Yale-Lilly Experiment: Adolescents Rx Toxic Drug for Presumed Mental Illness They Do Not Have

http://www.ahrp.org/cms/content/view/157/80/

When the Times refers to an experiment as "bold and controversial" the
reporter is sanitizing the fact that the experiment is UNETHICAL?it
violates medicine's cardinal rule "First, do no harm."
The New York Times reports: "In recent years, psychiatric researchers
have been experimenting with a bold and controversial treatment
strategy: they are prescribing drugs to young people at risk for
schizophrenia who have not yet developed the full-blown disorder."

The article goes on to describe an experiment reported in the American
Journal of Psychiatry (AJP) in which adolescents were treated with a
toxic drug for a mental disorder that they did not actually have. [1]

This experiment is akin to performing mastectomies on women who are at
risk of?but do not have?breast cancer. Because the treatment involves
risk, great care must be taken to ensure the risk of the disease
exceeds the risk of treatment. The risk of breast cancer in women has
been quantified, and patients are able to weigh this risk against the
risks and benefits of surgery.

Despite the fact that antipsychotic drugs entail serious risks of
irreversible harm, no such assessment is offered for this trial.
The experiment, sponsored by Eli Lilly, was conducted at Yale
University (and 3 added sites, 1997-2003). Sixty adolescents who did
not meet any criteria for a diagnosis of mental illness, were
prescribed the antipsychotic drug, Zyprexa (olanzapine), raising
serious ethical concerns. The speculative premise underlying this
experiment is not supported by ANY scientific evidence.

The principle investigators, led by Dr. Thomas McGlashan of Yale,
speculated?without evidence and without a validated tool for detecting
schizophrenia in unsymptomatic individuals--that Zyprexa would be
effective in delaying or preventing presumed psychosis and symptoms of
schizophrenia. Indeed, the authors of this belated report obliquely
acknowledge this limitation:
?the study addressed an essentially new clinical entity, which
required designing new ?prodromal? assessment instruments and a new
definition of psychosis onset.? [1, p.797]

However, the authors neglect to inform readers what their ?new
definition of psychosis onset? is.
They acknowledge recruitment problems compounded by ?the variable
fraction of patients with true versus false positive prodromes.? In
other words, many adolescents were falsely assessed as at risk of
psychosis. The investigators don?t disclose what the inclusion /
exclusion criteria were. We would venture to guess that no journal
other than in psychiatry would publish a clinical trial report that
failed to provide such fundamental information.

The report lags three years behind completion of this (admittedly)
underpowered, small trial, most likely because the sponsor was
reluctant to publish the negative finding: the experiment failed to
demonstrate a significant benefit of Zyprexa, and 54.8% of adolescents
prescribed Zyprexa compared to 34.5% on placebo refused to complete
the study (the 20% difference indicating substantial intolerable
safety problems with the drug). [1]

The investigators fail to report the adverse events. Disclosing only
that adolescents on Zyprexa had acute weight gain?averaging 13%
increase in body weight in one year?which they acknowledge may pose a
long-term risk for ?metabolic syndrome.? (See below American Heart
Association) Another highly significant reported finding: ?It is
striking that all of the olanzapine patients whose symptoms converted
to psychosis did so within the first weeks of the clinical trial.
These patients were among the most symptomatic.? [1, p. 798]

But the authors demonstrate feats of mental acrobatics when they offer
implausible explanations for this disturbing finding in an effort to
deny the possibility that the drug is to blame:
?It is possible that some patients were already psychotic but unable
to communicate this until, paradoxically, they received sufficient
olanzapine to convey effectively their state of mind?.some of these
patients may have been on the cusp of psychosis and were not medicated
rapidly or sufficiently enough to forestall conversion.? [1]
The plausible alternative hypothesis is that the drug itself may have
pushed them into psychosis.

The drug?s severe adverse effects were well-known to Eli Lilly and
were (or should have been) known to the investigators. Zyprexa?s
action blocks multiple brain receptors causing a laundry list of
adverse effects?some of which are lethal. At the time of the drug?s
approval, the FDA noted that the pre-marketing clinical trials of
Zyprexa were ?fundamentally flawed,? test design was biased, as was
the patient pool. [2] Zyprexa?s safety profile in pre-marketing trials
(lasting 6-weeks) showed the drug caused severe adverse effects in 22%
of patients.

During the 6-week trials, adverse effects included:
Cardiac & Hypotension - 10% to 15%; Serious weight gain - 50% had
gained 7% of their body weight; Parkinson-like motor dysfunction -
11.7%; Akathisia - 7.3%; FDA data reveals that the drop-out rate was
65%. There were 22 deaths of which 12 were suicides. The number of
attempted suicides has yet to be disclosed.

Indeed, internationally acknowledged expert psychopharmacologist, Dr.
David Healy, has pointed out that the rate of suicide, death, and
suicide attempts linked to Zyprexa in pre-marketing clinical trials
was ?greater than any other psychotropic drugs in history.? [3]

In fact, FDA?s summation of the safety data submitted by Eli Lilly
warned, that, given olanzapine?s broad action on multiple receptor
types, ?no one should be surprised if, upon marketing, events of all
kinds and severity not previously identified are reported in
association with olanzapine?s use.? [2, p. 281] That dire prediction
is being corroborated by the drug's casualties. Since its marketing,
Zyprexa has been shown to significantly increase the lethal risk of
metabolic syndrome which is manifested in obesity, hyperglycemia,
cardiovascular disease, diabetes, and pancreatitis. Patients are
dying.

In fact, Eli Lilly settled a lawsuit filed by 8,000 consumers of
Zyprexa who developed diabetes for $700 million, rather than risk
public disclosure of the documented evidence showing the magnitude of
this drug?s severe hazards in open court.

This dubious drug experiment was sponsored by Eli Lilly and several
Lilly employees are listed as authors. It is the worst example of
unethical market expansion through "disease mongering." Subjects were
recruited through advertisements for an experiment designed to expand
the market for the drug beyond severely ill patients disabled by
schizophrenia or manic-depression (bipolar) for whom it was
approved?no matter how harmful the consequences might be.

In April 2000, we filed a complaint with the federal Office of Human
Research Protections (OHRP), about the ethics of this dubious
experiment citing:

1. the shaky basis for the psychiatrists' conjecture that the children
would develop schizophrenia because one of their siblings has the
disorder when the scientific evidence does not support it.
"The risk of schizophrenia for the general population is 1%, for
siblings the risk increases to 8% to 15% - in other words there is a
90% likelihood that these children will not develop schizophrenia.
Even for those who already exhibit early signs ("prodromal symptoms"),
the estimated risk for developing schizophrenia is highly variable
(25% to 50%), given the absence of scientifically accurate tools for
interpreting psychiatric "symptoms."

2. FDA data showing evidence of the severe effects of Zyprexa. [See:
http://www.ahrp.org/Initiatives/YaleComplaint.php ]

Our complaint led to an investigation by OHRP whose letter of
determination (December 12, 2000, addressed to Yale?s Provost) states
that the informed consent documents reviewed and approved by the Yale
institutional review board (IRB): ?seriously breached federal
regulations.?

OHRP indicates that in its response the Yale IRB claimed ?some
confusion regarding informed consent documents that were misplaced or
not signed.?

The OHRP letter further states that the Yale IRB-approved informed
consent forms: ?failed to include a complete description of the
procedures followed and identification of any procedures which were
experimental;? and misrepresented the risk ?of worsening symptoms due
to olanzapine side effects? by falsely stating ?it is possible that
you will feel worse. This is a risk of your clinical condition, not a
risk of being in the study.? See:
http://www.hhs.gov/ohrp/detrm_letrs/dec00e.pdf

The negative results of the experiment and the high drop out rate were
predictable inasmuch as evidence of the drug?s intolerable effects and
hazards had been noted by FDA reviewers at the time of the drug?s
approval for adult schizophrenia?not for presumed ?prodromal? symptoms
in adolescents.

Given the absence of a diagnosable illness; the uncertainty
surrounding an ill-defined, ?prodromal? assessment which often results
in ?false-positives,? should have precluded its approval. All the more
so, given the documented evidence of immediate and long-term risks
posed by the drug. Yet, the Yale University IRB, one of the most
prestigious institutions in the U.S. approved it. The Yale IRB was
chaired (between1979-2000) by one of the most influential
authoritative bioethicists, Dr. Robert Levine. See:
http://cira.med.yale.edu/about_us/bios.asp?PID=1003

This experiment encapsulates the prevailing utilitarian culture and
ethical relativism that engulfs academic medicine demonstrating how
the symbiotic relationship between academia and the drug industry has
resulted in institutional betrayal of moral, professional, scientific
integrity, and public trust.

The published report lists the individual authors, as well as the
departments of psychiatry of the following institutions: Yale
University; University of Toronto; University of No. Carolina (Chapel
Hill); University of Calgary; Dallas VA Medical Center and University
of Texas, Southwestern Medical Center; Lilly Research Laboratories;
McLean Hospital and Harvard Medical.

In 1998, a clinical trial of Zyprexa was conducted at UCLA in which
the drug was tested in five hospitalized children (age 6 to 11. All
children suffered adverse events: "treatment was discontinued in all
five children within the first 6 weeks of treatment because of adverse
effects or lack of clinically significant therapeutic response."
Chasened by the drug's adverse effect on the children, the authors
cautioned clinicians: "Until more encouraging data are available,
clinicians should be cautious and conservative in their predictions
about the potential value of olanzapine in treating preadolescent
psychiatric disorders." [4]

Notwithstanding the fact that there is still no evidence of this
drug's safety or clinical efficacy to support the use of Zyprexa or
any other antipsychotic drug for children, psychiatrists are
encouraged to prescribe these drugs anyway. Indeed, two and a half
million children are prescribed antipsychotics for ill defined
conditions. USA Today documents prescription drug abuse by American
doctors who are harming children by prescribing these drugs
irresponsibly. (A companion Infomail will be follow).

AHRP has obtained a copy of a direct to consumer advertisement by
Harvard University, Massachusetts General Hospital, which is
recruiting young children for antipsychotic drug experiments. The ad
suggestis children's behavior may be an indication they are bipolar.
Harvard psychiatrists have subjected preschool toddlers--whose mean
age is 4 years old? to the hazardous effects of Zyprexa and Risperdal
(risperidone). [5]

Who will protect America?s children from institutionally sanctioned
market expansion masquerading as medicine or science?
Who will enforce informed consent requirements ensuring that parents
are (at least) fully informed about the risks of treatment?
If children are at all valued, then Congress must pass a law requiring
ALL research documents involving children to be publicly posted for
independent review. These should include: protocols, informed consent
forms, ALL efficacy and safety data in support of claimed
findings--including ALL adverse event reports.

References:
1. Thomas McGlashan, et al. Randomized, Double-Blind Trial of
Olanzapine Versus Placebo in Patients Prodromally Symptomatic for
Psychosis, American J of Psychiatry, May 5, 2006, 163:790?799.
2. Robert Whitaker, Mad in America, Perseus Books, 2002.
3. David Healy,Randomized Controlled Trials: Evidence Biased
Psychiatry, http://www.ahrp.org/COI/healy0802.php
4. Krishnamoorthy J, King BH J. Open-label olanzapine treatment in
five preadolescent children, Child Adolesc Psychopharmacol 1998;
8(2):107-13=20
5. Mick E, Biederman J, Aleardi M, Dougherty M . Open trial of
atypical antipsychotics in pre-schoolers with bipolar disorder
[abstract]. Acta Psychiatr Scand, (2004) 110: 29


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