Antipsychotic Polypharmacy in Schizophrenia, from Empirical Associations to Combined Selective Treatments

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Treatment with antipsychotics, APs has been a cornerstone of schizophrenia and other severe mental disorders for more than fifty years. Antipsychotics have been used in monotherapy or in a combination of two, or more drugs. Empirical polypharmacy, common after First Generation Antipsychotics, FGAs introduction, in 1960s, was replaced by monotherapy and the principle of "Minimally effective APs drug strategies" later on, at the end of the 20th Century. Despite current guidelines recommendations, promoting monotherapy with the newly introduced Second Generation Antipsychotics, SGAs, the practice of combining two antipsychotic drugs is routinely utilized. The aim of this review is to address the boundaries of the polypharmacy with APs, from epidemiological features to its clinical significance. At first APs prescription patterns in Italy and other countries were outlined. Then, a comparison between the theoretical rationale of monotheraphy and the pharmacokinetic and pharmachodynamic properties of the combined selective associations of two APs was performed, to assess if this practice might help in the care of treatment-resistant forms of schizophrenia. Finally, a PubMed literature search from 1957 to February 2013 led to the extraction of 118 papers regarding APs combined treatment, with data from larger RCTs to single case reports described in detail to provide reasons for rationale use of polypharmacy in routine practice. Although RCTs led to inconclusive results, case series revisions outlined the feasibility of combining APs with a complementary pharmacodynamic profile. The need for adequately targeted, clinically effective, lowcost APs combinations improving functional autonomy of schizophrenic persons is warranted.