According to the U.S. Department of Health and Human Services, in 2007, 88% of 1.4 million Medicare claims for second-generation antipsychotics (SGAs) in older adult nursing home residents were associated with a dementia diagnosis. Similar trends have been observed in Canada and Europe.1-4 In a retrospective analysis of medication data from older residents with dementia in 6 care homes in England, long-term (ie, >1 month) use of antipsychotics was the most frequent potentially inappropriate prescribing practice.3 In another study in 7 European countries and Israel, the overall prevalence of antipsychotic use among long-term care residents with dementia was 33%.1 Similarly, a recent literature review5 found that 22% to 86% of antipsychotic prescriptions to older individuals were off-label; this practice was particularly common for individuals with agitation.
Because of the aging population and widespread prescription of antipsychotics to older patients, clinicians need information on the relative risks of using these medications in this population. In the United States, all antipsychotics carry a FDA “black-box” warning of the increased risk of death in older adults with dementia. In addition, the risk of death is increased when prescribing antipsychotics to older adults with other conditions, such as Parkinson’s disease,6 and other safety and tolerability concerns, including falls and fractures, sedation, metabolic abnormalities, and extrapyramidal effects, are highly relevant to geriatric patients.
This 3-part review summarizes findings and recommendations on prescribing antipsychotics to older individuals with schizophrenia, bipolar disorder, depression, and dementia. This third and final installment:
- briefly summarizes the major studies and analyses relevant to prescribing antipsychotics to older patients with dementia
- provides a summative opinion on safety and tolerability issues in these older patients
- highlights the gaps in the evidence base and areas that need additional research.
Summary of benefits, place in treatment armamentarium
Behavioral and psychological symptoms of dementia (BPSD) include agitation, delusional beliefs, repetitive questioning, hallucinations, aggression, wandering, and various socially inappropriate behaviors.7 These occur almost universally in all types and stages of dementia.7 BPSD are among the most complex, stressful, and costly aspects of dementia care, and lead to a myriad of poor health outcomes, including excess morbidity, mortality, hospital stays, and early nursing home placement.8-11 Because BPSD usually occur across all types and stages of dementia,7,12-16 the prevalence of BPSD mirrors the overall prevalence of dementia.
Although all expert organizations, including the American Psychiatric Association,17 recommend nonpharmacologic strategies as first-line treatment for BPSD, for the most part, these recommendations have not been translated into standard clinical management or routine care.18 Because of a perceived lack of other options, the current mainstay of treatment is the off-label use of psychotropics such as antipsychotics. Of all the agents currently used for BPSD, SGAs have the strongest evidence base, although benefits are modest at best (standardized effect size 0.13 to 0.16).19,20 In terms of individual SGAs, only risperidone is indicated for aggression in Canada and in Europe (not in the United States); risperidone has the best evidence for efficacy, with a meta-analysis of 5 published randomized controlled trials (RCTs) reporting that risperidone is superior to other SGAs for aggression in dementia.21,22 As a class, first-generation antipsychotics (FGAs) have no clear evidence for BPSD as defined broadly; however, there may be slight benefit for haloperidol for aggression.23,24
Clinical Trials
Adverse effects. A meta-analysis of RCTs of SGAs found that, compared with placebo, SGAs have increased rates of several adverse effects. These include somnolence (17% drug vs 7% placebo; odds ratio [OR], 2.84; 95% confidence interval [CI], 2.25 to 3.58; P < .00001); extrapyramidal symptoms (13% drug vs 8% placebo; OR, 1.51; 95% CI, 1.20 to 1.91; P = .0005; primarily attributable to risperidone); abnormal gait (10% drug vs 2% placebo; OR, 3.42; 95% CI, 1.78 to 6.56; P = .0002; attributable to olanzapine and risperidone); edema (9% drug vs 4% placebo; OR, 1.99; 95% CI, 1.20 to 3.30; P = .008; attributable to olanzapine and risperidone); urinary tract infections/incontinence (16% drug vs 12% placebo; OR, 1.28; 95% CI, 1.02 to 1.61; P = .04); cognitive impairment measured as difference in Mini-Mental State Examination score (95% CI, 0.38 to 1.09; P < .0001)25; and stroke (1.9% drug vs 0.9% placebo, OR, 2.13; 95% CI, 1.20 to 3.75; P = .009).21,26
In the 42-site Clinical Antipsychotic Trials of Intervention Effectiveness Alzheimer’s disease RCT, 421 outpatients with Alzheimer’s disease and BPSD were randomized to an SGA (risperidone, olanzapine, or quetiapine) or placebo. Compared with placebo, SGAs had a higher rate of parkinsonism or extrapyramidal signs (olanzapine and risperidone groups); sedation; confusion/changes in mental status (olanzapine and risperidone); psychotic symptoms (olanzapine); and increase in body weight and body mass index.26
In the 2005 FDA black-box warning, pneumonia and cardiac adverse effects were cited as primary causes of death for patients with dementia taking SGAs. A subsequent observational study confirmed that use of either FGAs or SGAs in geriatric patients was associated with an increased risk of pneumonia, in a dose-dependent manner.27 Although there is limited data on cardiac adverse effects in older adults, especially those with dementia taking antipsychotics,28 1 observational study of nursing home residents29 found that those taking FGAs had a significantly higher risk of hospitalization for ventricular arrhythmia or cardiac arrest compared with those who were not taking FGAs. In contrast, there was no increased risk with SGAs.
Mortality. In 2005, the FDA announced that based on a reanalysis of 17 placebo-controlled trials (many of which were unpublished) that SGAs were associated with a 1.7-fold increase in mortality compared with placebo.30 As a result, the FDA issued a black-box warning for using SGAs in patients with dementia. The overall OR in a published meta-analysis of mortality with SGAs was 1.54 (1.06 to 2.23; z = 2.28; P = .02), with pooled events of 3.5% mortality vs 2.3% (drug vs placebo).21 This meta-analysis21 also included ad hoc analyses of haloperidol; using combined data from 2 contrasts of haloperidol (with risperidone and quetiapine; 243 patients receiving haloperidol and 239 receiving placebo) they also found 15 deaths (6.2%) with haloperidol and 9 (3.8%) with placebo, resulting in an OR of 1.68.