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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."

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