Antipsychotic polypharmacy (using multiple antipsychotics simultaneously) in schizophrenia appears to be a common practice in the real world. However, it has been a practice with substantial debate for its possible pros and cons. In this section, we systematically review clinical evidence on antipsychotic polypharmacy in schizophrenia. We first focus on the prevalence of antipsychotic polypharmacy in schizophrenia in the real-world clinical settings, to highlight the fact that it is becoming a frequent reality. Next, we discuss potential mechanisms that lead to such a controversial practice. Then, meta-analyses and systematic reviews that addressed the usefulness of antipsychotic polypharmacy in schizophrenia are qualitatively assessed.The results of this critical appraisal on the currently available evidence indicate that usefulness of antipsychotic polypharmacy in schizophrenia has been a focus of extensive research. However, there are practically too many possible combinations to be evaluated with each antipsychotic dosage also in mind. Evidence on antipsychotic polypharmacy currently remains equivocal at best even for polypharmacy involving clozapine; it is all the more questionable for other mode of antipsychotic combination therapy. Moreover, there has been no study that evaluated antipsychotic polypharmacy in reference with other various augmentation strategies that may potentially be effective.While a possibility cannot be denied for clinical usefulness of some mode of antipsychotic combination therapy in schizophrenia in general (e.g., combining prolactin-raising or metabolically problematic antipsychotics with more benign agents) or on an individual basis (i.e., for treatment-resistant schizophrenia), the currently available evidence supports the notion that prescribers should remain very conservative in resorting to antipsychotic polypharmacy. In other words, physicians should keep in mind the very basic of pharmacotherapy in every field of medicine; medications should be simple at least at early stages of treatment unless evidence unequivocally points to the contrary.An effort will be made to synthesize the currently available evidence to be translated into future directions on this critically relevant topic. Further, potential strategies to counteract antipsychotic polypharmacy in schizophrenia are discussed in detail. More work is clearly indicated for this important issue that will remain a matter of hot debate for the years to come.
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