Cognitive effects of atypical antipsychotic medications in patients with Alzheimer's disease: outcomes from CATIE-AD

Abstract

Objective: The impact of the atypical antipsychotics olanzapine, quetiapine, and risperidone on cognition in patients with Alzheimer's disease is unclear. The authors assessed the effects of time and treatment on neuropsychological functioning during the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease study (CATIE-AD).

Method: CATIE-AD included 421 outpatients with Alzheimer's disease and psychosis or agitated/aggressive behavior who were randomly assigned to receive masked, flexible-dose olanzapine, quetiapine, risperidone, or placebo. Based on their clinicians' judgment, patients could discontinue the originally assigned medication and receive another randomly assigned medication. Patients were followed for 36 weeks, and cognitive assessments were obtained at baseline and at 12, 24, and 36 weeks. Outcomes were compared for 357 patients for whom data were available for at least one cognitive measure at baseline and one follow-up assessment that took place after they had been on their prescribed medication or placebo for at least 2 weeks.

Results: Overall, patients showed steady, significant declines over time in most cognitive areas, including in scores on the Mini-Mental State Examination (MMSE; -2.4 points over 36 weeks) and the cognitive subscale of the Alzheimer's Disease Assessment Scale (-4.4 points). Cognitive function declined more in patients receiving antipsychotics than in those given placebo on multiple cognitive measures, including the MMSE, the cognitive subscale of the Brief Psychiatric Rating Scale, and a cognitive summary score summarizing change on 18 cognitive tests.

Conclusions: In CATIE-AD, atypical antipsychotics were associated with worsening cognitive function at a magnitude consistent with 1 year's deterioration compared with placebo. Further cognitive impairment is an additional risk of treatment with atypical antipsychotics that should be considered when treating patients with Alzheimer's disease.

Figure 1

Average cognitive summary score and Z-scores for MMSE, BPRS-Cog, and ADAS-Cogby study period for the full study population (including placebo).A one-unit change in Z-scores for MMSE, BPRS-Cog and ADAS-Cog represents a decline of one standard deviation of mean baseline score for the variable, with BPRS-Cog and ADAS-Cog Z-scores being further adjusted so that declines in the Z-score indicate declines in cognitive function. The cognitive summary is the normalized average of normalized cognitive scores (see Table 2). Mean raw scores at baseline, week 12, week 24, and week 36, respectively, were: MMSE 15.2, 14.5, 14.1, 13.3; BPRS-Cog: 5.3, 5.4, 5.4, 5.6; ADAS-Cog: 34.4, 35.0, 35.8, 36.9; cognitive summary: 0, −0.08, −0.14, −0.20.

Figure 2

Average MMSE, ADAS-Cog, and Cognitive Summary scores by study period and by antipsychotic treatment vs. placebo. Decreases in MMSE and the Cognitive Summary, and increases in ADAS-Cog are indicative of cognitive decline. Mean raw scores at baseline, week 12, week 24, and week 36, respectively, were: MMSE placebo: 15.2, 13.7, 15.2, 13.4; MMSE antipsychotic: 15.2, 14.8, 14.2, 13.0; Cognitive Summary placebo: .05, −.06, 0, −.04; Cognitive Summary antipsychotic: .05, .03, −.01, −.13; ADAS-Cog placebo: 34.4, 36.1, 33.4, 35.4; ADAS-Cog antipsychotic: 34.4, 34.1, 35.4, 37.8.