Pharmacological Management Of Behavioral Disturbance in Dementia: Atypical Antipsychotic Agents

26 Feb
2010

The atypical (“second-generation”) antipsychotic agents were introduced beginning in the 1990s and have largely supplanted the older, typical antipsychotic medications. The older drugs such as haloperidol decanoate (Haldol, Ortho-McNeil) and (GlaxoSmithKline) caused parkinsonian side effects (e.g., rigidity and tremor). The designation “atypical” refers to the relative lack of these extrapyramidal side effects with these medications.

The atypical antipsychotic agents include (Risperdal canadian, Janssen), drug olanzapine (Eli Lilly), (canadian Seroquel, AstraZeneca), (Geodon generic, Pfizer), and (Bristol-Myers Squibb/Otsuka). These agents have become the most widely used type of medication for BDD. The most commonly used of these medications for dementia are risperidone, quetiapine, and olanzapine (Table 5).

A number of small-scale, open-label studies have shown modest efficacy with reasonable tolerability for atypical antipsychotic agents in BDD. However, a small number of placebo-controlled trials have been published. For example, a six-week study of olanzapine in dementia revealed efficacy for 5- or 10-mg doses but worsening of behavior at a dose of 15 mg/day. A 12-week study of risperidone showed dose-related improvement in psychotic symptoms and agitation but also revealed greater levels of extrapyramidal symptoms at higher doses (up to 2 mg/day). A 52-week open-label study of quetiapine in elderly psychotic patients (with a mixture of diagnoses) revealed overall benefit as well as good tolerability with a mean dose of 138 mg/day.
Table 5   Dosing of the Most Commonly Prescribed Antipsychotic Agents in Dementia

• Risperidone (Risperdal, Janssen): 0.5-2 mg/day
• Quetiapine fumarate (Seroquel,AstraZeneca): 50-150 mg/day
• Olanzapine (Zyprexa, Eli Lilly): 2.5-7.5 mg/day

Reviewing the literature, Tariot et al. (2004) concluded that atypical antipsychotic agents were generally efficacious for agitation in dementia, with a less clear impact on psychotic symptoms, but they varied in their tolerability.

Sink et al. (2005) suggested that treatment with olanzapine or risperidone led to modest but significant reductions in behavioral symptoms and that psychiatric medications as a group had limited efficacy, with the atypical agents potentially showing the best results.

In a meta-analysis of all 16 published placebo-controlled trials of atypical antipsychotic agents for dementia, Schneider et al. (2006) concluded that aripiprazole and risperidone, but not olanzapine, showed efficacy. Smaller effects were noted in outpatients, who were presumably less ill; in patients with less severe dementia; and in those with psychosis. The overall dropout rate—about one third—did not differ between subjects who received active treatment or placebo.

Adverse events were typically somnolence and urinary tract infections or incontinence for all drugs. Extrapyramidal effects and gait disturbances were associated with risperidone and olanzapine, but increased injury, falls, and syncope were

not observed. Cognitive scores were worse in patients receiving atypical agents than in controls. There was an overall increased risk of cerebrovascular adverse events, especially with risperidone.

Recently, the Clinical Antipsychotic Trials in Intervention Effectiveness-Alzheimer’s Disease (CATIE-AD) showed limited efficacy and generally poor tolerability of atypical anti-psychotic medications in patients with dementia. The methodology of this large, double-blind, placebo-controlled study differed from most previous psychopharmacological trials in using duration of treatment as the primary outcome measure; that is, how long did the clinician and patient choose to maintain a particular medication? The study included olan-zapine, risperidone, and quetiapine as well as placebo.

The time to discontinuation of therapy attributable to a lack of efficacy favored olanzapine and risperidone over quetiapine and placebo. The time to discontinuation resulting from adverse effects favored placebo. There were no differences among the groups on the Clinical Global Impression of Change (CGI-C), a rating scale measure of effectiveness. The authors concluded that even though atypical antipsychotic medications were more effective than placebo, “adverse effects limited their overall effectiveness, and their use may be restricted to patients who have few or no side effects and for whom benefits can be discerned.”

Despite these results, it seems clear that individual patients do benefit from atypical antipsychotic therapy. The impact of BDD on quality of life is often so great that these risks are deemed acceptable, given the benefits in these cases. Some authors have suggested that patients with risk factors for stroke, early development of side effects, the “old-old” (over 85 years of age), and the frail are at greatest risk of experiencing negative effects from atypical antipsychotic medications.

In 2003, 2004, and 2005, the FDA issued several “black-box” warnings addressing atypical antipsychotic agents in dementia and suggested caution in their use. These warnings were issued to the medical community and the public in the form of advisories, and they mandated labeling changes in the package inserts of the affected medications. The initial warning cited an increased risk of cerebrovascular adverse events such as stroke and transient ischemic attacks in patients treated with risperidone and olanzapine. The magnitude of the increased risk was estimated at roughly two-fold to three-fold. Later, aripiprazole was added to the warning. This FDA review was prompted in part by an Australian study of risperidone that showed efficacy but an increased risk of cerebrovascular adverse events in patients with dementia.

An additional warning, published in 2005, addressed increased mortality (from all causes) in dementia patients treated with atypical agents as a class. This warning followed an FDA meta-analysis of all 17 placebo-controlled trials available at that time involving four different atypical agents. This analysis revealed the death rate from all causes (principally cardiovascular diseases and pneumonia) to be 1.6 to 1.7 times higher among patients taking an active drug compared with those taking placebo.

These concerns come amid other controversies surrounding the atypical antipsychotic medications, particularly their propensity to cause weight gain and to increase the risk of type-2 diabetes and other metabolic problems. The FDA has also addressed these concerns with changes in labeling that are not specific to dementia.

Table 6   Warnings Associated with Antipsychotic Agents Used to Treat Dementia

• Increased risk of cerebrovascular adverse events in dementia patients:
• risperidone (Risperdal, Janssen)
• olanzapine (Zyprexa, Eli Lilly)
• aripiprazole (Ability, Bristol-Myers Squibb/Otsuka)
• Increased mortality in dementia (entire class of atypical antipsychotic drugs)
• Risk of weight gain, type-2 diabetes mellitus, metabolic syndrome (not limited to dementia)

The methodology used in determining these risks has been controversial. Nevertheless, these warnings (Table 6) are part of the FDA labeling for all atypical antipsychotic drugs. Combined with the lack of an FDA indication, the warnings call for a special focus on documentation, informed consent, and monitoring for all patients with dementia who are taking atypical antipsychotic drugs.

Ironically, the older, typical (conventional) antipsychotic agents have not received similar black-box warnings despite abundant evidence that they pose greater risks than the atypical agents. A 2005 study revealed risks of death for patients with dementia who had been treated with the older drugs to be at least as great as that for atypical drugs. The authors advised against returning to the use of the conventional medications as a replacement for the newer agents.

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