Risks of Prozac revisited: Drug's link to violence not studied by FDA, data show

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> SSRI-Research

> Sun, 12 Sep 2004 20:35:47 -0400

> [sSRI-Research] Risks of Prozac revisited:

> Drug's link to violence not studied by FDA, data

> show

>

> The Denver Post

>

> Risks of Prozac revisited

> Drug's link to violence not studied by FDA,

> data show

>

>

> By Anne C. Mulkern

> Denver Post Staff Writer

>

> Sunday, September 12, 2004 -

>

>

http://www.denverpost.com/Stories/0,1413,36~11676~2394179,00.html#

>

> Washington - Federal regulators knew as far

> back as 1986 that some people taking Prozac hanged

> or shot themselves, attempted suicide, or fantasized

> about murder.

>

> The U.S. Food and Drug Administration said

> there was " no evidence to suggest " Prozac caused

> those events.

>

> Eighteen years later, as studies have shown a

> possible link between newer antidepressants and a

> higher suicide risk in children, the FDA is

> re-evaluating its position, hinting it may force

> antidepressant makers to increase their warnings for

> the second time this year.

>

> A revolution in the consumption of psychiatric

> medicine followed Prozac's approval in December

> 1987. Doctors last year wrote 142 million

> prescriptions for newer-generation antidepressants.

> In the intervening years, the FDA has repeatedly

> missed or ignored opportunities to scrutinize the

> wildly popular drugs, documents obtained by The

> Denver Post and a series of interviews show.

>

> In its review of FDA oversight of newer

> antidepressants, The Post found that:

>

> Despite repeated concerns about whether

> drugmakers had sufficiently examined the risk of

> violent reactions, the FDA never commissioned

> research that looked directly at the issue or

> instructed drug companies to do so.

>

> A key FDA administrator who for 20 years ran

> the psychiatric drugs division says

> second-generation antidepressants were approved by a

> regulatory process that requires only limited proof

> of efficacy and safety. " We don't know the risks

> that clearly. You're working in a sea of ignorance, "

> Dr. Paul Leber told The Post.

>

> Drug companies were aware of the need to

> sidestep the issue of suicidal and homicidal

> reactions, documents show.

>

> " I think both the industry and the FDA have

> been irresponsible in not educating doctors and the

> public more, " said Dr. Joseph Glenmullen, a Harvard

> University psychiatrist who wrote " Prozac Backlash. "

>

> " It's really clear the FDA dragged its feet

> for 15 years. They just let the whole thing get

> swept under the carpet until they got caught with

> their pants down. "

>

> British, Canadian alerts

> The FDA acted after British and Canadian

> health authorities had already taken aggressive

> stances. The FDA issued its warning after word

> leaked that one of its medical officers wrote a

> report documenting that children taking the drugs

> had an increased risk for suicidal acts. Glenmullen

> and others believe new evidence about children

> reopens questions about risks for adults.

>

> There was a series of opportunities to act

> sooner. Reports of Prozac patients' suicides came

> into the agency " in bunches " in 1990 and 1991. The

> FDA held a hearing and said there was no evidence to

> prove the drugs caused violence, but failed to ask

> for more targeted research.

>

> Over the next few years, as Prozac copycat

> drugs came up for approval, the FDA saw reports that

> showed cases of self-mutilation, mania and suicide.

> The FDA asked drug companies for more data but did

> not force them to study the issue further. It failed

> to have drug companies standardize data for suicidal

> thoughts or actions, which meant that information

> couldn't be easily analyzed.

>

> FDA officials refused repeated interview

> requests, saying they were awaiting hearings

> scheduled for this week to review a new study that

> shows a link between the drugs and higher risk of

> suicidal acts in adolescent children.

>

> Last week, the House Oversight and

> Investigations subcommittee held a hearing to look

> at whether drug companies withheld data on the

> efficacy of the drugs. Another hearing Sept. 23 will

> examine the safety issue.

>

> Long-term risks unknown

> Based on the number of prescriptions written

> for Prozac, Paxil, Zoloft, Luvox, Celexa, Lexapro,

> Effexor, Wellbutrin, Serzone and Remeron, most

> doctors clearly believe they are more helpful than

> harmful. Newer antidepressants are second only to

> codeine as the most commonly used prescription drug

> in the country, according to IMS Health, which

> tracks the drug market.

>

> Dr. Richard Kapit, who worked at the FDA for

> 20 years and reviewed Prozac, said that compared

> with older antidepressants, Prozac has fewer side

> effects and is quite safe. Prozac may or may not

> cause suicide and violence, but those also were risk

> factors of the older drugs. Post-marketing studies

> should have been done, he said.

>

> " Why weren't those studies done? I think it's

> basically that they didn't get around to it, " Kapit

> said. " People have made decisions that other

> priorities came first. "

>

> Another former FDA administrator said the

> long-term risks also are unknown.

>

> " I do have some doubts about their value in

> the big picture, " said Leber, a psychiatrist. He is

> now a consultant to the drug industry, advising on

> psychiatric and neurological drugs.

>

> Leber worked at the FDA for more than 20 years

> before leaving in January 1999. As director of the

> neuropharmacological drug products division for 15

> years, he recommended the approval of Prozac,

> Zoloft, Paxil and others.

>

> Leber believes the drugs are safe as defined

> by law but says little can be proved about

> relatively new drugs in terms of their risks. There

> aren't enough suicides to do a scientific study, he

> said.

>

> Antidepressants have been a huge moneymaker

> for the drug companies, with the FDA reaping some of

> that revenue. Drug companies are required to pay

> fees to the FDA - a total of $215 million in 2003,

> up from $34 million in 1993, the first year they

> were collected.

>

> Those fees were approved by Congress in part

> to hasten the drug approval process. The drug

> companies originally insisted that those fees not be

> used for studies of the drugs once they are on the

> market, Kapit said. That law was changed in 2002 and

> they cannot be used to study approved drugs where

> safety is an issue.

>

> When Prozac and copycat drugs were up for

> approval from 1986 through the early 1990s, the drug

> companies appeared aware of the need to keep the

> suicide issue from mushrooming.

>

> In a Feb. 7, 1990, Eli Lilly memo obtained by

> The Post, W. Leigh Thompson, a scientist in Lilly's

> clinical investigations unit, expressed concern

> after Leber asked Lilly to compare Prozac's rates of

> aggression and suicidal thinking with those of other

> antidepressants in a British health agency database.

>

> " Lilly can go down the tubes if we lose Prozac

> and just one event in the UK can cost us that, "

> Thompson wrote colleagues, expressing concern about

> a possible British review.

>

> Other memos from 1990 show Lilly fought

> against having its label changed to include any

> suicide data. And company officials believed Leber

> was going to be there for them, court documents

> show.

>

> Thompson called Leber at 6:15 a.m. on July 18,

> 1990, to talk about the suicide issue, according to

> a Lilly memo. Thompson noted that " Lilly and FDA are

> working together on the suicide issue. "

>

> In an interview, Leber said he was doing his

> job, which required him to ignore political

> pressures and evaluate drugs scientifically. " I like

> to believe that given the information I had at the

> time, I did what I should have done, " he said.

>

> " 20 deaths in a report "

> Naysayers within the FDA at that time appear

> to have been ignored. In a Sept. 11, 1990, memo,

> David Graham, an epidemiology director, charged a

> Lilly study with improperly excluding 76 of 97 cases

> when evaluating whether patients taking the drugs

> became suicidal.

>

> Graham wrote that Lilly also used misleading

> comparisons and that " the firm's analysis cannot be

> considered as proving that (Prozac) and violent

> behavior are unrelated. "

>

> At the same time, reports of " successful

> suicides " were coming in to the FDA " in bunches, "

> Martin Brecher, former FDA medical officer in the

> neuropharmacological drug division, testified in a

> March 13, 2003, court deposition. Brecher said that

> sometime in 1990 and the first half of 1991, he

> reviewed quarterly reports from Lilly documenting

> suicides by people who had been taking Prozac.

>

> " It was really quite extraordinary, especially

> in comparison to other annual reports where, you

> know, you had 20 reports of a cold and maybe two

> reports of some liver enzyme elevations, and here

> you are with 20 deaths in a report, " Brecher

> testified.

>

> " The volume of reports of completed suicides

> with Fluoxetine (Prozac) raised questions as to the

> relationship ... and it in no way suggested an

> answer. "

>

> A spokesman for manufacturer Lilly noted that

> it is " one of the most studied drugs in the history

> of medicine and has been proven safe and effective. "

>

> The issue of suicide didn't go away as the FDA

> approved other Prozac-like drugs. In a Jan. 20,

> 1994, memo, Dr. Roger Lane of the Pfizer Co. told

> colleague E. Giller-Groton that his suggestions to

> try to study Zoloft for use in patients with

> aggression problems would be " difficult to 'sell'

> within the company due to the problems Prozac has

> encountered. "

>

> " Marketing ... are very aware that a patient

> on Zoloft involved in an incident of mass homicide

> could severely affect the image and commercial

> success of Zoloft, " the memo states. Pfizer

> spokeswoman Shreya Prudlo said that " Pfizer has

> studied the impact of Zoloft on the treatment of

> symptoms of anxiety and depressive illnesses and

> carefully monitors and evaluates all adverse events

> including suicide and violence. "

>

> Parker resident Amber Hackett, 34, blames

> Zoloft on her daughter Holly Gerk's violent

> outburst. Gerk, 15, took Zoloft for about a year and

> then began drinking and taking drugs, behavior her

> mother described as new. Gerk one day attacked and

> cut her mother with a 7 1/2-inch kitchen knife,

> saying she wanted to kill her, Hackett said.

>

> " She was depressed before, but she could

> control herself, " Hackett said. " She never acted

> violently until after she started taking the pills. "

>

> U.S. Rep. Diana DeGette, D-Denver, said more

> information is needed. " The concerns about

> prescribing antidepressants to kids are too

> important to remain unresolved, " she said.

>

> There are ample studies, most of them funded

> by drug companies, showing the drugs do work and are

> safe. However, most drug trials are short, running

> six to eight weeks. Patients who drop out because of

> serious adverse effects, including suicide attempts

> and mania, are not counted in the final risk

> percentages.

>

> " In clinical trials ... from 15 to 21 percent

> discontinued the drug within six to eight weeks

> because of intolerable side effects, " said Thomas J.

> Moore, analyst at George Washington University

> Medical Center in Washington. " It would be hard to

> find another family of drugs in common use with such

> an abysmal record. "

>

> An attorney who said she has seen internal

> drug company documents still protected by court seal

> said the drug companies have been successful in

> hiding data from doctors and in some cases the FDA.

>

> " There's evidence ... to indicate the drug

> companies have known about a risk (of suicide and

> violence) since the 1980s, " said Karen Barth

> Menzies, who is representing about 100 people suing

> drugmakers because of suicides in their families.

>

> Doctors disagree on whether the FDA acted too

> slowly.

>

> Dr. John March, professor and chief of child

> and adolescent psychiatry at Duke University Medical

> Center, said " the FDA's done exactly all the right

> things. " March just completed the largest

> independent study to date of the generic version of

> Prozac and adolescents. British and Canadian health

> authorities " jumped to conclusions " while the FDA

> waited for a re-examination of drug company data, he

> said.

>

> Dr. Steven E. Hyman, who ran the National

> Institute of Mental Health and now is Harvard

> University's provost, said he believes the FDA has

> been cautious because the agency didn't want to send

> a " chilling " message that would keep people in need

> from taking the drugs.

>

> Hyman believes that most people benefit from

> the drugs,but he said he is troubled that so much is

> unknown.

>

> " I have a deep sense of disquiet that we

> really don't understand what's going on, " he said.

> " We need government-sponsored trials. Truly

> objective and dispassionate trials. "

>

> Staff writer Anne C. Mulkern can be reached at

> 202-662-8907 or amulkern .

>

>

--------

>

> Events that raised questions about risks of

> antidepressants:

> 1985: German health authorities raise concerns

> about Prozac's increased suicidal risk, which they

> say is five times that of older antidepressants.

> German health officials ultimately approve Prozac

> but with a stronger warning label than what will be

> approved in the U.S two years later.

>

> 1986: In a review of Prozac, prior to its

> approval, FDA Dr. Richard Kapit notes that the drug

> causes " anxiety, insomnia, agitation ... and

> psychotic episodes of a manic type. " Among other

> adverse effects he lists " bizarre homicidal and

> suicidal behavior. "

>

> 1989: During tests of Paxil, investigators for

> Beecham Laboratory (CQ) - part of what is now

> GlaxoSmithKline (CQ) - say Paxil " definitely " caused

> mania, suicide attempts, aggression and akathesia,

> or severe restlessness in some patients. Those

> reports were submitted to the FDA.

>

> 1990: Harvard psychiatrists Martin Teicher

> (CQ) and Jonathan Cole (CQ) publish study that

> indicates Prozac possibly increases risk of suicidal

> thoughts in 3.5 percent of patients.

>

> 1995: In a patent application, scientists

> working on a redesigned Prozac tell the government

> that their drug avoids Prozac's adverse effects of

> " severe anxiety leading to intense violent suicidal

> thoughts and self mutilation. " (Eli Lilly in 2000

> cancelled a $90 million deal to produce the drug.

> Generic Prozac remains on the market.)

>

> 1996: Pfizer, maker of Paxil, files report

> with FDA that says a drug-activated response is a

> " plausible " explanation for a manic reaction by a

> 9-year-old boy who choked himself with a tie and

> slashed his feet with a razor. The report otherwise

> blames depression as the reason for violent

> reactions seen in studies.

>

> 1998: The Journal Psychopharmacology publishes

> a study by Dr. Roger Lane (CQ) of Pfizer, which says

> selective serotonin reuptake inhibitors may produce

> akathesia. That symptom is believed to put patients

> at higher risk for suicide.

>

> February 2004: FDA Dr. Andrew Mosholder (CQ)

> writes a report and memo to the FDA director of

> neuropharmacological drug products that concludes

> nearly all selective serotonin reuptake inhibitor

> drugs increase the risk of suicidal behaviors in

> children and adolescents nearly two-fold over those

> on a placebo.

>

> THE DENVER POST

>

>

> [Non-text portions of this message have been

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