The Use of Antipsychotics in Patients with Dementia

by Eleanor Roberts, PhD

Up to 15% of adults aged over 65 are diagnosed with a form of dementia, the most prevalent of which is Alzheimer’s disease (AD). AD currently affects around 4.5 million Americans, and with nearly 100,000 deaths annually, it is the fourth leading cause of mortality in the United States. September 21st was World Alzheimer’s Day and one of the many issues surrounding the management of this disorder is the use of antipsychotics in those affected. Symptoms including delusions, hallucinations, agitation, and aggression occur in 60% to 80% of people with AD.(1) It is important to note that currently, there are no FDA-approved drugs for the treatment of dementia-related psychosis (including all types of dementia).

Following an April 2005 notification regarding just atypical antipsychotics, on June 16, 2008, the FDA issued a notification that “both conventional and atypical antipsychotics are associated with an increased risk of mortality in elderly patients treated for dementia-related psychosis.”(2) With this in mind, it is vital to question if antipsychotics are effective in controlling symptoms in elderly people with dementia, and if the effectiveness is significant enough to justify use despite the adverse event profile. While a full debate is beyond this piece, we examine two recent studies that address the issues of efficacy for specific symptoms and potential short-term danger for serious adverse events.

As part of the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD) study, Sultzer et al(3) examined the effectiveness of olanzapine, quetiapine, risperidone, or placebo on symptoms related to psychosis and agitated/aggressive behavior. This study involved 421 patients diagnosed with Alzheimer’s disease (mean age 77.9). They investigated a variety of symptoms using a number of rating scales including the Neuropsychiatric Inventory (NPI) (measuring psychosis, agitation/aggression, and depression among other factors), the Brief Psychiatric Rating Scale (BPRS) (which is concerned with psychiatric and behavioral symptoms), and the Clinical Global Impression of Change (CGIC) (which is based on a clinician’s rating of cognitive, behavioral, and functional changes).

The results showed that both olanzapine and risperidone produced significantly greater positive changes from baseline on the NPI (p < .001) compared to placebo, but only risperidone led to significant differences (p = .007) on CGIC ratings. There were no significant differences on the total BPRS score for any antipsychotic; however, when examining specific BPRS measures, patients on olanzapine or risperidone showed greater improvements on “hostile suspiciousness,” and with risperidone only on “psychosis,” and, to a lesser extent, “agitation.” Patients on olanzapine had worsening BPRS scores for “withdrawn depression” (although this was not shown on another depression scale), and they also showed “worsening of functional ability” compared to placebo on the Activities of Daily Living Scale. The authors concluded that “patients may benefit symptomatically from treatment with atypical antipsychotic medications,” especially for “suspicious thoughts, paranoid delusions, and hostile or aggressive behaviors.” Hence, without taking into consideration safety concerns, this study does show some benefits for this cohort; however, these vary according to symptom manifested and antipsychotic used.

The observational studies on which the June 2008 FDA notification(2) was based dealt with mortality rates only (at 30-180 days following antipsychotic administration), and only one of the studies examined elderly patients with dementia,(4) with the other including any elderly patients who had been newly prescribed an antipsychotic.(5) In contrast, a study published in May of this year by Rochon and colleagues(6) examined the occurrence of all serious adverse events (SAEs) that resulted in acute care or death within 30 days of the start of an antipsychotic regimen. This population-based retrospective cohort of older adults with dementia separately compared community-dwelling adults and those in nursing homes to matched controls. The types of SAEs were mostly unspecified, but they included hip fractures, extrapyramidal symptoms, and any cerebrovascular event, as well as death.

The investigators found that 13.9% of the community-dwelling adults prescribed an atypical antipsychotic (n = 6894) had an SAE within 30 days of initiation, with an odds ratio (OR) of 3.19 compared to controls. The mortality rate was 2.7% compared to 1.2% of controls. Corresponding figures for those on conventional antipsychotics (n = 6894), were all higher, with SAEs occurring in 16.0%, leading to an OR compared to controls of 3.81, and death occurring in 4.6% of patients. In the nursing home group, 9.4% of those on atypicals and 11.6% on conventionals (n = 6853 each) experienced an SAE, with respective ORs of 1.92 and 2.48 compared to controls, and mortality rates of 5.2% and 6.5% compared to 3.3% in controls.

The study concluded that there was an increased chance of an SAE (including mortality) for all antipsychotics, with higher percentages being shown in those taking conventional antipsychotics. This extends the finding of the studies used to justify the FDA warning(4,5) to show that the use of antipsychotics can lead to other SAEs besides death, and that these can occur within 30 days of antipsychotic administration. There was a decreased incidence of SAEs in nursing home residents, which may indicate that careful monitoring of patients from initialization of antipsychotic therapy is essential and could reduce the amount of SAEs in community-dwelling adults.

These are just two new studies of many that address the issue of off-label antipsychotic prescribing in people with dementia. They show that even though these medications can be useful, they appear to have different rates of effectiveness according to the antipsychotic chosen and the symptoms targeted. The CATIE-AD study(3) concluded: “whether the potentially beneficial effects of symptom reduction with antipsychotic treatment outweigh other undesirable clinical or adverse effects depends on an individual patient’s circumstances, including severity of symptoms, vulnerability to adverse effects, and the effectiveness or opportunity for behavioral interventions.”

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References

1. Jeste DV, Blazer D, Casey D, et al. ACNP White Paper: update on use of antipsychotic drugs in elderly persons with dementia. Neuropsychopharmacology 2008;33:957-970.
2. U.S. Food and Drug Administration. Information for Healthcare Professionals: Antipsychotics. FDA Alert 6/16/2008. http://www.fda.gov/CDER/drug/InfoSheets/HCP/antipsychotics_conventional.htm. Accessed 9/19/2008.
3. Sultzer DL, Davis SM, Tariot PN, et al. Clinical symptom responses to atypical antipsychotic medications in Alzheimer's disease: phase 1 outcomes from the CATIE-AD effectiveness trial. Am J Psychiatry 2008;165:844-854.
4. Gill SS, Bronskill SE, Normand SL, et al. Antipsychotic drug use and mortality in older adults with dementia. Ann Intern Med 2007;146:775-786.
5. Schneeweiss S, Setoguchi S, Brookhart A, et al. Risk of death associated with the use of conventional versus atypical antipsychotic drugs among elderly patients. CMAJ 2007;176:627-632.
6. Rochon PA, Normand SL, Gomes T, et al. Antipsychotic therapy and short-term serious events in older adults with dementia. Arch Intern Med 2008;168:1090-1096.