Atypical Antipsychotics for Dementia-Related Behaviors

Atypical Antipsychotics for Dementia-Related Behaviors

Antipsychotic drugs have been the primary
psychopharmacological mainstay of treatment
for psychosis, agitation, and aggression in
Alzheimer Disease (AD) and other dementias.

Conventional antipsychotic drugs such as haloperidol have been supplanted by newer, atypical antipsychotics (risperidone [Risperdal], olanzapine [Zyprexa], quetiapine [Seroquel], ziprasidone [Geodon], aripiprazole [Abilify]), although no medication has an FDA indication for the treatment of behavioral symptoms in patients with dementia.1-5

During the past 3 years, a number of placebo-controlled clinical trials of atypical antipsychotics for behavioral symptoms have reported small treatment effect sizes coupled with adverse effects at rates that exceed those observed in placebo-treated patients.6,7 Results from some prospective randomized controlled trials of dementia and subsequent meta-analyses suggest that atypical antipsychotic pharmacotherapy is associated with an increased risk of mortal-ity and cerebrovascular adverse events (CVAEs).8,9 These developments have fueled an ongoing debate over the appropriate prescribing of antipsychotics.9-11

Widespread acceptance of atypical antipsychotics for psychosis and behavioral symptoms preceded the availability of a supportive evidence base. In light of ongoing controversies and recently published data, it is essential that clinicians understand the most current information about the use of atypical antipsychotics in patients with dementia.


Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD) was the first head-to-head, prospective, randomized, double-blind, placebo-controlled effectiveness study of atypical antipsychotic therapy in AD.7 The unique design measured outcomes associated with real-world prescribing of these medications to treat behavioral symptoms. The goal of the study was to determine the effectiveness and tolerability of 3 atypical antipsychotics (compared with placebo) in the treatment of dementia-related behavioral symptoms in patients residing in community settings. The multicenter trial was funded by the National Institute of Mental Health.

In the initial, 36-week phase of the study, outpatients with mild to severe AD and behavioral symptoms (delusions, hallucinations, aggression, agitation) of at least moderate severity were randomly selected to receive flexible dosing with olanzapine (n = 100), risperidone (n = 85), quetiapine (n = 94), or placebo (n = 142). (Aripiprazole and ziprasidone were not included in the study because they were not available in the United States at the time the trial was designed.)

The study population was moderately cognitively impaired (Mini-Mental State Examination score, 15 ± 5.8). The mean age was 77.9 ± 7.5 years. Baseline behavioral symptoms were of moderate severity (Neuropsychiatric Inventory score, 36.9 ± 18.3), and 60% of the study participants received adjunctive acetylcholinesterase inhibitor therapy at study entry.

Participants who responded adequately to therapy could continue the trial up to 36 weeks. If the physician determined that response was inadequate for any reason after the initial 2 weeks of therapy, treatment was discontinued. Patients whose therapy was discontinued could enter phase 2 of the trial wherein they would be randomly selected to receive one of the other antipsychotics or citalopram under double-blind conditions. Only phase 1 data have been published at this time.

The primary outcome was time to discontinuation of treatment for any reason in phase 1 of the study. In this study design, "time to discontinuation" was a composite outcome that incorporated the combined effects of efficacy, tolerability, and caregiver burden for each treatment condition.


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