The newer antipsychotics: underlying mechanisms and the new clinical realities

Purpose of review The present review focuses on recent preclinical and clinical developments among newer antipsychotics, with an eye to reviewing putative underlying mechanisms. Recent findings The introduction of aripiprazole and the wider appreciation of amisulpiride are providing an interesting counterpoint to the extant serotonin-dopamine antagonist atypical antipsychotics. There is wide agreement and good evidence that all atypical antipsychotics show functional regional specificity (i.e. greater relative functional impact on limbic than on motor regions). Though there is some limbic evidence for preferential occupancy, precise mechanisms are not clear. To this picture are added the new possibilities posed by aripiprazole: partial agonism and dopamine stabilization. While strong leads emerge for each of these from in vitro data, more work is needed to confirm them in vivo in relevant preclinical models at relevant doses. As motor side effects decrease, hyperprolactinemia is still relevant for some agents. New data indicate a critical role for blood-brain barrier penetrability in prolactin elevation. Weight gain, and lipid and glucose dysregulation have now become more prominent. A prominent role has been attributed to histamine H1 receptor antagonism in weight gain and related lipid dysregulation. Interestingly glucose dysregulation has been linked to schizophrenia itself, and the role of antipsychotic medication in exacerbating this condition is not clearly understood. Summary This review highlights our current understanding of the mechanisms of action of newer antipsychotics and emerging clinical realities as the search for better antipsychotics continues apace.