placebo, but not statistically significant. Although the trial ended there, participants were followed naturalistically from 24 to 54 months. During this period, the mortality rate for participants who had been in the placebo group during the 12-month controlled experimental phase was considerably lower than that for participants in the antipsychotic group (eg, 71% vs 46% at 24 months; 59% vs 30% at 36 months; 53% vs 26% at 42 months).

These numbers seem alarming and worthy of further study, but there are limitations to applying them to patients with dementia in the general population. Only 1 atypical antipsychotic (risperidone) was included in the analysis, and there was no statistical difference in mortality during the controlled phase of the study. After the initial 12 months, the investigators had no idea what factors were at play with patients in each group—including whether persons originally taking antipsychotics stopped them or persons in the placebo group started taking antipsychotics. Nonetheless, the trends reinforce the notion that trial tapers off antipsychotics are a good idea whenever possible. The actual statistics, however, should probably not be used in quoting risks to patients/families until such data emerge in controlled trials.

CHECKPOINTS

■ Analyses of recent data indicate an increased risk of mortality in older persons with dementia treated with atypical antipsychotics compared with placebo.

■ Once a patient is clinically stable with an antipsychotic for a reasonable duration, a trial taper off the medication should be initiated. The dementia antipsychotic withdrawal trial, in which long-term–care residents with Alzheimer disease were randomized to continue their antipsychotic regimen or to have their regimen switched to placebo, found no significant differences in cognitive symptoms or global neuropsychiatric symptoms between the groups.

■ Antipsychotics can improve symptoms and quality of life for select older adults, but older adults’ sensitivity to the adverse effects of these medications warrants considerable vigilance.

Amid the concerns about the safety of antipsychotics for patients with dementia, additional disappointing news emerged from the Clinical Antipsychotic Trial of Intervention Effectiveness for Alzheimer Disease (CATIE-AD). CATIE-AD compared the effects of risperidone, olanzapine(Drug information on olanzapine), quetiapine(Drug information on quetiapine), and placebo in patients with Alzheimer disease who had psychosis and/or agitation.⁴ There was no difference in overall efficacy (time to treatment discontinuation) between any of the active treatment groups and the placebo group. The superior efficacy in symptom reduction with risperidone and olanzapine was offset by early treatment discontinuation secondary to adverse effects.

Other evidence also supports modest overall efficacy of atypical antipsychotics for psychosis and/or agitation in patients with dementia. When data for individual drugs were combined in a 2006 review of 15 randomized, controlled trials (RCTs), psychosis scores improved significantly in trials using risperidone; also, global neuropsychiatric symptoms improved with aripiprazole and risperidone.¹

Yet, even when antipsychotic therapy is effective, once a patient is clinically stable for a reasonable duration (perhaps 2 to 3 months—there is no evidence-based answer), a trial taper off the medication should be initiated. This suggestion is supported by recent data from the dementia antipsychotic withdrawal trial (DART-AD), in which long-term–care residents with Alzheimer disease were randomized to continue their current antipsychotic regimen or to switch their regimen to placebo and were followed for 12 months.⁴ There were no significant differences in cognitive symptoms or global neuropsychiat-ric symptoms—both of which worsened—between the groups. The only suggestion of between-group differences was less severe neuropsychiatric symptoms for participants maintained on antipsychotics who had relatively high baseline neuropsychiatric symptom severity.

The “graying” of America is no demographic secret, and as many as 50% of persons older than 85 years have some form of dementia (Alzheimer disease being the cause in at least two-thirds of cases). Neuropsychiatric symptoms are extremely common in dementia and often are the reasons caregivers/family members seek treatment—especially from psychiatrists. Psychosis occurs in approximately 40% of persons with Alzheimer disease, and agitation occurs in 80% or more of persons with dementia at some point.⁵ Although dementia is diagnosed on the basis of cognitive deficits, behavioral and psychological symptoms are often the primary cause of adverse outcomes in dementia—including increased caregiver morbidity, decreased patient and caregiver quality of life, and hastened patient institutionalization.⁶