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Did A Powerful Acne Drug Play A Role In A Palo Alto 14-Year-Old's Killing Himself?

Apr 27, 2003 | San Francisco Chronicle

On a cool, sunny morning last October, just before his first-period honors math class began, a 14-year-old freshman named Steven Wertheimer killed himself by standing in front of a 750,000-ton commuter train traveling northward beside the Palo Alto High School football field.

His suicide was discussed all over the affluent, articulate town where, in the words of a police captain, "the community has a sense bad things don't happen, but they do." Neighbors and friends, teachers, cops and kids were all sadly engaged by what seemed a tragic waste.

At a makeshift memorial, which has become such a staple of American grieving, Steven's pal Alex Rosenberg left a letter: "Dearest Friend, I always thought you were content with your life. I wish I could have been there at 8:06 to comfort you before you leapt in front of that train. I can't imagine how terrified you must have been, standing before that mighty machine; staring straight into the eyes of mortality. Rest in peace my dearest friend Steven."

Palo Alto is nothing if not concerned with its children. A consensus formed rapidly, perhaps best summed up by Rabbi Ari Cartun, who had prepared Steven for his bar mitzvah and now was counseling and comforting his distraught family.

"We will never know why. And we are going to have to live with that. It will forever be a mystery to us," said the rabbi at a funeral attended by hundreds of people. "We will never know what drove Steven to take his own life. "

At the same time, word was spreading that Steven had been treated for acne with a powerful ingestible medication called Accutane, which has been linked to other teen suicides. The most notable occurred four months after the Sept. 11 attacks, when a 15-year-old boy flew a small plane into a Tampa high-rise. Charles Bishop's mother has since filed an Accutane lawsuit against Hoffman-La Roche pharmaceutical company, which manufactures the drug.

But suicide is not commonly a one-dimensional act, and part of the reaction in Palo Alto was that it would be simplistic to blame Steven's desire to die on a zit pill. Carol Siegel is a licensed clinical social worker whose employer, Adolescent Counseling Services, contracts with the school district to place on-campus counselors at all the secondary schools.

We talked in her office. Outside her window, the quad of the high school everybody calls Paly was visible, students coming and going, passing by graffiti that months after his death remained: "A Fine Minstrel/ STEVEN/ We Love You."

"I want to believe that Accutane can create a toxic reaction," Siegel said. "But everything I know," after decades of treating teenagers, contradicts the conclusion that it could be the cause of a suicide. "If they perceive life sucks, if they perceive their friends reject them, if they perceive their prom date rejects them, if they had a horrendous fight and think their mother is impossible, if they have a gender identity problem, they crush. Easily. I see it in here every single day.

"I do not feel," she said, "that Accutane was a contributing factor in this. "

On the other hand, there is only one drug in America for which the U.S. Food and Drug Administration (FDA) compels a pharmaceutical company to attach a label warning that it may cause suicide, and that drug is Accutane.

"WARNINGS," reads the attachment to every box of the crystalline powder dispensed in capsules. "Accutane may cause depression, psychosis, and, rarely, suicidal ideation, suicide attempts, and suicide. Discontinuation of Accutane therapy may be insufficient; further evaluation may be necessary."

In 2000, when Roche, a Swiss pharmaceutical giant whose U.S. headquarters is in Nutley, N.J., added that language to its packaging under pressure from the FDA, it was already long-established medically that Accutane caused terrible birth defects and spontaneous abortions when taken by pregnant women. Women of child-bearing age are warned to use two kinds of contraception if they take Accutane, and to take those extreme precautions from a month before beginning a course of the drug until a month after they complete it.

By the mid-1990s, the FDA had also become alarmed at the increasing number of psychological Accutane side effects being reported. Among the more than 3,000 reports of what the agency calls serious adverse psychological events now in its MedWatch database are 190 suicides, many of them by teens, and scores more attempts since the drug was first marketed in 1982.

But the problem with how best to deal with these side effects, if that is what they are, is that Accutane works. In most cases, it clears up even the most severe acne in a matter of months. It changes lives for the better in a way no other acne drug ever has.

Naturally, it's much desired. Roche's worldwide sales hit $797 million in 2001, although the company says it slumped to about $600 million last year. It is the pharmaceutical company's second-best-selling product in the United States, and third worldwide. Not surprisingly, it's very expensive. Generally, it's a drug for kids whose families are fully insured.

Accutane has been available for 20 years, and cases of depression after taking it were reported in medical literature as early as 1985. Yet it has never been scientifically proved that what a Roche spokeswoman calls, "a powerful drug, a potent drug, a drug to be taken very seriously," can cause depression and suicide. The problem of demonstrating scientific causality is daunting.

So patients, and parents of teenage patients, are pretty much on their own in deciding whether the benefits outweigh the risks. Barry and Laurie Wertheimer did not answer a letter or a phone message explaining what this story is about and seeking permission to interview them.

In the balance of emotions experienced by grieving parents whose kids took the drug and then killed themselves, the lack of absolute scientific proof can weigh light as a feather.

Susan Turney lost her 16-year-old son, Matt, two years ago. His story bears a resemblance to Steven Wertheimer's. Both were apparently happy, well-adjusted kids, doing well at school, popular, musical and athletic. Friends and family saw no warning signs of what was to come. They were kids who suddenly one day -

Matt right after school, Steven just before - took their own lives.

Turney was asked to appear before a congressional committee, one of whose members, Rep. Bart Stupak, a Michigan Democrat, has crusaded against Accutane since his teenage son committed suicide while taking the drug. In December, the Watertown, N.Y., mother testified:

"The only thing that would have made a difference is if Roche would finally admit to dermatologists that there is a causal relationship between suicide and Accutane, and admit that it occurs without warning.

"Remember," she said, "(Our) dermatologist told us exactly what Roche continues to say and what every parent wants to hear - there is no scientific proof and these are unsubstantiated reports. What they are really saying is, `Don't worry, there must have been something wrong with those kids, those families, their lives.' Roche must know that is exactly what parents of a child considering this drug want to hear: It can never and will never happen to us.

"But it does." .

Side Effect

Four days before the Monday morning when he killed himself, Steven Wertheimer had a bad headache. His head hurt so much on Thursday that he couldn't bear to wear the blue University of Florida cap that he always sported.

"That cap was pretty much his trademark," says his pal, Cameron Savaree- Ruess. "There wasn't one day he didn't wear it."

Severe headaches can be an indication of internal cranial pressures caused by swelling of the brain that sometimes occurs as a side effect of Accutane. Because the swelling can lead to blindness or in rare instances death, prescribing dermatologists keep a wary eye out for headaches.

Months afterward, Cameron is still trying to puzzle out what happened to his funny friend, the pal who shared a thousand laughs and a thousand songs in their garage band.

Sitting barefoot in his pajamas on his family's sun porch, Cameron says: "He and I didn't keep anything from each other. I mean, this shouldn't have happened. I can't see it happening. I've been thinking about it the whole time,

seriously thinking about it." You get the sense it's the most serious thinking Cameron has done in his 14 years. "The whole time. Nothing makes sense."

Whatever caused Steven's headache, it was gone by Friday, when Steven was wearing his cap again. Steven was flamboyant, with a zany sense of humor. His reputation, says Beatrice Salaverry, the mother of another of his friends, was as the kid "who didn't care what people thought."

There were Steven's rings, for instance - cheap plastic doodads bought at a local novelty store, Diddam's. They were mock rubies, pearls, emeralds. Steven loved to wear them; he was known for it.

And he was expressive. "He didn't keep his emotions hidden," says Cameron. Steven was tough, too. He was a running back on the Paly junior varsity football team, and prided himself on popping right up after a hard hit.

Everything Steven did, say his many friends, he did with distinctive humor. He was a really fast runner, but when he lost a sprint at an all-star meet, Cameron remembers, Steven's take on it was that the kid who beat him must have cheated, "because I'm the fastest kid alive."

What struck Paly principal Sandra Person about Steven was that he had "multiple means of expression." He wrote songs, sang and played guitar for the garage band he and Cameron started and named Run Away Hagis. "The poetry he wrote was lovely," says Pearson. "Very few kids that age have so many means of expressing themselves."

Yet Steven did not express what he most needed to.

An inability to speak up, or perhaps to even know what was happening, characterizes the depression associated with Accutane, says Michael Lara, a psychiatrist who is medical director for Gardner Family Health Care Corp. in San Jose, and specializes in psychopharmacology. He has had numerous adolescent patients on the acne drug in his private practice in Woodside (and none among his largely poor, Latino patients in San Jose; the poor, he says, do not often see dermatologists).

"Typically, with garden-variety depression, the onset of symptoms is gradual over time," says Lara. "With Accutane, I've seen it be very dramatic, almost from one day to the next, into which the patient himself has no insight. " That description could fit what happened to 16-year-old Matt Turney, as well as it might fit Steven, whose father dropped him off at school that morning. Turney came home on a day when he had done well on a test and a girl had accepted an invitation to a dance, and shot himself with his father's gun.

Depression in adolescents is hardly unusual, of course, and has many causes.

About 6,000 teenagers a year kill themselves, making suicide the third- leading cause of death in their age group, after accidents and homicides. A recent survey of college students, the largest of its kind ever done, found that the percentage treated for depression doubled between 1989 and 2001, as did the percentage of suicidal students.

All of which confirms what we already know: Adolescence is best experienced in retrospect, and "The Catcher in the Rye" will go on being read so long as there are 16-year-olds.

Six weeks after Steven's death, a Child Death Review Team met in the office of medical examiner Dr. Gregory Schmunk. The team's deliberations are confidential, but its members, who include a pediatric psychiatrist, review every death of a child in Santa Clara County.

Steven's medical records contain an entry from Stanford Hospital Pediatric Dermatology Clinic stating that, beginning on Dec. 2, 2001, and continuing until the end of May or beginning of June 2002, Steven was taking Accutane, Schmunk says. The records indicate that he was alternating one and two 40- milligram tablets a day of the fat-soluble vitamin A derivative.

So Steven had taken Accutane, but not for about four months before his suicide. Nonetheless, his death has been included in the FDA's reporting system for Accutane. Because depression tends to be cyclical, the MedWatch system includes those cases where a patient took the drug, ceased taking it and then committed suicide. The reasoning is that a person could become depressed on the medication, initially feel better after he stops, and then experience a re-triggered, Accutane-induced depression. One Accutane expert likened it to postpartum illness, which can occur moments or months after giving birth.

When an FDA epidemiologist, Dr. Diane Wysowski, spoke in September 2000, during a two-day Dermatology Advisory Committee summit meeting of sorts devoted entirely to Accutane's adverse effects, she said that among the U.S. patients who had committed suicide, a bit more than a third had done so after stopping the drug. The median time between stopping the drug and the suicides was two months, she said.

Of the 110 U.S. patients hospitalized during the same period for severe depression, suicidal ideation or suicide attempts, she added, 25 had ceased taking the drug. The median time since they had last been on Accutane was three months.

"Most serious cases did not improve with Accutane discontinuation alone," she said. "Psychiatric intervention was frequently required.

"There are," she said, "high rates of depression and suicide in the teen years, making the independent contribution of Accutane with depression difficult to assess."

So it would seem entirely plausible to imagine a teenage boy experiencing the angst of adolescence, feeling, as so many teenagers would put it, "weird." At the same time it could be that the depressive chemical effects of Accutane were coloring a bleak mood blacker, sealing the existential escape hatches that allow most kids to grow up and move on. .

A Scapegoat

Steven's friend Danya Taymor acted and sang with him in a number of musicals, and admits to having had a crush on the handsome, blue-eyed boy in the eighth grade. She remembers that in December 2001, when Steven went on the medication, "He got sad for about three weeks," during a staging of "Snow White." "He was down a lot."

Danya didn't think Steven seemed sad on Friday, Oct. 4, only six weeks into their freshman year at Paly, a famously stressful transition to one of the best academic high schools in the state. That afternoon the JV football team lost to Saratoga High School. Steven, a backup, got into the game for only a few snaps.

Saturday, Steven worked on a project at the home of another friend, Alex Rosenberg, constructing a parabolic cooker capable of toasting marshmallows for Geometry/Algebra 2, the highest-lane freshman math class. The class was proving to be his most difficult, although Steven was also taking five other classes, including advanced biology, German and English. One reaction to Steven's death has been that Palo Alto High School has undertaken an extensive examination of the academic stresses on students, and how they might be relieved.

Alex is thoughtful, and he's inclined to dismiss any role Accutane might have played:

"My initial thoughts were maybe that's the reason he did this, Accutane made him depressed. But when something like this happens, people look for reasons. And I think Accutane is kind of a scapegoat."

Alex is still troubled, though, by a conversation he and Steven had perhaps 10 days before his suicide. It was during football practice. He has wanted to tell Steven's parents about it, but hasn't quite figured out how.

"We were just talking about death in a kind of morbid way, because a lot of those big guys out on the field want to hurt you. Steven kind of asked me, `What do you think it would be like getting hit by a train?'

" `You wouldn't feel much; it would be instantaneous,' " Alex answered.

" `It would be a good way to go,' " Steven said.

" `It wouldn't be honorable,' Alex said. `I'd like to go in some kind of sword fight.' "

Finishing his recollection, Alex's dark eyes become distant. "I don't know, " he says, "you just wonder a lot. What kind of pain was he going through that he hid so well?" .

A Cure

By the late 1970s, there was "a great longing" among dermatologists for an

experimental drug called isotretinoin that was scoring spectacular successes healing the most disfiguring cases of cystic acne in clinical trials,

says Thomas Hoffman. Hoffman is a clinical professor of dermatology at Stanford University; he has a private practice, and children at Paly.

Isotretinoin is a vitamin A derivative, a retinoid, that was being tested for use against some hard-to-treat cancers such as neck cancer when oncologists noticed it was also having an amazing effect on skin disorders, including acne. Nobody then, or now, understood exactly how isotretinoin worked.

"[It] reduces sebum (produced by the oil glands), which results in the development and eruption of severe nodular cysts," Roche vice president for public affairs Carolyn Glynn said in an e-mail. "The medication also decreases the amount of bacteria on the skin and in the hair follicle, and reduces the inflammation of the skin caused by the sebum [and] bacteria."

"Can we tell you exactly how?" she added in an interview. "No."

When Roche began marketing isotretinoin as Accutane after gaining FDA approval in 1982, it was intended exclusively for the kind of disfiguring pus- filled cysts that can have mortifying social and psychological effects.

"Basically, we saw dramatic turnarounds, especially with adolescents," says dermatologist Hoffman. "If I showed you pictures, 30 boils on the face and back, somebody whose life was miserable," but then after treatment with Accutane, "you'd see a happy person."

Even better, in most patients the acne did not return after the course of treatment typically four to five months, depending on dosage was completed.

Hoffman, whose son was a friend of Steven Wertheimer's older brother, Rob, was aware of the potential dangers. He was always cautious in prescribing and monitoring the drug, and now is even more so.

"This hit home," he says. "Is there a relationship? We try to be conservative; there's the consent form. But oh, my God," he says, his hand thumping his heart.

Beginning in 2001, an informed consent form was provided to all physicians who prescribe Accutane. Patients, or their parents, are asked to initial a series of warnings about the potential psychological risks associated with Accutane, as well as the severe risk of aborting a pregnancy, or giving birth to a deformed child that are well-established as side effects of the powerful medication (which is never supposed to be prescribed for a pregnant woman). Rep. Stupak compares the dangers to those associated with thalidomide.

The informed consent for psychological side effects was one in a series of steps the FDA has recommended to Roche during the 20 years that Accutane has been marketed. In 1986, the packaging insert was first amended to warn that depression had been reported in some patients. After a decade of negotiation between the FDA and Roche, the far stronger warning of psychiatric disorders, including suicide, was added in 1998.

Then in 2001, the FDA pressed Roche for a medication guide itemizing the dangers to every family physician, dermatologist, psychiatrist and pharmacist in the country. Only a tiny number of other drugs have such med guides.

Also in 1998, the FDA accused Roche of "false and misleading" advertising for suggesting that "Accutane has a positive effect on psychosocial effects, such as depression." In essence, Roche was claiming that because Accutane cleared up acne, and because acne can be depressing, Accutane helped in fighting depression caused by acne.

The FDA ordered the ads and promotional materials withdrawn. Today, Carolyn Glynn, the Roche spokeswoman, calls it "a matter of interpretation. What's most important is we took the FDA's warning very seriously and withdrew the ads."

But Roche's fundamental position on Accutane remains steadfast. "We do not believe that there is a cause-and-effect relationship between Accutane and these psychological effects including suicide," says Glynn. "There is no scientific basis for believing Accutane is going to cause these effects.

"But putting that aside, one suicide is one too many, and it's extremely important we do everything we can. We continue to evaluate, bring in outside experts, put as much information on the label as possible, and provide information to physicians."

Stupak does not agree that Roche is doing all it can do. Since the suicide of his son BJ in 2000 while on Accutane, the Michigan Democrat has campaigned to have both Roche and the FDA do more.

"The FDA's response to birth defects and psychiatric events has been inadequate, irresponsible and unacceptable," he says. Even the extensive warnings in the packaging and multiple mailings to providers of the drug demanded by the regulators are not enough, Stupak says.

As for the manufacturer, he said at a congressional hearing in December that "Roche have done everything possible to prevent the American people from learning of the psychiatric injuries and deaths associated with Accutane. É Our children are not collateral damage in the scheme of corporate profits."

Stupak says he knows of 200 suicides since 1982, 10 more than the FDA. But whatever the number, says Marilyn Pitts, a pharmacologist who does safety evaluations for the FDA, it is a byproduct of, "substantial underreporting. The FDA receives notification of only a fraction of adverse events. Estimates are as low as 1 percent."

There is no disagreement that Accutane use is on the rise. In a Journal of the American Academy of Dermatology article in 2000, FDA epidemiologist Diane Wysowski concluded that since 1992, "there has been a 250 percent increase in the number of dispensed prescriptions for isotretinoin in the United States. Data also reveal an increasing proportion of isotretinoin use for mild and moderate acne." Wysowski's data suggests that of the nearly 2 million prescriptions a year being written, 49 percent were for mild or moderate acne rather than the severe acne for which it is indicated as a last-ditch therapy where all other therapies have failed. Other critics put the number at as high as 80 percent.

"What happened," dermatologist Hoffman says, "is we got comfortable with the medication."

Others, pointing out that HMOs in California are paying as much as $350 to $500 for a 30-day supply, say that Accutane has taken on a kind of class privilege-based glamour. "It's a status symbol drug," says David Affinito, one of the attorneys representing the Turneys in a lawsuit they filed against Roche after the death of their son. "Kids want it if, God forbid, they have three pimples."

Steven Wertheimer's friends interviewed for this story do not remember him as having had especially bad zits when he went on the medication in eighth grade. Steven's medical records from the pediatric dermatology clinic at Stanford Hospital, says medical examiner Schmunk, indicate that he had "cystic acne." That phrase, several dermatologists said, may be a shorthand for a severe case of acne; on the other hand, it may also indicate the presence of just a few facial lumps or pimples.

Because of the dangers associated with the drug, "primary care physicians have largely been scared away from prescribing Accutane," Dr. Rudolph Brutoco wrote in a recent Brown University journal. "We are increasingly left then with dermatologists using a medication that potentially can have serious mental health effects, but not being in a good position to detect those problems and promptly intervene." The symptoms of depression can, we know, look a lot like the ordinary behavior of teenagers.

And who, after all, tells a dermatologist that he's depressed? .

Teen Pressures

Steven left a suicide note. It was found in his backpack under some bushes beside the railroad tracks. Although neither the police nor school authorities are willing to make it public, four different people who read it described its contents to me.

It was addressed to his parents, Barry and Laurie Wertheimer. The tone of the one-page handwritten note was affectionate, loving.

It began, says someone who read it: If you're reading this I'm probably dead. Don't blame yourselves.

It went on to say that they had been great parents but, according to two people who read it, Steven said he could not live up to their expectations, or become the person they hoped he would. But a third reader remembered distinctly that the word Steven had used was "deserved," he could not be the son they deserved.

"As a parent," said one reader, "the note is gut-wrenching."

"It was really, really neat, but the last line was wobbly," recalled one person. Just before Caltrain No. 43 arrived at the Churchill Street crossing that Monday morning, Steven was seen by another student crouching in the bushes, apparently writing something. This person thought the note, which was dated Oct. 6, Sunday, had been written at home on Sunday, but that Steven had added the last line beside the tracks on Monday morning.

It read: The red eyes and sniffles you saw last night were really my tears.

Steven spent Sunday at home, after declining an invitation to go to the 49ers game because, he told the friend who invited him, he needed to be with his family.

Like most adolescents, Steven hid some things from his parents. One of the things he hid was his struggle with math. In his last year of middle school, he showed his friend Danya a warning notice for math that he said he had snatched off his mom's desk before she saw it. At Paly, he talked his way into the most difficult freshman math course in a school full of math whiz kids. He was not doing well.

His math teacher sent a progress report to his parents informing them that Steven was getting a C-minus. It was a standard procedure, every teacher at Paly sent out such heads-up letters at that point in the school term. The C- minus may have had something to do with an outing Steven and his father took Sunday to buy him a new calculator. The notice would have arrived at the family's modest wood-frame ranch house on Thursday or Friday.

The math teacher has felt guilty ever since. "It couldn't have been he was getting a C in math," she said during a lengthy interview. "It couldn't be that."

Much more importantly, Steven hid from his friends and family whatever was happening in his mind and his heart. "He just masterminded it so well he left behind no clues," says his buddy Alex, the boy with whom Steven had discussed the best way to die. "I wish he had been able to confide some of his pain, because obviously he was suffering a lot of it."

If teachers and friends are still struggling months later with what they might have done differently, sifting through their memories for clues they missed, staving off guilt, what his parents are enduring is simply heartbreaking.

Police Capt. Torin Fischer was one of the people who had to tell the Wertheimers what had happened on the morning of Oct. 7.

"I'll never forget that, until the day I die," he said. "The look on their faces. Shock. Disbelief. Bewilderment. You know, as a person there's a terrible sense of wanting to help. And knowing at that moment there's not a damn thing you can do.

"We knew the hurt no, I don't want to say that," Fischer corrected himself. "We understood the hurt, because we'd never walked down that road. I felt like the morning lasted forever. Of course, for the parents, it will last forever."

Steven's suicide is an illustration of how hard it is to know what if any role

Accutane played in the scores of suicides and suicide attempts to which the drug has been linked. All people, all families, have their secrets, secrets which outsiders will never know.

For some, Steven's suicide note speaks for itself. When informed of the note's content, the Paly social worker Siegel said: "It's normal for an adolescent to not perceive an external event in the same way a more mature person might. É So when I look at an adolescent who attempts suicide, and might say what you surmised was in the suicide note, what reason would you have not to believe it? Say that before someone takes their life he says his life is not going in the direction he wants it to go. Why not believe it?"

For others who read the note, though, the reasons why Steven Wertheimer killed himself remain a mystery. So do the means, which suggest a desire for certainty and finality.

When an apparently happy and talented youngster takes his own life without warning, and that youngster has finished a five-month course of the only prescription drug in America with a suicide warning attached, for some people, the explanation lies not in the soul alone but in psychopharmacology.

Rep. Stupak says he acquired an internal FDA memo in which 12 suicides linked to Accutane were detailed. The median age of the deceased was 17, and "for the majority there was no antecedent history of depression, and the patients were not noted or known to be depressed in the time period prior to their suicide."

"There was no depression," says Susan Turney, whose son, Matt, did not leave a note, and was not one of the teens in that FDA memo. "There was no warning. There was nothing for us to look for. There was no reason for his death, other than Accutane." .

Studying Suicide

The problem Accutane poses for FDA regulators is about as recalcitrant as it gets.

"I'm not going to stand here and trivialize the suffering that severe acne causes," the medical reviewer for Accutane at the FDA told the September 2000 Accutane summit. "We are aware of no adequate evidence that acne, even severe

acne, causes the diagnosis of severe or serious depression.

"But if, in fact, acne contributes to it, or can cause it, then the last thing you would want to do, if there's no causal association with Accutane, is stop a drug that can, in many patients, cure the acne," said Dr. Kathryn O'Connell. "On the other hand, if Accutane does belong on the list of many drugs that have been implicated in causing psychiatric disease, then not stopping the drug could have very morbid or even fatal consequences.

"So, we think it is important, in this case especially important, to try to resolve the uncertainty." Some 2 1/2 years later the question remains: How?

Nobody has so far figured out a way through the thicket of scientific and ethical problems to design, let alone implement, a rigorous study that may result in a sure answer.

So many teenagers kill themselves, how do you determine afterward what role Accutane might have played in the deaths of kids such as Steven Wertheimer and Matt Turney? And of course pimples alone can get a kid down.

One method might be a retrospective epidemiological study. This has been tried, but the methodology did not satisfy other epidemiologists. A psychiatrist and suicidologist whose research was funded by Roche, Dr. Douglas Jacobs, told the 2000 conference that he had concluded that the number of reported suicides that might be associated with Accutane was overall about one- ninth the number you'd expect among 15- to 19-year-olds.

Short of performing complete psychiatric autopsies on every teenager who kills himself, there seems to be no way this method alone will work.

Perhaps then biological research on the effect of isotretinoin would help? Here, too, there are problems, not the least of which is that Roche says the precise mechanism by which Accutane works is not known.

"Roche has stated publicly for the past 17 years in every country," says Liam Grant, of the Ireland-based Roaccutane Action Group, " ÔWe do not know the mechanism by which this drug works. Therefore, there is no proof. We know it causes side effects. But why? Well, that's not our problem.' "

It is, however, a fact that retinoids such as Accutane do interact with the central nervous system, and there are retinoid receptors in the adult brain. Therefore, it is biologically plausible, a scientific term of art, that Accutane affects neuropsychiatric functioning.

The FDA has been working with the National Center for Toxicologic Research on designing animal studies that might show if isotretinoin changes brain function. The National Institutes of Mental Health has said it might fund some further basic research into the effects of retinoids on the central nervous system.

Lastly, there seems to be no way to conduct a large, random, controlled trial, the usual type that determines causality. Janet Woodcock, the FDA's director of drug evaluation, laid out the problems when she testified in December at a hearing held by a House committee on Accutane safety.

The drug, she pointed out, is already on the market. Why should anybody with terrible acne agree to take a placebo?

In addition, Accutane causes a drying out of the skin, mouth, eyes and nose that is easily recognizable. How then could you do a blind study in which participants do not know whether they are getting Accutane or a placebo?

Lastly, Woodcock said, "We cannot do a study where suicide is the end point; the less objective but related psychiatric end point, depression, is a problem because patients

already know this drug works. Thus, there would be a large incentive to hide psychiatric symptoms to avoid being discontinued from the study."

The FDA does not fund studies; that is the manufacturer's responsibility. At present, Roche is not sponsoring any research.

"We've spent the better part of 2 1/2 years trying to figure out how to conduct such a study, and it has baffled the best scientific minds at both the FDA and Roche," says Roche's Glynn. "We are committed to finding out if there is any possible link, but we haven't figured out how to do that."

However, Woodcock believes that somewhere down the line scientists will be able to determine whether Accutane causes psychiatric side effects. "We should be able to learn if Accutane is associated with disturbances of mood," she said in an interview. "But with suicide, that's different. That is something we probably will not be able to prove." In fact, no medication has ever been proved to cause suicide. Moreover, the high percentage of suicides committed while on the drug spurred great concerns with scientists in Canada (Accutane lawsuit there on average states one of the above mentioned psychiatric adverse reactions). Canada, alike the US, is one of the countries that suffered hugely from the controversial acne treatment.

So for the foreseeable future, when it comes to deciding whether the benefits outweigh the risks, families will continue to be on their own. Woodcock herself says that if one of her children had severe cystic acne for which no other medication worked, "certainly I'd let one of my children take Accutane, but I'd keep a close eye on them."

But Affinito, a lawyer for the Turneys, doesn't know what good keeping a close eye on a kid really does. "What good is it," he asks, "if there are no signs or symptoms of what is about to happen? Who knows what was going on in the Turney kid's mind? It was a spontaneous suicide without any symptoms whatsoever."

Was Steven's doom sealed because of a chemical reaction caused by a devastatingly potent drug, or a devastatingly potent emotion? We will never know for certain, and such uncertainty, especially where our children are concerned, makes us uneasy.

On the other hand, there are some things of which we can be certain. As sure as adolescents get pimples, some teenagers will kill themselves while taking, or soon after taking, the drug. The families will grieve, and Roche will continue to sell hundreds of millions of dollars' worth of Accutane.

Accutane Goes Global

In addition to the fears that Accutane may cause depression and suicide, and its awful consequences for some pregnant women and their fetuses, many other side effects have been linked to Accutane use. Included are acute pancreatitis (in rare instances leading to bleeding to death); elevated triglycerides; impaired hearing; hepatitis; inflammatory bowel disease; painful bone diseases; night blindness; and allergic reactions including hives and breathing difficulty.

Now two new dangers have recently emerged in relation to the potent acne drug isotretinoin.

Last February, the patent belonging to Hoffman-La Roche, which markets the drug in the United States as Accutane, expired. The FDA has granted permission to Mylan Labortories Inc., of Pittsburgh, to begin marketing a generic version that is called Amnesteem.

Meanwhile, Ranbaxy Laboratories Ltd. of India is also hoping to launch a generic version in the U.S. market.

Though both pharmaceutical companies are subject to all the same cautions and restrictions facing Roche, isotretinoin availability is increasing worldwide, and thanks to the generics, its cost is decreasing.

More worrisome by far than the generics are Internet sales of Accutane from foreign countries, most notably Mexico. "Accutane pours into this country from Mexico, where it can be purchased over the counter without a prescription," says Michigan Democratic Congressman Bart Stupak, whose 17-year-old son, BJ, committed suicide, a death Stupak blames on Accutane. "We found Accutane is being offered on the Internet at approximately 40 Web sites."

Just last month March, some Web pharmacies began selling Amnesteen as well.

The FDA recently called internet sales of isotretinoin "a significant public health risk," and asked the Customs Service to confiscate any of the medication it finds entering the country. The foreign-made versions being offered through Web sites, the FDA said, are "generally an unapproved version, " not held to the same rigorous tests for purity and safety required of FDA-approved medications.


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