Yale-Lilly Experiment: Adolescents Rx Toxic Drug for Presumed Mental Illness They...
[align=left]Yale-Lilly Experiment: Adolescents Rx Toxic Drug for Presumed Mental Illness They Do Not Have [/align]
AHRP | May 4 2006
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
