Conventional vs. Atypical Antipsychotic Medications

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Abstract
Wang et al. (Dec. 1 issue)1 report that, as compared with atypical antipsychotic medications, the use of conventional antipsychotic agents increased the death rate among elderly users. Although we appreciate the instrumental-variable analysis, we have two concerns. First, it seems as though confounding would still be possible if the instrumental variable (a physician's choice of a conventional antipsychotic medication as his or her most recent prescription) was independently associated with the outcome (risk of death of the index patient). This confounding could happen if physicians who choose conventional antipsychotic medications also tend to care for very sick patients or to be less aggressive than other physicians in prolonging those patients' lives. Second, in the instrumental-variable analysis, the authors report an increase of 7.3 percent in the absolute risk of death within six months with conventional antipsychotic medications, whereas for the primary analysis, they report only a 3.3 percent increase in this risk. Since the instrumental variable (the type of antipsychotic agent the physician most recently prescribed before the index prescription) is an imperfect measure of the exposure of interest (the type of antipsychotic agent the index patient received), why isn't the difference in risk in the instrumental-variable analysis biased toward 0 — that is, lower than 3.3 percent?