St. Paul Pioneer Press (Minnesota)
The death of Subject 13
By Jeremy Olson and Paul Tosto Pioneer Press
May 18, 2008

Subject 13 was dead.
Enrolled in a clinical trial testing the effects of anti-psychotic
drugs at the University of Minnesota, the schizophrenic had killed
himself May 8, 2004, in a grisly suicide.

Tragic, a U official wrote in a "serious adverse event" memo to the
U.S. Food and Drug Administration, but suicide was "unfortunately not
uncommon in this study population."

Unfortunate, but not unpredicted. Subject 13 had a mother who thought
that her son, Dan Markingson, wasn't getting better during his six
months in the study. Mary Weiss sent five letters and made numerous
calls to the researchers, complaining that her son, the 13th enrollee,
didn't have the wherewithal to consent to the study and requesting
that he be withdrawn.

St. Paul, Minnesota
The university disregarded her letters and calls. She later filed a
lawsuit, accusing Markingson's psychiatrist and the study's director,
Dr. Stephen Olson, of coercing him to sign up. The lawsuit claimed the
university kept Markingson enrolled to preserve its research and to
keep payments coming for his participation.

"Do we have to wait until he kills himself or someone else," she asked
three weeks before the suicide, "before anyone does anything?"

The death prompted reviews by the state mental health ombudsman and
the U.S. Food and Drug Administration about the conduct of the
university and Olson, who was Markingson's only psychiatrist at the
time he recruited him into the study. The reviews and the lawsuit
probed whether Markingson was coerced into the study by the threat of
commitment to a psychiatric hospital and whether the university
provides adequate protection of mentally ill research subjects. The
lawsuit also revealed the pressure to recruit research subjects.

Neither Olson nor the U has been blamed by any oversight agency for
the death, or cited for research violations. The U was dismissed from
the lawsuit in February, and Olson settled in April. Four years after
Markingson's death, the university has moved on. Weiss has not. She
endures the pain of a mother who says she couldn't get anyone to
listen.He fit the profile

Markingson was a celebrity-tour bus driver in Los Angeles in summer
2003 when his mother, from South St. Paul, arrived for a visit. Weiss
found a 26-year-old who believed that aliens had burned a spot on his
carpet and that a secretive world order would call on him to kill
people in a "storm."

Desperate to get her only son back home, Weiss sent him e-mails
pretending to be the "guardian angel" spirit of Markingson's dead
grandmother and suggesting the storm would start in Minnesota.

The deception worked, but the return home didn't seem to change
Markingson's mental state. He started having visions of killing his
mother in the storm. Markingson was taken Nov. 12, 2003, to Regions
Hospital in St. Paul, but it had no open psychiatric beds. He was then
transferred to the University of Minnesota Medical Center, Fairview.

Weiss said discussions about research started right away at the
hospital. Markingson was placed in Fairview's Station 12, a new unit
at the time created to treat psychotic patients and screen them for
research. Olson and Dr. Charles Schulz, head of the U's psychiatry
department, helped launch the unit in part to enhance the hospital's
startup schizophrenia program and meet the U's mandate to bring in
more research dollars.

Olson first recommended on Nov. 14 that a Dakota County District Court
commit Markingson to the state treatment center in Anoka because he
was not fit to make decisions about his care. He wrote to the court
that Markingson was convinced his delusions were real and that he
wasn't mentally ill.

The doctor changed his opinion about the commitment in less than a
week, telling the court Markingson had started to acknowledge the need
for help.

Reversals by patients are common, Olson explained in an interview with
the Pioneer Press last month. Schizophrenics often arrive for
treatment with delusions and denial but change their outlook while
hospitalized.

A judge agreed Nov. 20 with Olson's new recommendation, requiring
Markingson to follow the doctor's treatment plan. The next day,
Markingson signed a consent form to be part of a national
anti-psychotic drug study, Comparison of Atypicals for First Episode,
or CAFE.

Weiss didn't understand. How could her son be deemed incapable of
making decisions one day and then consent to a drug study the next?

The study, funded by drugmaker AstraZeneca and spread among 26
institutions, compared the effectiveness of three commonly used
anti-psychotic drugs -- Seroquel, Zyprexa and Risperdal.

Olson had been searching for recruits for more than a year. The study
required a very specific and elusive person -- a schizophrenic
experiencing his first symptoms. Markingson fit that profile.

Weiss wasn't expecting a schizophrenia diagnosis. At Regions, her son
responded well to a medication for bipolar disorder. The family has a
history of that disorder as well.Question of bias

Full participation required Markingson to take one anti-psychotic drug
for up to a year and to appear at the U for checkups. Markingson
received AstraZeneca's Seroquel. As Subject 13, Markingson was worth
$15,000 to the U, with some of that going to Olson's salary and the
psychiatry department. Switching or adding medications could have
disqualified Markingson and halted payments to Olson and the
department from AstraZeneca.

Overall, the study offered $327,000 to the U and an opportunity to
raise the profile of its schizophrenia program.

Weiss' lawsuit claimed that this money gave Olson a conflict of
interest regarding Markingson's care.

Four experts hired by Weiss' attorneys agreed that Olson had an
ethically questionable position -- as the gatekeeper over Markingson's
commitment, as his treating psychiatrist, and as the researcher with a
financial incentive to enroll patients.

"For a physician to exercise such medical, research and legal power
and control over a research subject is an extraordinary, if not
unprecedented, example of unethical coercive practices," said Dr.
Keith Horton, a Minneapolis psychiatrist who gave a written opinion in
Weiss' suit.

The university's own Web-based guidance on research ethics advises
recruiting "in a non-biased, non-power-based manner" and states that
"doctor-patient relationships between the investigator and
participants should be avoided, when possible, to eliminate any
power-based coercion."

In a recent interview, Olson said that it is difficult for an academic
physician to avoid this conflict and that in this case the conflict
didn't matter. As Olson's patient, Markingson was going to receive one
of the three anti-psychotic drugs being tested in the study anyway. As
a study participant, Olson said, Markingson would receive more
attention and monitoring.

Olson also said in his deposition that participation in the study was
never linked to the commitment decision. Markingson could have
selected standard treatment or backed out of the study, Olson said.

Weiss doesn't believe her son understood he could have those options.
Markingson signed a consent form that said he was "not under any
obligation to participate in a research project offered by your
doctor." He also signed a hospital discharge plan that warned him to
follow Olson's instructions, take his medication and show up for CAFE
study appointments.

"Consequences for not following this plan," it stated, "could result
in court commitment to the hospital."Mother's intuition

Markingson was transferred from the hospital Dec. 8, 2003, to a West
St. Paul halfway house where he was often reclusive -- spending entire
days in his room -- but showed no delusions or psychotic episodes.

Notes from Fairview's day treatment program showed no problems either,
though Markingson often tuned out group discussions and wore
headphones.

Weiss said her son no longer verbalized his most outlandish delusions
-- about the killing storm or his "sister" Angelina Jolie. But Weiss
still saw signs. Markingson believed he should return to California to
resume an acting career he never had. He called himself bulletproof
and said his mom would be bulletproof, too, while with him.

Weiss' letters to Olson and Schulz, who was a co-investigator in the
study, urged them to consider different treatment options for her son,
which would have disqualified him from the study. But the doctors were
unconvinced by her pleas. Screenings as part of the U study showed
that the drug had managed Markingson's delusions and disordered
thoughts.

Weiss was infuriated. Why didn't anyone trust a mother's insights? She
looked into a legal guardianship so she would have the power to
withdraw her son.Recruiting pressure

Recruiting patients for psychiatric research is a challenge, but CAFE
presented special problems. First-episode schizophrenics aren't easy
to locate. They don't go to clinics or support groups. Some don't
admit to an illness until they are brought to a hospital against their
will.

CAFE was an early opportunity at the U for Olson to add research
experience to his academic credentials. The U had recruited him in
2001 for his expertise in schizophrenia.

It was a slow start. Olson recruited one patient in 2002, and CAFE
study leaders considered dropping him altogether, according to monthly
recruiting summaries. Olson and the university had been dropped from a
previous study because of low recruiting numbers, the doctor later
said in his court deposition.

Exchanges between local and national study officials made it clear
that there was pressure for results and a "risk" that the study would
be shut down if it didn't recruit enough patients.

The opening of Station 12 -- which evaluated every patient for
research -- made a difference, Olson and Schulz said. One-third of the
U's patients for CAFE came from this unit. By mid-2003, CAFE leaders
were praising Olson and his recruiter, Jeannie Kenney, and asking them
to share recruiting tips.Warning signs

Trouble dotted Markingson's final weeks. Screenings at the U showed an
increase in symptoms. Markingson neglected his appearance, wearing the
same clothes daily. He read a headline about Easter and then told a
halfway house worker he'd never heard of that word.

Two changes seemed to add stress for Markingson. His mother drove his
car and belongings back from California. He was furious. Also, his
county case manager, David Pettit, recommended he seek an apartment
and a job.

More than ever, Weiss worried that the research study was failing her
son. She didn't think he would listen to her face to face, so she
wrote her concerns in a May 7 letter to him. Writing had always
connected them, even when Markingson went to college in Michigan and
then moved to California.

Her son would never open his mother's letter.

May 8 started normally. A worker wasn't surprised when Markingson took
a midnight shower -- he often did. But then an hour passed and he
didn't come out.

The worker burst in to find Markingson dead in the bathtub. He killed
himself in ritualistic fashion, mutilating himself with a knife. A
note on his nightstand said, "I went through this experience smiling!"

Questions surfaced. An autopsy showed no medication in Markingson's
bloodstream, and a coroner's photo showed a sealed bottle of his
medication. Had he been taking his drugs?

Study officials could have been fooled. They only counted drugs left
in pill bottles instead of testing blood levels in patients.

While others were baffled, Weiss was angry. When a sympathy plant
arrived from the university, she drove it back with new words on the
card:

"How dare you!"Lack of oversight?

Olson originally recommended that Markingson be committed, but then
advised a judge to stay the commitment for six months. Olson did not
disclose to the court that he was Markingson's only psychiatrist at
the same time he recruited him for his drug study.

Markingson's county case manager learned of Olson's dual roles, but
after Markingson had enrolled in the study.

Two weeks before Markingson's death, Olson recommended another
six-month stayed commitment to prevent his patient from moving back to
California. Olson's letter to the case manager stated that Markingson
had "little insight" into his illness and would be at "risk" on his
own of slipping back into delusional behavior.

The letter didn't mention the study, which had several months left.

The university's Institutional Review Board acted as the safety
watchdog of the study, but leaders of the IRB said in court
depositions that they never learned about Weiss' concerns or how
Markingson was recruited until after he died.

The FDA's involvement came after the death as well. The agency
inspects 1 percent of the thousands of U.S. clinical trial sites each
year.

The state ombudsman raised concerns after Markingson's suicide,
including the method of ensuring that patients were taking their pills
and the ethics of one doctor both recruiting and treating a patient.
The report also questioned whether Markingson was truly eligible for
the study, because he wasn't diagnosed with schizophrenia until
several weeks after he had enrolled.

Weiss' attorneys found other concerns about the study as they built
their case. Olson fell behind in required training to evaluate CAFE
study subjects, according to e-mails from national study leaders.
Records suggested Olson had met two or three times with Markingson in
his last six months, while Kenney, a social worker, conducted most of
the screenings.

Olson waited several weeks before notifying participants of a new
diabetes risk with anti-psychotic drugs. The U's records also showed
an office visit with Markingson that would have occurred after his
death.

The lawsuit ended this year after a judge ruled that the university
had statutory immunity from such lawsuits and that AstraZeneca
shouldn't stand trial because there was no convincing proof that its
drug caused Markingson's death. Weiss settled with Olson, the only
defendant left. She said she was granted $75,000, which went entirely
toward legal bills.Final chapter

CAFE's results came out in June 2005. They showed little difference in
the effectiveness of the three drugs or the amount of unhealthy weight
gain by study participants.

Some observers believed AstraZeneca had backed the study to prove that
its drug, Seroquel, caused less weight gain than the others. Buried in
CAFE's results: There had been five attempted suicides, two completed
suicides.

Researchers weren't shocked. The lifetime suicide rate among
schizophrenics is as high as 10 percent. Two deaths among 400 study
participants wasn't unexpected.

U leaders believe that their system to protect human research subjects
is effective and that Markingson was a sad aberration.

"It is a tragedy" to lose a patient to suicide, Olson said. "We're
just redoubling our efforts to understand what goes on in the mind of
someone whose mind isn't working properly."

Olson is enrolling patients in studies, including another AstraZeneca
drug trial called HALO, and worries that publicity of the suit will
make recruiting harder.

The university is demanding $57,000 from Weiss to cover its legal
bills.

QUESTIONING THE QUESTIONERS

Clinical research drives medical progress but presents risks to
participants. Here are 10 questions to ask before signing up:

1. Why do you want to study me or people like me?

2. Who is running the study and paying for it?

3. Who from the study can I go to with ideas, questions or complaints?

4. Can I quit the study after signing the consent form? Will anything
happen to me?

5. What will I get out of this study?

6. How could I be harmed in this study and how will I be protected?

7. If I am harmed, who will take care of me and who pays if I need
treatment?

8. Is there a written guarantee of privacy?

9. How much of this study have you already done? Have there been any
problems so far?

10. Will results be in places where the public can see them?

Source: U.S. Centers for Disease Control and Prevention

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