When does research into a preventive treatment become unethical? In many areas of medicine this is a familiar question; the ethics around immunizations is solidly grounded in such thought. However, in psychiatry, wholly preventive psychopharmacologic treatments have been unusual.
Unfortunately, such research is fraught with ethical dangers. In a recent study by McGlashan et al., “Randomized, Double-Blind Trial of Olanzapine Versus Placebo in Patients Prodromally Symptomatic for Psychosis,” it seems psychiatry may have crossed into ethically questionable territory.
Preventive treatments pose difficult ethical problems for researchers. By their nature, the clinicians are treating a person who presents, for the moment, without symptoms or entirely lacking a disease. We give them care that will, hopefully, prevent them from manifesting the illness or symptoms. Unfortunately, treatments frequently have side effects and complications. Thus, we sometimes harm people when trying to prevent an illness that they might get.
It would seem the calculus between helping and harming would need to account for several variables, including these:
- How likely is it that the disease will manifest?
- How severe is the disease, if it were to manifest?
- How likely is it that the treatment will create significant side effects or complications?
- How severe are those complications?
- How long will the complications impair the patient?
- How likely is it that the treatment will prevent the disease?
In McGlashan's study, the 14 authors cooperated under a Merck and NIMH grant and conducted their research in four clinical sites in the United States and Canada. The study examined whether olanzapine (Zyprexa) could be used in patients that appeared to be “prodromal” for schizophrenia to prevent or delay the onset of the disease. Just as some people feel tired or irritable a day or two before getting a cold, the psychosis that is the hallmark of schizophrenia is usually preceded by a motley set of other symptoms: changes in personality such as increased anger, anxiety, restlessness, moodiness, apathy, social withdrawal, odd behavior, paranoia, and/or declining school performance are often seen by the patients, friends, and family. Retrospectively, when diagnosing schizophrenia, these sorts of "prodromal" changes are frequently seen for several months before patients actually become psychotic. Unfortunately, the prodromal symptoms are also remarkably common, diffuse, and unspecific, especially when one considers that the patient is usually young – adolescence is a period of life that is normally marked by tumultuous changes in personality.
McGlashan’s team screened subjects for their study using a set of symptoms thought to be associated with the schizophrenia prodrome. They tried to select patients who were not yet psychotic but who seemed at high risk for developing schizophrenia. They then randomized their sample, giving olanzapine to one group and placebo to the other. They treated each group for one year and then observed them for another year.
Many patients dropped out of the study, and the findings were inconclusive. However, the data seemed to suggest that olanzapine might delay the onset of psychosis in those patients that are schizophrenic.
Regardless of the actual findings, though, the study never should have been performed. That it was poses a major challenge to the integrity of the controls that ensure research remains ethical.
The questions above suggest four reasons why the study is so disturbing.
How likely is it that the disease will manifest? Psychiatrists are not yet able to accurately predict who will manifest schizophrenia. The psychological testing instrument the authors used in the study had a large false positive rate. In prior studies, 46% to 80% of those tentatively labeled "prodromal" never developed schizophrenia after up to two years of observation – they were false positives. In McGlashan's experiment, 16 of 29 subjects (55%) who were given placebo failed to progress to schizophrenia over the two years they were examined. Thus around half of those treated with olanzapine were getting the neuroleptic for a disease they, too, did not have.
How likely is it that the treatment will create significant side effects or complications? During the period of the study, olanzapine was known to be associated with several serious complications. Specifically, one should worry that, after one year of exposure at doses ranging from 5 mg to 15 mg, patients would develop metabolic syndrome or, possibly, diabetes. Also, at the time the study went to IRB, olanzapine was known to be strongly associated with large weight gains. Indeed, McGlashan's paper showed those subjects getting olanzapine gained, on average, about 19 pounds over the placebo group. Finally, olanzapine, like all neuroleptics, can significantly alter a patient's personality and/or sleep. At the doses received, personality and sleep changes would be the rule, not the exception.
How severe are those complications? Metabolic syndrome and associated diseases, like diabetes, have significant morbidity associated with them. With regards to weight gain, there is well-established morbidity and mortality risks correlated to obesity. Finally, it is unclear how the quality of one’s life will be affected during and after one year of getting daily neuroleptic. Forming and solidifying new relationships occupies much of the time in adolescence and young adulthood. As neuroleptics affect cognition and emotionality, we might expect olanzapine to influence one's ability to build relationships, for better or worse.
How long will such complications impair the patient? The median age of the subjects was 16 years. One subject was remarkably young – 12 years old. Given their young age and the chronic nature of all the complication discussed above, we might anticipate they would have a large impact over the patient's life.
Early and aggressive treatment of psychosis is probably useful in reducing the severity and length of psychotic breaks. Moreover, it seems that a patient's functioning when in remission is improved if the period of psychosis can be shortened and made less severe. Thus there is an incentive to treat psychosis early and aggressively. However, if we treat too soon, we risk catching many nonschizophrenic youngsters in our net. As antipsychiotics are hardly benign, treating these individuals for a year or longer is quite risky; doing so will cause much illness, no matter how good our intent.
If (1) the antipsychotic had fewer side effects, (2) the subjects were much older, or (3) our tests for prodromal schizophrenia were much more specific, such a protocol might be worth considering. These are details that are worth considering. However, that a study with such glaring problems got federal funding and worked its way through one or more IRBs is alarming. What happened to the system that allowed such a trial to occur? While it is understandable and even admirable for investigators to get caught up in clinical ambition and hope to head off a tragic disease like schizophrenia, one should wonder what happened to the gatekeepers? How could one or more IRBs ignore the obvious problems with this study?
Finally, one should note that the study could affect many more people than the 31 patients immediately involved. When you have a trial with so many distinguished investigators from elite institutions appearing in a top-notch psychiatric journal, it sends the message to those reading it: prescribing neuroleptics for similar patients is alright. The article implies that treating a troubled adolescent with a neuroleptic for a year for symptoms that are suggestive of schizophrenia's prodromal syndrome is entirely ethical. I believe we have established no such thing and that such research may legitimate what is, at present, bad practice.
- Jerald Block