Clinical Question: Are newer antipsychotics safer and more effective than older agents?

Setting: Outpatient (any)

Study Design: Randomized controlled trial (double-blinded)

Allocation: Uncertain

Synopsis: Although they are widely used, the evidence that newer antipsychotic agents are more effective than older agents in clinically important ways is incomplete and inconsistent. In this study, 1,493 adults with schizophrenia at 57 U.S. clinical sites were randomly assigned to one of the following agents: olanzapine (Zyprexa) 7.5 mg; quetiapine (Seroquel) 200 mg; risperidone (Risperdal) 1.5 mg; ziprasidone (Geodon) 40 mg; or the older antipsychotic perphenazine (Trilafon) 8 mg. The final dosing range was between one and four capsules daily depending on the patient’s response. The average doses were olanzapine 20 mg; quetiapine 543 mg; risperidone 4 mg; ziprasidone 113 mg; and perphenazine 21 mg. Thus, the typical dosage was between two and three capsules per day. Patients had a mean age of 41 years, approximately 75 percent were men, and approximately 33 percent were black. Patients who had previously required clozapine (Clozaril) or who had experienced extrapyramidal side effects in the past were excluded. The primary outcome was the percentage of patients who discontinued the medication during the 18-month study, which was high for all five medications: 64 percent for olanzapine; 75 percent for perphenazine; 82 percent for quetiapine; 74 percent for risperidone; and 79 percent for ziprasidone. Discontinuation for lack of effectiveness also was somewhat less common in the olanzapine group (15 versus 24 to 28 percent); however, olanzapine also was discontinued more often because of intolerability (19 versus 10 to 16 percent) The rest of the patients who discontinued medication did so by mutual agreement between patient and physician or did not give a reason. Compared with the other agents, olanzapine also caused greater increases in weight, glucose levels, and lipid levels, which are disease-oriented outcomes of uncertain clinical significance. Patients were slightly more likely to discontinue perphenazine because of extrapyramidal side effects (8 versus 2 to 4 percent), but this difference may have been smaller than expected because of the relatively low dose of perphenazine used in the study.

Bottom Line: There are few differences among newer antipsychotics and few differences between newer agents and perphenazine, an older agent. Olanzapine seems to offer somewhat greater effectiveness but is not well tolerated and can produce some adverse changes to physiologic endpoints. All the newer antipsychotics also are much more expensive. Based on its similar effectiveness and better-than-expected tolerability, per-phenazine at a dosage of up to 20 mg per day should remain a treatment option for psychosis. (Level of Evidence: 1b)