Boston Globe

Just as the 14-year patent on Prozac is about to expire and the drug's maker, Eli Lilly and Co., is preparing to launch a new version, a body of evidence has come to light revealing the antidepressant's dark side.

The company's internal documents, some dating to the mid-1980s, as well as government applications and patents, indicate that the pharmaceutical giant has known for years that its best-selling drug could cause suicidal reactions in a small but significant number of patients. The reports could become critical as Lilly seeks government approval for its new Prozac.

Among the findings:
--Internal documents show that in 1990, Lilly scientists were pressured by corporate executives to alter records on physician experiences with Prozac, changing mentions of suicide attempt to "overdose" and suicidal thoughts to "depression."

--Three years before Prozac received approval by the US Food and Drug Administration in late 1987, the German BGA, that country's FDA equivalent, had such serious reservations about Prozac's safety that it refused to approve the antidepressant based on Lilly's studies showing that previously nonsuicidal patients who took the drug had a fivefold higher rate of suicides and suicide attempts than those on older antidepressants, and a threefold higher rate than those taking placebos.

--Lilly's own figures, in reports made available to the Globe, indicate that 1 in 100 previously nonsuicidal patients who took the drug in early clinical trials developed a severe form of anxiety and agitation called akathisia, causing them to attempt or commit suicide during the studies.

--Though Lilly has steadfastly defended the drug's safety and downplayed studies linking Prozac to suicide, the patent for the new Prozac, R-fluoxetine, expected to be marketed by Lilly beginning in 2002, notes that the new version will not produce several existing side effects including "akathisia, suicidal thoughts, and self-mutilation," which the patent calls "one of its more significant side effects."

--A McLean Hospital researcher and associate professor at Harvard Medical School, Dr. Martin Teicher, whose early 1990s studies linked Prozac to akathisia and suicide, is a co-inventor of the new Prozac, which Lilly plans to market, along with Timothy J. Barberich, the CEO of Sepracor Inc., a Marlborough, Mass. drug company, and James W. Young.

--A just-published book, "Prozac Backlash," by a Cambridge psychiatrist, Dr. Joseph Glenmullen, has drawn Lilly's ire for discussing Prozac's link to suicide, tics, withdrawal symptoms, and other side effects of Prozac and similar antidepressants.

Lilly officials continue to defend the drug's effectiveness, saying its track record is borne out by the fact it is still the most widely prescribed drug of its kind. In a written statement, Jeff Newton, a Lilly spokesman, said: "There is no credible evidence that establishes a causal link between Prozac and violent or suicidal behavior. There is, to the contrary, scientific evidence showing that Prozac and medicines like it actually protect against such behaviors."

Using figures on Prozac both from Lilly and independent research, however, Dr. David Healy, an expert on the brain's serotonin system and director of the North Wales Department of Psychological Medicine at the University of Wales, estimated that "probably 50,000 people have committed suicide on Prozac since its launch, over and above the number who would have done so if left untreated."

Healy, meanwhile, is conducting a new study that he says is the first of its kind, giving antidepressants to healthy people to study possible links to suicide. The results are expected to be published in June.

Prozac's success is certainly unquestioned. The introduction of the drug to the US market in the late 1980s changed the way Americans viewed their most intimate emotions and limitations. Billed as a wonder drug to combat depression by boosting levels of the brain chemical serotonin, Prozac and others like it were also said to remedy a host of human frailties from poor self-esteem and concentration to fear of rejection.

By the end of last year, more than 35 million people worldwide were using the drug, which provided Lilly with more than 25 percent of its $10 billion in 1999 revenue.

Yet the problems with Prozac were known even before it was introduced to the US market. Figures in a 1984 Lilly document indicated that akathisia, the severe agitation that can lead to suicide, occurs in at least 1 percent of patients, a level considered a "frequent" event, and as such must be disclosed in a company's product literature and package inserts. But there is no such disclosure in Prozac's US literature, and it is not clear whether the FDA panel charged with approving Prozac simply overlooked or did not have access to certain critical data of Lilly's.

As a result, researchers say that most US doctors do not know to warn patients of the potentially dangerous effect which, according to published literature on the topic, can be alleviated with sedatives or by going off the drug.

German regulators, who eventually approved Prozac for use in that country, require a warning label about the risk of suicide and suggest the concurrent use of sedatives when necessary.

Akathisia is listed in Lilly's US product literature, but as an infrequent event in Prozac users. No mention is made of its potential relationship to suicide.

A relationship, however, was found in a Globe search of US patents. The patent for the new Prozac or R-fluoxetine (US Patent no. 5,708,035), which Lilly will market after the existing patent expires in 2001, contains a wealth of information about the original Prozac. According to the patent, the new Prozac will decrease side effects of the existing Prozac such as headaches, nervousness, anxiety, and insomnia, as well as "inner restlessness (akathisia), suicidal thoughts and self-mutilation" - the same effect Lilly has contended has not occurred in any substantial way in some 200 lawsuits against it over the past decade. Most of the suits were settled out of court and the terms kept confidential.

A 1990 COMMUNIQUE
In an electronic communique obtained by author Glenmullen dated Nov. 13, 1990, from Claude Bouchy, a Lilly employee in Germany, to three Lilly corporate executives at the company's Indianapolis headquarters, Bouchy says he and a colleague "have problems with the directions our safety people are getting from the corporate group (Drug Epidemiology Unit) and requesting that we change the identification of events as they are reported by the physicians. . . . Our safety staff is requested to change the event term "suicide attempt' (as reported by the physician) to "overdose.' "

Bouchy continued that ". . . it is requested that we change . . . "suicidal ideation' to "depression.' "

And then Bouchy makes an appeal to his US Lilly colleagues: "I do not think I could explain to the BGA, to a judge, to a reporter or even to my family why we would do this especially on the sensitive issue of suicide and suicide ideation. At least not with the explanations that have been given to our staff so far."

Lilly has also aggressively sought to discredit researchers who published data linking its product to suicide. One of its early targets was Dr. Martin Teicher, an associate professor of psychiatry at Harvard Medical School and a McLean Hospital researcher, who wrote a crucial paper on the link between suicide and Prozac in 1990; he found that 3.5 percent of patients put on Prozac either attempt or commit suicide due to severe agitation from akathisia. As a result of Lilly's campaign, many in the psychiatric community say they believe Teicher has distanced himself from his original work. But in a rare interview with the Globe, Teicher said that he stood by his work, and that the ability of Prozac to induce suicide in a minority of patients "is a real phenomenon."

Teicher, Barberich, and Young filed their patent for the new Prozac in August 1993, the same year Teicher published another report, this one in the journal Drug Safety titled "Antidepressant Drugs and the Emergence of Suicidal Tendencies."

The paper was a direct challenge to data reported in the March 1991 issue of the Journal of Clinical Psychiatry by Drs. Maurizio Fava and Jerrold Rosenbaum of Massachusetts General Hospital. Their study found no significant difference in "suicidal ideation" in patients treated with fluoxetine compared to those receiving other antidepressants.

Teicher wrote in his 1993 paper that Fava and Rosenbaum's statistics were flawed. Using Fava and Rosenbaum's data, Teicher came to the opposite conclusion: namely, that patients on Prozac were at least three times more likely to become suicidal than those on older antidepressants.

The FDA came up with similar results even before Teicher published his 1993 data. Dr. David Graham, chief of the FDA's Epidemiology Branch, wrote on Sept. 11, 1990, that Lilly's data on suicide and Prozac, as well as the Fava and Rosenbaum study, were insufficient to prove that Prozac was safe. In an internal FDA memo, Graham wrote: "Because of apparent large-scale underreporting, the firm's analysis cannot be considered as proving that fluoxetine and violent behavior are unrelated."

"PROZAC BACKLASH"
Now a decade later, Lilly has targeted Dr. Joseph Glenmullen, whose book "Prozac Backlash" has apparently incensed Lilly executives.

Glenmullen, a clinical instructor in psychiatry at Harvard Medical School and a clinician at the Harvard University Health Services, says he wrote the book because he was alarmed by the number of patients who were reporting severe side effects from the serotonin-boosting antidepressants including Prozac, Paxil, Zoloft, and Luvox. "The two most upsetting side effects were patients becoming suicidal on the drugs, and the development of disfiguring facial tics," he said in an interview.

After obtaining hundreds of pages of FDA documents through the Freedom of Information Act, as well as internal Lilly memos that are part of the public record in lawsuits filed against the drug company, Glenmullen wrote that Lilly had tried to downplay side effects of Prozac for years.

Lilly alerted newspapers and TV stations to the book and began a campaign to discredit the author, saying that Harvard Medical School professors were unfamiliar with his work and didn't recognize his name. Glenmullen, a graduate of Harvard Medical School, is one of 415 clinical instructors in medicine at Harvard.

BLAST FROM A CRITIC
Chief among Glenmullen's critics is Mass. General's Rosenbaum, a professor of psychiatry at Harvard Medical School, who, in a written statement sent to the Globe calls "Prozac Backlash" a "dishonest book" that is " manipulative" and "mischievous."

But Rosenbaum's objectivity has also been questioned. Not only was his 1991 study on Prozac and suicide criticized by at least two sets of researchers as well as the FDA, documents obtained by the Globe show that Rosenbaum's relationship to Lilly is a cozy one: he has served as a Prozac researcher and sat on a marketing advisory panel for Lilly before Prozac was launched.

When asked in an interview why he was speaking out against Glenmullen's book, Rosenbaum said that the suicide controversy was "old news" and that the book presents the information as new research. He noted that akathisia is "pretty rare" and that "it doesn't occur more than in people given a placebo."

But because there is no official reporting system for drug side effects, no one knows how common drug side effects are, said Larry Sasich, a research analyst at Public Citizen in Washington, D.C.

"There is no active surveillance system to look at adverse events," he said. "Unless something very unfortunate happens and a large number of people are harmed in a unique way, no one is going to look at it; nobody ever puts two and two together."

SEPRACOR'S PATENT
On April 12, the Federal Trade Commission opened the way for Lilly to market Teicher's, Barberich's, and Young's new Prozac, for which Sepracor holds the patent. The new Prozac, R-fluoxetine, is a modified form of an ingredient found in Prozac, which, according to Sepracor, not only has fewer side effects but more potential uses and benefits than the original.

In making the decision, the FTC rejected arguments from its lawyers and the generic drug industry that the agreement unfairly limits generic Prozac competition.

According to a Sepracor press release dated April 13, the company will receive an upfront payment and license fee of $20 million from Lilly and an additional $70 million based on the progression of the drug. Sepracor will receive royalties, and in exchange, Lilly will get the exclusive world rights to R-fluoxetine for all indications and uses. Lilly will be responsible for the development of the drug, regulatory submissions, product manufacturing, marketing and sales, according to the release.

Glenmullen wonders whether the new Prozac will, in fact, be little more than an effort to prolong the life of a product with a soon-to-expire patent. Although it is touted as having fewer side effects, no one knows what effects may surface once large numbers of people begin taking it for months or years. In the epilogue to his book, he simply says: "Like any new drug, it too will be an ongoing experiment."

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