For patients with schizophrenia who do not respond to an initial trial with an antipsychotic drug, clozapine (Clozaril) appears to be a more effective second treatment than other drugs, investigators report in the American Journal of Psychiatry. However, clozapine’s side effects can be more serious than those of other agents.

In a second paper in the journal, investigators report that, among the “atypical” class of antipsychotics, risperidone (Risperdal) and olanzapine (Zyprexa) were more effective than quetiapine (Seroquel) and ziprasidone (Geodon) following discontinuation of a previous atypical agent.

Both studies comprise phase 2 of the Clinical Antipsychotic Trials for Interventions Effectiveness (CATIE) investigation, funded by the National Institute of Mental Health.

Dr. Joseph P. McEvoy, from John Umstead Hospital in Butner, North Carolina, and his associates ran the “clozapine” study involving 99 subjects, most of who discontinued their first drug because of inefficacy, and were randomly assigned to clozapine or an atypical agent.

Based on their results, McEvoy recommends that if a patient does not respond to one antipsychotic, “it’s not unreasonable to try olanzapine, because the burden of monitoring for side effects for clozapine is greater. But if the patient still suffers serious psychopathology that limits their ability to enjoy life, results strongly suggest that rather than dither around with several other trials it may make sense to move on to clozapine.”

Because patients on clozapine are at greater risk of certain heart and blood problems, routine monitoring is a must, he said.

Dr. T. Scott Stroup, from the University of North Carolina at Chapel Hill, and his associates included in their “ziprasidone” trial 444 subjects who discontinued treatment in phase I and were randomly assigned to olanzapine, risperidone, quetiapine, or ziprasidone.

Results of the symptoms scores showed olanzapine was significantly more effective than quetiapine and ziprasidone, but not risperidone.

According to Stroup’s group, olanzapine was associated with more weight gain than the other drugs, averaging 1.3 pounds per month, whereas ziprasidone was associated with a mean loss of 1.7 pounds per month. Olanzapine was also associated with increases in total cholesterol and triglycerides.

“These studies point up the great medical need of schizophrenia,” Dr. Carol A Tamminga, from the University of Texas Southwestern Medical Center in Dallas, notes in an accompanying editorial. “Only knowledge of the molecular basis of this psychotic illness will facilitate rational treatment development.”

SOURCE: American Journal of Psychiatry, April 2006.