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CATIE Comes to Surprising Conclusions

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

Comments on News and Primary Papers
Comment by:  Daniel Weinberger, SRF Advisor
Submitted 18 October 2005 Posted 18 October 2005

The Lieberman et al. CATIE study is a landmark large-scale clinical trial of antipsychotic drug therapy and will generate considerable discussion in the coming months. It offers important insights about real-world treatment of individuals with the diagnosis of schizophrenia, in the sense of typical practices in clinics around the country and the clinical experience of many practitioners. It probably comes as no surprise that the response to available antipsychotic agents is suboptimal and that differences between drugs are not dramatic in many cases.

One of the questions that comes to my mind about the results is whether and to what degree they are generalizable. Do the results of this study accurately characterize the effects of these drugs across the spectrum of patients with chronic schizophrenia who are treated with them? In other words, are the patients in the CATIE trial representative of the patients with chronic schizophrenia who are in need of these medications? I believe there are several indicators to suggest that they may not be. First, of the subjects in this...  Read more

View all comments by Daniel Weinberger

Comment by:  Scott Hemby
Submitted 19 October 2005 Posted 19 October 2005
  I recommend the Primary Papers

Comment by:  David Lewis, SRF Advisor
Submitted 19 October 2005 Posted 19 October 2005
  I recommend the Primary Papers

Comment by:  Max Schubert
Submitted 19 October 2005 Posted 19 October 2005
  I recommend the Primary Papers

I also have not seen the response at that dose of perphenazine and even the atypical antipsychotics in chronic schizophrenics. In fact, the only medication that seemed to have an adequate "real-life" dose was olanzapine.

View all comments by Max Schubert

Comment by:  Iulian Iancu
Submitted 20 October 2005 Posted 20 October 2005
  I recommend the Primary Papers

It seems that the doses used are not equivalent, and the researchers have used somewhat lower doses of perphenazine and risperidone (in favor of olanzapine). Thus, it is obvious that perphenazine and risperidone have showed smaller efficacy.

View all comments by Iulian Iancu

Comment by:  Xiang Zhang
Submitted 20 October 2005 Posted 21 October 2005
  I recommend the Primary Papers

There is evidence that the Chinese traditional medicines may be an alternative approach in the treatment of schizophrenia. Our recent studies indicate that the extraction of gingko biloba may increase the effectiveness of antipsychotic drugs, but reduce their side effects. This finding may provide a new clue to develop a novel therapeutic drug for treatment of schizophrenia.

1. Zhang XY, Zhou DF, Zhang PY, Wu GY, Su JM, Cao LY. A double-blind, placebo-controlled trial of extract of Ginkgo biloba added to haloperidol in treatment-resistant patients with schizophrenia. Journal of Clinical Psychiatry. 2001; 62(11):878-83. Abstract

2. Zhang XY, Zhou DF, Su JM, Zhang PY. The effect of extract of ginkgo biloba added to haloperidol on superoxide dismutase in inpatients with chronic schizophrenia. Journal of Clinical Psychopharmacology 2001;21(1):85-88. Abstract

View all comments by Xiang Zhang

Comment by:  Alonso Montoya
Submitted 21 October 2005 Posted 21 October 2005
  I recommend the Primary Papers

Comment by:  Alexander Miller
Submitted 21 October 2005 Posted 21 October 2005
  I recommend the Primary Papers

Comment by:  Marvin Swartz
Submitted 26 October 2005 Posted 26 October 2005

Reply to Dr. Weinberger's questions about the generalizability of the CATIE sample, by Marvin Swartz, for the CATIE investigators
As CATIE investigators, we have been mindful of concerns about the generalizability of the CATIE sample. In response to a similar concern, our colleague Jeffrey Swanson at Duke compared CATIE participants to a quasi-random sample of 1,413 patients enrolled in the Schizophrenia Care and Assessment Program (SCAP), an observational, non-interventional study of schizophrenia treatment in usual care settings in the United States. The two samples were similar in demographic characteristics, e.g., gender (70 percent male in SCAP, 74 percent male in CATIE), age (mean age = 43 years in SCAP, mean age = 41 years in CATIE), and education (36 percent of SCAP participants had a high school education and 28 percent attended college; in CATIE these percentages were 35 percent and 39 percent, respectively). The CATIE study had a lower proportion of participants from racial minority backgrounds (40 percent vs. 54 percent). The samples also resembled...  Read more

View all comments by Marvin Swartz

Comment by:  William Carpenter, SRF Advisor (Disclosure)
Submitted 26 October 2005 Posted 26 October 2005

The antipsychotic drugs mainly treat psychosis (in contrast to cognition impairments and primary negative symptoms). In the CATIE study, the drugs tested share the same mechanism of action (D2 antagonism). Clozapine aside, the second-generation drugs (SGA) have not established superior efficacy over first-generation drugs (FGA). The FDA has granted no such claim, and the Cochrane reviews do not support superior antipsychotic efficacy. The appearance of superiority, including the terrific organization of data in the Davis meta-analyses, may be extensively based on last observation carried forward, excessive dose of the FGA, failure to pretreat with anti-parkinsonian drugs, sponsor bias, and a number of other methodological problems including the fact that most study subjects are doing poorly on FGA when recruited into comparative studies. "Atypical antipsychotic" means only low extrapyramidal symptoms at therapeutic dosing. In this regard, the CATIE findings are not surprising, but simply point to the considerable shortfall in effectiveness associated with current treatments....  Read more

View all comments by William Carpenter

Comment by:  Daniel Weinberger, SRF Advisor
Submitted 29 October 2005 Posted 30 October 2005

Dr. Swarz's comment providing data from the SCAP study is helpful in confirming that CATIE patients are similar in many phenomenological respects to other patients in schizophrenia treatment programs. Indeed, in terms of PANSS ratings, sex ratios, age at enrollment in the study, and history of recent hospitalizations, CATIE patients are not substantially different from patients we see at the NIH in Bethesda, Maryland and we saw when our program was located at St. Elizabeths Hospital in Washington, D.C. In my comment, I asked specifically about three CATIE characteristics that seemed atypical to me: age at first antipsychotic treatment (26), precentage of patients who were or had been married (40%), and percentage of patients who were unmedicated at the time they volunteered for the study (30%). It would enlighten this discussion if Dr. Swarz would report these data from the SCAP study.

View all comments by Daniel Weinberger

Comment by:  Robert McClure (Disclosure)
Submitted 31 October 2005 Posted 1 November 2005
  I recommend the Primary Papers

It would be interesting to learn from Dr. Swartz and the CATIE investigators (a) the age at first antipsychotic treatment, (b) the percentage of patients who were or had been married, and (c) the percentage of patients who were unmedicated at the time they volunteered for the study in the SCAP sample. I suspect these three variables, if available, will more closely resemble those of the CATIE trial sample than the CBDB sibling study sample.

Dr. Weinberger has suggested that the CATIE trial inadvertently enrolled patients more in the schizophrenia spectrum end of the distribution, or maybe the size and breadth of the CATIE trial obscured the signal from the more classic patient with schizophrenia, so the results may not be generalizable. I suspect that differences in criteria for recruitment and retention between the CBDB sibling study and the CATIE study explain the differences among the demographic variables of the samples.

The clinical characteristics of the CBDB sibling study sample are what one would expect in a study whose purpose is to find associations between...  Read more

View all comments by Robert McClure

Comment by:  Captain Johann Samuhanand
Submitted 7 November 2005 Posted 7 November 2005

Is there any published evidence that gingko biloba could be useful in containing the side effects of clozapine and other atypicals, or are there studies in progress?

View all comments by Captain Johann Samuhanand

Comment by:  Xiang Zhang
Submitted 8 November 2005 Posted 9 November 2005
  I recommend the Primary Papers

Reply to comment by Johann Samuhanand
To our best knowledge, there is no published evidence that gingko biloba could be useful in reducing the side effects of clozapine and other atypicals. However, using the same group of patients with schizophrenia as we reported previously (Zhang et al., 2001), our recent study has shown that chronic patients with schizophrenia demonstrated significantly lower CD3+, CD4+, and IL-2 secreting cells, together with CD4/CD8 ratio, than did healthy controls at baseline. After a 12-week treatment, EGb added to haloperidol treatment increased the initially low peripheral CD3+, CD4+, and IL-2 secreting cells, together with CD4/CD8 ratio. There was only a significant increase in CD4+ cells in the placebo plus haloperidol group. These findings suggest that ginkgo biloba may improve the decreased peripheral immune functions in schizophrenia (Zhang et al., 2006).

As we have known, although clozapine is superior over the other drugs in terms of efficacy,...  Read more

View all comments by Xiang Zhang

Comment by:  Patricia Estani
Submitted 25 November 2005 Posted 25 November 2005
  I recommend the Primary Papers

I recommend this clear and well-written paper for students to understand the basis of the CATIE studies.

I agree with Dr. Weinberger about the variables that could obscure the results in the target population or the schizophrenic population. His remarks about the control conditions or the dissection of the variables in the study are important. The difference between typical and atypical drugs is clear in these data.

New drugs, diferent from the typical and atypical drugs, based on new genetics research and new genetic routes must be developed in order to achieve new successes in the treatment of schizophrenia.

I think that atypical antipsychotics do not mean only low extrapyramidal symptoms at therapeutic doses. Several studies have demonstrated that atypical drugs(especially olanzapine) are better than typical drugs in important characteristics such as cognitive functioning.

View all comments by Patricia Estani

Comment by:  Mike Irwin
Submitted 29 November 2005 Posted 29 November 2005
  I recommend the Primary Papers

Comment by:  Patricia Estani
Submitted 13 December 2005 Posted 13 December 2005
  I recommend the Primary Papers

The most important current development of new antipsychotic drugs is focused on two mechanisms, the α7-nicotinic receptor agonists that are good new candidates for the management of the disease (Martin et al., 2004) and, most recently (and I think probably the closest to development), is the one that focuses on glutamatergic neurotransmission (Coyle and Tsai, 2004).

On the other hand, I think that behavioral and cognitive therapy, as well as family support and family management given by a professional in this area of health, are important to ensure an excellent result in schizophrenic patients.

Martin LF, Kem WR, Freedman R. Alpha-7 nicotinic receptor agonists: potential new candidates for the treatment of schizophrenia. Psychopharmacology (Berl). 2004 Jun ;174(1):54-64. Abstract

Coyle JT, Tsai G. The NMDA receptor glycine modulatory site: a therapeutic target for improving cognition and reducing negative symptoms in schizophrenia. Psychopharmacology (Berl). 2004 Jun ;174(1):32-8. Abstract

View all comments by Patricia Estani

Comment by:  Robert Fisher
Submitted 24 December 2005 Posted 28 December 2005
  I recommend the Primary Papers

[Disclosure: R. Fisher was Study Coordinator, Recruiter, and Diagnostician for the Byerly Group at UT Southwestern CATIE site, the second-largest enrollment site in the study.]

The CATIE study is likely the best designed and implemented research project ever conducted regarding schizophrenia and relevant psychopharmacology. The extensively collected data will have an enormous heuristic value in the study and evaluation of this disorder in all aspects of schizophreinia. I found Drs. Lieberman and McEvoy to be true professionals in this study design.

View all comments by Robert Fisher

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