Letters to the Editor Challenges in Estimating Mortality Risk From Antipsychotics in People With Alzheimer’s Disease To the Editor: I read with interest the article by Lopez et al. (1) in the September 2013 issue on the long-term effects of antipsychotics in people with Alzheimer’s disease, which suggested that after controlling for psychiatric symptoms, neither typical nor atypical antipsychotics were associated with time to death. I would like to expand on one of the limitations noted by the authors, as I believe it is critical to interpreting the results. Previous research suggests that the excess mortality associated with antipsychotics is greatest early in treatment, with the relative risk trending toward no mortality effect of drug as the duration of antipsychotic use increases (2). The Lopez et al. study assessed medications every 6 months, without tracking interim changes. Periodic assessments such as this create challenges when interpreting results that are related to adverse events for which the greatest excess risk occurs early in treatment. This is a particularly important issue in a dementia sample, where death is not a rare occurrence. That is, if someone both started an antipsychotic and died during the time between two assessments, there would be no record that the individual received an antipsychotic before they died, and only those who survived the early treatment period would be recorded as receiving an antipsychotic. Thus, data are lost from individuals who may be particularly vulnerable to the adverse event of interest, in this case death. This is termed “depletion of susceptibles” and may lead to bias in effect estimates, as those who survive treatment through an initial high-risk period are often less susceptible to an adverse effect. This is one reason that newuser designs are generally preferred in pharmacoepidemiology studies of adverse drug effects (3). Lopez et al. have presented a compelling case that psychotic symptoms are a prognostic marker for increased mortality in people with dementia and an influential unmeasured confounder in observational studies of antipsychotics and mortality. However, the design limitations make it difficult to fully discern the role of the psychiatric symptoms relative to that of antipsychotics that were received but not recorded. I admire the authors’ efforts to address this important question but do not place higher weight on these results than on those of randomized controlled trials that identify an increased risk of mortality associated with antipsychotic use in dementia. Randomized trials have their own limitations, such as highly selected samples, shorter follow-up, and small numbers of events in any given trial. Yet Schneider et al.’s meta-analysis of these trials (4) showing greater mortality with antipsychotics compared with placebo included more than 10 times as many antipsychotic users as were in the Lopez et al. study. I hope the null mortality result in this study is not interpreted as an indication that caution and restraint are not necessary when considering the use of antipsychotics in this vulnerable patient population. References 1. Lopez OL, Becker JT, Chang YF, Sweet RA, Aizenstein H, Snitz B, Saxton J, McDade E, Kamboh MI, DeKosky ST, Reynolds CF III, Klunk WE: The long-term effects of conventional and atypical

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antipsychotics in patients with probable Alzheimer’s disease. Am J Psychiatry 2013; 170:1051–1058 2. Wang PS, Schneeweiss S, Avorn J, Fischer MA, Mogun H, Solomon DH, Brookhart MA: Risk of death in elderly users of conventional vs atypical antipsychotic medications. N Engl J Med 2005; 353: 2335–2341 3. Ray WA: Evaluating medication effects outside of clinical trials: new-user designs. Am J Epidemiol 2003; 158:915–920 4. Schneider LS, Dagerman KS, Insel P: Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA 2005; 294:1934– 1943

RYAN M. CARNAHAN, PHARM.D., M.S.

From The University of Iowa College of Public Health, Department of Epidemiology, Iowa City, Iowa. Dr. Carnahan reports no financial relationships with commercial interests. He has received funding for research and education related to antipsychotic use in dementia from the Agency for Healthcare Research and Quality, the Health Resources and Services Administration, and the Patient Centered Outcomes Research Institute. This letter (doi: 10.1176/appi.ajp.2013.13091231) was accepted for publication in December 2013.

Response to Carnahan To the Editor: We thank Dr. Carnahan for his letter commenting on our study published in the Journal. We agree that, in general, observational studies can miss essential medical aspects of the treatments that are important to the study endpoints. However, there are two aspects of our study that are relevant for the interpretation of our findings. First, we examined a group of probable Alzheimer’s disease patients with mild-to-moderate dementia who were followed as outpatients at a research center for Alzheimer’s disease. Second, all patients were carefully evaluated by geriatric psychiatrists and neurologists, and they did not have a history of severe mental illness or medical-neurological disorder (e.g., strokes) before the study entry. These are the most important differences between our study and those from the majority of the placebo-controlled trials. Those studies were conducted in very heterogeneous groups of institutionalized patients with advanced dementia syndromes, some with Alzheimer’s disease, some with other disease processes that can cause dementia, some with lifetime history of psychotropic exposure, and some with multiple life-threatening comorbid conditions (see the Introduction of our article). However, the finding that the psychotic/agitated phenotype is the most important predictor of mortality and not the medication used to treat it should not be viewed as if these medications were completely safe. Indeed, they should continue to be used only with extreme caution. OSCAR L. LOPEZ, M.D. JAMES T. BECKER, PH.D.

From the Departments of Psychiatry, Neurology, and Psychology, University of Pittsburgh, Pa. The authors’ disclosures accompany the original article.

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