Antipsychotic Trials in Schizophrenia: The CATIE Project

From the beginning of the use of chlorpromazine and other neuroleptic drugs, signs of parkinsonism (e.g., tremor, rigidity, and bradykinesia) were observed as frequent side effects and, despite numerous studies to the contrary, were considered to be inextricably linked to therapeutic antipsychotic effects. Within a few years, investigators also observed an association between these drugs and abnormal involuntary movements that came to be known as tardive dyskinesia (TD). These and other drug-induced extrapyramidal side effects (EPS) can be mistaken for or worsen primary psychotic symptoms, are sometimes irreversible or lethal, often necessitate additional burdensome side effects from antiparkinsonian agents, can be disfiguring and stigmatizing, and have been shown to influence compliance, relapse, and rehospitalization. As a result, EPS dominated concerns about tolerability of antipsychotic drugs for decades, and their elimination served as a major impetus for new drug research and development. In 1988, clozapine was found to have broader efficacy in schizophrenia with negligible EPS, stimulating the search for other antipsychotics with improved tolerability. The drugs that were introduced after clozapine came to be known as atypical or second-generation antipsychotics (SGAs) while the earlier drugs were now called typical or first-generation antipsychotics (FGAs). Industry-sponsored clinical trials suggested that SGAs were superior to FGAs in the treatment of schizophrenia, reducing psychotic symptoms and causing fewer EPS. Cumulative evidence supporting reduced liability for EPS with SGAs contributed to the widespread dominance of these drugs in the marketplace and fostered the concept of “atypicality” in the mechanism of action of the new drugs.