Can Unethical Research Ever Lead to "Best Evidence?"

Study Was Expected to Make Psychotic Patients Worse

Posted Nov 30, 2011

As readers of this blog know, in my book Anatomy of an Epidemic, I investigated what science has to say about how psychiatric medications shape the long-term outcomes of major mental disorders, and it's fair to say that, given what I reported, some in the field of psychiatry are not happy with the book. Recently, Dr. William Glazer, a long-time consultant and advisor to Eli Lilly, penned a two-part "rebuttal" of Anatomy of an Epidemic in Behavioral Healthcare journal. In turn, I posted a long response to his piece, inviting readers to assess whether Dr. Glazer, in his citation of studies, had done so honestly.

But there was one part of his rebuttal that, I have to confess, caused me to gasp in disbelief. It brings up an obvious ethical question. 

In his rebuttal, Dr. Glazer stated that evidence that antipsychotics improve the long-term course of schizophrenia can be found in a 1999 study of 104 patients treated at Hillside Hospital in Queens during the late 1980s for a first episode of schizophrenia or schizoaffective disorder, who were then followed for five years. Dr. Glazer reported that those treated with "antipsychotics were five times less likely to relapse than were patients who stopped such medication," and thus this study "is one of the best demonstrations of the beneficial impact of long-term antipsychotic therapy."

I happened to know that particular research well. I first wrote about it in 1998, when I co-wrote a series for the Boston Globe on abuse of patients in psychiatric research settings.

Here's the background to that research. Starting in the 1970s, researchers investigating the "dopamine hypothesis" of schizophrenia reasoned that if too much dopamine could cause psychosis, then a drug that caused brain neurons to release dopamine -- amphetamine, methylphenidate, L-dopa -- should make psychotic patients much worse. They began running experiments to see if that was so, and in the 1970s, David Janowsky, a physician at the University of California at San Diego School of Medicine, reported that dopamine-releasing drugs did indeed make psychotic patients much worse. Methylphenidate, which caused a doubling in the severity of symptoms, was the most potent of the dopamine-releasing agents when it came to making patients more psychotic.

In the late 1980s, psychiatrists at Hillside Hospital decided to repeat this experiment in first-episode patients who came to their emergency room for help. Rather than treat the patients with neuroleptics, they gave them methylphenidate, expecting taht this drug would exacerbate their psychotic symptoms. In two studies published in 1993, the researchers reported that methylphenidate caused 59 percent of them to become "much worse" or "very much worse." The patients were then placed on neuroleptics, but they took longer than usual to stabilize. "We were surprised by the length of time required for patients to recover," the investigators reported.

The patients did not give their "informed consent" to be in that study. The researchers, of course, did not tell the patients stumbling into their emergency room that they would be giving them a drug expected to worsen their symptoms, for of course nobody would agree to be in such a study.

The Hillside researchers then followed that patient group for another five years, and it is this follow-up data that they reported on in 1999. Eighty-two percent of the patients relapsed at least once during the five years (after recovering from their initial episode), and a significant percentage suffered several relapses during that period. Those patients who discontinued their medications and remained in the study -- the study doesn't state how many patients were in this category -- relapsed at a five-fold higher rate than those who continued on the drugs. In Dr. Glazer's view, this finding is one of the "best demonstrations" that exists in the scientific literature of the long-term benefits of antipsychotics.

Now, quite apart from the unethical nature of the study, the findings in this study don't reveal anything new. There is a long line of evidence that once patients are exposed to antipsychotics, they are at great risk of relapse when they withdraw from them, particularly if they do so abruptly. One presumed reason for that is that the drugs modify the brain in ways that increase a person's biological vulnerability to psychosis. Furthermore, such drug-withdrawal studies don't reveal anything about how well the drug-maintained patients are functioning; they don't provide any information about how their long-term outcomes might compare to patients treated initially in a psychosocial manner but without antipsychotics; and they certainly don't tell anything about how the drug-maintained patients fare physically, emotionally, and cognitively over a longer period of time. Finally, in this particular study, there were 13 patients who were stable off medication who then dropped out of the study, and the researchers didn't know whether those patients subsequently stayed well or relapsed. Naturally, those who relapse after going off meds regularly return to the hospital, while those who stay well tend to disappear from the system, which may have been what happened in this study. 

But that is not the important point here. The remarkable thing is that Dr. Glazer, when searching for evidence of the longer-term benefits of antipsychotics, could not find any study more compelling than this one, which involved initially treating the patients with a drug known to worsen psychotic symptoms.

And so now my question: Should an unethical study, one so clearly abusive, ever be incorporated into the evidence base for a drug therapy, and cited as one of the "best demonstrations" of its efficacy?