Journal of Psychosocial Nursing and Mental Health Services

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Psychopharmacology 

Risks and Benefits of Antipsychotic Drugs in Elderly Patients with Dementia

Robert H. Howland, MD

Abstract

Memory impairment and other cognitive disturbances characterize dementia, but other noncognitive behavioral and psychiatric symptoms are very common. The most important behavioral and psychiatric symptoms associated with dementia (BPSAD) are agitation, aggression, and psychosis, and they have serious consequences for patients and caregivers. No medication has been approved for the treatment of BPSAD, but antipsychotic drugs are the best studied and most commonly used. However, in addition to these drugs’ expected side effects, cerebrovascular adverse events and death are two serious adverse effects associated with their use in dementia patients. This article highlights the studies examining the risks and benefits of antipsychotic drugs for BPSAD. Weighing small but significant risks compared with possible benefits is a complex treatment decision.

Abstract

Memory impairment and other cognitive disturbances characterize dementia, but other noncognitive behavioral and psychiatric symptoms are very common. The most important behavioral and psychiatric symptoms associated with dementia (BPSAD) are agitation, aggression, and psychosis, and they have serious consequences for patients and caregivers. No medication has been approved for the treatment of BPSAD, but antipsychotic drugs are the best studied and most commonly used. However, in addition to these drugs’ expected side effects, cerebrovascular adverse events and death are two serious adverse effects associated with their use in dementia patients. This article highlights the studies examining the risks and benefits of antipsychotic drugs for BPSAD. Weighing small but significant risks compared with possible benefits is a complex treatment decision.

Dr. Howland is Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania.

The author discloses that he has no significant financial interests in any product or class of products discussed directly or indirectly in this activity, including research support.

Address correspondence to Robert H. Howland, MD, Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213; e-mail: HowlandRH@upmc.edu.

More than 25 million people worldwide have dementia (Ferri et al., 2005). In the United States, the prevalence of dementia is approximately 5% to 15% among adults older than age 65 (Plassman et al., 2007). Memory impairment and other cognitive disturbances (i.e., aphasia, apraxia, agnosia, executive dysfunction) are the hallmark characteristics that define dementia, but other noncognitive behavioral and psychiatric symptoms are very common in these patients. The most important behavioral and psychiatric symptoms associated with dementia (BPSAD) are agitation, aggression, and psychosis, and they have serious, clinically relevant consequences for patients and caregivers (Jeste et al., 2008). BPSAD occur in more than 50% of patients with dementia living in the community and in more than 80% living in nursing homes (Steinberg et al., 2003; Testad, Aasland, & Aarsland, 2007). The lifetime risk of developing BPSAD approaches 100% (Lyketsos et al., 2000). The U.S. Food and Drug Administration (FDA) has not approved any medication for the treatment of BPSAD, but antipsychotic drugs are the most commonly used. Consistent with their general clinical popularity, the atypical second-generation antipsychotic drugs (SGAs) have been better studied and more often used than typical first-generation antipsychotic drugs (FGAs) in elderly patients with BPSAD.

The Effectiveness of Antipsychotic Drugs for BPSAD

Eight placebo-controlled randomized clinical trials (RCTs) have been conducted with FGAs and 18 with SGAs (Ballard & Howard, 2006; Jeste et al., 2008). The studies lasted 6 to 12 weeks; only two lasted for 6 months or longer. Most of the RCTs included the FGA haloperidol (Haldol®) or the SGAs risperidone (Risperdal®), olanzapine (Zyprexa®), quetiapine (Seroquel®), or aripiprazole (Abilify®). Approximately half of the clinical trials of antipsychotic drugs in dementia patients recruited individuals primarily with psychosis, whereas the other half selected individuals primarily with agitation or global behavioral disturbances. Because most trials of psychosis did not exclude agitation and most trials of agitation did not exclude psychosis, the vast majority of studies therefore included patients with an admixture of BPSAD.

Overall, SGAs appear to have modest efficacy at best for treating psychotic symptoms, and some studies did not find a significant advantage for active drug over placebo with respect to psychotic symptoms. Although some analyses suggested a better antipsychotic symptom benefit for risperidone, there was no clear difference in efficacy among the SGAs. Some RCTs, but not all, demonstrated modest efficacy for reducing aggression and agitation with antipsychotic drugs.

In direct comparison, only one of four nonplacebo-controlled RCTs found significantly greater efficacy with SGAs compared with the FGA haloperidol (Jeste et al., 2008). Despite the perceived greater tolerability, lesser risk for parkinsonian side effects, and lower risk for tardive dyskinesia of SGAs compared with FGAs, other potential side effects of SGAs in older adults include sedation, postural hypotension, gait disturbances, and falls. In the four comparative studies, haloperidol was associated with more parkinsonian side effects than were the SGAs. No large-scale studies of antipsychotic drug-associated obesity, diabetes, and other metabolic disturbances among elderly patients with BPSAD have been published. In recent years, however, two serious adverse events have been associated with the use of antipsychotic drugs in dementia patients: cerebrovascular adverse events (CVAEs) (e.g., stroke, transient ischemic attacks) and death.

Serious Adverse Events and the Use of Antipsychotic Drugs for BPSAD

Concerns about an increased risk of stroke associated with SGAs first arose in Canada in 2002 (Douglas & Smeeth, 2008). Based on RCTs available at that time, a warning that highlighted this risk was issued by Health Canada (a regulatory body in Canada similar to the FDA). In 2004, the Committee on Safety of Medicines (similar to the FDA) in the United Kingdom recommended avoiding the specific use of the SGAs risperidone and olanzapine in dementia patients (Mowat, Fowlie, & MacEwan, 2004).

In the United States, the FDA first issued a warning titled “Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients with Dementia” in 2003. This warning stated that CVAEs, including some deaths, were reported in elderly patients in the risperidone trials for BPSAD. In a combined analysis of data from three published placebo-controlled RCTs, 12 of 744 patients taking risperidone (1.6%) developed serious CVAEs, a rate significantly greater than the 4 of 562 patients taking placebo (0.7%). Four patients taking risperidone and 2 taking placebo died. In a second analysis that pooled data from three published and three unpublished placebo-controlled RCTs, the rates of serious CVAEs for risperidone (15 of 1,009 patients [1.5%]) and for placebo (4 of 712 patients [0.6%]) were not significantly different. Risperidone-treated patients, however, had significantly higher rates of nonserious CVAEs (18 of 1,009 [1.8%]) than did placebo-treated patients (4 of 712 [0.6%]) (Herrmann & Lanctot, 2005).

Soon after, the FDA (2005a, 2005b) applied a similar warning to olanzapine and aripiprazole. In five olanzapine RCTs, the relative risk of CVAEs was not significantly different than placebo. An analysis combining all 11 studies of risperidone and olanzapine found that 48 of 2,187 drug-treated study participants (2.2%) experienced CVAEs compared with 10 of 1,190 placebo-treated participants (0.8%), which was significantly different (Herrmann & Lanctot, 2005). In two other placebo-controlled trials, there was an increased incidence of CVAEs, including some deaths, in aripiprazole-treated patients (the specific incident rates were not reported). Analysis of data from two RCTs demonstrated no significant difference in CVAE rates for quetiapine (0.9%) compared with placebo (1.9%). A meta-analysis of all RCTs found that CVAE rates were significantly different for SGA-treated patients (1.9%) compared with placebo-treated patients (0.9%) (Schneider et al., 2006).

In April 2005, the FDA (2008) issued a new public health advisory warning about an increased risk of death associated with the use of SGAs compared with placebo in elderly patients with BPSAD. Analyses of 17 placebo-controlled RCTs (enrolling 5,377 patients for 10 to 12 weeks) revealed a risk of death in drug-treated patients (4.5%) that was significantly greater than that seen in placebo-treated patients (2.6%). According to the FDA, the causes of death varied. Most appeared to be related either to cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) causes. A published meta-analysis of 15 RCTs documented that the risk of mortality associated with SGAs (3.5%) was significantly greater than that associated with placebo (2.3%) (Schneider, Dagerman, & Insel, 2005). On the basis of Schneider et al.’s (2005) analysis, the FDA requested that the manufacturers of all SGAs include information about this risk in a Boxed Warning and in the Warnings section of the drugs’ prescribing information.

Most recently, the FDA issued an updated advisory in June 2008 extending its warning about risk of death to include FGAs. This warning was based on two published observational epidemiological studies that examined the risk of death in elderly patients treated with FGAs. Between April 1997 and March 2002, Gill et al. (2007) conducted a retrospective cohort study in Ontario, Canada of 27,259 elderly adults with a diagnosis of dementia. The study compared the risk for death with use of an SGA versus no anti-psychotic drug and the risk for death with use of an FGA versus an SGA. The use of SGAs was associated with increased mortality compared with no antipsychotic drug use, beginning as early as 30 days and persisting until study end at 180 days. In addition, FGA use was associated with a marginally higher risk of death compared with SGA use. The causes of death were not reported in this study.

In the second study, Schneeweiss, Setoguchi, Brookhart, Dormuth, and Wang (2007) conducted a retrospective cohort study in British Columbia, Canada of 37,241 elderly adults who were prescribed FGAs or SGAs for any reason (not just dementia) between January 1996 and December 2004. The study compared the 180-day all-cause mortality with use of an FGA versus an SGA. The risk of death in FGA-treated patients was comparable to, and possibly greater than, the risk of death in SGA-treated patients. The causes of death with the highest relative risk were cancer and cardiac disease. A more recent analysis of these data demonstrated that patients taking FGAs had significantly higher noncancer death rates attributable to cardiovascular, respiratory, nervous system, and other causes (Setoguchi et al., 2008).

Despite methodological limitations of epidemiological studies and the characteristics of the patient populations studied, the FDA concluded that the overall weight of evidence, including these and previous studies, indicated that the FGAs share the increased risk of death in elderly patients with BPSAD that has been observed for the SGAs. The FDA mandated that prescribing information for all antipsychotic drugs include the same risk information in a Boxed Warning and in the Warnings section.

Comparing Antipsychotic and Alternative Drugs for BPSAD

The management of BPSAD should always include non-pharmacological approaches, although their effectiveness has been demonstrated mostly in studies of patients with mild to moderate symptom severity (Ayalon, Gum, Feliciano, & Arean, 2006). The overuse or misuse of medications should be avoided. For more severe cases, however, it is not necessarily reasonable to stop prescribing medications completely because of safety concerns. Antipsychotic drugs, especially SGAs, have the best supporting evidence, even though their efficacy is modest and their side effects potentially more serious.

A clinically useful way of looking at efficacy and safety data from RCTs is through two statistical concepts: “Number Needed to Treat” (NNT) and “Number Needed to Harm” (NNH). NNT is the number of patients who need to receive a therapy to successfully treat one person. An NNT of one is ideal; a value of 10 or less is considered clinically significant. Similarly, NNH is the number of patients who would need to receive a therapy before a harmful outcome (e.g., a serious adverse event or death) would be seen. In the meta-analysis of RCTs for BPSAD, the NNT for SGAs ranged from 5 to 14 depending on the individual studies (Schneider et al., 2006). Hence, treating 5 to 14 patients with an SGA would be needed to benefit 1 patient. By contrast, the mortality NNH for SGAs was approximately 100 (Schneider et al., 2005). That is, for every 100 patients treated with an SGA, there would be one death due to the SGA. By combining the NNT and NNH calculations, the likelihood of benefit versus serious risk would be modest: For every 9 to 25 patients helped with SGAs, one death would be expected (Jeste et al., 2008).

There are relatively few evidence-based medication alternatives to the use of antipsychotic drugs. These RCTs have been limited to patients with mild to moderate symptoms. Among the FDA-approved treatments for dementia, there is only weak evidence for the use of cholinesterase inhibitors, such as donepezil (Aricept®) and rivastig-mine (Exelon®), and memantine (Namenda®) in the treatment of BPSAD (Howard et al., 2007; Maidment et al., 2008). A small number of RCTs of anticonvulsant drugs found some benefit for carbamazepine (Tegretol®) but not valproic acid (Depakene®, Depakote®) (Jeste et al., 2008). Several RCTs of the antidepressant drug citalopram (Celexa®) also demonstrated a significant benefit (Pollock et al., 2007). Limited evidence suggests that antipsychotic drugs are associated with a greater mortality risk in elderly patients with BPSAD compared with other psychotropic drugs (Kales et al., 2007).

Conclusion

Antipsychotic drugs should be used judiciously, after a careful assessment of risks and benefits. Weighing small but real risks (e.g., stroke, death) compared with possible benefits (e.g., being able to live in a less restricted environment) is a complex decision involving patients, families, and other caregivers. For BPSAD, nurses should be familiar with the relative risks and benefits of antipsychotic medications and possible alternative therapies. This knowledge will be important in their work with patients and families, assisting in the treatment planning process.

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Authors

Dr. Howland is Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania.

Address correspondence to Robert H. Howland, MD, Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213; e-mail: .HowlandRH@upmc.edu

10.3928/02793695-20081101-05

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