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From: "Alex Constantine" <[EMAIL PROTECTED]>
To: "Lloyd" <[EMAIL PROTECTED]>
Subject: Illicit Psychiatric Experimentation
Date: Wednesday, September 13, 2000 5:13 AM

Boston Globe
     ''It is extremely wrenching to see how easily a group regarded as
misfits, or as not good enough, or as socially and economically useless, can
be made into objects for other people's purposes.''
------------------------------------------------------------------------
DOING HARM: RESEARCH ON THE MENTALLY ILL
Testing takes human toll
By Robert Whitaker, Globe Correspondent and Dolores Kong, Globe Staff,
11/15/98

PORTRAIT ARTIST SHALMAH PRINCE painted "Second Coming" - meant to depict
hope in the midst of chaos - after her harrowing experience in a research
experiment.
First of four parts
The light flickered on for Shalmah Prince one day in 1994.
Sitting in a doctor's office, she spotted an article in U.S. News & World
Report on human radiation experiments conducted in the 1950s. Her mind, she
said, raced back to a wrenching experience from her past.
She had been in an experiment of some type. Had she too been used?
Prince, a portrait artist who suffers from manic depression, also known as
bipolar disorder, dug into her medical history and documented a chilling
story.
In 1983, she had been in an experiment in which investigators withdrew her
medication, did nothing to intervene as she became increasingly manic, and
then injected her with apomorphine, a chemical that other researchers had
tested to see if it could provoke psychosis.
Prince became so delusional that she had to be placed in leather restraints,
a descent into madness that didn't fully subside for 10 days.
''I was never the same person again,'' Prince said. ''My perception of
myself and who I was completely changed. I had a sense of shame and
embarrassment. Who would have ever thought that doctors would create
psychosis like that?''
Prince's story provides a window into a troubling corner of psychiatric
research that continues to this day. She is one of more than 2,000 mentally
ill patients who over the past 25 years have been ushered into a disturbing
series of experiments by psychiatric researchers exploring the biology of
psychosis.
In their published accounts, doctors have told of injecting mentally ill
patients with drugs designed to exacerbate their delusions and
hallucinations. In prestigious journals, they have described studies in
which they withheld effective antipsychotic medication from desperate
patients who stumbled into hospital emergency rooms. In precise, clinical
terms, they have reported how they deliberately stopped giving medication to
stabilized schizophrenic patients to see how quickly they became sick again.
These studies were designed to gain knowledge that might lead to improved
treatments for schizophrenia and related illnesses. But the experiments
offered no possibility of therapeutic benefit to the subjects and exposed
them to some measure of psychic pain and risk of long-term harm.
Moreover, this controversial line of experimentation has been marked by
repeated instances in which researchers failed to fully disclose the risks
to the mentally ill patients and obscured their true purposes.
Those are the very themes of the story Shalmah Prince pieced together:
On Jan. 14, 1983, fearing the onset of a manic episode despite the lithium
she had been taking for two years, Prince went to University Hospital in
Cincinnati seeking help. Her medical records show that she arrived
well-groomed, in control of her emotions, and thinking fairly clearly.
Standard procedure would have been to test the lithium level in her blood
and adjust the dosage, but that's not what happened.
Prince signed a consent form that said she was agreeing to take part in a
study designed to ''clearly diagnose her illness.'' In their research
protocol, however, the psychiatrists said the purpose of the study was to
explore ''schizophrenia subtypes,'' based on the patients' response to
apomorphine. The consent form didn't mention any risks associated with
stopping the medication, even though Dr. David Garver, who ran the study,
later acknowledged in a sworn deposition that without medication, the
research subjects might ''have a delusion that they were capable of flying,
leap out a window, [and] injure themselves.''
''They assured me they were there to treat me,'' Prince recalled. ''And I
just wanted to be kept safe. I knew that I didn't have insurance and that I
was extremely vulnerable. I needed help and a regular doctor was $150. So I
was really stuck.''
Without her lithium, Prince quickly deteriorated. By the fourth day she was
wildly manic, yelling and threatening suicide. She also ''got in the face''
of another patient, she said, and he started beating her. Still, she was
given no medication.
On the fifth day, researchers injected her with apomorphine. Her manic and
delusional behavior soared. During the next three days, when her friends and
family visited, they found her in restraints, a humiliation that has never
left her.
''Everything they did to me was for the purposes of their research,'' she
said, her voice tinged with bitterness even today. ''As my medical record
shows, when I went into the hospital I was calm and cooperative. I was just
worried and vulnerable. I came out thinking I was crazy, and my parents
thinking I was crazy, and my friends thinking I was crazy. My family and I
believed that every psychotic feeling and behavior was natural to me, rather
than caused by their experiment.''
The final blow came when she got a hospital bill. Prince was asked to pay
nearly $15,000 for the experience.
Attorney Ken Faller, who defended Garver and his coresearcher, Dr. Jack
Hirschowitz, in a lawsuit brought by Prince, sees her experience
differently. ''No one disputes that patients ought to be given information
concerning meaningful risks,'' he said. ''In her particular case ... we
don't believe that there were significant undisclosed risks involved. ''
Although the judge in Prince's lawsuit said he found the facts troubling, he
dismissed Prince's case, saying she should have filed her complaint within
two years of the experiments. Faller also said that the hospital forgave
more than three-quarters of her bill.
''She did receive treatment and the treatment benefited her to this day,''
he said. ''She was a sick person when she went into the hospital and she
came out seemingly in pretty good shape.'' Psychiatric researchers called
for an accounting
Prince's story, and scores of clinical reports of schizophrenia studies in
scientific journals, evoke troubling echoes of past stains on American
medicine. Perhaps the most notorious are the post-World War II radiation
experiments that Shalmah Price read about and the 1932 to 1972 Tuskegee
syphilis studies in which infected black men were denied treatment, blots on
the remarkable achievements of US medical researchers in the 20th century.
Even as psychiatric researchers boast they are now gaining insights into the
biology of psychotic illnesses, they are being asked to account for how that
knowledge was gained.
But unlike Tuskegee or the Cold War radiation studies, this line of
psychiatric research, much of it federally funded, is ongoing. This year,
according to research protocols obtained by the Globe, Yale University
physicians have been recruiting people with schizophrenia for experiments in
which they will hospitalize them, stop their medications, and infuse them
with tetrahydrocannabinol, the psychoactive ingredient in marijuana.
Columbia University researchers have been giving amphetamine to
schizophrenic patients so they can take images of their brains while they
are psychotic. At the National Institute of Mental Health, in Bethesda, Md.,
researchers have been injecting ketamine, the chemical cousin of the
notorious street drug angel dust, into unmedicated schizophrenic patients.
Deliberate withdrawal of medication for experimental purposes is an element
in other active schizophrenia studies.
''I think [these experiments] are in a category that is worse than Tuskegee
and the radiation experiments,'' said Adil Shamoo, professor of biochemistry
at the University of Maryland School of Medicine and founder of the journal
Accountability in Research. ''There are large numbers [of subjects], and
these are current practices. Do they cause harm? Of course they do.''
Shamoo, who has an adult son with schizophrenia, has been a leading critic
of symptom-exacerbation and medication-withdrawal experiments.
The Globe, in a three-month investigation, found a trail of both harm and
deceit.
*  Since 1972, psychiatric researchers have used a variety of agents -
L-dopa, amphetamine, methylphenidate, m-cholorophenyl piperazine, ketamine,
and tetrahydrocannabinol - to deliberately provoke psychotic symptoms in
more than 1,200 schizophrenia patients. In some instances, the chemicals
drove the psychosis to levels the researchers called ''severe.''
Symptom-provocation experiments like these have been conducted by prominent
researchers at the National Institute of Mental Health and at close to a
dozen leading medical schools. They have drawn their psychotic subjects
largely from outpatient clinics, Veterans Affairs hospitals, state mental
institutions, and emergency rooms - settings that regularly provide care to
the poor and uninsured. In the few studies that recorded the ethnic makeup
of patients, 54 percent were minorities.
Symptom-exacerbation studies do not appear to have been conducted in
Massachusetts, but prominent researchers here defend the approach.

*  In the '80s and early '90s, researchers conducted experiments in which
they withdrew medications from schizophrenic patients whose condition was
stabilized, including some living in community settings, and studied them
until they had a full relapse. The prevailing view is that following a
relapse, particularly the first one after a psychotic break, patients may
never return to the same level of functioning. During a relapse,
schizophrenic patients are also at a dramatically higher risk of self-injury
and suicide.

*  There is evidence in researchers' sworn testimony, written
correspondence, citations by the federal Office of Protection from Research
Risks, and patients' own accounts that investigators have routinely failed
to fully disclose the true purposes of their experiments, and withheld
information about risks.
The Globe's review of informed-consent forms for symptom-exacerbation
studies at the NIMH and four other leading psychiatric institutions failed
to turn up a single one in which the researchers directly stated that a
chemical agent would be used purposely to exacerbate psychotic symptoms.
When in 1993 researchers at the University of Maryland began injecting
schizophrenic patients with ketamine, the consent form said only that the
experiment's purpose was ''to study a medication named ketamine for
schizophrenia.''
OPRR, the federal agency charged with protecting research subjects, has
found fault with informed consent practices of psychiatric researchers at
the University of Maryland; the University of California, Los Angeles; and
the National Institute of Mental Health, and has ongoing investigations of
the Bronx Veterans Affairs Medical Center, New York State Psychiatric
Institute, and the University of Cincinnati.
Such practices do not typify all psychiatric research. There is much
experimentation that does not put mentally ill subjects at risk of harm,
conducted by physicians who take pains to ensure that subjects know what
they're getting into.
But there is no similar type of experimentation, in which patients' symptoms
are deliberately exacerbated for research purposes only, on people of sound
mind.
''We let researchers do things to people with mental illness that we would
never let them do to people with physical illness,'' said George Annas,
chairman of the Health Law Department at Boston University School of Public
Health. Schizophrenia resists divulging its secrets
As researchers note, schizophrenia is a poorly understood illness that has
resisted giving up its secrets. It afflicts about one in every 200 adults,
typically beginning in early adulthood. The disease brings on delusions,
hallucinations, and bizarre thoughts (called positive symptoms) and often a
striking lack of outward emotion and extreme social withdrawal (negative
symptoms). It has no consistent course. Some experience an initial psychotic
episode and never relapse; others relapse repeatedly as the disease becomes
chronic.
Symptom-exacerbation experiments were pioneered by Dr. David Janowsky of
Vanderbilt University. In 1974, he reported success in developing a new tool
for studying schizophrenia. He found that giving schizophrenic patients
methylphenidate (Ritalin) caused ''a dramatic intensification of preexisting
symptoms, such as hallucinations and delusions,'' and that amphetamine also
exacerbated their psychosis. Both drugs are known to release dopamine, a
messenger chemical in the brain, and Janowsky's experiments provided
indirect evidence that the biological mechanism of psychosis involved an
overactive dopamine system.
His work also established the idea that psychosis-inducing drugs could be
used as ''challenge agents'' to turn patients into models for studying
psychotic illnesses.
''They are uniquely human conditions and there is no animal model for
developing treatments,'' said Dr. Stephen Strakowski, associate professor of
psychiatry at University of Cincinnati Medical School, who has used
amphetamine as a challenge agent. ''Challenge tests are used to understand
complex disorders, and without them, we would lose a significant way to do
that.''
In the past decade, researchers have turned to new types of psychostimulants
to conduct these studies. Their findings, researchers say, may lead to
better drugs. It is this prospect, they say, that justifies risks to
patients, and the psychic distress they may suffer.
The researchers also say the psychotic symptoms they induce are transient,
usually lasting only a few hours, and generally cause patients only modest
discomfort.
''What we are talking about is very short-lived increases in symptoms that
patients have experienced over years and decades,'' said Dr. David Shore,
associate director for clinical research at NIMH, where ketamine-challenge
experiments are underway. ''To say that increasing a particular symptom -
like hearing voices for a couple of hours in somebody who has been hearing
voices for 10 years - is causing [suffering] rather seems like a stretch.''
Dr. Jeffrey Lieberman, who conducted methylphenidate challenge tests for
more than a decade at Hillside Hospital, a division of Long Island Jewish
Medical Center in New York, acknowledged that the induced symptoms are
sometimes ''scary and very unpleasant.'' Some patients get worse, he said,
''but in my experience, the symptoms never exceeded the range of severity
that occurred in the course of their illness previously.''
Dr. Paul Appelbaum, chairman of the psychiatry department at the University
of Massachusetts Medical School, said challenge studies can be justified
''if the question researchers seek to answer is an important one'' and the
research subjects have given ''good consent, adequate consent.'' Even the
use of a drug like ketamine can be justified, he said, as long as patients
have given informed consent.
''The investigators [using ketamine] are quite persuasive, from my
discussions, that they are not causing outrageous levels of harm,''
Appelbaum said.
But a different view emerges from the researchers' own medical journal
reports, from people who suffer from mental illness, and from families of
patients who have been in such studies. They tell of fragile minds filled
with pain and suffering, and of lives made worse.
The scientific literature provides a few glimpses of individual patients.
This 1987 account by researchers at the National Institute of Mental Health
describes a patient with bipolar disorder who was injected with
methylphenidate: ''Within a few minutes after the infusion, Mr. A
experienced nausea and motor agitation. Soon thereafter he began thrashing
about uncontrollably and appeared to be very angry, displaying facial
grimacing, grunting and shouting ... 15 minutes after the infusion, he
shouted, 'It's coming at me again, like getting out of control. It's
stronger than I am.' He slammed his fists into the bed and table and
implored us not to touch him, warning that he might become assaultive.
Gradually over the next half hour, Mr. A calmed down and began to talk about
his experience.''
That is what outside observers could see. Those who have lived through
psychotic episodes describe an interior landscape that can be filled with
fear and terror as delusions and hallucinations become more florid.
''When you are psychotic, there are a lot of unusual processes going on,''
said Michael Susko of Baltimore, who suffered a psychotic break when he was
25 years old. He is editor of a book about schizophrenia, ''Cry of the
Invisible.''
''You might be having death experiences, feeling like you are dying and
melting,'' he said. ''You give somebody a drug that amplifies that, you run
the risk of overwhelming them. It's like a bad trip.''
Franklin Marquit, founder of the National Artists for Mental Health, has
suffered from a variety of mental illnesses, including manic depression,
panic disorder, and obsessive-compulsive disorder. Last fall, in preparation
for a hearing held by the New York State Department of Health, he gathered
opinions from 25 mental health ''consumers,'' including some with psychotic
disorders, on symptom-exacerbation experiments. All objected vigorously to
the idea that such studies present little danger or cause only minimal
discomfort.
''Have it done to yourself and see how the symptoms are,'' Marquit said.
''Someone who doesn't experience this traumatizing feeling, how would they
know? With panic disorder, I feel like jumping off the edge of the earth at
times, it is so bad. I can't imagine the rationale for exacerbating
symptoms, especially a brain symptom. If a person had an arrhythmia problem,
would you speed the heart up and say that it is OK because they are used to
it?''
Whether symptom-exacerbation experiments and the cutoff of antipsychotic
medication that often accompanies such research cause long-term harm is a
thorny issue. Although these experiments have been ongoing for 25 years, the
question hasn't been studied.
Researchers argue that the temporary increase in psychosis does not amount
to a relapse. Although they acknowledge there is a growing suspicion that
acutely psychotic episodes may be toxic to the brain, causing a type of
scarring of neurons, they do not believe exacerbation experiments are likely
to trigger such damage.
''There is a risk there,'' said Dr. Stephan Taylor, assistant professor of
psychiatry at the University of Michigan, who has used challenge agents to
study anxiety and post-traumatic stress disorder. ''My sense is that the
sort of psychosis that reaches a toxic level is much more significant than
what a few doses of amphetamine will produce. It's a fairly small risk.''
The ultimate question, however, is how exacerbation experiments can be
reconciled with a standard of good medical care that runs contrary to such
practices. Psychiatrists agree that patients do best when physicians catch
the psychosis at an early stage and quickly curb their delusions and
hallucinations with medications. Relapse, often defined as a return of even
moderate psychosis, is seen as a life-threatening event that needs to be
prevented. Most clinicians believe that repeated relapses, particularly for
a person early in the course of the illness, lead to a worse long-term
outcome.
Moreover, critics say that the administration of symptom-inducing drugs is
only part of the harm. Patients in these studies are typically taken off
their medication first and may not receive effective treatment for days and
even weeks, exposing them to an extended period of psychosis. A chilling
example of this was detailed by University of Maryland researcher Carol
Tamminga and colleagues in a 1995 article on their first ketamine
experiment. One of their subjects was a 29-year-old man who at the start of
the experiment was described as doing well on his medication. His medication
was stopped and he was injected three times with ketamine, which caused him
to become ''floridly delusional.'' The researchers allowed his disease to
progress even after the ketamine study ended.
''During a later drug-free period unrelated to this study, his clinical
symptoms were that of paranoid schizophrenia,'' Tamminga wrote. ''There were
similarities between his disease symptoms and those induced by ketamine.''
Along with whatever harm such experiments cause, critics say that they
necessarily violate the trust between doctor and patient that is vital to
the healing process.
''If the patients have any idea about what is being done to them, they know
that they are being used as guinea pigs,'' said Dr. Peter Breggin, director
of the Center for the Study of Psychiatry and Psychology in Bethesda and an
outspoken critic of mainstream psychiatry. ''If they are mentally
unbalanced, and their condition is worsened by doctors for the purpose of
serving the doctors' scientific careers, of course that is going to make it
harder for them to trust anyone again.''
The voices that are hardest to find are those that matter the most: the
mentally ill patients who have been the subjects of these
symptom-exacerbation experiments.
Last fall, however, the mother of one patient stepped forward to tell the
National Bioethics Advisory Commission, a presidential panel that advises
the government on ethical issues in biomedical research, what happened to
her mentally ill daughter after she apparently was given multiple doses of
intravenous amphetamine.
In April 1987, Janice and Carl Becker brought their daughter Laura, 26 at
the time and ill with schizophrenia, to the Maryland Psychiatric Research
Center, outside Baltimore. Researchers emphasized that she would get
excellent care while on the ward, Janice told the commission.
A few months after Laura was admitted, researchers stopped her medications
as part of a research protocol, and her condition quickly deteriorated.
Twice when her mother visited, she found Laura bound with sheets to a chair,
the knots so tight around her wrists and ankles that it took 20 minutes to
free her.
Laura's appearance changed. She lost 40 pounds. She would pace for hours on
end. Alarmed and getting no answers from the staff, her parents pored
through protocols, and found one describing an amphetamine study. They
concluded that the amphetamine explained many aspects of her deterioration:
her weight loss, the hyperactive behavior, the increased psychosis.
Laura's parents never got a copy of any consent forms Laura may have signed
and, to this day, do not know for sure whether their daughter signed the
form for the amphetamine study.
''It was heartbreaking to watch Laura's condition deteriorate,'' Janice told
the commission. ''We had not expected that she would be required to endure
such painful symptoms without medication for years. Nor had we expected that
she would be given drugs that would make her psychotic symptoms worse.''
Today, Laura is on her own, taking medication for her illness, living in a
group home and holding a job. But her mother believes that Laura's story
shows that the researchers put science first and patient care second.
''The physician's creed of 'do no harm' does not apply to research
physicians,'' Janice said from the kitchen of her rural Maryland home. ''I
was wrong to trust that my daughter would be protected.''
Chris Hart, a spokesman for the University of Maryland, said, ''Because
there are issues of patient confidentiality involved, we can't comment.''
Troubling methods surface in relapse studies
Relapse studies conducted during the '80s and early '90s are at least as
troubling as the symptom-exacerbation experiments. In one line of
experimentation, researchers withdrew medications from stable patients
precisely to study the biology of relapse, expecting the patients to become
sick again. After their subjects' descent into sickness could be studied,
they planned to put them back on their medications.
One of the largest studies of this type was led by Dr. Daniel van Kammen at
Highland Drive Veterans Affairs Medical Center in Pittsburgh. From 1985 to
1995, he conducted experiments that involved withdrawing medication from
more than 150 stabilized schizophrenic patients and using spinal taps to
analyze their spinal fluid. The researchers then followed the patients until
they relapsed, which was defined as exhibiting worse symptoms for three days
straight.
During the 10-year Pittsburgh study, virtually all the schizophrenic
patients either relapsed or stopped coming to the hospital and were, in the
researchers' own words, ''lost to follow-up.''
There is considerable evidence that this relapse study put research subjects
directly in harm's way. Patients in relapse have been found to have seven
times the risk of falling victim to antisocial behavior, such as assault,
and 2.5 times the risk of self-injury, including wrist cutting, poisoning,
and attempted hanging, according to a published study.
''You do not put patients through pain and suffering, with experiments that
have a high-risk design, with no benefit to their future,'' said research
critic Shamoo, at the University of Maryland. ''You just don't do that.''
Van Kammen has since left the Pittsburgh VA; his coresearcher on some of
this research, Dr. John Gurklis, is still there, but he declined to be
interviewed. At UCLA, researchers conducted a long-running
medication-withdrawal study. Gregory Aller of Los Angeles was a subject, and
his experiences led him to file a complaint with federal officials.
UCLA psychologist Keith Nuechterlein began his research 15 years ago, and in
an update published in 1988 he detailed how schizophrenic patients admitted
to UCLA's Aftercare Clinic had been taken off medication and allowed to
deteriorate into ''clear'' relapse.
Aller, 24 at the time, became a patient at the clinic in 1988, after
suffering an initial bout of psychosis. At first, he was put on
antipsychotic medication, Prolixin decanoate, and thrived, earning a 3.8
grade-point average at Santa Monica College. But in late 1989, he entered a
medication-withdrawal experiment led by Nuechterlein and fell into a severe
relapse. He growled on buses; he lapped water out of a toilet like a dog.
One evening while visiting his parents, he said he picked up a butcher knife
in the kitchen and called out his mother's nickname: ''Come here, Poo!''
Aller said he needed to exorcise the devil that he believed inhabited her.
''It was so bizarre,'' said Aller, a mild-mannered man who looks younger
than his 34 years. ''I couldn't believe it.'' On Jan. 12, 1990, his parents
argued with researchers that Gregory needed his medication. They detailed
his psychotic behavior in a letter, but, according to the Allers, the
researchers made no attempt to remedicate him. Exactly when the researchers
attempted to put Gregory back on an antipsychotic drug is in dispute; what
is clear is that Gregory did not resume taking medication until May 15.
By then, however, the harm had been done. Gregory is doing well today, said
his father, Robert, but ''he never returned to his previous level of
function.''
UCLA clinical psychologist Nuechterlein says he cannnot discuss Aller
because of patient confidentiality, and the family has not given written
permission waiving the confidentiality.
But he justified the study as helping to determine how soon patients with
early-onset schizophrenia could be taken off antipsychotic medications, and
how long they could stay off. It was an important question because of the
side effects of the medications available at the time.
He also defended the 1988 update as a retrospective look at patients'
records and measurement of relapse after the fact, rather than a study in
which researchers purposely waited for patients to worsen.
In 1993 Dr. Jay Katz, professor emeritus of law, medicine, and psychiatry at
Yale, reviewed documents in the Aller study at the family's request.
''The patients were withdrawn from medication, indeed, required to do so for
research purposes until the needs of the study, and not those of the
individual patient, had been satisfied,'' Katz wrote in a law journal
article.
By any standard, the symptom-exacerbation experiments, the relapse studies,
and the patients' stories all add up to an unsettling record, one that has
imposed some measure of suffering on thousands of vulnerable patients and
exposed them to the risk of long-term harm, often without adequate informed
consent.
Until now, it is also a record that has escaped any broad examination,
despite the efforts of a handful of people to hold researchers accountable.
Chief among them is Vera Sharav, founder of Citizens for Responsible Care in
Psychiatry and Research, a New York-based group made up of families with
sons and daughters who suffer from schizophrenia.
For years, Sharav has labored to bring this research to light, digging deep
into the scientific literature, hectoring reporters to write about it, and,
in a variety of public forums, questioning researchers about its ethics.
It is a record of experimentation, she said, that could only be done on the
powerless.
''That is why I am so passionate about it,'' she said. ''It is extremely
wrenching to see how easily a group regarded as misfits, or as not good
enough, or as socially and economically useless, can be made into objects
for other people's purposes.''


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