Old or New, Schizophrenia Treatments Modestly Effective

CHAPEL HILL, N.C., March 1 -- Some of the newer atypical antipsychotics are better than others at controlling schizophrenia in patients who were previously taking perphenazine, reported investigators in the latest analysis of data from the NIH-funded CATIE study.

The 114 patients who had been randomly assigned to perphenazine, and then discontinued it as part of the study, tended to do better on quetiapine (Seroquel), and to a lesser extent olanzapine (Zyprexa) than on risperidone (Risperdal), reported T. Scott Stroup, M.D., M.P.H., of the University of North Carolina here, and colleagues.

But the study results also showed that the treatment of schizophrenia requires individualized therapy to achieve the most effective balance for each patient, the authors wrote in the March issue of the American Journal of Psychiatry.

"These results reinforce the fact that finding the most effective medication for each patient sometimes means trying multiple medications," said Dr. Stroup. "They remind us of the considerable variability in clinical circumstances and of our need to be responsive to an individual's needs and preferences."

The CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) study, funded by the National Institute of Mental Health, found that olanzapine was the most effective of the newer medications for schizophrenia, but also found that many of the older agents work nearly as well.

In the latest iteration, the investigators dug down through the CATIE data to look at 114 people with schizophrenia who had been randomized to perphenazine but then discontinued the drug in phase I of the study.

The patients were randomly reassigned in a double-blinded fashion to treatment with olanzapine at 7.5 to 30.0 mg/day, quetiapine at 200 to 800 mg/day, or risperidone at 1.5 to 6.0 mg/day (38 patients in each group).

The main study outcome was time to treatment discontinuation as a measure of the relative effectiveness of each drug. Secondary outcomes included reasons for treatment discontinuation, and measures of drug tolerability.

The authors found that patients on quetiapine had a median time to discontinuation of 9.9 months, compared with 7.1 months for olanzapine (7.1 month and 3.6 months for risperidone). There were no significant differences between the treatments in discontinuations due to lack of efficacy, intolerability, or patient decision, however.

Although the drugs were generally comparable in their side effect profiles, with no difference in serious adverse events, patients on olanzapine did gain significantly more weight -- a mean of 1.6 lbs per month -- than patients on the other two drugs. A larger proportion of patients on olanzapine gained more than 7% of their baseline body weight.

Discontinuations due to weight gain or metabolic side effects occurred in 13% of patients on olanzapine and 5% of patients on risperidone, but in none of the patients on quetiapine.

Olanzapine was associated with a 1.36% increase in mean hemoglobin A1c (HbA1c) levels, compared with a 0.06% increase for quetiapine, and a 0.09% decrease for risperidone.

Total cholesterol levels rose by 20.9 mg/dL over baseline among patients on olanzapine, compared with 1.3 mg/dL for those on quetiapine and 4.4 mg/dL for those on risperidone. Olanzapine was associated with a 107.1 mg/dL rise in triglycerides, compared with 25.6 and 7.4 for quetiapine and risperidone, respectively.

"Among this group of patients with chronic schizophrenia who had just discontinued the older antipsychotic perphenazine, quetiapine and olanzapine were more effective than risperidone, as reflected by longer time to discontinuation for any reason, the investigators wrote. "In the context of other results from the CATIE study, the effectiveness and acceptability of antipsychotic drugs appears to vary considerably according to clinical circumstances."

In an accompanying editorial, Stephen R. Marder, M.D., of the Semel Institute for Neuroscience at the University of California at Los Angeles noted that some of the differences in discontinuation rates may have been due to subtle differences in side effects that CATIE was not powered to detect.

"Mild extrapyramidal side effects may be embedded in the 32% of the risperidone patients whose discontinuation was classified as 'patient decision'," he wrote. "These may have been individuals who disliked their drug but were unable to give an explanation that could be categorized as a side effect."

He acknowledged that the study data provided only weak support for speculations about mild extrapyramidal side effects accounting for some of the treatment discontinuations.

"Nevertheless, they suggest an important principle for treating schizophrenia," he wrote. "Finding an antipsychotic regimen that patients can live with comfortably is an essential part of an effective management strategy. Each antipsychotic trial provides an opportunity to understand the factors --particularly the side effect sensitivity -- that may affect how a patient feels while taking the next drug."

In a separate study in the same issue, headed by Marvin S. Swartz, M.D., of Duke in Durham, CATIE investigators reported that for patients on the atypical antipsychotics, perphenazine, or ziprasidone (Geodon) there was a modest improvement in psychosocial functioning for the one-third who the reached the primary endpoint, as measured by a change in the psychosocial functioning portion of the Quality of Life Scale.

The treatments were equally effective at six, 12 and 18 months, but early treatment discontinuations, generally among patients with the lowest baseline function, made it difficult for the analysis to detect meaningful differences in efficacy, the authors noted.

While therapy produced some modest gains, "more substantial improvements would likely require more intensive adjunctive psychosocial rehabilitation interventions," they wrote.

"The Swartz et al. study confirms that improving quality of life does not come prepackaged in a medication bottle," commented John Lauriello, M.D., of the department of psychiatry at the University of New Mexico in Albuquerque.