16 October 2005. Should some of the older, and cheaper, antipsychotic drugs be pulled out of semi-retirement in the United States and given a chance to compete with the atypical (second-generation) drugs? With the report of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) in the New England Journal of Medicine on September 19, this is a question that psychiatrists and patients must grapple with, not to mention those who hold the purse strings for public and private health payers.
The CATIE study, led by Jeff Lieberman of Columbia University and a host of colleagues at other institutions, found no significant differences in effectiveness (as measured by time to discontinuation) of the older generation drug perphenazine versus the second-generation drugs quetiapine, risperidone, or ziprasidone. The atypical drug olanzapine did show modest advantages over the other drugs in the study, a fact tempered by olanzapine's metabolic side effects.
Notably missing was the "original" atypical antipsychotic drug, clozapine. Clozapine was excluded from the study because the authors felt it had demonstrated its superiority over the other drugs in terms of efficacy, but also because it can severely deplete white blood cells, and its use has diminished with the development of other atypical drugs. Indeed, as Robert Freedman of the University of Colorado notes in an accompanying editorial, the atypical drugs in this study represent attempts to emulate clozapine's success—believed to stem from lower affinity than earlier drugs for the dopamine D2 receptor and greater affinity for serotonergic and noradrenergic receptors—without clozaril's danger to the immune system. While they have been successful in this regard, the newer atypical antipsychotics brought along other, albeit milder, side effects, such as disruptions of metabolic function (for a review, see Newcomer, 2004). Freedman also notes that the newer atypicals were approved on the basis of efficacy results equivalent to those of the older drugs, not that of clozapine.
Despite a relative lack of data on the real-world effectiveness of the atypical antipsychotics, they account for some 90 percent of antipsychotic sales in the United States, and about 50 percent in Europe. That's a big slice of a market estimated at more than $10 billion annually.
Real-world Assessments of Effectiveness
Funded by the National Institute of Mental Health, the CATIE study gathered data from 2001 through 2005, recruiting nearly 1,500 patients at 57 diverse U.S. sites, ranging from university clinics and Veterans Affairs centers to private practices. The patients were randomized to receive one of the aforementioned drugs for 18 months in a double-blind format.
The primary endpoint of the CATIE study was time to discontinuation of the drug, a quite different endpoint from the efficacy studies conducted to win drug approval, which report on reductions in positive or negative symptoms during a short trial of several months. But the length of time a patient sticks with a drug is an endpoint that makes a lot of sense in a disorder where all the drugs have notable side effects and patients routinely stop taking the drugs, either as a consequence of their illness or because of side effects.
And by this measure, the study reinforces what patients and psychiatrists know from experience—the drugs are not well tolerated. Seventy-four percent of patients stopped taking the drug to which they had initially been randomized. This included 64 percent of those randomized to olanzapine, 74 percent taking risperidone, 75 percent taking perphenazine, 79 percent taking ziprasidone, and 82 percent taking quetiapine. That perphenazine fell in the middle of the pack is a big surprise.
Supporting an earlier meta-analysis (Davis et al., 2003), olanzapine proved more successful than the other candidates in the study, with a somewhat longer time to discontinuation. However, olanzapine brought on greater metabolic side effects, such as elevated blood glucose, cholesterol, and weight gain.
Searching for New Directions
There is no doubt that new treatments are needed. Among the current possibilities, Freedman has been working on the α-7 nicotinic acetylcholine receptor as an alternative target for treatment (for a review, see Martin et al., 2004). There is hope that work in glutamatergic systems could produce drug candidates (for a review, see Coyle and Tsai, 2004), and tweaking the current drugs may also pay off, at least in terms of reducing side effects. For example, partial agonism can achieve results similar to receptor antagonism, a strategy successfully pursued in hypertension treatment. The partial dopamine D2 agonist aripiprazole may prove to have fewer side effects than do the current crop of drugs, hopefully with equivalent or better efficacy (for a review, see Ohlsen and Pilowsky, 2005).
And as Robin Murray mentions in his interview with SRF, there is evidence that cognitive or behavioral modification therapy can make a substantial difference with some symptoms of schizophrenia. However, such therapy is expensive, requiring a sophisticated, ergo expensive, healthcare system able to maintain contact with mentally ill patients over the long term.
Are there other places we can look to for hope within the current understanding of schizophrenia pathophysiology? We invite you to leap into the Schizophrenia Research Forum community with commentary on the significance of this study, any methodological objections, or on the directions you think are most promising for further therapeutic advances.—Hakon Heimer.
Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK; Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005 Sep 22;353(12):1209-23. Epub 2005 Sep 19. Abstract
Freedman R. The choice of antipsychotic drugs for schizophrenia. N Engl J Med. 2005 Sep 22;353(12):1286-8. Epub 2005 Sep 19. Abstract