Time to discontinuation for lack of efficacy was significantly longer for participants receiving risperidone(Drug information on risperidone) (26.7 weeks) or olanzapine(Drug information on olanzapine) (22.1 weeks) than for those receiving placebo (9.0 weeks). Notably, overall effectiveness (as measured by time to treatment discontinuation for any reason) was not significantly different between any of the active-treatment groups or the placebo group. Except for quetiapine(Drug information on quetiapine) (at a 56.5-mg dose), the mean daily dose of olanzapine (5.5 mg) and risperidone (1.0 mg) at the study's end point was within the usual accepted range for treatment of neuropsychiatric symptoms.
The lowest rate (5%) of intolerable adverse effects or death was seen in placebo-treated patients. Significantly higher rates of discontinuation for adverse effects were reported in all active-treatment groups: 24% in the group that received olanzapine, 18% in the group that received risperidone, and 16% in the group that received quetiapine.
Sedation occurred more frequently with active treatment than with placebo for all antipsychotics, while confusion and psychotic symptoms were observed at significantly higher rates with olanzapine than with placebo or the other atypical antipsychotic drugs. Treatment-emergent parkinsonism occurred more commonly in patients assigned to receive either olanzapine or risperidone. Although higher rates of parkinsonism and sedation were observed in the active-treatment groups, no differences in the incidence of falls, fractures, or injuries across all treatment groups were observed.
CATIE-AD was the first prospective head-to-head study to explore whether an association existed between atypical antipsychotic treatment and development of metabolic adverse effects in older adults with AD. The mean changes in weight and in blood glucose, total cholesterol, and triglyceride levels for risperidone, olanzapine, and quetiapine treatment groups were not significantly different from the observed changes in the placebo group. A small but significant increase in body mass index (BMI) and monthly weight gain was reported for participants receiving olanzapine (1.0 lb), quetiapine (0.7 lb), or risperidone (0.4 lb) during the study compared with a weight loss of less than 1 lb and 20.2 BMI units per month for those receiving placebo.
Although significant changes in serum glucose and lipid levels have not been reported in earlier short-term (6- to 12-week) placebo-controlled trials of atypical agents for dementia, the association of atypical antipsychotics with weight gain and metabolic abnormalities in younger patients has been a long-standing concern for clinicians treating older patients.12-14 Analyses of post-marketing reports of treatment-emergent hyperglycemia and diabetes in patients with schizophrenia or bipolar illness have identified the mean age at onset as between the third and fifth decades of life.15
The risk of significant metabolic effects appears to differ between atypicals. In younger patients, clozapine and olanzapine appear to be most commonly associated with hyperlipidemia and hyperglycemia, whereas aripiprazole(Drug information on aripiprazole) and ziprasidone(Drug information on ziprasidone) are least implicated.15 Risperidone and quetiapine have intermediate effects on weight gain and metabolic parameters. It remains unclear whether antipsychotic-induced metabolic effects are a class effect or a consequence of the interaction of antipsychotics with the complex diathesis of psychiatric illness, ge- netics, and dietary factors.16,17
GUIDELINES ON OFF-LABEL USE
Efficacy and Comparative Effectiveness of Off-Label Use of Atypical Antipsychotics, a publication of the Agency for HealthCare Research and Quality, retrospectively reviewed efficacy and safety of clinical trial data related to the most common off-label uses for the atypical antipsychotics: treatment of agitation in dementia, depression, obsessive-compulsive disorder, posttraumatic stress disorder, personality disorders, and Tourette syndrome.18 It was published online in January 2007 (http://effectivehealthcare.ahrq.gov/reports/topic.cfm?topic=8&sid=34&rType=3).
Data for the agitation in dementia analysis were drawn from randomized controlled trials in dementia, including the CATIE-AD study. Conclusions about the relative effectiveness of risperidone, olanzapine, quetiapine, and aripiprazole were in general agreement with results of a recently published meta-analysis of 15 placebo-controlled atypical antipsychotic trials that reported small but significant benefits on agitation and psychosis for risperidone and aripiprazole.19 A trend favoring the effectiveness of olanzapine for psychosis in dementia that did not reach statistical significance also was noted.
No conclusions were reached about quetiapine or ziprasidone use in dementia. Design and outcome measures of the 3 available trials of quetiapine for dementia were too different to be included in the analysis, and no randomized controlled trials have been conducted for ziprasidone in dementia.