Healthy Skepticism Library item: 6406

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Publication type: news

Full text:

BY JERALD BLOCK
GUEST COMMENTATOR

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.

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Healthy Skepticism Library item: 6406

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