To the Editor: Dr. Centorrino et al. are to be commended for addressing an important issue that is becoming more and more a focus of clinical concern, given the growing use of multiple antipsychotic medications administered simultaneously (1). This has increasingly become the case, given the favorable side effect profile of atypical antipsychotic medications, which allow combination strategies to be considered more readily as an option. However, while the authors imply that short-term combination treatment strategies are associated with "major increases in drug exposure, adverse events, and time in the hospital but with no apparent gain in clinical benefit" (p. 700), the authors failed to consider seriously the option that this patient subpopulation receives only antipsychotic combinations because it does not respond to single antipsychotic medications after a period of time and may therefore be considered treatment resistant. Thus, they may fall into a subclass of schizophrenia patients who exhibit a biological subtype of the illness that is treatment resistant and more prone to side effects (in addition to higher doses and a longer treatment period). Therefore, the assumption that the increase in adverse events and hospital time is associated with combination strategies may be incorrect and rather be a function of a different and more severe subtype of the illness in which patients are administered higher doses and multiple agents. For example, it has been suggested that tardive dyskinesia vulnerability may be a constitutional feature of a more severe schizophrenia phenotype that requires typical antipsychotic drug exposure for its expression and also includes poorer therapeutic response and greater severity of negative symptoms (2). Since these patients do not respond as well to single medications, they are administered polypharmacy schedules of medications with more side effects as a result and poorer response based on subtype of illness but not necessarily as a reflection of multiple antipsychotic medication use. While the authors do briefly address the option of treatment resistance as a limitation, it is not emphasized enough, and this point may in fact be an obvious fatal flaw of the study. Furthermore, the comparison of the two study subgroups as analyzed by the authors appears incorrect. It clearly seems that the patients who were treated and who quickly improved with monotherapy only were in a less severe state compared to the patients treated with polypharmacy, a treatment modality used as "the last resort" in overcoming treatment resistance. In order to determine whether polypharmacy is "good" or "bad," studies are required to compare similar populations of schizophrenic patients. One option, for example, would be to divide treatment-resistant patients into two groups—one treated with monotherapy and the second with polypharmacotherapy.