9 October 2006. A clinical study carried out in England has reached the same conclusion as last year’s CATIE trial: second-generation (atypical) antipsychotic drugs are not superior to less expensive, first-generation drugs. The study, headed by Peter Jones at the University of Cambridge and published in the October issue of Archives of General Psychiatry, was designed to test effectiveness in a “real-world setting.”
Amid claims of superior efficacy, second-generation antipsychotics now dominate the global market (estimated at $10 billion in the U.S. alone), but those claims are increasingly under scrutiny. In this study, Jones and colleagues set out to ask whether the extra money spent on the new drugs was worth it, either in terms of improved quality of life, or savings in other areas of care. In this sense, the U.K. National Health Service-funded CUtLASS 1 (Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study), like the U.S. NIH-funded CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness; see SRF news story and follow up), and an earlier U.S. comparison of olanzapine and haloperidol (Rosenheck et al., 2003) was designed to test drugs in actual clinical practice, as opposed to the often artificial paradigms of Phase 2–4 clinical trials, which may demonstrate benefits that don’t translate to the “real world.”
Jones and colleagues recruited 227 people ages 18 to 65 from 14 community health centers in England who were switching medications because of poor response or side effects. The patients were randomized to receive one of the class of first-generation antipsychotics (FGAs) or a second-generation drug (SGA). The exact drug they received was left to the physician’s discretion. The subjects were followed for one year. At the end of the year, the investigators saw no difference in any outcomes, which included quality of life, adverse effects, satisfaction, or cost of care.
"All the data suggest that careful prescribing of first-generation antipsychotics, at least in the context of a trial, is not associated with poorer efficacy or a greater adverse effect burden, both of which would translate into lower quality of life in the medium term," the authors conclude. "This suggests that despite recent policy statements and prescribing patterns, further randomized and other evaluations of second-generation antipsychotics would still be useful in establishing their role in the long-term management of schizophrenia and, likewise, the continued role of older drugs."
In an accompanying commentary, Jeffrey Lieberman of Columbia University in New York, the lead investigator on the CATIE study, acknowledges that each of these two studies has methodological limitations, such as choice of drugs or drug equivalencies. However, considering recent meta-analyses of SGA clinical trials, which generally fail to support great superiority over FGAs, he concludes that “any reasoned and objective view of the evidence in light of CUtLASS 1 and CATIE must lead to the conclusion that with the possible exception of clozapine, the SGAs are not the great breakthrough in therapeutics they were once thought to be; rather, they represent an incremental advance at best.”
In addition, Lieberman writes, “This convergence of evidence should dispel the illusion of the vast superiority of the SGAs and should have wide-ranging effects on practice patterns and policies.”
Although in general agreement with Lieberman’s assessment, Robert A. Rosenheck of the Department of Veteran Affairs Connecticut Health Care System in New Haven argues in a separate commentary that the new data should not be used to make sudden changes in treatment recommendations. "Data from clinical trials are only one type of information of relevance to public discourse," he writes. "A comprehensive public dialogue is needed prior to policy action and should involve patients, health care professionals, researchers, industry representatives, and other stakeholders. Policy change may eventually be warranted, but potentially polarizing decisions are best delayed until thoughtful public deliberation gives a chance for comprehensive review, consensus building, and shared understanding."
Because some patients seem to respond better to SGAs than to FGAs, clinicians and patients would like to retain the option to try the more expensive SGAs within government and private insurer drug formularies. In a press release, the National Alliance on Mental Illness (NAMI) urges more study before making any decisions to restrict access to any medications (see their press release). NAMI calls for the maximum flexibility for doctors to prescribe the full range of antipsychotics based on individual patient needs.
While these results seem to confirm that older, cheaper drugs should receive equal consideration in choosing antipsychotic therapy, there is broad agreement in calling for research that will lead not just to third-generation, “me-too” dopamine receptor antagonists, but of brand-new approaches to schizophrenia research and treatment. As Lieberman writes, the results underscore “the urgent need for greater progress in developing novel therapeutics for schizophrenia and related psychotic disorders.”—Pat McCaffrey.
Jones PB, Barnes TR, Davies L, Dunn G, Lloyd H, Hayhurst KP, Murray RM, Markwick A, Lewis SW. Randomized Controlled Trial of the Effect on Quality of Life of Second- vs. First-Generation Antipsychotic Drugs in Schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry. 2006 Oct; 63(10):1079-87. Abstract
Lieberman JA. Comparative Effectiveness of Antipsychotic Drugs: A Commentary on Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1) and Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). Arch Gen Psychiatry. 2006 Oct; 63(10):1069-72. Abstract
Rosenheck RA. Outcomes, Costs, and Policy Caution: A Commentary on the Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry. 2006 Oct; 63(10):1074-6. Abstract