Ask the Expert: Old Versus New Antipsychotics

This Month’s Expert Old Versus New AntipsychoticsTCPR:You were an investigator on the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) trial, an effectiveness study comparing four atypical antipsychotics (olanzapine [Zyprexa], quetiapine [Seroquel], risperidone [Risperdal], and ziprasidone [Geodon]) and one first generation antipsychotic (perphenazine [Trilafon]). Briefly, what did this trial reveal?

Dr. Rosenheck: Basically, the CATIE trial showed that the new drugs have no advantage over the old drug used (perphenazine) except that olanzapine and quetiapine make you gain weight. Unfortunately, it hasn’t really changed the way psychiatrists use antipsychotics today.

TCPR: How is it possible that the NIMH spent $50 million on this study and yet its results have no impact on practice?

Dr. Rosenheck: One reason is that drug companies did a good deal to minimize the impact of CATIE. They had meetings in which they essentially diverted attention from CATIE. They sponsored editions of commercial journals in which articles criticized CATIE. We published a study in JAMA that showed that olanzapine showed no advantages over haloperidol (Haldol) (Rosenheck R et al, JAMA 2003;290(20):2693–2702), but it, too, was ignored. Drug company influence essentially nullified the informational value of CATIE. Psychiatrists seem to be more influenced by what key opinion leaders tell them than what the science tells them. Also, it has been hard for science to affect practice because people developed practice habits and beliefs before these studies were completed that are hard to change.

TCPR: Did this happen with other trials, too?

Dr. Rosenheck: Yes. For example, the authors of EUFEST (European First Episode Schizophrenia Trial) initially hypothesized that in first-episode schizophrenia, atypical antipsychotics would be superior to haloperidol, but the objective measures showed that wasn’t true (Kahn RS et al, Lancet 2008;371:1085–1097). And the subjective measures were highly biased; the study was done in the early 2000s at the height of the enthusiasm for atypicals. The TEOSS (Treatment of Early Onset Schizophrenia Spectrum Disorders) study was another study of first-episode schizophrenia in which molindone (Moban) did just as well as risperidone and olanzapine (Sikich L et al, Am J Psychiatry 2008;165(11):1420–1431). Interestingly, the olanzapine arm of the study had to be stopped prematurely by the data-safety monitoring board for the trial because it caused such adverse metabolic consequences. But this has had no impact on policy or practice. The CUtLASS (Cost Utility of the Latest Antipsychotic Drugs) trial also found that the new drugs are not superior to the older drugs (Jones PB et al, Arch Gen Psychiatry 2006;63:1079–1087).

TCPR: So why are these drugs so widely used?

Dr. Rosenheck: It’s interesting to see the process our profession went through. We have sometimes been fraudulently led to believe things about these medications that aren’t true. Eli Lilly paid a $1.4 billion judgment for marketing olanzapine for off-label uses—at the time, the largest criminal penalty ever paid by a US company. The Justice Department summary said that they had trained their sales staff to break the law. As discussed in an exposé in The New York Times, the key reason for this was to get the drug to the primary care market, and to use this antipsychotic for people who had anxiety and other disorders. [Eds note: you can read about Lilly’s campaign to market olanzapine to primary care at Spielmans GI, Soc Sci Med 2009;69(1):14–20.] Not surprisingly, there has been widespread use of olanzapine for anxiety (Comer JS et al, Am J Psychiatry 2011;168(10):1057–1065).

TCPR: What does this mean for how we should use these medications?

Dr. Rosenheck: The drugs are largely off-patent. So from the cost perspective it doesn’t matter anymore. But when the drugs were first marketed they clearly were not cost effective. I prefer to use the economic term “dominant choice.” A dominant choice is a drug that works better and costs less. Perphenazine was a drug that worked just as well as all the atypicals and cost significantly less. This was the “dominant choice.”

TCPR: So what questions then should we be asking and what should we be looking for in the science when new drugs come out and are promoted to us?

Dr. Rosenheck: First of all, more research must be done on these drugs. The problem is that independent research is often done many years after drug companies have had a chance to shape opinions. But if the science contradicts what everybody already believes, there will be reluctance to believe in the science. After all, who would want to believe that the great step forward was an illusion?

TCPR: Can you describe any advantages of the atypical antipsychotics?

Dr. Rosenheck: One of the frequent statements is that we need lots of different antipsychotics because if a patient doesn’t respond to one, they may respond to another. I only know of two actual studies of that possibility, both of which failed to support it (Essock SM et al, Am J Psychiatry 2006;163(12):2090–2095; Rosenheck et al, Schizophr Res 2009;107:22–29). So if your patient isn’t doing well and you switch them, they may do better, but that doesn’t show that the second medication was more effective than the first. You would have to do some kind of randomized trial where you would leave some patients on the first drug and then randomize other patients to be switched. Nobody has an incentive to do those trials.

TCPR: Can we use the unique receptor-binding profiles of atypical antipsychotics to predict efficacy?

Dr. Rosenheck: I don’t think there is any evidence to support that as a basis for clinical decision making. In the end it depends on how you think medicine should be practiced: do we make decisions about patients on the basis of things that could be or do we make decisions on the basis of data that we have? And when things could be, do we falsely conclude that they are, or can we somehow test these hypotheses? The thing that sadly seems to happen in our field is that we substitute speculation for truth because there is much we don’t know.

TCPR: What are your thoughts about the uses of atypical antipsychotics in non-psychotic illnesses such as anxiety and mood disorders?

Dr. Rosenheck: The problem is that the data on depression and the long-term treatment of mania and bipolar disorder are based on six- or eight-week trials. We don’t know the trade-off between benefits and risks over the longer term, and these tend to be longer term illnesses. Most studies that are done these days are by drug companies that need two, usually short-term, trials to get FDA approval for their drug to go on the market, and that is what drives the clinical science of psychiatry.

TCPR: What could be an alternative to these short-term trials?

Dr. Rosenheck: In the past, the NIMH was responsible for testing the effectiveness of medicines. But today they say they are about the business of understanding the basic science of mental illness. This shift occurred in 1990, when employees of a drug company first appeared as authors in a major medical journal in an article about Prozac. This is commonplace today. If you were working for a company, would you see it as in your career interest to publish a paper that said that the company’s drug was less than wonderful? This is how our field operates.

TCPR: How might independent evaluation of therapeutics work?

Dr. Rosenheck: I’ve put forth the idea that once a drug sells more than $1 billion of product, the company should be required to pay a very small tax (1% or 2%) that would fund an independent comparative effectiveness trial of the value of that drug as compared to other available drugs. There is little incentive for anyone to fund those studies, but these are precisely the studies that practitioners need. Psychiatrists know that they should give antipsychotic drugs for schizophrenia; the question is, is any drug better than any other drug, and what are the differences in long-term side effect profiles? Few studies examine these questions over longer periods of time, which is what we need to guide practice. The companies have little incentive for doing studies of this type because they obviously want to show that their drug is superior as quickly as possible. Some have proposed that the federal government should fund agencies to do comparative effectiveness research. The federally funded Patient Centered Outcomes Research Institute (PCORI) has been funded to do this kind of work, which has been an important step forward.

TCPR: Is there anything unique to psychiatry that might make us more susceptible to using medications without sufficient evidence?

Dr. Rosenheck: Yes. We don’t have a single disease with a known etiology. We don’t have a single biomarker of any mental illness. At the current stage, we don’t have evidence that our diagnoses are clinically meaningful because drug companies have shown that some drugs are good for many distinct mental illnesses. The original dream of DSM-III was that you would be able to find the right drug for the right illness at the right time. But the drug companies have led us to believe, whether true or not, that their drugs are good for many, many mental illnesses.This is because we don’t have a reliable definition for any mental illness and no mental illness has any known etiology, except perhaps for post-traumatic stress disorder.

TCPR: Hopefully your comments will make us wiser consumers of information.

Dr. Rosenheck: I think the deeper issue is that psychiatrists need to be aware recent legal actions suggest that fraudulent information has been provided to the public for the purpose of misleading them. Do psychiatrists want to know this? Do they want patients to know it?

TCPR: But shouldn’t we know it?

Dr. Rosenheck: Actually, I find that audiences are very interested in these findings, but find them disconcerting. Our patients are in extraordinary pain, and it is not just that they are in pain, but that their lives are severely impacted at a very young age. Their ability to function is markedly impaired in many cases. These are horrible diseases, but we don’t know what causes them, and we have treatments that seem to be effective—but we don’t know how, and our sources of information are imperfect in some cases. I think that the main thing that psychiatry has to offer is that people who are in the field have extensive experience being with people who have mental illnesses, and the best of them are adept at actually listening to them, which is a good thing.

TCPR: Thank you, Dr. Rosenheck.

Ask the Expert: Old Versus New Antipsychotics

This article originally appeared in:

The Carlat Psychiatry Report
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This article was published in print 1/2013 in Volume:Issue 11:1.