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WASHINGTON, April 19 (UPI) -- Lariam and the Suicide Effect

(Copyright 2002, UPI)

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By MARK BENJAMIN and DAN OLMSTED

of the UPI Washington Bureau

WASHINGTON (UPI) -- Mounting evidence suggests that the anti-malaria drug Lariam -- prescribed to Peace Corps volunteers, travelers and U.S. soldiers -- has triggered mental problems so severe that in a small percentage of users it has led to the ultimate side effect: suicide.

Lariam -- also known as mefloquine -- is a product of Hoffmann-La Roche, a giant Swiss pharmaceutical company with U.S. headquarters in Nutley, N.J. Lariam has been prescribed to more than 22 million people worldwide since 1985. It was cleared for use in the United States in 1989.

Some health experts charge that neither patients nor doctors in the United States are being adequately warned about the risk of suicide from taking Lariam, which is prescribed by U.S. doctors 1,000 times every day.

Advertisement

In a two-month investigation, United Press International reporters found:

* In thousands of pages of internal Roche documents obtained by UPI spanning a decade, the company tracks increasing reports of suicides, suicidal behavior and other mental problems among Lariam users.

* A 1994 safety report notes that because Lariam can cause depression and depression can lead to suicide, "a causal link to Lariam can in theory not be ruled out."

* Dozens of soldiers, Peace Corps volunteers, other government workers and private travelers who said they had no history of mental illness before taking Lariam, but then attempted or considered suicide. Families gave similar accounts of several who succeeded in killing themselves.

* An activist group said it has heard from 120 Somalia veterans who had problems they attributed to Lariam, including suicide attempts. Military medical officers in charge of giving Lariam to more than 20,000 U.S. troops there in 1992 and 1993 said they saw no evidence of a problem. Officials at Walter Reed Army Medical Center said troops in Afghanistan would be given Lariam for malaria prevention as the weather warmed.

* The U.S. Food and Drug Administration's files contain reports over the past four years alone of 11 suicides, 12 suicide attempts, 41 cases of thinking about suicide and 144 cases of depression among Lariam users. The FDA says these reports could represent as little as 1 percent of actual cases.

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* A statistical analysis of FDA data, commissioned by UPI, indicates that Lariam users are five times more likely to report having mental problems that could lead to suicide than those taking a different drug -- the antibiotic doxycycline -- also used to prevent malaria.

* One recent peer-reviewed clinical study said 29 percent of Lariam users reported neuropsychiatric side effects.

* More than a dozen lawsuits over the alleged effects of Lariam have been filed in the United States -- at least seven against Roche, and the others against doctors or pharmacists. Roche shortly is expected to settle a lawsuit filed by Linda Perry, an Ohio nurse who contends her husband Charles shot and killed himself in 1999 because of Lariam. Several other Lariam lawsuits have been dismissed or settled out of court. A jury ruled in one case that plaintiff lawyers failed to prove that Lariam made a man jump out a window and break his back.

"There have been a number of cases of suicide, both in the United States and abroad, that are clearly associated with the use of Lariam," said Susan Rose, an adjunct assistant professor at George Washington University's public health school and an attorney who has represented plaintiffs suing Roche.

Advertisement

"Suicidal thoughts and impulses are far more commonly experienced than the current product information sheet would lead physicians or consumers to believe."

"This is critical, life-saving information that must be conveyed now to travelers and the medical community," Rose said.

Roche consistently has denied there is evidence that shows taking Lariam can cause the kinds of mental problems that could lead to suicide. The company says Lariam is an important drug for combating malaria.

"Believe me, as a company we support this drug and stand behind it," said Roche spokesman Charles Alfaro. "Roche works with all regulatory authorities both before and after product approval to ensure recommendations for product use that take into account current medical evidence."

"It (Lariam) remains a drug of choice for the prevention and treatment of malaria by such leading health authorities as the CDC (Centers for Disease Control), the WHO (World Health Organization) as well as many travel organizations, clinics, and individual physicians," Alfaro said.

Adverse side effects of drugs are voluntarily reported by physicians and others to the FDA and drug companies. Dr. Raymond Woosley, dean of the University of Arizona Medical School and an expert on drug side effects, said the actual number of suicides associated with Lariam over the past four years might be 100 times greater than the 11 reported.

Advertisement

Experts said the FDA lacks the resources to follow up on side effect reports even for drugs recently approved.

"I would be very surprised if there's very much surveillance of this drug (Lariam) at all," said Woosley. "It's 12 years old. The FDA probably wouldn't have the people power. They're understaffed, they have inadequate resources and they're putting out fires and looking at new drugs."

The FDA said in a written statement to UPI that it would have taken action if it had confirmation that Lariam caused suicide. But the FDA said confirmation required either biological or statistical evidence. While the FDA database included reports of 11 deaths, all but one of them outside the United States, the FDA said "to 'blame' Lariam for all these cases is not scientifically justified."

"On balance we believe the risk of such rare and poorly substantiated events is more than offset by the benefit in preventing malaria deaths," the FDA statement said.

Under "less frequently reported adverse events," on Lariam's label, Roche added in 1999: "Suicidal ideation (thinking) has also rarely been reported, but no relationship to drug administration has been established."

In the United States, what is called a drug "label" is actually the fine-print information sheet doctors and pharmacists receive -- but patients often do not see.

Advertisement

Other nations have acted to ensure consumers receive warnings of possible adverse reactions to Lariam -- a member of the quinolone group of drugs long documented as capable of causing mental problems.

In 1997, the British Malaria Advisory Committee, for instance, stopped recommending Lariam for trips of two weeks or less. Patients who do take it receive a written warning that includes: "Effects on nervous system: psychiatric reactions which may be disabling and last for more than several weeks. ... If you experience any of these effects you should immediately stop taking Lariam and consult a doctor."

In Canada, "Information for the Consumer" from Roche states: "It is best to avoid alcoholic drinks during treatment with Lariam." No such warning appears on the U.S. label despite increasing concerns that alcohol can be a problem when mixed with Lariam.

"I think alcohol, in particular, can be a confounder with Lariam," said Dr. Alan Magill, a Walter Reed Army Medical Center official who was in charge of the health of U.S. soldiers deployed to Somalia in the early 1990s.

Magill said he saw no major side effects among troops taking Lariam. By contrast, Jeanne Lese, information manager of the activist group Lariam Action, said "more than 120 Somalia vets have contacted us about Lariam and 11 said they have considered or tried suicide - one tried it 10 times and shot herself twice" but survived.

Advertisement

The CDC declared Lariam its "drug of choice" in March 1990. In the fall of 1990, the CDC recommended that doses of Lariam should be doubled from once every two weeks to once a week, after the first four weeks of weekly doses. Because the CDC is the guidepost for malaria prevention in the United States, other government agencies agreed to the change.

That recommendation followed a survey of 562 Peace Corps volunteers led by the CDC's chief malaria expert, Dr. Hans Lobel. The study results eventually appeared in the Journal of the American Medical Association in January 1991.

"No serious adverse reactions were observed," Lobel wrote of the volunteers who took Lariam. Because some of those volunteers contracted malaria, a sometimes-deadly disease, Lobel said weekly doses of Lariam "should be considered."

Some doctors said the U.S. government never should have used Lobel's Peace Corps study as a basis for increasing doses of Lariam.

The dose increase was "an astonishing piece of non-evidence-based science," said Dr. Ashley Croft, a British army major who has done extensive research on Lariam and who said he believes it can cause serious mental problems that increase as doses rise.

Lobel's relationship with Roche is unclear. In a 1994 internal document the company said it relied on an evaluation from Lobel that the Lariam package insert was adequate. He was director of the CDC's malaria prevention program at the time. Lobel said he never has been a consultant for Roche. The CDC is looking into the issue.

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UPI reviewed thousands of pages of Roche's internal safety reports for the decade after the drug dose was increased. "Eight patients attempted suicide, three by leaping out a window," reads one Roche safety report of side effects documented through 1993, in a section titled "Depression with Suicidal Tendency."

The safety report for 1994 notes "the first report of suicide with the use of Lariam" and goes on to say, "Roche has received eight reports of attempted suicide, four of them associated with depression (previous [medical] history unknown)."

"Fourteen additional patients reported suicidal thoughts. All were associated with psychiatric disturbances" including depression, the 1994 report said.

The first report of suicide in 1994 was of Canadian Army Cpl. Scott Smith, who was stationed with the United Nations in Rwanda. Although he complained of having hallucinations he attributed to Lariam in the months before his death, the Roche safety report made no mention of that and said the use of Lariam was "more likely coincidental," especially since Smith had been drinking.

Canadian Member of Parliament John Cummins, who has investigated Lariam side effects, called Roche's failure to mention the hallucinations in the safety report "gross negligence."

The 1994 Roche safety report also said suicide might simply reflect a growing social problem.

Advertisement

But in that document, Roche notes that because Lariam can cause depression and depression can lead to suicide, "therefore a causal link to Lariam can in theory not be ruled out." The 1994 report concluded: "The current package insert adequately addresses suicidal ideation under 'depression' in view of the isolated reports received. No change in the package insert is required at present."

By 1998, Roche had added a new appendix to the annual safety report entitled, "Special Review: Lariam and Suicide, Suicide Attempt and Suicidal Ideation" (thinking about suicide) and the company was tracking seven suicides, 13 suicide attempts, 46 cases of thinking about suicide and 3,419 "psychiatric events."

For the men and women troubled by Lariam, those dry statistics were very real and sometimes deadly experiences.

"I was a raving, crazy lunatic," Martin Giannini said in a telephone interview last month from Dublin, where he is trying to rebuild a life he says was shattered by Lariam. He took Lariam from June 1995 through Sept. 1996 as a Peace Corps volunteer while in Togo in West Africa. His mental problems started with nightmares, headaches and dizziness. Two months later he needed a medical evacuation because of a quickly enveloping psychosis.

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Giannini said he considered suicide. "There were times ... It was amazing I survived."

"I just went to pieces," Giannini said. "I'd been telling (Peace Corps medical personnel) since Day One that I had been having problems with this drug."

Peace Corps medical officials said that reports of mental problems among volunteers are due to the onset of schizophrenia that can show itself in the early 20s, when most volunteers join up, but not because of Lariam.

"We do get people who develop schizophrenia in the Peace Corps, but it is not associated with mefloquine," said Russell Gerber, chief of the epidemiology unit at the Peace Corps.

In March 1998 the U.S. Department of Labor wrote Giannini a letter saying the department agreed to pay his medical expenses and compensate him for lost wages, "for a single, sustained, but acute psychotic reaction to mefloquine use" that lasted a full year.

UPI talked to 32 doctors, scientists and other experts and 27 people who said they suffered side effects. UPI reporters also reviewed dozens of e-mails from around the world - soldiers, travelers and medical experts in the field - about problems with Lariam.

For example, in Australia, John O'Callaghan committed suicide after being treated with Lariam for malaria he contracted on a surfing trip to Indonesia. "Almost immediately," his mother Jan wrote in an e-mail, "he suffered severe neuropsychological and physical side effects. For a couple of years he tried to return to his previous healthy lifestyle. Finally, in September 2000, he took his own life. He left a note, 'I will never forgive the bastards who gave me Lariam. No one should be expected to live like this.'"

Advertisement

Two statistical studies of the FDA database, commissioned by UPI, showed a far higher incidence of problems that could lead to suicide in people taking Lariam than in those taking doxycycline, an antibiotic recommended by the CDC as another drug to prevent malaria.

The studies' authors said both drugs are recommended by the CDC for prevention of malaria, so a comparison of reported mental problems among users of both drugs is valid.

The FDA said in a statement to UPI that suicide rates of patients taking doxycycline and Lariam cannot be validly compared, because most people treated with doxycycline receive it for acute bacterial infection and not for prevention of malaria. The FDA also said doxycycline has its own drawbacks: it cannot be used in children, sensitizes people to the sun, has to be taken daily while Lariam is taken weekly, and causes anorexia, nausea and vomiting.

Doxycycline is the malaria preventive President Clinton was prescribed when he traveled to India and Pakistan in early 2000.

PharmaGenesis of Bethesda, Md., and Fibonacci Group, a Philadelphia-based consulting group, conducted two separate studies of FDA raw data. Both firms do work with attorneys suing drug companies.

In one study for UPI, PharmaGenesis determined that people taking Lariam were five times more likely to have reported mental problems that could lead to suicide than people taking doxycycline. In the other, Fibonacci examined the FDA data and calculated the rate of side effects per prescription.

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The studies did not find a single successful suicide associated with doxycycline in the past four years, even though doxycycline, an antibiotic, is prescribed 25 times more often than Lariam, which is used only for treatment and prevention of malaria. Lariam is prescribed some 350,000 times a year, doxycycline is prescribed 9 million, according to data from IMS Health, a healthcare information company.

Experts on drug side effects warn that the FDA's data cannot solely be used to draw conclusions about drug safety, but they agreed that analyses from 1997 forward are best. That year the FDA dramatically changed the criteria in its reporting system, which before 1997 did not even track suicides.

The PharmaGenesis analysis found three reports prior to 1997 are "high probability" Lariam-associated suicides and two others are "possible."

Roche's documents said seven suicides were reported by the end of 1998 as associated with Lariam use, including one in 1994, two in 1997 and four in 1998.

Roche and the CDC's Lobel have said mental problems in those taking Lariam might be related to increased stress during travel. Keith Altman of Fibonacci Group said he thinks the 1997-2001 data debunk that assertion -- particularly considering the different prescription totals for the two drugs.

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A clinical study in October 2001 in the peer-reviewed Clinical Infectious Diseases journal showed that 29 percent of travelers taking Lariam complained of neuropsychiatric side effects and that 5 percent were so bothered they quit taking the drug altogether.

The "randomized controlled trial" was done among 976 travelers in the field.

Another drug company, Glaxo-Wellcome, funded the study and used Lariam as a control pill to gauge the safety of its own anti-malaria drug, Malarone, approved by the FDA in July 2000. FDA data shows two suicides reported among Malarone users.

Croft, the British army major, said that study shows that the U.S. government warnings for Lariam "need to be revised urgently now that there is good evidence for the potential harms of mefloquine."

Roche also makes Accutane, the popular acne drug that has also been associated with reports of suicide mainly among young people. In one high-profile case in Florida, the mother of Charles Bishop filed suit against Roche April 16, alleging that Accutane made Bishop, 15, fly a Cessna plane into a Tampa high-rise and kill himself in January.

Roche and some drug experts have both said there is no concrete scientific evidence to link Accutane to suicide.

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Unlike its approach with Lariam, however, Roche in May 2000 put new language on the Accutane label warning of suicide risks, almost 20 years after the FDA approved the drug in 1982.

With Accutane, the company responded to intense pressure from the FDA and now sends a written, FDA-regulated warning of the risk of suicide directly to potential patients.

But the FDA has been barred by Congress from regulating the prescription drug information given consumers except in the cases of a few drugs with particularly severe side effects. The agency also focuses its scarce resources on ensuring safety of new drugs.

A researcher who formerly reviewed Lariam side-effect reports at Roche said he now believes the company has developed a pattern of not alerting physicians and consumers to side effects that emerged after a drug had been approved.

"Roche has developed an attitude of not adjusting the information it supplies to physicians and patients about the performance and safety characteristics of their drugs," said Dr. Donald H. Marks, former associate director of clinical research at Roche.

Marks said there is "ample reason" to believe Lariam causes suicide. Marks said Lariam can cause "spontaneous neurological activity" and "irritation of certain sensitive areas inside the brain" that could lead to suicidal behavior long after someone stops taking it.

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Roche did not respond to UPI's written questions about Dr. Marks' comments. Alfaro, the Roche spokesman, said: "Roche takes the issue of safety very seriously and is diligent in monitoring the safety of all its drugs."

An alleged failure to provide adequate warning of Lariam side effects was at the heart of the Perry lawsuit in Ohio. Charles Perry, 54 and a father of seven with no history of mental illness, took Lariam in 1998 during an African safari to celebrate his 30th wedding anniversary with his wife, Linda.

The Perry lawsuit alleged the information provided by the pharmacy that filled their Lariam prescription warned only of possible "nausea, diarrhea, stomach upset, vomiting, dizziness or vision problems" and to "report difficulty breathing."

Linda Perry contended that before Charles Perry took the fourth pill, he was hallucinating. She said after returning to Ohio, they followed directions and took another four pills over the next four weeks to ensure they did not contract malaria. But Charles Perry spiraled into psychosis. He was hospitalized in the weeks before he killed himself with a shotgun in January 1999. His physician filed a report with the FDA blaming the suicide on Lariam. Roche contended in court that there was nothing to prove Lariam can cause suicide.

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Perry's wife said they would have stopped taking Lariam if they had been clearly warned of the risks. In an interview in the months after her husband's death, she said: "There was absolutely nothing on the bottle, from the pharmacy or from the health department that would have indicated that we should stop taking this."

2nd version

Lariam and the Suicide Effect

(Copyright 2002, UPI)

By MARK BENJAMIN and DAN OLMSTED

of the UPI Washington Bureau

WASHINGTON (UPI) -- Mounting evidence suggests that the anti-malaria drug Lariam -- prescribed to Peace Corps volunteers, travelers, and U.S. soldiers -- has triggered mental problems so severe that in a small percentage of users it has led to the ultimate side effect: suicide.

Lariam -- also known as mefloquine -- is a product of Hoffmann-La Roche, a giant Swiss pharmaceutical company with U.S. headquarters in Nutley, N.J. Lariam has been prescribed to more than 22 million people worldwide since 1985. It was cleared for use in the United States in 1989.

Some health experts charge that neither patients nor doctors in the United States are being adequately warned about the risk of suicide from taking Lariam, which is prescribed by U.S. doctors 1,000 times every day.

Advertisement

In a two-month investigation, United Press International reporters found:

* In thousands of pages of internal Roche documents obtained by UPI spanning a decade, the company tracks increasing reports of suicides, suicidal behavior and other mental problems among Lariam users.

* A 1994 safety report notes that because Lariam can cause depression and depression can lead to suicide, "a causal link to Lariam can in theory not be ruled out."

* Dozens of soldiers, Peace Corps volunteers, other government workers and private travelers who said they had no history of mental illness before taking Lariam, but then attempted or considered suicide. Families gave similar accounts of several who succeeded in killing themselves.

* An activist group said it has heard from 120 Somalia veterans who had problems they attributed to Lariam, including suicide attempts. Military medical officers in charge of giving Lariam to more than 20,000 U.S. troops there in 1992 and 1993 said they saw no evidence of a problem. Officials at Walter Reed Army Medical Center said troops in Afghanistan would be given Lariam for malaria prevention as the weather warmed.

* The U.S. Food and Drug Administration's files contain reports over the past four years alone of 11 suicides, 12 suicide attempts, 41 cases of thinking about suicide and 144 cases of depression among Lariam users. The FDA says these reports could represent as little as 1 percent of actual cases.

Advertisement

* A statistical analysis of FDA data, commissioned by UPI, indicates that Lariam users are five times more likely to report having mental problems that could lead to suicide than those taking a different drug -- the antibiotic doxycycline -- also used to prevent malaria.

* One recent peer-reviewed clinical study said 29 percent of Lariam users reported neuropsychiatric side effects.

* More than a dozen lawsuits over the alleged effects of Lariam have been filed in the United States - at least seven against Roche, and the others against doctors or pharmacists. Roche shortly is expected to settle a lawsuit filed by Linda Perry, an Ohio nurse who contends her husband Charles shot and killed himself in 1999 because of Lariam. Several other Lariam lawsuits have been dismissed or settled out of court. A jury ruled in one case that plaintiff lawyers failed to prove that Lariam made a man jump out a window and break his back.

"There have been a number of cases of suicide, both in the United States and abroad, that are clearly associated with the use of Lariam," said Susan Rose, an adjunct assistant professor at George Washington University's public health school and an attorney who has represented plaintiffs suing Roche.

Advertisement

"Suicidal thoughts and impulses are far more commonly experienced than the current product information sheet would lead physicians or consumers to believe."

"This is critical, life-saving information that must be conveyed now to travelers and the medical community," Rose said.

Roche consistently has denied there is evidence that shows taking Lariam can cause the kinds of mental problems that could lead to suicide. The company says Lariam is an important drug for combating malaria.

"Believe me, as a company we support this drug and stand behind it," said Roche spokesman Charles Alfaro. "Roche works with all regulatory authorities both before and after product approval to ensure recommendations for product use that take into account current medical evidence."

"It (Lariam) remains a drug of choice for the prevention and treatment of malaria by such leading health authorities as the CDC (Centers for Disease Control), the WHO (World Health Organization) as well as many travel organizations, clinics, and individual physicians," Alfaro said.

Adverse side effects of drugs are voluntarily reported by physicians and others to the FDA and drug companies. Dr. Raymond Woosley, dean of the University of Arizona Medical School and an expert on drug side effects, said the actual number of suicides associated with Lariam over the past four years might be 100 times greater than the 11 reported.

Advertisement

Experts said the FDA lacks the resources to follow up on side effect reports even for drugs recently approved.

"I would be very surprised if there's very much surveillance of this drug (Lariam) at all," said Woosley. "It's 12 years old. The FDA probably wouldn't have the people power. They're understaffed, they have inadequate resources and they're putting out fires and looking at new drugs."

The FDA said in a written statement to UPI that it would have taken action if it had confirmation that Lariam caused suicide. But the FDA said confirmation required either biological or statistical evidence. While the FDA database included reports of 11 deaths, all but one of them outside the United States, the FDA said "to 'blame' Lariam for all these cases is not scientifically justified."

"On balance we believe the risk of such rare and poorly substantiated events is more than offset by the benefit in preventing malaria deaths," the FDA statement said.

Under "less frequently reported adverse events," on Lariam's label, Roche added in 1999: "Suicidal ideation (thinking) has also rarely been reported, but no relationship to drug administration has been established."

In the United States, what is called a drug "label" is actually the fine-print information sheet doctors and pharmacists receive -- but patients often do not see.

Advertisement

Other nations have acted to ensure consumers receive warnings of possible adverse reactions to Lariam -- a member of the quinolone group of drugs long documented as capable of causing mental problems.

In 1997, the British Malaria Advisory Committee, for instance, stopped recommending Lariam for trips of two weeks or less. Patients who do take it receive a written warning that includes: "Effects on nervous system: psychiatric reactions which may be disabling and last for more than several weeks. ... If you experience any of these effects you should immediately stop taking Lariam and consult a doctor."

In Canada, "Information for the Consumer" from Roche states: "It is best to avoid alcoholic drinks during treatment with Lariam." No such warning appears on the U.S. label despite increasing concerns that alcohol can be a problem when mixed with Lariam.

"I think alcohol, in particular, can be a confounder with Lariam," said Dr. Alan Magill, a Walter Reed Army Medical Center official who was in charge of the health of U.S. soldiers deployed to Somalia in the early 1990s.

Magill said he saw no major side effects among troops taking Lariam. By contrast, Jeanne Lese, information manager of the activist group Lariam Action, said "more than 120 Somalia vets have contacted us about Lariam and 11 said they have considered or tried suicide - one tried it 10 times and shot herself twice" but survived.

Advertisement

The CDC declared Lariam its "drug of choice" in March 1990. In the fall of 1990, the CDC recommended that doses of Lariam should be doubled from once every two weeks to once a week, after the first four weeks of weekly doses. Because the CDC is the guidepost for malaria prevention in the United States, other government agencies agreed to the change.

That recommendation followed a survey of 562 Peace Corps volunteers led by the CDC's chief malaria expert, Dr. Hans Lobel. The study results eventually appeared in the Journal of the American Medical Association in January 1991.

"No serious adverse reactions were observed," Lobel wrote of the volunteers who took Lariam. Some of those volunteers, however, contracted malaria, a sometimes-deadly disease. So Lobel said weekly doses of Lariam "should be considered."

Some doctors said the U.S. government never should have used Lobel's Peace Corps study as a basis for increasing doses of Lariam.

The dose increase was "an astonishing piece of non-evidence-based science," said Dr. Ashley Croft, a British army major who has done extensive research on Lariam and who said he believes it can cause serious mental problems that increase as doses rise.

Lobel's relationship with Roche is unclear.

Advertisement

In a 1994 internal Roche document, the company said it relied on an evaluation from Lobel that the Lariam package insert was adequate. Lobel was director of the CDC's malaria prevention program at the time.

"According to a consultant expert in the field of malaria, Dr. H. Lobel, CDC, Atlanta, the current package insert adequately addresses suicidal ideation under 'depression', in view of the isolated reports received," the 1994 Roche safety report read. "No change in the package insert is required at present."

CDC rules prohibit compensated or uncompensated consulting without express written permission. CDC spokesman Tom Skinner said his organization does not have records indicating that Lobel received such permission, if it was needed.

"I have never been a consultant for Roche," Lobel told UPI. Lobel said he often worked as a consultant for other organizations, such as the World Health Organization, but not for Roche.

Roche declined to discuss Lobel with UPI.

After UPI asked about Lobel and Roche, Skinner said the CDC had opened an ethics inquiry. "There is a formal process the CDC must go through to determine if any action needs to be taken," Skinner said.

Lobel, now retired, recently appeared as an expert witness for the government, testifying about the value of Lariam as an anti-malaria drug and arguing there is no evidence Lariam causes mental problems. "I've never seen a report of anything serious or severe," he said last month in federal court in Philadelphia. He testified in the fraud case against former Rep. Ed Mezvinsky, D-Pa., who contends Lariam aggravated a bipolar disorder.

Advertisement

UPI reviewed thousands of pages of Roche's internal safety reports for the decade after the drug dose was increased. "Eight patients attempted suicide, three by leaping out a window," reads one Roche safety report of side effects documented through 1993, in a section titled "Depression with Suicidal Tendency."

The safety report for 1994 notes "the first report of suicide with the use of Lariam" and goes on to say, "Roche has received eight reports of attempted suicide, four of them associated with depression (previous [medical] history unknown)."

"Fourteen additional patients reported suicidal thoughts. All were associated with psychiatric disturbances" including depression, the 1994 report said.

The first report of suicide in 1994 was of Canadian Army Cpl. Scott Smith, who was stationed with the United Nations in Rwanda. Although he complained of having hallucinations he attributed to Lariam in the months before his death, the Roche safety report made no mention of that and said the use of Lariam was "more likely coincidental," especially since Smith had been drinking.

Canadian Member of Parliament John Cummins, who has investigated Lariam side effects, called Roche's failure to mention the hallucinations in the safety report "gross negligence."

The 1994 Roche safety report also said suicide might simply reflect a growing social problem.

Advertisement

But in that document, Roche notes that because Lariam can cause depression and depression can lead to suicide, "therefore a causal link to Lariam can in theory not be ruled out."

By 1998, Roche had added a new appendix to the annual safety report entitled, "Special Review: Lariam and Suicide, Suicide Attempt and Suicidal Ideation" (thinking about suicide) and the company was tracking seven suicides, 13 suicide attempts, 46 cases of thinking about suicide and 3,419 "psychiatric events."

For the men and women troubled by Lariam, those dry statistics were very real and sometimes deadly experiences.

"I was a raving, crazy lunatic," Martin Giannini said in a telephone interview last month from Dublin, where he is trying to rebuild a life he says was shattered by Lariam. He took Lariam from June 1995 through Sept. 1996 as a Peace Corps volunteer while in Togo in West Africa. His mental problems started with nightmares, headaches and dizziness. Two months later he needed a medical evacuation because of a quickly enveloping psychosis.

Giannini said he considered suicide. "There were times ... It was amazing I survived."

"I just went to pieces," Giannini said. "I'd been telling (Peace Corps medical personnel) since Day One that I had been having problems with this drug."

Advertisement

Peace Corps medical officials said that reports of mental problems among volunteers are due to the onset of schizophrenia that can show itself in the early 20s, when most volunteers join up, but not because of Lariam.

"We do get people who develop schizophrenia in the Peace Corps, but it is not associated with mefloquine," said Russell Gerber, chief of the epidemiology unit at the Peace Corps.

In March 1998 the U.S. Department of Labor wrote Giannini a letter saying the department agreed to pay his medical expenses and compensate him for lost wages, "for a single, sustained, but acute psychotic reaction to mefloquine use" that lasted a full year.

UPI talked to 32 doctors, scientists and other experts and 27 people who said they suffered side effects. UPI reporters also reviewed dozens of e-mails from around the world - soldiers, travelers and medical experts in the field - about problems with Lariam.

For example, in Australia, John O'Callaghan committed suicide after being treated with Lariam for malaria he contracted on a surfing trip to Indonesia. "Almost immediately," his mother Jan wrote in an e-mail, "he suffered severe neuropsychological and physical side effects. For a couple of years he tried to return to his previous healthy lifestyle. Finally, in September 2000, he took his own life. He left a note, 'I will never forgive the bastards who gave me Lariam. No one should be expected to live like this.'"

Advertisement

Two statistical studies of the FDA database, commissioned by UPI, showed a far higher incidence of problems that could lead to suicide in people taking Lariam than in those taking doxycycline, an antibiotic recommended by the CDC as another drug to prevent malaria.

The studies' authors said both drugs are recommended by the CDC for prevention of malaria, so a comparison of reported mental problems among users of both drugs is valid.

The FDA said in a statement to UPI that suicide rates of patients taking doxycycline and Lariam cannot be validly compared, because most people treated with doxycycline receive it for acute bacterial infection and not for prevention of malaria. The FDA also said doxycycline has its own drawbacks: it cannot be used in children, sensitizes people to the sun, has to be taken daily while Lariam is taken weekly, and causes anorexia, nausea and vomiting.

Doxycycline is the malaria preventive President Clinton was prescribed when he traveled to India and Pakistan in early 2000.

PharmaGenesis of Bethesda, Md., and Fibonacci Group, a Philadelphia-based consulting group, conducted two separate studies of FDA raw data. Both firms do work with attorneys suing drug companies.

In one study for UPI, PharmaGenesis determined that people taking Lariam were five times more likely to have reported mental problems that could lead to suicide than people taking doxycycline. In the other, Fibonacci examined the FDA data and calculated the rate of side effects per prescription.

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The studies did not find a single successful suicide associated with doxycycline in the past four years, even though doxycycline, an antibiotic, is prescribed 25 times more often than Lariam, which is used only for treatment and prevention of malaria. Lariam is prescribed some 350,000 times a year, doxycycline is prescribed 9 million, according to data from IMS Health, a healthcare information company.

Experts on drug side effects warn that the FDA's data cannot solely be used to draw conclusions about drug safety, but they agreed that analyses from 1997 forward are best. That year the FDA dramatically changed the criteria in its reporting system, which before 1997 did not even track suicides.

The PharmaGenesis analysis found three reports prior to 1997 are "high probability" Lariam-associated suicides and two others are "possible."

Roche's documents said seven suicides were reported by the end of 1998 as associated with Lariam use, including one in 1994, two in 1997 and four in 1998.

Roche and the CDC's Lobel have said mental problems in those taking Lariam might be related to increased stress during travel. Keith Altman of Fibonacci Group said he thinks the 1997-2001 data debunk that assertion -- particularly considering the different prescription totals for the two drugs.

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"If you look at rates-per-prescription, you're talking about a 40 times greater rate of suicide attempts in Lariam than in doxycycline," Altman said. "Look at depression: the rate of depression is 150 times greater in Lariam. I just can't see a 150-times-greater rate of depression when you consider that a lot of these people are happy they're going on a trip."

In 2001 a clinical study, a "randomized controlled trial," was done among 976 actual travelers in the field.

The October 2001 study in the peer-reviewed Clinical Infectious Diseases journal showed that 29 percent of travelers taking Lariam complained of neuropsychiatric side effects and that 5 percent were so bothered they quit taking the drug altogether.

Another drug company, Glaxo-Wellcome, funded the study and used Lariam as a control pill to gauge the safety of its own anti-malaria drug, Malarone, approved by the FDA in July 2000. FDA data shows two suicides reported among Malarone users.

Croft, the British army major, said that study shows that the U.S. government warnings for Lariam "need to be revised urgently now that there is good evidence for the potential harms of mefloquine."

Roche also makes Accutane, the popular acne drug that has also been associated with reports of suicide mainly among young people. In one high-profile case in Florida, the mother of Charles Bishop filed suit against Roche April 16, alleging that Accutane made Bishop, 15, fly a Cessna plane into a Tampa high-rise and kill himself in January.

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Roche and some drug experts have both said there is no concrete scientific evidence to link Accutane to suicide.

Unlike its approach with Lariam, however, Roche in May 2000 put new language on the Accutane label warning of suicide risks, almost 20 years after the FDA approved the drug in 1982.

With Accutane, the company responded to intense pressure from the FDA and now sends a written, FDA-regulated warning of the risk of suicide directly to potential patients.

But the FDA has been barred by Congress from regulating the prescription drug information given consumers except in the cases of a few drugs with particularly severe side effects. The agency also focuses its scarce resources on ensuring safety of new drugs.

A researcher who formerly reviewed Lariam side-effect reports at Roche said he now believes the company has developed a pattern of not alerting physicians and consumers to side effects that emerged after a drug had been approved.

"Roche has developed an attitude of not adjusting the information it supplies to physicians and patients about the performance and safety characteristics of their drugs," said Dr. Donald H. Marks, former associate director of clinical research at Roche.

Marks said there is "ample reason" to believe Lariam causes suicide. Marks said Lariam can cause "spontaneous neurological activity" and "irritation of certain sensitive areas inside the brain" that could lead to suicidal behavior long after someone stops taking it.

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Roche did not respond to UPI's written questions about Dr. Marks' comments. Alfaro, the Roche spokesman, said: "Roche takes the issue of safety very seriously and is diligent in monitoring the safety of all its drugs."

An alleged failure to provide adequate warning of Lariam side effects was at the heart of the Perry lawsuit in Ohio. Charles Perry, 54 and a father of seven with no history of mental illness, took Lariam in 1998 during an African safari to celebrate his 30th wedding anniversary with his wife, Linda.

The Perry lawsuit alleged the information provided by the pharmacy that filled their Lariam prescription warned only of possible "nausea, diarrhea, stomach upset, vomiting, dizziness or vision problems" and to "report difficulty breathing."

Linda Perry contended that before Charles Perry took the fourth pill, he was hallucinating. She said after returning to Ohio, they followed directions and took another four pills over the next four weeks to ensure they did not contract malaria. But Charles Perry spiraled into psychosis. He was hospitalized in the weeks before he killed himself with a shotgun in January 1999. His physician filed a report with the FDA blaming the suicide on Lariam. Roche contended in court that there was nothing to prove Lariam can cause suicide.

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Perry's wife said they would have stopped taking Lariam if they had been clearly warned of the risks. In an interview in the months after her husband's death, she said: "There was absolutely nothing on the bottle, from the pharmacy or from the health department that would have indicated that we should stop taking this."

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