Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease
Schneider LS, Tariot PN, Dagerman KS, Davis SM, Hsiao JK, Ismail MS, et al.;
Commented by , 26 Oct 2006
Aim of the study
Assess the effectiveness of second-generation (atypical) antipsychotic drugs in outpatients with Alzheimer’s disease (AD) demonstrating psychosis, aggression or agitation.
Method
42-site in the USA, double-blind, randomized trial comparing olanzapine (mean dose 5.5 mg per day), quetiapine (mean dose 56.5 mg per day), risperidone (mean dose 1.0 mg per day) to placebo over 36 weeks. Doses were adjusted as needed. Subjects had MMSE between 26 and 5 and had to have signs and symptoms of psychosis, aggression or agitation nearly daily over one week or intermittently over four weeks.
Main outcomes were time to discontinuation of treatment for any reason and number of patients with minimum improvement on the Clinical Global Impression of Change (CGIC) at 12 weeks.
Results
421 subjects were randomized and received at least one dose. There was no significant difference among treatments for time to discontinuation for any reason (range of 5.3 to 8.1 weeks, P=0.52). Time to discontinuation due to lack of efficacy favored olanzapine (22.1 weeks) and risperidone (26.6 weeks) compared to quetiapine (9.1 weeks) and placebo (9.0 weeks) (P=0.002).
More patients on antipsychotic (range 16 to 24%) than placebo (5%) discontinued due to intolerability (P=0.009). No significant differences were found in regard to improvement on the CGIC (range of 21 to 32%, P=0.22) at week 12, at which time 63% of subjects had discontinued treatment.
Professor Gauthier's comments
The authors conclude that adverse effects offset advantages of atypical antipsychotic drugs for the treatment of psychosis, aggression and agitation in AD. They acknowledge the following limitations of the study: doses were lower than some clinicians would have used, patients could be discontinued (main end point) and switched randomly to another of the study drugs. The rate of discontinuation of treatment ranged from 77 to 85% among the four study groups.
An accompanying editorial by J. Karlawish (ref. 1) highlights the novelty of the trial design with primary endpoints that would more accurately reflect clinical events, e.g. patients, families and clinicians will change atypical neuroleptic after 2 to 4 weeks if there are side effects or an apparent lack of benefit.
There will be much discussion of this study in the coming months. One possible interpretation is that non-pharmacological interventions and non-neuroleptic drugs should be tried first. Antidepressants, anti-epileptic drugs and the NMDA-antagonist memantine could be tried in individual patients for their "antipsychotic drugs-sparing effects" - possibly another CATIE-AD study will be required to demonstrate the effectiveness of these drugs for psychosis, aggression and agitation in AD.
References
1. Karlawish J. Alzheimer's disease - clinical trials and the logic of clinical purpose. New England Journal of Medicine 2006; 355 (15); 1604-1606