Drs. Schneider, Zheng, and Mack Reply

To the Editor: Drs. Bagepally and Drs. Prakash hypothesize a differential effect for antipsychotics, such that 1) lack of weight gain in men is a result of increased energy expenditure and decreased food intake consequential to continued wandering, aggression, and inappropriate activity and 2) weight gain in women is a result of greater arthritis and osteoporosis and more sedate and improved behavior. This hypothesis requires that medication was more effective for women than men. Although there was an interaction of weight gain with gender, changes in clinical rating scales between men and women were not significantly different and do not support this hypothesis. Another consideration for our findings is differential metabolism. For example, in our sample olanzapine plasma clearance was greater in men than in women, resulting in less drug exposure in men (1) .

With regard to other antipsychotics received by the remaining 152 patients, these subjects received combinations of the study medications, as reported on page 585 (43 received olanzapine and quetiapine, 42 olanzapine and risperidone, 43 quetiapine and risperidone, and 24 had all three at some time during the study period).

There is no reason to think that older patients with Alzheimer’s disease are inherently less susceptible to the metabolic effects of antipsychotics than younger patients with schizophrenia or bipolar disorder, and we can safely conclude that metabolic adverse effects of antipsychotics occur in Alzheimer’s disease patients. Cross-cultural studies are useful but are not required in order to make conclusions about this risk. We would not wait for further placebo-controlled trials of atypical antipsychotics in Alzheimer’s disease in order to become concerned.

Finally, metabolic and other adverse events should be considered in the context of efficacy. In these CATIE-AD patients, atypical antipsychotics were generally not effective in terms of all-cause discontinuation (2), although during phase I of the trial there were small salutary effects on behavioral rating scales relative to placebo (3) . Thus, metabolic effects should be added to the list of adverse effects of antipsychotics that pose risk and may limit their overall effectiveness in Alzheimer’s disease.

We continue to suggest that the use of antipsychotics be restricted to patients who have few or no adverse effects and for whom benefits can be discerned and that clinicians, patients, and family members consider both risks and benefits of antipsychotic medications in order to optimize a patient’s care (3) .