Yale-Lilly Experiment: Adolescents Rx Toxic Drug for Presumed Mental Illness

[Guest guest]

Yale-Lilly Experiment: Adolescents Rx Toxic Drug for Presumed

Mental Illness They Do Not Have

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. "

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 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. 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.

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.

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. 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. Whitaker, Mad in America, Perseus Books, 2002.

3. 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

http://www.ahrp.org/cms/

http://www.nytimes.com/2006/05/01/health/01psych.html?

ex=1147147200 & en=1a9ef

a6f722d3bf9 & 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. 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. Carpenter, director of the

Psychiatric Research Center at the University of land, 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.

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

http://www.americanheart.org/images/interface/spacer.gif

American Heart Association

What is the metabolic syndrome?

The metabolic syndrome is characterized by a group of metabolic risk

factors

in one person. They include:

* Abdominal obesity (excessive fat tissue in and around the abdomen)

* Atherogenic dyslipidemia (blood fat disorders - high triglycerides,

low HDL cholesterol and high LDL cholesterol - that foster plaque

buildups

in artery walls)

* Elevated blood pressure

* Insulin resistance or glucose intolerance (the body can't properly

use insulin or blood sugar)

* Prothrombotic state (e.g., high fibrinogen or plasminogen activator

inhibitor-1 in the blood)

* Proinflammatory state (e.g., elevated C-reactive protein in the

blood)

People with the metabolic syndrome are at increased risk of coronary

heart

disease and other diseases related to plaque buildups in artery

walls (e.g.,

stroke and peripheral vascular disease) and type 2 diabetes. The

metabolic

syndrome has become increasingly common in the United States. It's

estimated

that over 50 million Americans have it.

The dominant underlying risk factors for this syndrome appear to be

abdominal obesity and insulin resistance. Insulin resistance is a

generalized metabolic disorder, in which the body can't use insulin

efficiently. This is why the metabolic syndrome is also called the

insulin

resistance syndrome.

Other conditions associated with the syndrome include physical

inactivity,

aging, hormonal imbalance and genetic predisposition.

[Guest guest]

Yale-Lilly Experiment: Adolescents Rx Toxic Drug for Presumed

Mental Illness They Do Not Have

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. "

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 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. 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.

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.

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. 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. Whitaker, Mad in America, Perseus Books, 2002.

3. 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

http://www.ahrp.org/cms/

http://www.nytimes.com/2006/05/01/health/01psych.html?

ex=1147147200 & en=1a9ef

a6f722d3bf9 & 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. 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. Carpenter, director of the

Psychiatric Research Center at the University of land, 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.

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

http://www.americanheart.org/images/interface/spacer.gif

American Heart Association

What is the metabolic syndrome?

The metabolic syndrome is characterized by a group of metabolic risk

factors

in one person. They include:

* Abdominal obesity (excessive fat tissue in and around the abdomen)

* Atherogenic dyslipidemia (blood fat disorders - high triglycerides,

low HDL cholesterol and high LDL cholesterol - that foster plaque

buildups

in artery walls)

* Elevated blood pressure

* Insulin resistance or glucose intolerance (the body can't properly

use insulin or blood sugar)

* Prothrombotic state (e.g., high fibrinogen or plasminogen activator

inhibitor-1 in the blood)

* Proinflammatory state (e.g., elevated C-reactive protein in the

blood)

People with the metabolic syndrome are at increased risk of coronary

heart

disease and other diseases related to plaque buildups in artery

walls (e.g.,

stroke and peripheral vascular disease) and type 2 diabetes. The

metabolic

syndrome has become increasingly common in the United States. It's

estimated

that over 50 million Americans have it.

The dominant underlying risk factors for this syndrome appear to be

abdominal obesity and insulin resistance. Insulin resistance is a

generalized metabolic disorder, in which the body can't use insulin

efficiently. This is why the metabolic syndrome is also called the

insulin

resistance syndrome.

Other conditions associated with the syndrome include physical

inactivity,

aging, hormonal imbalance and genetic predisposition.

[Guest guest]

Yale-Lilly Experiment: Adolescents Rx Toxic Drug for Presumed

Mental Illness They Do Not Have

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. "

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 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. 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.

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.

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. 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. Whitaker, Mad in America, Perseus Books, 2002.

3. 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

http://www.ahrp.org/cms/

http://www.nytimes.com/2006/05/01/health/01psych.html?

ex=1147147200 & en=1a9ef

a6f722d3bf9 & 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. 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. Carpenter, director of the

Psychiatric Research Center at the University of land, 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.

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

http://www.americanheart.org/images/interface/spacer.gif

American Heart Association

What is the metabolic syndrome?

The metabolic syndrome is characterized by a group of metabolic risk

factors

in one person. They include:

* Abdominal obesity (excessive fat tissue in and around the abdomen)

* Atherogenic dyslipidemia (blood fat disorders - high triglycerides,

low HDL cholesterol and high LDL cholesterol - that foster plaque

buildups

in artery walls)

* Elevated blood pressure

* Insulin resistance or glucose intolerance (the body can't properly

use insulin or blood sugar)

* Prothrombotic state (e.g., high fibrinogen or plasminogen activator

inhibitor-1 in the blood)

* Proinflammatory state (e.g., elevated C-reactive protein in the

blood)

People with the metabolic syndrome are at increased risk of coronary

heart

disease and other diseases related to plaque buildups in artery

walls (e.g.,

stroke and peripheral vascular disease) and type 2 diabetes. The

metabolic

syndrome has become increasingly common in the United States. It's

estimated

that over 50 million Americans have it.

The dominant underlying risk factors for this syndrome appear to be

abdominal obesity and insulin resistance. Insulin resistance is a

generalized metabolic disorder, in which the body can't use insulin

efficiently. This is why the metabolic syndrome is also called the

insulin

resistance syndrome.

Other conditions associated with the syndrome include physical

inactivity,

aging, hormonal imbalance and genetic predisposition.

[Guest guest]

Yale-Lilly Experiment: Adolescents Rx Toxic Drug for Presumed

Mental Illness They Do Not Have

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. "

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 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. 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.

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.

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. 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. Whitaker, Mad in America, Perseus Books, 2002.

3. 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

http://www.ahrp.org/cms/

http://www.nytimes.com/2006/05/01/health/01psych.html?

ex=1147147200 & en=1a9ef

a6f722d3bf9 & 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. 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. Carpenter, director of the

Psychiatric Research Center at the University of land, 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.

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

http://www.americanheart.org/images/interface/spacer.gif

American Heart Association

What is the metabolic syndrome?

The metabolic syndrome is characterized by a group of metabolic risk

factors

in one person. They include:

* Abdominal obesity (excessive fat tissue in and around the abdomen)

* Atherogenic dyslipidemia (blood fat disorders - high triglycerides,

low HDL cholesterol and high LDL cholesterol - that foster plaque

buildups

in artery walls)

* Elevated blood pressure

* Insulin resistance or glucose intolerance (the body can't properly

use insulin or blood sugar)

* Prothrombotic state (e.g., high fibrinogen or plasminogen activator

inhibitor-1 in the blood)

* Proinflammatory state (e.g., elevated C-reactive protein in the

blood)

People with the metabolic syndrome are at increased risk of coronary

heart

disease and other diseases related to plaque buildups in artery

walls (e.g.,

stroke and peripheral vascular disease) and type 2 diabetes. The

metabolic

syndrome has become increasingly common in the United States. It's

estimated

that over 50 million Americans have it.

The dominant underlying risk factors for this syndrome appear to be

abdominal obesity and insulin resistance. Insulin resistance is a

generalized metabolic disorder, in which the body can't use insulin

efficiently. This is why the metabolic syndrome is also called the

insulin

resistance syndrome.

Other conditions associated with the syndrome include physical

inactivity,

aging, hormonal imbalance and genetic predisposition.