The optimal strategy for the treatment of behavioral complications in patients with probable Alzheimer's disease (AD) remains unclear. Prior studies from this group indicate that the neuroleptic haloperidol in doses above 4 mg daily cannot be tolerated by many AD outpatients, and that oral haloperidol 2-3 mg daily demonstrates significantly superior efficacy (61.1% response) to either oral haloperidol 0.5-0.75 mg daily (31.6% response) or placebo (26.3% response), with mild to moderate EPS as the main side effect. The proposed study involves two phases. In phase 1, 107 AD outpatients with behavioral complications will receive 16-20 weeks of open haloperidol treatment with an oral dose of 1-4 mg daily, titrated individually to achieve the optimal trade-off between efficacy and side effects. Responders to Phase 1 will participate in Phase 2, a 24-week continuation trial in which Phase 1 responders will be randomized to continuation haloperidol (n=30) or placebo (n=30). Measures of efficacy, side effects, and blood levels will be evaluated. This study will address three key issues: predictors of response (Phase 1), the need for continuation treatment (Phase 2), and predictors of relapse and time to relapse (Phase 2). In the critical Phase 2 continuation trial, we propose to test the following hypotheses: the relapse rate on haloperidol will be greater than that of placebo, longer duration of target symptoms and greater severity of residual symptomatology (end-Phase 1) will predict relapse in Phase 2. In Phase 1 open treatment, we will test the hypotheses that longer duration of target symptoms will predict poor response, haloperidol will impair neuropsychological performance on tests of motor ability but not other cognitive domains, and plasma haloperidol levels will show stronger associations than oral dose with changes in outcome measures. In addition, specific hypotheses will be tested about the relative treatment responsivity and likelihood of relapse in patients with predominantly behavioral versus psychotic target symptoms. The continuation trial will provide important clinical information on the trade-off between the likelihood of relapse and the persistence of side effects (including long-term side effects like tardive dyskinesia) in patients randomized to continuation haloperidol or placebo. Overall, this study will provide new information on the prediction of response to neuroleptics in behaviorally disturbed AD out patients, the first controlled data on the need for continuation neuroleptic treatment, and new information on predictors of relapse and time to relapse. These clinical data will be important in improving the management of AD patients with behavioral complications.
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