Challenge to Atypical Antipsychotic Drug Effect on Cognition

To The Editor: In the July 2007 issue of the Journal, Richard S.E. Keefe, Ph.D., et al. (1) reported on the effects of olanzapine, quetiapine, and risperidone on neurocognitive function. Dr. Keefe et al. concluded that all three drugs produced significant improvements in neurocognition. The authors noted that cognitive improvement was modest, but they suggested clinical importance based on correlations of 0.14 and 0.18, with a component of the Quality of Life Scale, accounting for only 2%–3% of the variance. Even this small effect cannot be attributed to drug efficacy.

The study design did not include a comparison group. The drugs studied had a similar effect on cognition, but we do not know whether the effect was better, worse, or the same as placebo or treatment with a first-generation antipsychotic. In a study conducted by Keefe et al. (2), published in Archives of General Psychiatry, olanzapine, quetiapine, and risperidone failed to separate from perphenazine, a “typical” antipsychotic, using cognition data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study.

If the improvement observed is real, the following other causal explanations cannot be excluded:

1) The natural course of illness may lead to cognitive improvement when the baseline assessment is near the time of an exacerbation. Inpatient units and emergency rooms were used as recruitment sites.

2) Other symptoms were significantly reduced, perhaps facilitating test-taking ability.

3) Entering a clinical trial is often associated with clinical improvement. Expectation and enhanced clinical care may contribute.

4) Prior drug therapy may have had an adverse effect on cognition, and study drugs had less adverse effect (3) .

5) Practice effects causing improved scores on later test administration (4) .

6) Industry-sponsored studies tend to report more favorable effects of drug treatment.

7) Missing data from attrition of subjects may bias observations to the best cases.

The data presented give emphasis to the lack of meaningful cognitive enhancing efficacy of these “atypical” antipsychotic drugs. The authors’ interpretation of a significant drug-caused improvement is not compatible with the study design that did not include a comparison group. Other potential causes appear more compelling as explanations for the modest improvement in test scores.

To test an efficacy hypothesis for cognition in schizophrenia, there is a consensus design intended to control for pseudospecific causes of improved cognition (5) .