Objective: Antipsychotics comprise the bulk of long-term care prescriptions for psychotropic drugs. Over the past decade atypical antipsychotics have largely replaced conventionals in this area. Yet this is an off-label use and there are few clinical trials of atypicals in this population. We conducted independent systematic reviews (i.e., meta-analyses) of atypical antipsychotics and haloperidol trials in people with dementia in order to better understand their methods and limitations and to quantify, where possible, evidence for efficacy, extent of adverse events, and estimate effectiveness. Previously work has not dealt with this systematically or quantitatively, has been company-sponsored limited analyses, or antedated the atypical trials.
Design and Methods: Established methods were used for searching and abstracting materials (Cochrane, 2002). Randomized, placebo-controlled, double blind clinical trials of atypicals and haloperidol - when compared to atypicals - were selected. Trials were compared, ITT outcomes were combined, and effect sizes calculated using standard techniques and expressed as standardized mean differences, d, and rate differences (Borenstein et al 2002). In addition deaths across all antipsychotics, and cerebrovascular events within the risperidone trials were assessed.
Results: The following reported trials were identified: 3 risperidone in nursing homes: 2 olanzapine; one each quetiapine and tiapride; and 3 haloperidol comparisons. Unreported and ongoing trials were identified as well. Inclusion criteria varied from only patients with AD to allowing other dementia, as did critical symptoms from requiring only mild agitation to the presence of psychosis. Interventions were with fixed, adjusted, or individualized dosing of medications. Trial lengths were generally 10-12 wks (range, 3 to 12 wks). Outcomes included global impressions, rating scales, compliance and adverse event ratings. Risperidone and haloperidol contrasts allowed for statistical combining, the few trials reported for the other drugs allowed only for an assessment of selected adverse events.
839 NH patients were included in the risperidone, 1 mg/d contrasts. Patients had agitation or aggression, not necessarily psychosis; about 70% had AD and 22% had vascular dementia; trials were 12 wks. Risperidone had clear incremental effects over placebo for clinical scale change and for 30% improvement (0.23 d, 95% CI [0.10, 0.37] and 0.13 rate difference [0.01, 0.24]). The modest effects were attenuated somewhat by non-completion in both groups and accumulated serious adverse events in this medically compromised population. The single 2 mg/d fixed dose comparison markedly increased adverse events, to the extent of negating overall effectiveness compared to 1 mg/d
Conclusion: Individual patient meta-analyses are needed as well as significant changes to clinical trials methods in order to better assess effectiveness, in contrast to efficacy, of these drugs in dementia.
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