Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia
Comprehensive Overview
Published in the New England Journal of Medicine in 2005, this study, known as the CATIE trial, asked how well the newer, second-generation antipsychotic drugs actually perform compared with an older, first-generation antipsychotic in the real-world, long-term treatment of chronic schizophrenia, since the newer drugs had become dominant in clinical practice despite incomplete evidence of their superiority. Researchers recruited 1,493 patients with schizophrenia at 57 sites across the United States and randomly assigned them, under double-blind conditions, to receive one of four newer drugs, olanzapine, quetiapine, or risperidone from the start, with ziprasidone added partway through after its FDA approval, or the older drug perphenazine, for up to 18 months. The primary outcome was discontinuation of the assigned treatment for any reason, a deliberately broad measure chosen because stopping or switching medication is common in schizophrenia care and captures patients' and clinicians' combined judgment of a drug's effectiveness, safety, and tolerability. The topline result was that most patients in every treatment group stopped their assigned medication well before 18 months, though the rate at which this happened, and the specific reasons why, differed meaningfully across the five drugs studied.
Outcomes and Implications
The most important finding was that olanzapine had the lowest discontinuation rate of the five drugs, with 64% of patients stopping it before 18 months compared with 74% to 82% for the other treatments, and patients stayed on olanzapine significantly longer than on quetiapine or risperidone, though not significantly longer than on perphenazine or ziprasidone once adjusted for multiple comparisons. Notably, the older and far less expensive drug perphenazine performed similarly overall to three of the four newer, second-generation drugs, challenging the assumption that atypical antipsychotics are broadly superior. The reasons patients stopped their medication varied distinctly by drug: olanzapine was associated with more discontinuations due to weight gain and metabolic side effects, while perphenazine was associated with more discontinuations due to movement-related, extrapyramidal side effects. Consistent with this pattern, olanzapine caused substantially more weight gain than any other drug, along with larger increases in blood glucose, cholesterol, and triglyceride levels, changes with potential long-term implications for metabolic health. Risperidone was linked to a significant rise in prolactin levels. There were no significant differences among the drugs in the incidence of new cataracts, QT-interval prolongation on cardiac monitoring, or suicide attempts and suicidal ideation. The authors conclude that antipsychotic medications, though effective, have substantial real-world limitations, with the majority of patients switching or stopping treatment regardless of which drug they received, and that clinicians, patients, and policymakers must weigh each drug's efficacy against its distinct side-effect profile and cost when choosing a treatment.