Atypical antipsychotics: are some more atypical than others?

On the heels of clozapine, we now have a number of newer agents (risperidon e, olanzapine, quetiapine, sertindole, and ziprasidone), Are they all the s ame? What are the differences? How do we best understand them? In this arti cle we review current clinical evidence to compare these issues on four mea sures of atypicality: EPS, prolactin elevation, superior efficacy in refrac tory/positive symptoms and efficacy against negative symptoms. All the newe r agents are superior on EPS and, with the exception of risperidone, avoid prolactin elevation. Clozapine shows the most convincing efficacy in refrac tory schizophrenia, although comparative data concerning risperidone's bene fit in this respect are also emerging. It is unclear, however, whether any of the agents produce a greater effect than conventional antipsychotics aga inst positive symptoms in responsive patients. Both clozapine and olanzapin e have demonstrated superior efficacy against negative symptoms, although i t remains controversial whether this is an effect on primary or secondary s ymptoms. The precise pharmacologic mechanisms underlying "atypicality" rema in unclear, but several conceptual frameworks are highlighted that characte rize, and perhaps differentiate, these newer agents.