New serotonin/dopamine antagonists for the treatment of schizophrenia: are we making real progress?

The introduction of second-generation antipsychotics (SGAs), heralded by clozapine in 1990, represented an important advance in the pharmacologic treatment of schizophrenia. However, several recent comparative effectiveness trials found that non-clozapine SGAs provided little or no advantage in efficacy over first-generation antipsychotics, and all agents had substantial safety and tolerability concerns. Clearly, there remains a great unmet need for more effective and better-tolerated antipsychotics. Relatively potent antagonism of serotonin 5-HT2A receptors coupled with relatively weaker antagonism of dopamine D2 receptors is the central pharmacological characteristic shared by most SGAs. This profile continues to be a favored model for developing new SGAs, commonly defined as serotonin/dopamine antagonists. In the past ten years, aripiprazole, paliperidone, asenapine, iloperidone, and lurasidone have been introduced. Studies suggest that the newer agents have similar short-term efficacy to earlier serotonin/dopamine antagonists, and several demonstrate at least modest improvements in safety and tolerability profiles, particularly metabolic measures. However, as a group, the newer serotonin/dopamine antagonists are pharmacologically heterogeneous, and their side-effect burden can still be considerable. Moreover, their putative clinical advantages have not yet been well demonstrated via direct comparative studies. The absence of such evidence adds to the challenges in defining their place among more established treatment choices, or in providing clinicians with clear indications to guide treatment choices for individual patients. Long-term, head-to-head comparative studies are required to clarify the risk/benefit profiles of the newer antipsychotics and their roles in the treatment of schizophrenia.