Drugs in development for the treatment of schizophrenia

The overall outcome in schizophrenia is generally poor, despite the undisputed efficacy of antipsychotics in treating the acute symptoms of psychosis. There remains a subset of patients who are refractory to treatment. Also, for most patients treatment is not effective against the full spectrum of symptoms including negative and cognitive symptoms, and severe functional deficits persist. Further, while the newer drugs produce fewer motor side effects, other safety and tolerability concerns have emerged. Since the advent of antipsychotic therapy in the early 1950s, subsequent advances have been modest. While the mechanism of action of the first-generation antipsychotics appears closely linked to D2 antagonism, the second-generation antipsychotics have broader receptor-binding profiles, particularly 5-HT receptor antagonism. Attempts are now being made to develop antipsychotics with a wider spectrum of efficacy and a more favourable safety and tolerability profile by further exploring the therapeutic potential of D2 and 5-HT2 receptors, as well as investigating other putative mechanisms of action. This article adds to the current literature by providing an up-to-date review of antipsychotic drugs currently in development, focusing on the findings to date for compounds that are presently in Phase III clinical trials. While no exciting breakthroughs appear imminent, several drugs in early development have great potential.