Atypical Antipsychotics
Most initial published data on atypical antipsychotic drugs in the elderly are clinical trials in nondemented patients with schizophrenia or Parkinson’s disease. In the last two to three years, controlled trials evaluating risperidone (Risperdal) and olanzapine (Zyprexa) in patients with dementia have been published. There is now evidence that these two atypical antipsychotic drugs offer efficacy in this patient population with fewer adverse effect concerns than the typical antipsychotic drugs.
Risperidone (Risperdal). In 1999, Katz et al. published the first large multicenter, double-blind, placebo-controlled study of risperidone in treating psychosis and behavioral disturbances in an elderly demented population. Among the 625 patients, 73% had a diagnosis of Alzheimer’s disease; average age was 83 years; and their mean baseline Mini-Mental State Examination (MMSE) score was 6.6+6.3, indicative of the most severe stages of dementia. In this 12-week trial, patients received either placebo or risperidone 0.5 mg, 1 mg or 2 mg daily. At endpoint, significantly greater reductions in Behavioral Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD) total scores, as well as the psychosis and aggressiveness subscale scores were seen in patients receiving daily doses of 1 mg (p=0.005) and 2 mg (p=0.001) of risperidone compared to those receiving placebo. The 0.5 mg daily dose of risperidone was superior to placebo at week 12 in reducing BEHAVE-AD aggression scores (p=0.02). Improvement based upon total BEHAVE-AD scores for risperidone 1 mg or 2 mg was 56% in patients under 85 years old and 72% in older patients, while placebo response rate was 51% and 54%, respectively. While risperidone was clearly efficacious, the high placebo response rate indicates what Schneider (1999) described as “the waxing and waning and evanescence of disruptive behavior” in this patient population. The most common adverse effects from risperidone were motor symptoms, dose-related sedation and mild peripheral edema. Extrapyramidal symptoms did not differ significantly between placebo and risperidone 0.5 mg or 1 mg. Risperidone 2 mg daily produced significantly more parkinsonism and hypokinesia than placebo.
A 13-week study compared risperidone and haloperidol (flexible doses of 0.5 mg to 4 mg; 1 mg mean daily doses for both drugs) to placebo in 344 patients with dementia. At week 12, a reduction of 30% in the BEHAVE-AD total score was observed in 72%, 69% and 61% of patients receiving risperidone, haloperidol and placebo, respectively, and in 54%, 63% and 47% of patients by intention-to-treat analysis (no statistically significant difference). At endpoint, risperidone-treated patients did have significantly greater reductions in the aggressiveness scores compared to placebo. The most common adverse effects for both haloperidol and risperidone were sedation and falls, with haloperidol causing significantly more extrapyramidal effects.
Olanzapine (Zyprexa). In 2000, Street et al. published a large double-blind, randomized, placebo-controlled trial evaluating olanzapine in patients with Alzheimer’s disease. In this six-week trial, 206 patients were given placebo or a fixed olanzapine daily dose of either 5 mg, 10 mg or 15 mg. Mean baseline MMSE scores were 6.7+6.4, indicating severe dementia. Significantly greater improvements in agitation/aggression and delusions/hallucinations were observed in patients treated with olanza-pine 5 mg or 10 mg compared to placebo and olanzapine 15 mg. The most improvement was seen in patients treated with 5 mg. The total MMSE score did not change significantly over the course of the clinical trial, although there was a modest improvement in the 5 mg dose group and a modest decline in the 10 mg and 15 mg dose groups. Somnolence was the most common dose-related adverse effect, occurring in 25% to 36% of olanzapine-treated patients compared to 6% with placebo. Gait disturbance occurred in patients receiving 5 mg or 15 mg (20% and 17%, respectively), compared to 2% with placebo. There was no significant cognitive impairment, increase in extrapyramidal effects or central anticholinergic effects at any olanzapine dose compared to placebo. Vital signs and laboratory and electrocardiogram measures were unchanged in each dose group compared to placebo.
Discussion
The modest efficacy of conventional antipsychotic drugs in patients with dementia, coupled with their high potential for extrapyramidal effects, tardive dyskinesia, anticholinergic effects and worsening cognition has meant that many patients’ behavioral symptoms and psychosis have been inadequately treated. The atypical antipsychotic drugs, notably risperidone and olanzapine, now have evidence supporting their efficacy and lower potential for adverse effects. Daily doses of no more than 1 mg to 2 mg of risperidone or 5 mg to 10 mg olanzapine can provide significant therapeutic benefit without the risk of significant adverse effects compared to conventional antipsychotic drugs.
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