By Jeremy Olson and Paul Tosto Pioneer Press
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that her son, the 13th enrollee, didn’t have the wherewithal to consent to the study and requesting that he be withdrawn.
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