Abstract

The unprecedented level of activity in the development of new antipsychotic medications can be traced to the 1989 approval of clozapine by the US Food and Drug Administration for treatment of refractory schizophrenia. This has encouraged the development of other new agents that share some of clozapine's receptor binding characteristics. A wide range of clinical trial designs are being used during the development of new antipsychotic medications. This article describes both basic designs and more innovative ones: flexible-dose designs that include placebo and conventional neuroleptic agents as controls; fixed-dose designs with multiple doses of experimental medication; and fixed-dose designs with multiple doses of the experimental and comparator medication. The strengths and weaknesses of each are identified. The need for long-term maintenance studies of newer agents is emphasized because psychotic disorders in general, and schizophrenia in particular, are chronic relapsing illnesses. The current status of four newer antipsychotic medications is considered: clozapine, risperidone, olanzapine, and sertindole. The importance of direct comparison among the newer antipsychotic medications in both short- and long-term trials is highlighted.