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Late one morning in June 2008, 57-year-old Southern California real estate agent Linda Ware was driving with her cousin along a desolate highway near Lancaster when she began hallucinating. Envisioning in the distance a sign that read “God Is in the Realm,” she pulled over suddenly and ordered her cousin out of the car. Then, just as abruptly, Ware burst out laughing and—before her cousin could do anything—pulled back onto the road again.

This was weird behavior, to say the least. Although Ware suffered from depression, as her daughter Cary Ussery later told me, she’d never acted like this. A few days earlier, however, she had started taking Chantix, a pill meant to help her quit smoking by suppressing the effects of nicotine on the brain.

The day after the driving incident, a family friend found Ware slumped by her bed, dead from a fatal cocktail of prescription drugs, a suicide note at her side.

While Chantix has helped some smokers kick the habit, its record has been plagued by tragedy ever since it was first approved by the Food and Drug Administration in May 2006. By mid-2009, the agency had received reports of nearly 300 suicide attempts—about a third were successful—and close to 5,000 serious psychiatric events in all, including symptoms like psychosis, blackouts, and aggression. Hundreds more reports have streamed in since.

While people with mental health problems are overrepresented among smokers (and, therefore, potential Chantix users), a review of the drug’s history shows that Pfizer, its manufacturer, never tested Chantix on people with psychiatric problems—including people with a recent history of depression. FDA regulators, for their part, approved Chantix after a sped-up “priority review” process; the agency didn’t bother asking Pfizer to do a follow-up study on mentally ill Chantix users, even though its own safety reviewer reported that the exclusion of these smokers may have undermined the clinical trials.

Only after three years and reports of thousands of serious side effects did the FDA finally ask Pfizer to conduct trials on this group; it also slapped a black-box warning, the agency’s strongest alert, on the medication. But by that time, claims of problems with the drug had triggered a torrent of lawsuits. Some 1,000 cases are now pending in federal court, and plaintiffs’ lawyers expect they’ll bring at least 1,000 others. About half of the current batch is related to suicides or suicide attempts, the lawyers say.

The lawsuits argue that Pfizer—the world’s largest pharmaceutical company, with sales of more than $60 billion this year—neglected to test Chantix adequately prior to its release, hid evidence of potentially serious side effects, and failed to sufficiently warn consumers of its risks. Pfizer counters that it “acted responsibly and appropriately at all times in connection with the development, approval, and marketing.” The FDA also says it acted properly. “The agency does not feel any mistakes were made,” says spokeswoman Sandy Walsh. “We can never speculate as to what may happen with a drug once it goes into widespread use after approval.”

But the agency’s failure to insist that psychiatric patients be included in the clinical trials points to a potentially serious flaw in FDA safety practices. While the mentally ill are commonly excluded from drug trials, they are a key part of Pfizer’s target market in this case. “You need to think about who is going to be taking the drug,” says Dr. Karen Lasser, a Boston University physician and researcher who has studied the link between mental illness and smoking and says she was baffled by the oversight.

Chantix takes the pleasure out of smoking by blocking nicotine receptors in the brain. It also spurs the release of dopamine, which tickles the brain’s pleasure centers the way smoking can. Pfizer officials saw Chantix as a potential blockbuster: With nearly 70 percent of the estimated 45 million American smokers hoping to quit, the market seemed vast. Indeed, sales of the drug soared to $883 million in 2007. (Sales have since dropped, likely due to stricter labeling and bad publicity; for the first nine months of 2010, sales totaled $522 million.)

Pfizer launched its marketing effort with a news release spotlighting the dire statistics on quitting: Fewer than 7 percent of wannabe nonsmokers make it past the one-year mark. The trials showed that about 22 percent of Chantix users who took the drug for three months were able to kick the habit for a year or more. “It’s all about getting there,” said a 2007 Chantix TV ad featuring a turtle and a hare, but no warnings related to a user’s mental health history.

Pfizer has spent about $300 million on Chantix advertising, according to the Nielsen company. Early on, it promoted the drug with a multiplatform ad blitz that, without mentioning the product, sought to sell people on quitting. The “My Time to Quit” campaign drew smokers to a website that, after providing quick facts about smoking cessation, segued to information about Chantix. The company also paid doctors to give talks to colleagues about smoking cessation, and gave money to universities. The University of Wisconsin-Madison, a university spokesperson says, got more than $3 million because it provides courses to doctors on the subject.

The company’s promotional machine eventually had to address rising concerns about the drug. In 2008, Joseph Feczko, then Pfizer’s chief medical officer, published an op-ed in the Wall Street Journal. Headlined “Smoking Has Side Effects Too,” it tried to offset growing negative publicity about Chantix by reminding people of the hazards of smoking. It also explained how regulators and drug companies conduct follow-up research and alert the public after receiving reports of serious side effects.

“You need to think about who is going to be taking the drug,” says a researcher puzzled by Pfizer’s failure to test Chantix on the mentally ill.

Pfizer’s Chantix research, however, has been the subject of criticism. In 2007, company scientists published a study in the journal Current Medical Research and Opinion deeming the drug safe for long-term use—whereupon Dr. John Spangler, a smoking cessation expert at Wake Forest University’s School of Medicine, wrote to the journal to complain. The article, he said, failed to provide a statistical analysis to support its central claim. In fact, he wrote, the data indicate that Chantix patients are 2.5 times more likely than people taking a placebo to suffer serious side effects. “I don’t know what they were trying to accomplish,” Spangler told me later. “A faulty study has been included into the world’s medical literature.” The journal insisted in an email that the article “underwent rigorous and independent peer review, and full disclosure of the authors’ employment and funding was made.” Pfizer declined comment.

In further studies, Chantix hasn’t exactly soared above other options for quitting. A 2008 paper in the journal Thorax showed that it beats the nicotine patch for some people but not for others. Other researchers have concluded that nicotine gum is just as effective. “I would say that it’s a pretty good drug, but it’s not the first resort” for treatment, says Lirio Covey, a professor of clinical psychology at Columbia University who worked on Pfizer’s clinical trials. “Chantix does have some utility.”

For Covey, who says she has received nearly $80,000 from Pfizer this year to study the effects of smoking cessation on mood, the key facts are these: Millions have taken Chantix, so the number of people claiming severe side effects is relatively small. (In her estimation, the drug’s benefits outweigh its risks.) She also says it’s still not clear whether the side effects are the direct result of the drug, or of nicotine withdrawal.

That seems like the kind of thing a company should know before it puts a new drug on the market. Indeed, questions about why Chantix’s safety was never fully evaluated extend at least back to May 2006, when Dr. Howard Josefberg—the FDA safety reviewer assigned to the trials—submitted his report. He recommended that Chantix be approved, but also wrote that Pfizer’s trials may have been “too carefully screened.” They excluded people who’d been treated for depression over the previous 12 months, Josefberg noted, as well as “those with histories of panic disorder, psychosis or bipolar disorder…The patient population studied, then, may not represent the true target population.”

An FDA safety reviewer warned that Chantix trials may have been “too carefully screened,” and “may not represent the true target population.”

The exclusion of mentally ill subjects from drug trials, researchers say, can be justified in some cases; sometimes the people are too sick to give their consent—or they stray from the recommended course of treatment. (See our recent piece about corruption in clinical trials for the psych drug Seroquel.) Excluding them also makes it easier to evaluate trial results. But many experts say it also leaves the real-world effects of the drugs in question, since an estimated one in four Americans adults—close to 60 million people—suffer from a diagnosable mental disorder in a given year. (About 6 percent of US adults have a serious mental illness, adds the National Institute of Mental Health.)

These numbers are especially relevant for Chantix, given the higher rates of smoking among people with mental illness. In April 2010, for example, the Centers for Disease Control and Prevention reported that 43 percent of adults with depression smoke, compared with 22 percent of those who aren’t depressed.

In November 2007, the FDA issued a notice that some patients taking Chantix had reported suicidal thoughts and erratic behavior. (“Posting this information,” it clarified, “does not mean that the FDA has concluded there is a causal relationship between the drug products and the emerging safety issue.”) Two months later, the agency ordered revised labeling, indicating that Chantix’s safety for mentally ill patients had not been established. The Federal Aviation Administration, meanwhile, banned pilots and air traffic controllers from using Chantix.

But it wasn’t until July 2009 that the FDA belatedly embraced the notion of testing Chantix on the mentally ill. “There is a disproportionate [number who] smoke, and they would be potentially exposed to this drug,” said Dr. Curtis Rosebraugh, an FDA drug evaluation official, in a media briefing. “We have no idea if that subgroup population is at higher risk or not, and so we do want to get some sense of that.”

Chantix users like Brandon Campbell already have some sense of that. In July 2007, Campbell, a 33-year-old IT technician at Duke University Hospital, gave the drug a try after enrolling in an employee wellness program to quit smoking. Although Campbell, like Ware, had a history of depression, there was no indication at the time that the safety of the drug hadn’t been established for people like him. Soon after finishing the recommended 12-week course of treatment, Campbell recalls, he started experiencing severe symptoms. He says he felt disconnected from reality, had trouble remembering things, and became emotionally unstable—breaking down over trifles. He also contemplated suicide. He’d been depressed before, but had never felt—as he put it—like driving over a cliff.

The problems persisted. This past summer, Campbell told me, he sat in his garage in Durham, North Carolina, with the doors shut tight and the car running, hoping to die. Then the cops started beating on the door, and he was rushed to the hospital. Campbell still smokes, and he says he still wants to quit. But he’s exceedingly wary of trying any more pharmaceuticals. “It’s like playing Russian roulette,” he says.

This story originated with the investigative website FairWarning.org.