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Report raises concerns that mind-altering pills are being overprescribed
The number of children taking antipsychotic medicines soared 73 percent
in the four years ending in 2005, far outpacing the increase in adults, according
to a Medco Health Solutions Inc. report released Tuesday.
Use of the new class of drugs known as atypical antipsychotics by people 19
and younger skyrocketed 80 percent in the same time period, according to the
pharmacy benefit manager.
Antipsychotic drug prescriptions for that age group comprise a relatively small
amount of the total for such medicines, Medco said. In 2005, 15 percent of prescriptions
for such drugs were for children while 85 percent were for adults.
Still, the sharp increase is noteworthy because the powerful drugs are for individuals
with serious psychosis such as schizophrenia so there is some concern the medicines
may not always be prescribed appropriately, said Dr. Amita Dasmanapatra, senior
director of medical affairs at Medco. She said it is possible that some doctors
are prescribing the drugs for children with behavioral problems, which would be
better controlled by other means. Medco's analysis of over 2 million insured Americans
didn't explore the reasons for the increase.
Additionally, the atypical antipsychotics aren't approved for use in children
although doctors are free to prescribe drugs as they see fit.
The number of children on antipsychotics rose to 6.6 per 1,000 in 2005 from
3.81 per thousand in 2001. In contrast, 11 adults per 1,000 were taking one
of the drugs. The increase in the number of adults taking antipsychotics rose
13 percent in the four years ended in 2005.
However, the rate of prescription growth in children has been slowing although
the analysis was not designed to determine the reason. For example, the rate
of prescription growth in all antipsychotics was 3.38 percent last year, down
from 14 percent in 2004 and 22 percent in 2003. Meanwhile, last year prescription
growth for atypical antipsychotics was nearly 5 percent, down from nearly 13
percent in 2004 and 24 percent in 2003.
Dr. David Kessler, a child and adolescent psychiatrist in Burlington, Vt., speculated
that the decrease in growth is tied to concern about atypical antipsychotics link
to diabetes.
In 2003, The U.S. Food and Drug Administration asked manufacturers of atypical
antipsychotics to add warning labels describing the increased risk of high blood
sugar and diabetes. The drugs include Eli Lilly & Co.'s Zyprexa, AstraZeneca
PLC's Seroquel, Bristol-Myers Squibb Co.'s Abilify and Pfizer Inc.'s Geodon.
Also, last year the FDA determined that elderly patients with dementia that
were being treated with atypical antipsychotics had an increased risk of death.
The FDA asked manufacturers to include a warning on the drugs' label about the
risk, and note that the drugs are not approved to treat behavioral problems
in patients with dementia.
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From Alliance for Human Rsearch Protection
http://www.ahrp.org/cms/content/view/157/80/
Yale-Lilly Experiment: Adolescents Rx Toxic Drug for
Presumed Mental Illness They Do Not Have
Wednesday, 03 May 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
Contact: Vera Hassner Sharav
veracare@ahrp.org
_____________________________
http://www.nytimes.com/2006/05/01/health/01psych.html?ex=1147147200&en=1a9efa6f722d3bf9&ei
=5070&emc=eta1
THE NEW YORK TIMES
Mixed Result in Treating Schizophrenia Pre-Diagnosis
By BENEDICT CAREY
May 1, 2006
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 hope is that while exposing some to drugs unnecessarily, preemptive treatment
may help others ward off or even prevent psychosis, sparing them the agonizing
flights of paranoia and confusion that torment the three million American who
suffer schizophrenia.
Yet the findings from the first long-term trial of early drug treatment, appearing
today in The American Journal of Psychiatry, suggest that this preventive approach
is more difficult to put into effect — and more treacherous — than
scientists had hoped.
Daily doses of the antipsychotic drug Zyprexa, from Eli Lilly, blunted symptoms
in many patients and lowered their risk of experiencing a psychotic episode
in the first year of treatment, the study found. But the drug also caused significant
weight gain, and so many participants dropped out of the study that investigators
could not draw firm conclusions about drug benefits, if any.
The long-awaited study, which was financed by Eli Lilly and the National Institute
of Mental Health, raised more questions than it answered, experts said.
"The positive result was only marginally significant, and the negative
result was clear," said Dr. Thomas McGlashan, a professor of psychiatry
at Yale and the study's lead author. "This might discourage people, and
legitimately so, from using this drug for prevention because of the weight gain,
but hopefully it won't discourage study" of other drugs.
Critics have charged that treating people for a disorder that has not yet been
diagnosed is not only premature but stigmatizing, especially for adolescents.
The new study was intended in part to clarify the trade-off between the risks
and the potential benefits of preemptive treatment.
"Unfortunately, the study's numbers are so small that it cannot be decisive
on the key issue, which is whether it's prudent to treat people early when there
are uncertainties about the diagnosis and given the effect of stigma and adverse
effects," said Dr. William Carpenter, director of the Psychiatric Research
Center at the University of Maryland, who was not involved in the study.
The study was plagued by recruitment problems from the beginning, in 1997.
Mild, psychosis-like symptoms are rare in adolescents, and families often wait
until symptoms are pronounced before seeking treatment, Dr. McGlashan said.
Good candidates trickled in slowly; and the researchers added several recruitment
sites along the way to increase the numbers of people in the study.
They eventually enrolled 60 people, most of them adolescents, who scored highly
on a scale that assesses risk for psychosis. The scale rates severity of more
than a dozen symptoms, including suspiciousness, grandiosity and bizarre thoughts.
From 20 to 45 percent of people who score high on the scale go on to develop
full-blown psychosis, in which these symptoms become extreme, researchers have
found.
The researchers split the participants into two groups, one that received drug
treatment and one that took placebo pills. In the first year of a two-year trial,
5 of the 31 of those on medication developed full-blown psychosis, compared
with 11 of 29 of those who were taking dummy pills.
But by then, more than two-thirds of the young people in both groups had dropped
out, making it difficult to interpret differences between them. Some left the
study without explaining why; others moved; and 10 of those on medication quit
the study because they felt the drug was not working, could not make the appointments
or did not like the side effects, among other reasons.
Those on medication gained an average of 20 pounds during the study. Weight
gain is a common side effect of Zyprexa.
"It's a pessimistic trade-off, the weight gain and other side effects
for what looks like a modest delay in the acute psychotic episode," said
Dr. Steven Hyman, a professor of neurobiology at Harvard . "It's clear
we need more efficacious drugs with milder side effects."
Copyright 2006 The New York Times Company
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What is the metabolic syndrome?
