Charles Schulz under scrutiny for Seroquel study suicide
Mary Weiss knew something wasn't right with her son.
Only a year before, Dan Markingson had seemed perfectly normal. But his latest letter from Los Angeles suggested a troubled mind.
He claimed he was about to become famous. He was at a crossroads in his life, and would soon have more free time. He even had a big movie premiere in the works.
"I knew then that something was wrong," says Weiss. "I knew that there wasn't a premiere, and when he said he was going to have a lot more free time, I thought he was quitting his job."
Weiss immediately jumped in her car and drove to California. When she arrived, she found her son far worse off than she'd feared. He was talking nonsense and couldn't be reasoned with.
Weiss tried to convince Markingson to come back to Minnesota, where she could look after him. But he had a stipulation: He would only return home if his dead grandmother Daisy told him to.
Weiss went to an internet cafe down the street and created an email account under the name "GuardianAngelDaisy." Pretending to be her own deceased mother, she urged Markingson to return to Minnesota. Eventually, he agreed.
He was home for only 10 days before he decided to return to California. Weiss pleaded with him to stay, but he refused. She could either drive him to the airport, or never see him again.
Weiss followed him to Los Angeles, where she again tried to urge her son to go back to Minnesota. But this time, his grandmother's emails weren't enough. Markingson wanted to talk to a higher authority: Michael the Archangel.
Weiss created another fake email account as Archangel Michael. The two exchanged emails for more than a week before Markingson finally agreed to fly home.
Once he was back, Weiss called the South St. Paul police. An officer came to her home to evaluate her son. During the interview, Markingson casually mentioned he would soon be attending a devil-worshipping event in Duluth, and might be ordered to kill people.
That triggered a trip to Fairview University Medical Center, where Markingson was diagnosed with psychosis and placed on a 72-hour hold.
In order to be released, Markingson agreed to a stay of commitment, which would allow him to leave the hospital as long as he followed a treatment plan. The plan involved Markingson enrolling in a study called Comparison of Atypicals in First Episode, or CAFE. The research was sponsored by AstraZeneca, maker of Seroquel, one of the anti-psychotic drugs being investigated.
When Weiss found out her son was a human guinea pig, she was furious. She called the hospital and tried to pull her son out of the treatment plan, to no avail. Although Markingson was mentally unfit, he was somehow able to consent to the drug trial.
Over the next few months, Markingson's condition only worsened, Weiss says. His doctor wouldn't return her calls, so she tried writing a letter to the head of the department, Dr. S. Charles Schulz. He didn't reply.
It wasn't until April 28, after Weiss's third letter, that she received a cursory response, in which Schulz wrote, "it was not clear to me how you thought the treatment team should deal with this issue."
Ten days later, on May 8, Markingson sat in the bathtub of the halfway house where he was staying and stabbed himself to death with a box cutter.
"I left this experience smiling!" read the suicide note.
MARKINGSON'S SUICIDE HAS cast a harsh spotlight on the University of Minnesota psychiatry department. The Federal Drug Administration, the Attorney General's Office, and the college's Internal Review Board all wanted to know how a 26-year-old research subject ended up dead.
So did his mom. After a year of combing through studies and public records, Weiss filed a malpractice suit against Schulz and the U of M, accusing them of putting Big Pharma's bottom line ahead of her son's mental health.
In December, a group of eight bioethicists at the U of M wrote a letter to the college's Board of Regents, demanding the appointment of an independent board to investigate whether lapses in ethics and judgment led to Markingson's suicide.
"This goes beyond everything and anything, and this should have brought the house down on the university," says Vera Sharav, president of the Alliance for Human Research Protection, a patient-advocacy group. "There has to be zero tolerance, because a lot hangs on it, including lives."
The issue will soon come to a head. The U of M has been investigating a complaint about Schulz's connections to Big Pharma and is expected to issue the results in a matter of weeks.
"If there's any question that the investigation was superficial, it ought to be by an independent group that can determine what the facts are," says Jerome P. Kassirer, former editor of the New England Journal of Medicine, who is familiar with the circumstances surrounding the Markingson case. "It looks worrisome to me."
DR. SCHULZ DIDN'T start out on a traditional path to psychiatry. As an undergrad at the University of Southern California, he majored in history even though he planned on becoming a doctor.
Years later, as a medical student at the University of California-Los Angeles, Schulz still didn't know what field he would specialize in. He thought of practicing general medicine, but a visit to the Camirillo State Mental Hospital brought his life into focus.
At the time, conditions like schizophrenia and autism were generally considered to be untreatable. Camirillo was a progressive facility, and one of the few hospitals to offer hope.
"I...was stunned by how seriously ill the schizophrenic patients were and worried about who was going to care for them," Schulz explains in an email.
It was then that he decided to pursue psychiatry.
By the time he graduated from college and finished his residency, Schulz had begun to narrow his focus to schizophrenia in teenagers. Thorazine, Haldol, and Stelazine were the only drugs available at the time, and Schulz was troubled by their long-term side effects, such as impaired motor movement.
So when a second generation of antipsychotics known as Atypicals hit the market, Schulz plunged in with both feet. Throughout the '80s and '90s, Schulz earned headlines in high-profile scientific journals studying the new drugs.
In 1999, Schulz received an offer for a prestigious position at one of the best medical schools in the country. He accepted the offer to become the head of psychiatry at the University of Minnesota.
AROUND THIS TIME, AstraZeneca introduced a new pill to the world of antipsychotics: Seroquel.
According to AstraZeneca's marketing campaign, Seroquel was the next big thing in treating schizophrenia. It would make older drugs like Haldol and Thorazine look primitive.
But Seroquel wasn't exactly flying off the shelves. When Schulz came to the U of M, the drug was in its third year on the market and its sales paled in comparison to that of competitors.
In an effort to change this, AstraZeneca commissioned studies to prove Seroquel's superiority to the existing drugs on the market. Internal emails detail a plan to place the results of these studies in a scientific journal.
The man who would help make it happen was the University of Minnesota's new head of psychiatry: Charles Schulz. He was scheduled to present an analysis of the research at the upcoming American Psychiatric Association conference.
But in March 2000, all was not going according to plan.
"The data don't look good," AstraZeneca publications manager John Tumas wrote on March 23, 2000. "What seems to be the case is that we were highlighting the only good stuff, and that our own analysis supports the 'view out there' that we are less effective than Haloperidol and our competitors."
Yet Schulz painted a much rosier picture at the APA conference just two months later. Despite AstraZeneca's findings that Seroquel did not perform as well as older antipsychotics, Schulz declared it "significantly superior" to haloperidol, a competing medication.
"I hope that our findings help physicians better understand the dramatic benefits of new medications like Seroquel because, if they do, we may be able to help ensure patients receive these medications first," Schulz said in an AstraZeneca press release sent out that day.
That wasn't the last time Schulz did the heavy lifting to promote Seroquel. A review published in Science Direct claimed a generic version of Seroquel called quetiapine was superior to haloperidol in some measures and should be used as a "front-line treatment for schizophrenia."
While Schulz says he designed the study, AstraZeneca clearly had a strong hand. The third person listed as an author is Martin Brecher, the executive director of medical science for the drug company. A footnote at the end of the study credits the pharmaceutical company's role in preparing the article.
That's not the only questionable decision. A graph in one of the seven studies Schulz cites is actually incorrect, says Dr. Glen Spielmans, a psychiatry professor at Metro State University who analyzed Schulz's work for City Pages.
The article references an earlier trial conducted by five Japanese psychiatrists comparing the two drugs. Schulz's article shows a graph of quetiapine slightly outperforming haloperidol. However, the original study shows the two performed exactly the same, Spielmans says.
"How do you come up with this?" asks Spielmans. "Sometimes honest mistakes happen. I'm not at all implying that this was intentional cooking of the books or anything, but something's not right."
OVER THE YEARS, Schulz continued to conduct research funded by AstraZeneca. In 2001, he agreed to be the co-investigator for Study 41, designed to prove that Seroquel SR—a new, longer-lasting version of the drug—was more effective than a placebo.
AstraZeneca set up 45 study sites in the United States and four in Canada. For six weeks at a time, psychiatrists interviewed patients every few days.
But after a year of running the tests, it was clear that the study was a failure—Seroquel SR was barely more effective than a sugar pill. Instead of publishing the results, however, AstraZeneca decided to keep a lid on the data, according to internal emails.
"This information should be kept in the strictest confidence," warned Scott French, AstraZeneca's study delivery manager.
A month later, Seroquel's brand manager, Simon Hagger, also emphasized the importance of suppressing the negative data.
"You will all be aware that we are under clear instruction from the highest level within AstraZeneca at this time not to discuss the details surrounding trial 41 with any external customers," Hagger wrote in an email to fellow employees.
A few years later, AstraZeneca decided to re-run the trial in the hope of achieving more favorable results. Now named Study 132, the design was almost exactly like Study 41, save for a few minor variable changes.
This time, however, the results demonstrated longer-lasting Seroquel's positive effects.
Study 132 was published in the Journal of Clinical Psychiatry in June 2007. Schulz is listed as the second author, even though all of the trial sites were held out of the country. Six of the other seven authors of the study are employees of AstraZeneca or on the company's advisory board.
Studies 41 and 132 represent a widespread controversy in clinical trials controlled by pharmaceutical companies. Industry-designed studies almost always produce favorable results or never see the light of day, explains Dr. Eric Campbell, a Harvard Medical School professor who has studied this trend.
"If a study is funded by industry, it's very likely—if not certain—that by the time that study reaches publications, it's going to favor that company's products and services," says Campbell. "At the end of the day, what matters for the drug companies is getting new drugs to market. And convincing physicians to use them, regardless of whether they're better."
Schulz says more than marketing interests were at stake. "Study 132 was designed for the approval of the long-acting quetiapine," he maintains, adding that all the data were properly submitted. "It was designed in order to receive FDA approval."
MARKINGSON HAD COLLECTED a strange assortment of items in the few months he lived in the halfway house: a pile of clothes clearly too big to fit, a couple of books, and an old raincoat.
Weiss stepped into the bathroom; she was visiting within two hours of finding out her son had died. No one had bothered to clean up after the coroner came to collect Markingson's body—or if they did, hadn't done a very thorough job. A few inches of black fluid still ringed the bottom of the bathtub.
"I was in shock," says Weiss. "I was just numb."
In Markingson's wallet, Weiss found a $20 check from the CAFE study.
The next few weeks went by like she was watching someone else's life. Weiss couldn't accept that she would never see her son again. She wanted to understand why it had happened.
Weiss began digging up documents and filed a formal request with the University of Minnesota, obtaining a file of her son's medical records. She was stunned by what she found.
It turned out that when Markingson arrived at Fairview, his doctor, Stephen Olson, had approached him about a treatment plan involving the CAFE study. Olson was also the principal investigator for the study, and has received more than $100,000 from AstraZeneca over the years.
More alarming was that Schulz—the man to whom Weiss had appealed for help getting her son out of the program—was a co-investigator on the CAFE study.
"He had the opportunity to take Dan out of the study," Weiss says of Schulz. "He had the opportunity and he didn't."
In summer 2005, Weiss hired two attorneys to represent her in a malpractice lawsuit against Schulz, Olson, the University of Minnesota, and AstraZeneca.
One of the lawyers was Dr. Chris Barden. As both a psychologist and an attorney, he had the expertise to dissect the complicated case.
Barden subpoenaed Schulz for two depositions over the course of the next year. On video camera, Barden pressed the professor on his long history of taking money from pharmaceutical companies and whether it influenced his judgment in the CAFE study.
"From '99 through the time that Dan Markingson was a subject in the CAFE study—that is through 2004—how much money have you received from drug firms?" Barden asked.
"I can only make an estimate," Schulz replied, pegging the number somewhere between $150,000 and $180,000.
In a separate deposition, Barden read an excerpt from a bioethics book arguing for the importance of informing patients about a doctor's financial ties to drug companies.
"Do you agree or disagree with that statement?" asked Barden
"I don't agree with that statement," replied Schulz, arguing that disclosing this information could "confuse" the situation.
"Have you had any training in biomedical ethics?" pressed Barden.
"I've taken the courses at the University of Minnesota that are required for us to participate in clinical research."
"And isn't this part of that training?"
"I'm not aware," said Schulz. "I don't recall that."
A cornerstone of Barden's case was Markingson's monetary value to the U of M as a patient. The university stood to make $15,648 for every subject who completed the trial—a total of $327,000.
But the judge ruled that there wasn't enough evidence to prove culpability. Olson settled for $75,000—an amount Weiss says didn't even cover her legal fees. Schulz, AstraZeneca, and the U of M got off scot-free.
ON A WEDNESDAY morning in March 2009, Weiss sat at a long, rectangular conference table in the Minnesota Capitol building. It had been five years since her son's suicide, and her anger had not ebbed one bit.
"Right now, what I want to see is that no other family has to go through what I went through, and has to lose a child totally unnecessarily," Weiss told the legislators.
She had contacted Rep. Karla Bigham, who had in turn authored a bill that would make it illegal for a patient under a stay of commitment to be enrolled in a clinical study.
"I thought this was just wrong," Bigham says. "If somebody would have listened to her, and if these safe measures were there, it might not have happened."
Weiss's story made an impression. After she testified, the Minnesota Legislature unanimously approved the bill, and Dan's Law went into effect in August 2009.
But that didn't mean that Weiss had finished her quest. She and family friend Mike Howard had continued investigating Schulz and the U of M psychiatry department in an effort to expose their role in the tragedy.
The deeper Weiss and Howard looked, the more the evidence they discovered about Schulz's relationship with Big Pharma. From 2005 to 2010, he had received at least $522,000 from pharmaceutical companies for research, consulting fees, and other compensation, according to public disclosure reports. He'd been paid more than $86,000 by AstraZeneca alone.
Yet for all the boxes of carefully annotated studies, Weiss didn't have a forum for her case.
Then Howard found the University of Minnesota's code of conduct.
Weiss may no longer have legal standing, but she could still file a grievance with Schulz's employer.
The complaint accuses Schulz of allowing drug companies to use his name on studies he didn't write or research, hiding research results that didn't come out favorably to drug company interests, and violating the U of M's ethics policies by not disclosing his financial relationships to patients.
For his part, Schulz says he's done nothing wrong, and maintains that he hasn't violated any U of M policies. The FDA, state Attorney General's Office, and the U of M's Internal Review Board all found no link between Markingson's suicide and the CAFE study. Schulz also points out that he started looking into quetiapine before it was even branded as Seroquel by AstraZeneca.
"I haven't been particularly focused on quetiapine, in my opinion, but on the best ways to help schizophrenic people," Schulz wrote in an email.
A college spokesman confirmed the probe is "pending," but wouldn't give any further details. A decision is expected in the next couple of weeks.
In the meantime, the outrage has only grown. Eight U of M bioethicists wrote a letter to the Regents asking that an independent board look into the Markingson case. Other faculty members and the Graduate and Professional Student Assembly have formally joined the push for an outside investigation.
"Schulz should be fired," Weiss says. "And if he's not, I will certainly, until the end of my life, make his life miserable."
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