Side Effects: A Prosecutor, a Whistleblower, and a Bestselling Antidepressant on Trial

by Alison Bass

  When he called Firestein from Albany that day, Conway wasted no time on chitchat.

  "Hi, Rose. Heard anything from Wick?" he asked.

  "No. I think they're going to stonewall," Firestein said.

  Conway laughed. To Firestein, the bureau chief seemed annoyingly cheerful.

  "Nah, they'll call," he said. "Just watch"

  Sitting at her desk, surrounded by piles of papers that only she could find, Firestein smiled wryly through her anxiety. Conway hadn't always been so supportive. When she had first concocted the idea of going after GlaxoSmithKline for consumer fraud, Conway and others in the AG's office had been openly skeptical, if not dismissive. It had taken her weeks of persistent arguing, backed up by reams of documentation, to bring first Stark and then Conway around. And now all those months of hard work, browsing through the fine print of scientific papers, FDA transcripts, and internal G1axoSmithKline documents until her eyes stung, might have been for naught. All because Tom Conway wanted to see if the other guy blinked first.

  That afternoon, Firestein had trouble concentrating. She was tired of waiting for the phone to ring, only to have her hopes dashed every time it turned out not to be Wick. She had just begun work on another consumer fraud case, this time against Guidant, the makers of a defective heart valve stent that was alleged to have caused patients' deaths. Firestein and her colleagues were hoping to build their case against Guidant around the same theory that had guided the Glaxo action: if they were able to prove that the stent maker had known about defects in the heart valve stents (which would later be recalled) but hadn't disclosed them quickly enough, they could show that the medical device company had defrauded consumers. But although she had plenty to do on the Guidant investigation, her heart wasn't in it. Late in the afternoon, her sister Janice called. Would Rose still be able to take Ellie to ballet class that evening? Ellie loved strutting around their Brooklyn apartment in her tutu. She had a mischievous side too. Sometimes she'd sneak up on Firestein's left side, where she had no vision, and shout, "Boo," startling her. But Firestein didn't mind. She much preferred Ellie's playfulness to the pity of strangers who saw her walking with her cane in downtown Manhattan. She found it ironic that many people assumed that she couldn't function without their help. They never seemed to stop and consider how she had made it to that particular intersection in the first place. One woman had even grabbed Firestein by the elbow, and when she wrenched her arm away-she hated being grabbed unawares-the woman had gotten testy and called Firestein an ungrateful bitch. Those were the times when Firestein wanted to throw her cane into the Hudson. Yet she knew it gave her a sense of independence that she wouldn't otherwise have. Essentially, it boiled down to pride versus mobility, and for Firestein, mobility almost always won.

  AROUND NOON THE NEXT DAY, Wick called. He told Firestein that GlaxoSmithKline would delay launching its online registry, since that seemed to be such a big sticking point. He added that Glaxo was still interested in talking about settlement and said he would be in touch. Firestein carefully hung up the phone, stood up, and brought her fist down on the desk in jubilation. Yes! Conway's all-or-nothing ploy had worked. She had been wrong to doubt him. Rounding her desk with care she was always bumping into sharp edges-Firestein walked off to tell him and Stark the good news.

  IN BUILDING THE CASE against GlaxoSmithKline, Firestein had sought advice from a number of medical experts, including several who had studied the link between antidepressants and suicidal behavior. One of them was Dr. David Healy, a British psychiatrist and director of the North Wales Department of Psychological Medicine at the University of Wales. Healy was intimately familiar with the research literature on the SSRIs, having reviewed clinical trial studies that the drug companies had submitted to the FDA to gain approval of these drugs. By the late 1990s, the FDA had collected a wealth of clinical trial data about the SSRIs and similar antidepressants like Effexor and Serzone, which were also known to boost serotonin levels. There was only one problem: the data wasn't available to the public. For the most part, these "proprietary" research results could only be pried from the pharmaceutical companies under subpoena in civil or criminal lawsuits. Even then, the information was often sealed from public disclosure.

  Healy was one of the few medical experts to have gained access to this data, while working as an expert witness in several lawsuits against the drug companies. What he uncovered was alarming. The drugmakers' own clinical trial data showed that adults and children taking the newer antidepressants were at least twice as likely to attempt or commit suicide as those taking a placebo. And the FDA knew this. In the late 1990s, the agency had come under considerable pressure from drugmakers to scrap placebos in antidepressant trials. The drug researchers argued that the use of these sugar pills exposed depressed patients to a higher risk of suicide. In an effort to defend the placebo standard, Dr. Thomas Laughren, an official in the FDA's Psychiatric Drug Products Group Division, had examined the available clinical trial data for eight of the newer antidepressants (Prozac, Zoloft, Paxil, Wellbutrin, Serzone, Effexor, Remeron, and Celexa). In his analysis published in the November 2001 issue of the journal European Psychiatry, Laughren reported that there were no excess suicides in the placebo groups-therefore using placebos as a point of comparison was not dangerous to patients.

  In fact, the data from these trials showed that the active drug or antidepressant was twice as likely as placebo to be associated with suicides in adults. While Laughren did not discuss these results in his paper, they were listed in two tables in the text. When asked about this outcome years later, Laughren, who is still with the FDA as director of the Division of Psychiatry Products, became testy. "That was not the intent of my paper," he said. "I'm quite sure I didn't include a statistical analysis [of suicidality] in my paper. It's really disingenuous of you to present that to me when I don't have the paper in front of me"

  Intentional or not, Laughren's 2001 paper is not the only evidence that the FDA knew years ago that there was an increased risk of suicide in the SSRI trial data. In toxicity studies of Zoloft performed by Pfizer on healthy volunteers and submitted to the FDA in the late 1980s, some of the patients randomized to Zoloft developed severe anxiety or agitation, a state known as akathisia. Patients with akathisia became so agitated that they often felt like jumping out of their own skin. Teicher and his colleagues at McLean had found the same phenomenon occurring in some of their suicidal Prozac patients. At the 1991 FDA hearing on Prozac and in a follow-up paper to his first case report on Prozac, Teicher had hypothesized that akathisia could make some patients so miserable that they wanted to kill themselves. Yet while the clinical trial data linking the SSRIs to akathisia and higher rates of suicidal behavior was known to the FDA, it had not been reported in mainstream medical journals or to the general public. Healy was eager to publish his findings, but his paper was rejected by a number of journals, including the prestigious Archives of General Psychiatry. The Archives may have rejected his paper, Healy said, because it contained a negative conclusion, and most medical journals were (and still are) not particularly interested in publishing negative findings. Although many journals derive a lucrative income from the drug ads they publish, their desire for clear-cut results that will attract readership and publicity probably plays a bigger role in their bias against negative findings.

  Dr. Mark Helfand, a professor of medicine at Oregon Health and Science University, has studied this issue as head of the Evidence-Based Practice Center there. Journals "want to publish results that get them the top headlines," he told me. "They are not interested in publishing the subtle clues that might reflect a mixed message, a more balanced view."

  Many prominent physicians agree. Dr. Joseph M. Heyman, a trustee of the American Medical Association, was quoted in a press release as saying, "Studies with positive findings are more likely to be published than studies with negative or null results."

  Finally, in 2003, a little-known periodical called Psychotherapy and Psychosomatics
published Healy's paper linking the SSRIs to akathisia and suicidal behavior. Healy's outspokenness did not endear him to the SSRI makers. They routinely tried to discredit him as a biased gadfly out to enrich himself at their expense. Pfizer, for instance, called Healy a practitioner of "junk science" in an attempt to have him disqualified as an expert witness in a lawsuit brought by the parents of a thirteenyear-old boy who hanged himself while taking Zoloft. Lilly also tried (and failed) to have Healy disqualified from another case involving a man who had killed himself and his wife while taking Prozac.

  While the pharmaceutical companies were unable to discredit Healy in court, they did succeed in muddying his reputation to the point where many psychiatrists and journalists in the United States viewed him as "controversial." In fact, in 2001, the University of Toronto rescinded Healy's appointment as a professor of psychiatry at its Centre for Addiction and Mental Health (CAMH) after Healy gave a speech at the university in which he talked about the link between SSRIs and suicidal behavior. At the end of his lecture, Healy showed a slide of the British serial killer Harold Shipman -a doctor who killed his patients by giving them lethal injections of painkillers-to make the point that patients should not always put their trust in the medical profession. In rescinding its job offer, CAMH wrote a letter to Healy saying that it was alarmed at the "extremity" of his views. Healy and his supporters countered that there might be another reason why CAMH had revoked its job offer: Eli Lilly, the maker of Prozac, was then CAMH's largest sponsor, having donated more than $645,000 to the institute.

  In other circles, however, Healy was considered a modern-day Sinclair Lewis. The BBC, in large part because of Healy's prodding, had aired several Panorama programs about the SSRIs, which eventually caught the eye of the Medicines and Healthcare Products Regulatory Agency (MHPRA), Britain's equivalent of the FDA. By the summer of 2003, when Rose Firestein caught up with Healy, his biography listed him as the author of 120 scientific articles and twelve books on psychiatry and the history of medicine. Firestein, for her part, found the British psychiatrist extremely knowledgeable, his opinions about the SSRIs grounded in scientific research. "David is the person who really brought this to the MHPRA. He has been cast in a bad light, but he's as far from a crackpot as anyone in the field, she said."

  Now, LITTLE MORE than a month after the AG's lawsuit had made front-page news, Healy was in New York to do research for his latest book, a history of electroshock therapy. He called Firestein to let her know he was in town, and the assistant attorney general said she'd love to meet him for coffee.

  Which they did, on July 8, in the newly refurbished art deco lobby of the Metropolitan Hotel in Midtown Manhattan, where Healy was staying. Even though Firestein had told him she would be toting a cane, Healy, a tall, lanky Irishman with a Beatles haircut, had to mask his surprise at seeing a small, slightly stooped woman walk haltingly into the lobby with the trademark white cane.

  "She was a bit different from what you'd expect," he recalled with typical British understatement. Healy had been on the lookout for someone taller and, well, more formidable-looking. "You don't expect a person who is five foot zero and has to struggle with blindness to cause such problems for a major pharmaceutical company."

  Over coffee at a shop next door, Firestein pressed Healy for his thoughts on other pharmaceutical companies her office should look into. She didn't mention any names, but Healy got the distinct impression that the AG was already hot on the trail of another drugmaker. Firestein made no mention of how the AG's lawsuit against GlaxoSmithKline was progressing, and Healy knew better than to ask. Having been an expert witness, Healy understood how delicate and unpredictable the negotiations could be. He also knew that plaintiffs' attorneys, whether they worked for private firms or for the government, were extremely tight with information before their cases had settled and sometimes afterward as well. That was fine with Healy. It was enough for him to know that a government agency in the United States had finally put consumer safety ahead of pharmaceutical company profits.

  LATER THAT AFTERNOON, Firestein, back at 120 Broadway, was reading a brief on her large-print computer screen when the phone rang. It was Wick. He was calling to let her know that his office had just filed a motion to remove the Glaxo case to federal court.

  "You'll probably get notice tomorrow," he said.

  "Oh, hell," Firestein muttered under her breath. This was bad. It meant that the pharmaceutical giant was going to fight the complaint. It also meant that she and her colleagues now had to prepare the papers necessary to get the case remanded to state court. And even if they won, that battle wouldn't be decided for six months or more. With the case being removed to federal court, they were looking at a long-drawn-out war.

  "Thanks for letting me know," Firestein said, her voice drained of emotion. She hung up and sat back in her chair, suddenly too tired for words.

  artin Teicher stood back and studied his creation with pride. It was magnificent! He had built the cherrywood rolltop desk from scratch in the basement workshop of his home. It was almost an exact replica of a desk he had coveted at Crate and Barrel. The salesman at the Chestnut Hill furniture store had been good enough to take a Polaroid of the desk for him, and Teicher had measured its dimensions and scanned them into a computer program that gave him the exact measurements he needed. Building the desk had been a labor of love. Now all he had to do was figure out how to get it up the stairs.

  Teicher had taken up woodworking in the dark days after the Massachusetts Board of Medicine decided to reopen its complaint against him. The news had devastated Teicher, and he found that working with wood-designing the pieces, planing the edges, applying the stain-was therapeutic. It calmed his nerves and took his mind off his troubles. Matters had gone from bad to worse. First came the decision by the state board to reopen its investigation into the sexual misconduct charges his former patient had levied against him. Then the drug company Lilly-in the guise of its avenging attorney had ripped his dignity to shreds on the stand. Finally, his ex-wife had actually gone and taken the job with Lilly, moving to Indiana with their children. She had purchased a house in a suburb of Indianapolis and made it clear that Teicher was welcome to visit at any time. But he only saw his children on holidays now. One of the things he missed most were those early morning chats with his daughter when he would drive her to school in Belmont.

  After his family moved away, Teicher turned to woodworking with a vengeance. He bought thousands of dollars in woodworking tools and read every how-to book and magazine on furniture construction he could lay his hands on. He spent a lot of time in his basement workshop, making one piece after another, each more complicated than the last. First he made a nightstand. Then he constructed a coffee table and an ornately carved bookcase.

  IN AUGUST 1997, Teicher was summoned to the state medical board's headquarters in downtown Boston and compelled to testify before the administrative judge assigned to review his case. It was an incredibly painful ordeal, with the board's prosecutor, an attorney named Muriel Finnegan, dredging up every sordid detail of the sexual misconduct allegations against him. It was clear that Finnegan saw Teicher as public enemy number one. To her, Teicher was just the latest in a long line of psychiatrists she fervently believed were guilty of sexual misconduct. By the time Teicher's case came before the state agency's administrative judge in the summer of 1997, at least thirtysix psychiatrists had lost or resigned their medical licenses after having been charged by the disciplinary board with making inappropriate sexual advances to patients.

  Yet in the end, the administrative judge for the state board found for Teicher. He ruled that the woman who had accused Teicher of having sex with her was not a reliable witness. Her testimony at the hearings conflicted with previous sworn testimony she had given in depositions and was, in some cases, contradicted by written records. The judge ruled that although Teicher had violated ethical boundaries by sending the woman cards and giving her a cheap pair of earrings, he had done so out of con
cern for her well-being, with the intent of helping a severely depressed and suicidal patient. The judge found him not guilty of any sexual misconduct. On November 19, 1997, over Muriel Finnegan's vehement objections, the board of medicine agreed with the judge's ruling and dismissed its complaint against Teicher, for the second and last time. By then, however, Teicher had taken his attorney's advice and settled the separate malpractice suit his former patient had brought against him. The settlement of the private malpractice case cost $450,000, most of it paid by Teicher's insurance.

  BY THE TIME the state board of medicine absolved Teicher once and for all, he had already resolved to replicate the elegant rolltop desk from Crate and Barrel. And he had succeeded, devoting every spare minute to the task over the next few months. There was just one problem. He couldn't get it out of the basement. He enlisted the help of a friend, but neither of them could figure out how to get the huge desk up the stairs and out the basement door without damaging it. As he stared at the piece sitting on its rollers at the bottom of the stairs, it suddenly came to him: he would have to dismantle the roll top from the desk and rebuild the mechanism so he could remove the top and slide it back in place on a dovetail assembly. Teicher spent much of his spare time painstakingly reconstructing the desk. His solution worked. In less than a month, the desk claimed its rightful place in his home office on the first floor.

  The other piece of good news for Teicher that spring was the signing of the contract between McLean Hospital and Sepracor for a percentage of the royalties from the Prozac alternative he was helping the biotech company to develop. He had convinced Sepracor executives that the compound in fluoxetine they should be developing was different from the one they had initially settled on. Both compounds, labeled R- and S+, were isomers (mirror images of each other) of the main chemical found in Prozac. Teicher had steered Sepracor to R- because it had a shorter duration of action than S+ and might therefore be less toxic to patients. Teicher's lab had already completed animal studies to determine that R- was not toxic in rats. In January 1998, the U.S. Patent and Trademark Office granted a patent on R- fluoxetine to Teicher and two executives at Sepracor: James Young and Timothy Barberich. The patent states that the three inventors intend to develop R- as an antidepressant. It notes that fluoxetine, or Prozac, as a mixture of both isomers and a chloride salt, had certain disadvantages. According to the patent, Prozac "produces a state of inner restlessness (akathisia)" and "in some patients ... is associated with severe anxiety leading to intense violent suicidal thoughts and self-mutilation." The patent concludes that it would be "desirable to find a compound with the advantages of fluoxetine which would not have the above-described disadvantages."