Lambasting the Times for a Naive Front Page Article

Here is a letter I wrote to Gardiner Harris in response to a disappointing article that appeared on the front page of the New York Times:

I was not able to respond to your article on the effectiveness of antidepressants in adolescents in a timely manner because I was attending my surviving daughter’s graduation at Princeton. I also wanted to do further research on the Emslie-March study, which I have now completed.

The exuberant tone of your article surprised me given the caution you have demonstrated in previous coverage of this issue. Why do you say “Antidepressants seen as effective” in your headline when only one – Prozac -- is being studied in the trial? You label the study a “landmark” event in the debate and state that Prozac is “far” better than talk therapy. How carefully did you really examine the design and the premature conclusions of this study before rushing to judgment and putting this on the front page of the paper? Why do you use the past tense when you say the study “was” the first to compare psychotherapy and drug treatment? It is still going on and will not be finished until 2006. There is a long way to go before asserting that Prozac is better than Cognitive Behavioral Therapy (CBT). Only the short term comparison has been completed and it is quite possible that the 12 week window is exactly the point at which antidepressant treatment may be at its most beneficial after the short term adverse effects are over and before the long term ones set in; it also may be too soon to measure the full benefit of CBT. Let’s remember that another study was published recently which showed that relapse in the year following treatment is higher in those on antidepressant medication than it is in those who had talk therapy.

Yes, the study is government rather than industry financed but that still does not mean it is being conducted objectively. Graham Emslie and John March both have extensive ties to the pharmaceutical industry as consultants. Graham Emslie, in particular, was responsible for the principle trial that purported to demonstrate Prozac’s effectiveness in adolescents and thus allowed it to be approved for use in children by the FDA. His reputation might be at stake if effectiveness is disproved now, hardly making him an independent researcher in this new study. His initial trial took place in 1997, involving 96 patients, half of which were on placebo and half on Prozac, and only lasted 8 weeks. 36 (37.5%) patients dropped out before the study was completed – 19 (39.6%) of those on placebo and 7 (14.6%) on Prozac. Except for one patient complaining of side effects, all those on placebo dropped out because of “non response”; on Prozac, however, only 3 dropped out for non response. 3 others (6.3% of the total on Prozac) dropped out because of the onset of manic symptoms and 1 for a severe rash. Despite this alarming development (3 out of 48 becoming manic) the drug was still approved for use in adolescents because of its reputed effectiveness in the rest of the group, yet at the conclusion of the study only 15 of the original 48 on Prozac actually had “minimal” symptoms of depression compared to 11 of the placebo group. The rest felt better but still met the criteria for a diagnosis of major depression. (Archives of General Psychiatry. 1997;54:1031-1037). This is the trial that allowed Prozac to go on to be prescribed “legitimately” to millions of children. Would you let your child take Prozac after understanding the details of how the numbers are used so selectively? The approval process depends on percentages, but the specific line data seems to tell a different story than the authors have really portrayed. Sadly, this is often the case in clinical trial reporting.

You do acknowledge that even if overall benefit is demonstrated there still may be a subgroup that is vulnerable and this is a step forward. Acknowledgement of a group that gets worse is long overdue. The question of how much worse needs to be addressed. Why is it not a shocking revelation that 5 adolescents attempted suicide on Prozac and only 1 on placebo? (And yet every effort was made to exclude anyone with a previous history of suicidality from participation.) At least you report this finding but seem to brush over it as nothing particularly important. You even quote John March as saying “The take-home message is that these adverse events are extremely rare.” Probably less than 200 adolescents were taking Prozac. At least 2.5% of those tried to commit suicide. I don’t call this “extremely rare” given the seriousness of what we’re talking about. Why did 61 out of 439 (that’s 1 out of 7 or 13%) drop out? How many of those dropped out because of adverse reactions to Prozac and exactly what were the adverse reactions? Exactly what does “non response” to Prozac consist of? And in practice these drugs are consistently being given to patients with a history of suicidality. What would happen to the number of suicide attempts if such patients were included in the trial?

As a reporter covering this important issue I wish you were asking these critical questions. Many medical professionals are bemoaning the controversy surrounding antidepressants and reiterating the threat of suicide in untreated depression. As a “suicide survivor” I want to remind everyone that the risk of suicide in antidepressant treated depression may actually be higher than in untreated depression. No one knows for sure. It is shameful that statistics comparing the number of suicides in treated and untreated patients are not readily available, but at the moment no one is tracking the number of completed suicides which occur in those on antidepressants or investigating them in detail.

It was fortuitous that Eliot Spitzer filed his suit on the very day you reported the preliminary Prozac trial results announced in Phoenix. It provided a much needed antidote to your exuberance. I hope that the next time there is a laudatory announcement about antidepressants you will approach it with the critical eye it deserves.

Here's the article

June 2, 2004

ANTIDEPRESSANTS SEEN AS EFFECTIVE FOR ADOLESCENTS
By GARDINER HARRIS

In the midst of a worldwide debate on whether depressed children should be treated with antidepressant drugs like Prozac, a landmark government-financed study has found that Prozac helps teenagers overcome depression far better than talk therapy. But a combination of the two treatments, the study found, produced the best result.

The study, sponsored by the National Institute of Mental Health, was the first to compare psychotherapy and drug treatment for depressed adolescents. Statistically, the researchers found, talk therapy -- in which a patient discusses problems with a therapist -- was by itself no more effective in reducing the depression than treatment with placebos. But when combined with drug treatment, psychotherapy appeared to provide added benefit and to reduce the risk of suicide.

The findings are likely to reassure psychiatrists, pediatricians and others who increasingly prescribe antidepressants to teenagers and children. Millions of young people take the drugs.

Experts said that the study was notable for its size and for the fact that it was carried out without financing by drug manufacturers. Data on the effects of antidepressants in adolescents is in short supply. Most studies of the question have been small trials sponsored by pharmaceutical companies and have failed to show that the drugs are effective for depressed teenagers.

''This study should put to rest doubts about whether these drugs work in teenagers with severe depression,'' said Dr. Graham Emslie, a professor of psychiatry at the University of Texas Southwestern Medical Center and an author of the study, which was presented here on Tuesday at a meeting of psychiatric drug researchers.

Still, the findings are unlikely to resolve the controversy over whether Prozac and similar drugs lead a small number of teenagers and children to become suicidal.

Such concerns led the Food and Drug Administration to warn earlier this year that patients taking the drugs should be watched closely for signs of suicide or other harmful behavior in the first weeks of therapy. The agency is reanalyzing suicidal events that occurred during drug-company trials of antidepressants in children and teenagers. British drug regulators have banned the use of all but Prozac in those younger than 18.

The government study, called the Treatment for Adolescents with Depression Study, involved 439 youths ages 12 to 17 who were suffering from moderate to severe depression.

The adolescents were randomly assigned to be treated for a period of 36 weeks with either Prozac, the antidepressant drug made by Eli Lilly & Company; a form of talk therapy known as cognitive behavioral therapy; placebo pills; or a combination of Prozac and talk therapy.

The researchers collected data on the subjects for a year, but have only analyzed information from the first 12 weeks so far. Of the youths recruited for the study, 378 completed the first 12 weeks of treatment. Their mean age was 15. Depression levels were measured using several common psychological scales.

Using one measurement scale, the researchers found that after 12 weeks, 71 percent of the subjects who received Prozac and talk therapy responded well to treatment, compared with 61 percent of those who received Prozac alone, 43 percent of who received talk therapy alone and 35 percent of those who received a placebo treatment. By another measure, talk therapy alone fared no better than treatment with placebos.

The researchers also found that patients became significantly less suicidal, no matter which treatment they were given. No patient committed suicide during the trial. But the risk of a suicide attempt among the patients given Prozac was twice that of those who were not, the study found. There were five suicide attempts among those given Prozac and just one among other patients.

Dr. John March, a professor of psychiatry at Duke University and the study's lead investigator, said that the findings showed Prozac's benefits for depressed teenagers and children far outweighed its risks. ''The take-home message is that these adverse events are extremely rare,'' Dr. March said.

He acknowledged, however, that the controversy about suicide and antidepressant therapy was far from resolved. ''We're all holding our breath to see what the F.D.A. is going to do,'' Dr. March said.

Psychologists, who are often the providers of talk therapy and who cannot prescribe drugs, are likely to be disappointed in the finding that cognitive behavioral therapy was found to be little better than a sugar pill. A recent major trial comparing drugs with talk therapy in children with attention-deficit disorder also showed that the drugs worked better.

But the findings of another study presented on Tuesday suggest that for some conditions, talk therapy may be more effective than antidepressants. That study compared cognitive behavioral therapy with Zoloft, an antidepressant made by Pfizer that is similar to Prozac, in teenagers who suffered from obsessive compulsive disorder. Those who received the talk therapy, the study found, improved more than those who were treated with the drug.

Dr. Thomas Insel, director of the National Institute of Mental Health, said he was pleased the results of the depression study were so clear. The institute spent $17 million over six years financing the trial. ''The most striking thing about the study is that, in all groups, there was a dramatic decrease in the amount of suicidal thinking,'' he said, suggesting that all the therapies were protective.

Dr. David Brent, a professor of psychiatry at the University of Pittsburgh not involved with the study, suggested that another form of talk therapy called interpersonal therapy might have fared better than cognitive behavioral therapy.

In interpersonal therapy, clinicians focus on a patient's relationships with peers and family members and the way they see themselves. In cognitive behavioral therapy, clinicians teach patients to try to think more positively and do things that make them happy.

Dr. Brent said it was good news that drugs produced better results than talk therapy ''because it's hard to get people into cognitive therapy anymore. They just don't want to take the time.''

The researchers said they planned to publish the preliminary results of the study this summer, with further analyses later.

Dr. Insel said that the most useful information from the study is yet to come. ''We need to know which treatments work best for what kinds of kids and who may be the most vulnerable to the side effects,'' he said. Those sorts of answers would come from more data analysis, he said.

''We're going to get a lot out of this study that the public really needs to know right now,'' Dr. Insel said.

Clinical Trial Machinations

Drug Makers Seek to Bar 'Placebo Responders' From Trials
June 18, 2004, The Wall Street Journal, 1068 words
They are the people who ruin clinical trials for drug companies: placebo responders, who get better on sugar pills. Drug makers want to get rid of them, especially in trials of depression drugs, ...

My response to the writer of this article on trying to rule out "placebo responders" from clinical trials:

I am the mother of a wonderful young woman who died from a Paxil induced suicide. I have been working for greater drug awareness since the day she died. I testified at the FDA hearing in February. In my hearing statement I said I was "shocked by what I had learned about the clinical trial process." This latest maneuver to bar placebo responders comes as no surprise. Once again the drug companies demonstrate that their primary motive is getting the drug approved, not understanding what really makes a depressed person improve or how these medications really work. Focusing on "placebo responders" at great expense seems ironic to me too. The clinical trials already exclude a large group of people who are routinely prescribed these drugs; these are patients with a history of suicidal behavior and/or psychosis. Money should be spent on studying them, not people who are getting better spontaneously. Antidepressants have never really been studied in this group as every effort is made to exclude them from clinical trials. I think this is terribly wrong given that SSRI use is encouraged in this group of patients by the drug companies. If placebo responders are excluded then I certainly hope this other group will be included so we can see what really happens to suicide attempts and completed suicides when this group is put on antidepressants. It is shameful that statistics comparing the number of suicides in treated and untreated patients are not readily available, but at the moment no one is tracking the number of completed suicides which occur in those on antidepressants or investigating them in detail. Instead medical professionals are bemoaning the controversy surrounding antidepressants and reiterating the threat of suicide in untreated depression. In fact the risk of suicide may actually be greater in antidepressant treated depression than it is in untreated depression. No one really knows for sure.

More on Columbine

This is a letter I wrote in response to David Brooks op-ed column attributing the Columbine tragedy to Eric Harris's psychopathic behavior but not linking this, as it should have been, to misguided and inappropriate treatment with antidepressants:

I think David Brooks still has it “wrong” about Columbine. Apparently the FBI and some psychiatric experts have labeled Eric Harris a “psychopath”; what they fail to acknowledge is that Eric was on an antidepressant for over a year before the shootings and that many of the symptoms they describe – grandiose thinking, emotional blunting, violent ideation about death -- are adverse effects of antidepressants that are finally getting some of the attention they deserve with the new FDA advisory. No one should blithely dismiss the possibility that Eric was reacting adversely to antidepressants. The stage is being set for another incident in schools all over America with the mindless and unsupervised drugging of troubled adolescents.

Eric was on Luvox for a year before the shootings; three months before, his dose was doubled, often a precursor to intensified problems, as the advisory states. Before Luvox he was on another antidepressant Zoloft and told his doctor he was having trouble with his medication. He was unable to concentrate and felt restless. Luvox was linked to another rampage shooting/suicide in Connecticut. It has been withdrawn from the market. Eric’s reaction is extreme but, if he was manic, or potentially so, before his treatment commenced, the medication could have exacerbated his condition and triggered the onset of psychosis. In 2001 Dr. Adrian Preda found that over 8% of psychatric admissions to hospital were caused by antidepressant induced mania and psychosis. It is long overdue that this possibility be treated with the seriousness it deserves. Lives in schools all over America are at stake if this danger is not addressed.

EDITORIAL DESK | April 24, 2004, Saturday

The Columbine Killers

By DAVID BROOKS (NYT) Op-Ed 793 words
Late Edition - Final , Section A , Page 17 , Column 6

ABSTRACT - David Brooks Op-Ed column, noting that Eric Harris and Dylan Klebold shot up Columbine High School five years ago, holds that it is now clear that much of what was believed about massacre was wrong; cites Dave Cullen article in Slate magazine revealing conclusions of lead FBI investigator Dwayne Fuselier and others who studied Columbine shootings; holds that killers were not outcasts; maintains that Klebold was troubled kid who could have been saved, but holds that Harris was icy killer.

And here is a patient testimonial I found on the web of a grown woman having an adverse reaction to Luvox, the drug Eric Harris was on. If a grown woman can react this way it certainly is not unlikely a teen-age boy might be even more at risk.

What does bipolar disorder feel like (after a few doses of an antidepressant) ?
A Patient's Testimonial

(used by permission, thank you Ms. B.  This is a very high-functioning, fully employed woman and mother with a high-expectation job.  I've highlighted some particularly telling comments in bold type -- JP).  
I was diagnosed with OCD by several physicians.  The last one I saw prescribed Luvox.  Because I knew about the cautions for BPII's against taking anti-depressants, I did not fill the prescription.  Several months later the OCD seemed to be overwhelming me, my attempts to manage it on my own were now no longer successful.  I went to my PCP and asked for a new prescription of Luvox.  Because he, too, knew of the drug precautions, he gave me a very, very low dosage (25mg/day).  I took it that night before I went to bed.  When I woke up in the morning I felt crazy - literally.  I was convinced I was in someone else's body - both physically and mentally.  I seemed to have lost the ability to think clearly.  I became extremely volatile (since I already have an issue with irritability due to the BPII, this was a nightmare).  I had never before thought of hurting myself, but now I was convinced it would "make everything better".  The only sensible thing I was able to do was make the decision to go to work.  

I wanted to crawl under my bed... or run in front of a truck... I couldn't decide what I wanted to do, the thoughts were too fast.  I decided I had to go to work because I new that if I stayed home I would harm myself physically.  I went to work and ate and drank a lot, and did tons of exercise... trying to somehow get this drug out of my body.  The feeling was gone by the next morning.  But the effects wore on.  I was never the same from that point on.  I was constantly cycling higher and higher.....

 


[here's an email she read to me later because she wanted to make sure I understood -- JP]:

 
 


my whole "hate-fest" is getting worse all the time.  But it isn't just hate, it's also a complete lack of caring.  I can't seem to get out of it.  It lasts longer and longer.  and, unfortunately, this feeling of hate and indifference makes me completely uninterested in trying to fix it.  I hate my life - what it is, what it isn't, and what it is, or isn't, becoming.  I hate marriage, feel no interest in having one.  I hate being around people, wish I could just be completely alone.  The feelings of hurting myself are starting to come more frequently now - but I haven't so far.  I never had them until a few months ago.  That feeling I had that day when I took the Luvox - I feel like I'm stepping into that realm, like it's a big ocean and I'm slowly walking into it... getting my feet wet, then my ankles...etc... I've never felt like I wanted to die before - sometimes only because of my kids - but nonetheless, I wouldn't ever do it.  I don't feel anymore like there is any convincing reason why I shouldn't.  Why is this happening?  I take my meds like I should.  I don't feel like this is a "go see a therapist" kind of thing - but then again - how would I know.  I feel like my grasp on reality is slipping (at least I can still recognize THAT... I think...) but I'm starting not to care what is reality and what isn't.  Jeckle and Hyde are starting to mix.  I'm not hungry anymore and don't care about my appearance.  I don't care if I come to work, I don't care if we go in the poorhouse.  I constantly have this "hot" feeling inside - like you might if you were TOTALLY nervous about something that was SUPER-important.  Like you can't breathe or sleep or eat.  Like you could cry at any minute - like you already ARE crying,all the time, at some level of your being.  I feel like I'd rather be locked up in an asylum so that I didn't have to make an effort anymore.  I just don't feel like trying.  The reasons I tried before are starting to get fuzzy.  [Husband] keeps asking if I'm mad at him, or if something is wrong.  I don't know how you express to someone that you are "NOTHING".  How do you say "I am a complete lack of anything".  It doesn't make sense to anyone and I don't feel like explaining it anyway - back to that whole "indifference" thing...  Not sure what to do, I've lost the energy to figure it out, to fight and struggle to come back.  What is wrong with me???????? 

School Shooting Debate

I have corresponded with Katherine S. Newman a number of times and she is close-minded about any link between school shootings and the psychiatric drugging of adolescent boys. She wrote this column on the occasion of the fifth anniversary of Columbine. This was my response:

Five years have passed since the Columbine shooting. Only five weeks have passed since the FDA’s advisory on antidepressants. Almost no one is making any connection between these two. This is a tragedy. The possibility is high that the increase in school violence over the past decade is linked to the escalating and misguided use of psychotropic drugs for every psychosocial ill a young child or adolescent can feel. The social forces contributing to the making of a school shooter are real and adults working with students should be vigilant for signals from misfits. But when medical professionals rush to treat disaffected behavior with pills even more vigilance is required. Too often it is adding gasoline to smoldering embers with tragic consequences.

Eric Harris was on Luvox for a year before the Columbine shooting. Before that he was on Zoloft and told his doctor that it made him agitated and unable to concentrate. If he was manic or potentially so, antidepressants could have exacerbated his symptoms and triggered new ones, including psychosis. No one even knows if Dylan Klebold, the other shooter, was on medication. He was in the same anger management class as Eric. Coroners are rarely asked to look for blood levels of prescription drugs and gag orders are placed on the medical records of school shooters. This conceals valuable evidence for public health and safety. Every school shooter should be investigated for the presence of antidepressants and the warning that these drugs increase suicidal -- and homicidal -- impulses should to be taken seriously.

Local Paper Dismisses Dangers of Antidepressants

Here is a letter I wrote in response to a simplistic article published in the local paper followed by the full text of the article.

I think you have painted a very one-sided view of the benefits of antidepressants. I wish you had found a few young people willing to talk about their greatly increased agitation and suicidal ideation on the drugs. I know they are out there. Since I testified at the FDA hearing on February 2nd about my own daughter's death two and a half weeks after starting Paxil, I have fielded numerous calls from frantic parents about their children's behavior on antidepressants. I can tell you that my daughter had never been suicidal; from her autopsy we learned that her blood level of Paxil was skyhigh. She had not been metabolizing it. Furthermore she was prescribed the pills by a psychiatrist and seen on the last day of her life and the doctor had no idea what she was witnessing. No one dreamed my daughter was suicidal. This is not simply a case of non-specialists making mistakes; doctors simply are not being told all the facts by the pharmaceutical reps upon whom they rely for their information. She had drug-induced akathisia and should have been prescribed a sedative immediately. It would have saved her life.

In my advocacy work I have heard scores of similar stories of young people with no prior history of serious illness or suicidality committing suicide within one month of starting the drug or after having a dose changed abruptly. 65 families testified at the hearing and the stories were highly repetitive. I know this is only the tip of the iceberg as far as people who have been harmed. These drugs are more dangerous than is generally recognized and, furthermore, create a chemical dependency which has never been properly studied. If the truth is frightening then so be it. It is still the truth. How you can suggest in good conscience that it is best for doctors and patients to enter into a treatment with possibly life threatening consequences with blinders on? It is imperative that everyone understand the risks in full and be on the lookout for them and also commence with the smallest possible dose that might be effective. I am certain my daughter would be alive today if her doctor and I had understood in full the potential adverse effects. Be assured that the FDA is basing their advisory, not just on the testimonies of people like myself, but also on clinical trial evidence that has been kept under wraps for years.

I have been studying the trends in suicide rates as well and have never seen a 33% decline in youth suicide across 15 countries reported anywhere. In this country there has been a slight decrease in suicides among 15-19 year olds and a 20% increase in suicides among 10-14 year olds. Antidepressant usage has increased by a factor of 6 in both groups. Far more telling than the vague conclusions which can be drawn from epidemiological studies in which evidence is far from conclusive are the analysis of antidepressant clinical trials. In these trials it has been shown repeatedly that suicidal acts increase in antidepressant treated patients over those on placebo, while symptom improvement is only marginally better than placebo. Furthermore there have been challenge, dechallenge, rechallenge trials run in which suicidal symptoms (even in healthy volunteers) exhibit with the onset of treatment, disappear with cessation, and recur with re-initiation of treatment.

This whole issue is far more complex than what you have portrayed. Please remember to respect those who have suffered terribly with these drugs. They are far more numerous than you imply.

In addition I wrote the following more general paper about the FDA advisory that I also sent to the paper in response to this article:

Many patients, doctors and journalists have been quick to dismiss the FDA advisory as lacking in credibility. This is unfortunate. Few people are aware that the controversy over antidepressants and suicidality has been raging for at least 15 years. It has taken enormous effort by a dedicated group of professionals as well as suicide survivors to get to this point and convince very reluctant regulatory agencies on both sides of the Atlantic of the need for warnings. Assumptions about the safety and benefit of antidepressants are widespread. Those who feel they benefit undoubtedly do feel frustration and discomfort at the notion their vision of safety may be misplaced. But to say it’s “awful” that there is a huge scare fails to acknowledge the suffering of those who believe their loved ones died through adverse reactions to these drugs.

The first FDA hearing on the subject occurred as long ago as 1991. This followed many adverse reports as well as a milestone article by two Harvard doctors in 1990 alerting the public and doctors to the potential for Prozac induced suicide. The panel looking into Prozac’s safety exonerated the drug but it was hardly as unanimous as the manufacturer Eli Lilly proclaimed. A research study was proposed but never undertaken. Lawsuits were filed against Eli Lilly and documents had to be handed over revealing the company’s awareness of the issue even before approval and their effort to control it. In Germany, Lilly was required by the regulatory agency to include in their package insert a warning for the possible need for a concomitant sedative in the initial weeks of treatment. This was not on the label in the U.S.

Many other antidepressants came on the market in the next ten years and sales skyrocketed. Paxil, in the same class as Prozac, has a shorter half life, comes out of the system more quickly, and causes more problems in withdrawal or with missed doses. It became the number one selling antidepressant in Britain and awareness of problems with withdrawal became widespread prompting an investigation by BBC reporters. After a documentary was aired on national television the BBC received an unprecedented response from over 65,000 people. Included in the many responses were stories of at least two dozen suicides linked to Paxil. This led to another documentary on the suicide issue. Pressure mounted on the regulatory authority in Britain to do further investigation and when they did, they found a number of clinical trials which had never been published showing “inconvenient” results about both the risk and benefit of the drug. Last year the MHRA (the British equivalent of the FDA) issued a ban on all antidepressants except Prozac for use in children. Shortly afterward Eli Lilly changed their doctor’s fact sheet in the U.K. to state that Prozac was not recommended for use in children. They have not made this change in the U.S.

This is some of the background to the February hearing and recent advisory. The evidence from trials which have not been published is dramatic. Two major articles are being published this month, one in the British Medical Journal and one in Lancet, attesting to a lower benefit and higher risk demonstrated in several unpublished trials. Many people do not understand that clinical trials for drug approval are designed, financed and analyzed by the companies seeking approval. Only trials that help with approval are usually published. This does not make for a very objective process. The FDA simply does not have the means at its disposal to keep rigorous control especially in the field of psychiatry where symptom diagnosis and improvement are subjective. Most antidepressant trials only run for 8-10 weeks and no follow-up on long-term use has ever been done. Yet patients are being put on these drugs and left on them for years. Furthermore no study of suicidal effects has been undertaken. In general every effort is made to rule out suicidal patients in clinical trials. No objective way of measuring degrees of suicidality has ever been defined. Despite this, suicidal acts have still been shown to increase in patients taking antidepressants over those on placebo when they are compared in clinical trials.

The FDA has not issued the advisory lightly on the basis of a cursory reading of misrepresented data or on claims of bereaved and, some would say, misguided families. To say this is dangerous and naïve. While it is true that no child has committed suicide out of the 1700 in the few trials that are under immediate review of the FDA now, in a much wider review by Dr. Arif Khan that covered over 71,000 adult trial participants the number of suicides on antidepressants was substantial and higher than in untreated patients. The FDA panel is aware of evidence like this. Over 60 families testified at the hearing on February 2nd and the stories were chilling as well as highly repetitive. The people who are dying are not ones, in most cases, who were given the drug for major depression or people who had ever expressed suicidal thoughts. This was a refrain heard over and over again. The drugs were prescribed for insomnia, racing thoughts, anxiety, social adjustment problems, anger management, often "minor" psychosocial ills. These were not people anyone was expecting to commit suicide, not people who needed to be watched for suicidality. This is a very important point.

This phenomenon is not about the underlying disease or some pre-existing condition, but about what the drugs do to the brain (especially if someone can't metabolize it, is given too large a dose, or withdraws too quickly). These suicides are not ones committed out of a sense of hopelessness and despair as we so often assume suicides are. They are impulsive, violent, and out of character. People who have survived suicide attempts on the drugs describe an out of body, intensely dissociative state. No one should underestimate the ability of these drugs to do this. Even if there is only one in a hundred or one in a thousand chance that the drug would do this to any one individual, it is such a catastrophic effect that everyone needs to be aware of the possibility, especially when benefits have been exaggerated.

An epidemiological decrease in suicides has been noted in the last ten to fifteen years since antidepressants have been on the market. In fact this has been extremely slight overall and not consistent across age groups most affected by antidepressant usage. An article published last year in World Biological Psychiatry (4: 184-190) is entitled “A Stubborn Behavior: the Failure of Antidepressants to Reduce Suicide Rates.” There was a dramatic increase in the suicide rate between the 1950’s and 1980’s from a much lower rate that had preceded it for decades. The very slight decrease which has occurred in the last years of the ‘90’s could be attributed to other causes and still has not brought us back to where we were before the great increase of the past two generations (which -- perhaps randomly -- happens to coincide with the introduction of older classes of psychotropic drugs). To call epidemiological evidence proof of “overwhelming” benefit is poor science and poor logic.

According to Kay Redfield Jamison, an expert in mental illness, at least 40% of the people who commit suicide have in fact been treated with psychiatric drugs or perhaps “mistreated” is more accurate. The failure of government authorities to collect data on suicides and suicide attempts is hindering a resolution of this issue. Coroners and emergency rooms should be investigating every suicide and suicide attempt for a link to psychiatric drugs. There should be a thorough documentation of the treatment history and analysis of the blood levels of prescription medications should be as routine as it is for illegal drugs and alcohol. This information should be in the public domain. It could be preserved anonymously to protect privacy but it should be collected. Public health and safety are at stake.

How many people are aware that many school shooters in the past decade were on antidepressant medication? Eric Harris, the Columbine shooter, was one. He had been on Luvox, now withdrawn from the market, for a year. Three months before the shooting his dose was doubled. Before Luvox, he was on Zoloft and he told his doctor he was having trouble with it. He was unable to concentrate and felt restless. This information about Eric would have been lost from public view forever if a Harris neighbor had not been aware that Eric’s application to the Marines was rejected because of his treatment with an antidepressant. It took a special request to get the coroner to test his blood level for the presence of the drug. Dylan Klebold, the other shooter, had a clean toxicology report, but it is quite possible that he was never tested for the presence of an antidepressant. He was in the same anger management class as Eric and antidepressants were standard treatment for this problem.

Antidepressants are acknowledged to induce mania and psychosis and yet this seems to be widely overlooked by doctors and the general public. In 2001 the Journal of Clinical Psychiatry (62:1, 30-33) published an article indicating that over 8% of psychiatric admissions to hospital were due to antidepressant induced mania or psychosis. This is a significant number. The danger to anyone who might be vulnerable to mania is substantial and this might include young minds with greater “plasticity.”

To imply that these drugs are correcting a “chemical imbalance” is one of the greatest hoaxes ever to be perpetrated on an unsuspecting public and medical community by the pharmaceutical industry. Some physicians are aware this is a dumbed down representation of depression, but they seem to be in a minority. Steven Hyman, director of the National Institute of Mental Health, wrote in 1996, “Chronic administration of psychotropic drugs [i.e. drugs with psychological effects] creates perturbations [imbalances] in neurotransmitter function that likely exceed the strength and time course of almost any natural stimulus.” This “hyperstimulation” triggers “compensatory” reactions in the brain in its efforts to achieve “a new adapted state which may be qualitatively as well as quantitatively different from a normal state.” To think that a drug can isolate its effect to one neurotransmitter greatly underestimates the complexity of the brain and mistakes the role of serotonin as a modulator for the primary neurotransmitters, glutamate and GABA. No one neurotransmitter works in isolation from the others. They are all linked and dramatic changes in one, like boosting serotonin, trigger comparable changes in others. Given the great mystery surrounding these processes, assumptions of safety and benefit must be made with the greatest caution.

Furthermore, far from restoring a “normal” balance, these drugs create a chemical dependency about which few people are warned when they commence treatment; some people who try to stop taking the drugs experience symptoms far worse than their original depression. It can take weeks, if not months, to feel normal. For years doctors have mistook this rebound effect for a relapse of depression. People believe they have “endogenous” depression when in fact it is simply chemical dependency on the drug. Suicide can occur if withdrawal is not handled carefully.

The FDA advisory should be treated with the utmost respect and caution given the great seriousness of these issues. Despite its tone it still falls far short of the ban issued in England.

Publication Date: Wednesday, April 14, 2004

The Rx Factor
Despite new warning about antidepressants, local families and psychiatrists say drugs that combat depression in youth are safe

by Jocelyn Dong

When Palo Alto teenager Julia Brown* sleeps over at a girlfriend's house, she packs more than her pajamas -- she takes her bottle of Wellbutrin, too.

As innocent as the medication may sound -- suggesting some peace-promoting form of Motrin, perhaps -- the drug is no over-the-counter happy pill. A popular and powerful anti-depressant, Wellbutrin was prescribed to Julia after she tried to commit suicide (see sidebar) a few years ago.

She credits the drug, along with psychotherapy and another medication called Paxil, with giving her a normal teenager's life.

So it's with some frustration that Julia heard about recent controversy surrounding Wellbutrin and other antidepressant drugs that allegedly trigger suicidal thoughts in some children and adolescents.

Last year, the U.S. Food and Drug Administration (FDA) issued a warning that doctors should closely monitor their young medicated patients for suicidal tendencies. It was sparked by a similar warning from the United Kingdom Department of Health that advised a ban on certain antidepressants for youth under 18. The FDA is reviewing the research that prompted the concerns.

"It's awful that there's this huge scare," Julia said. She's never experienced any problems with the drugs and worries that kids who need medication will now be afraid to take it.

The issue of medication safety comes at a time of simmering public worries over whether overburdened parents too often -- and too blithely -- turn to prescription drugs for help with their kids' every tantrum, sulk and outburst.

At the same time, teen depression and suicide are genuine concerns in Palo Alto. Two high-school boys committed suicide in the past 18 months, leading school and community groups to mount an assault on teen stress through forums on how to handle pressure and by sponsoring no-homework nights.

It's almost a Catch-22 for parents: Are they doing too much -- or not enough?

Ironically, recent progress in identifying and treating depression among children and teens has contributed to this conundrum. Palo Alto school psychologists started seeing an increase in the number of kids taking antidepressants at school about five to eight years ago, according to Linda Lenoir, school nurse for the Palo Alto Unified School District.

But while that trend could reflect the growing pressures on kids, it could also show that health professionals have become more skilled at recognizing depression and anxiety disorders. In other words, it's not that kids are getting worse, but doctors are getting better. Over the past three years, Lenoir added, the number of depressed students seems to have stabilized.

The development of new, improved drugs has also played a role in the increase in kids on medication. Over the past 20 years, the field of antidepressants has taken a leap forward, with new drugs that are more effective and have fewer side effects, according to Dr. Alan J. Rosenthal, a child and adolescent psychiatrist at the Palo Alto Medical Foundation.

Today, about 60 percent of kids diagnosed with depression receive prescriptions, studies show.

So what's at the heart of this controversy over medication safety, and why is it cropping up now? Psychiatrists offer a variety of explanations.

First, antidepressants like Wellbutrin and Paxil haven't been completely tested on children, thus raising doubts about their efficacy and safety. Drug companies conduct trials with adults first, Rosenthal said, and studies on children come later, usually after the drug is already being widely used.

Second, even without FDA approval of most antidepressants to treat illnesses in kids, psychiatrists commonly prescribe them anyway, based on scientific data and their clinical experience with adults. It's a practice called "off-label usage," said Dr. Shashank Joshi, a child psychiatrist and pediatrician with Stanford Medical Center.

Not all health-care providers have been careful when they've prescribed antidepressants, however, Joshi said. Child and adolescent psychiatrists typically are able to spend ample time with their patients both before and after the prescription, but primary care physicians -- who frequently prescribe the drugs -- aren't typically set up to do that, he said. That lack of contact can be dangerous, especially during the first few months of treatment or after a dosage increase, when side effects usually appear.

"Most primary-care providers do a thoughtful job, but occasionally medications are being prescribed willy-nilly, without a thorough psychosocial workup," Joshi said. "We've come a long way, and still have a long way to go."

For that reason, some psychiatrists welcome the FDA advisory, despite the alarm it's causing.

"The warning is good. (Kids) will come to specialized care. Pediatricians and family doctors don't have time and are not comfortable talking about emotional issues," said Dr. Lena Osher, a child and adolescent psychiatrist with the Children's Health Council. She's received many calls from parents asking about the safety of the drugs. None of her patients' parents have taken their children off of the medication as a result.

Joshi has also fielded numerous inquiries on the issue. He tells parents what he already told them when first putting their children on the medications: Be vigilant. At the first sign of agitation or a feeling of "jumping out of one's skin," they should discontinue the drug and call their doctor immediately. Those symptoms could possibly precede suicidal thinking.

In spite of the regulatory-agency warnings, Joshi and his fellow child psychiatrists at Stanford continue to have faith in the medications.

"In general, we're not prescribing any less than we used to," he said.

One significant reason is that studies have shown the drugs' overwhelming benefits. As more antidepressants have been prescribed to adolescents over the past 14 years, youth suicide rates have declined -- about 33 percent across at least 15 countries, according to the American College of Neuropsychopharmacology.

What's more, in the controversial research that now casts doubt on antidepressants, not one child of the 1,700 studied actually killed him or herself.

Barbara Langdon* is one Palo Alto parent who believed so strongly in the power of antidepressants, she fought to get her daughter on them following the teen's emotional breakdown one Christmas. Barbara should know -- she was on Lexapro herself for years.

Initially, a pediatrician refused to prescribe the psychiatric medication. But eventually a psychiatrist did, and the change in the teen's life is like night and day, Barbara said. "It's made a world of difference."

Before, her daughter felt hopeless and struggled in school. Mother and daughter fought constantly. But recently, Barbara said, "she came home and put her arms around me and said, 'I love you, Mom.'"

She, like Julia, is concerned about the antidepressant warnings, saying they might scare kids and their parents off from something helpful.

"I don't want depressed kids walking around. We should be talking about this," Barbara said.

Julia also wants people to give antidepressants a chance. She dismisses the research that reported some kids thought more about suicide after taking the drugs. She figures it has more to do with kids being open to talking about their suicidal thoughts once they're feeling stable, and less to do with new suicidal impulses.

Besides herself, she has five friends who are also on antidepressants.

Julia's mom calls the drugs "a Godsend." They're a vast improvement over old antidepressant medications like lithium, she said, which "had huge side effects. They shortened people's lives."

She acknowledges there are health risks, however, especially since the drugs are relatively new and their long-term effects are unknown.

For that reason, Julia's psychiatrist took her off Paxil last month, leaving her just on Wellbutrin. He didn't want her exposed to chemicals if she didn't need it, she said. So far, the teen has adjusted just fine.

And that goes for her whole life right now, which is pretty much like any other teen's -- full of extracurricular activities, friends and renewed self-confidence.

Having been helped by medical professionals, and antidepressants, Julia now lends a caring ear to other friends who are struggling, and even recommended her own psychiatrist to one girl.

"It's good all around right now," she said.
*Names have been changed to protect privacy

Response to Letters in WSJ

Detecting Suicide Before It Happens 1000
April 7, 2004; Page A19
That antidepressant medications are recommended for warning labels by the FDA because of their potential for increasing suicide risk ("Antidepressants Get FDA Warning," March 23) misses the point; the warning label needs to be put on the practitioner, not the pill.

With few exceptions, the American health-care industry is undertrained and generally incompetent to detect and assess suicide risk in the patients for whom they prescribe these otherwise helpful agents. Writing a prescription for an antidepressant for an already suicidal patient is a national problem, and especially among older citizens. Among the findings published in the 2002 Institute of Medicine report "Reducing Suicide, a National Imperative," are the following:

1. Most people who complete suicide had contact with a health professional within a year of death, and 40% of these contacts were within one month of their deaths. Many people die by overdose on the prescription medications provided them at these visits.

2. Screening for depression, substance abuse and suicide potential is not routine in primary care, even though primary providers are often the "first and only medical contact" suicidal patients have with the health-care system. As a result, suicide risk is not detected. Primary care physicians lack training and evidence-based screening, assessment, and referral practices for suicidality.

Before we frighten away the people who need these potentially life-saving medications from their proper use under competent medical supervision, perhaps we should require non-psychiatric healthcare providers to learn something about how to detect, assess and manage those at risk for suicide before reaching for their prescription pads. In the matter of suicidal, depressed people, the current "don't ask, don't tell" don't work.

Paul Quinnett, Ph.D.
Spokane, Wash.
(The author is president and CEO of QPR Institute, a training organization devoted to preventing suicide, and editor-in-chief of Preventing Suicide: the National Journal.)

It is disappointing to again see the media sensationally slanting the picture about a current medical issue, in this case Leila Abboud's "Should Family Doctors Treat Serious Mental Illness?" on March 24.

From my perspective as a general pediatrician who prescribes some of the psychotropic drugs mentioned, the matter of greatest interest is the paucity of psychiatrists. It usually takes months to get a child to see a psychiatrist, and it can be much longer if sub-specialty care, like an autism clinic, is the parents' choice or my recommendation. Sometimes we can't find anyone qualified in the patient's insurance network.

I often prescribe these drugs after brief telephone consults with a psychiatrist, or by emulation of the psychiatric care of another patient, clinically similar to the one not seeing the psychiatrist. I know I am providing a needed service for my patients with autism, severe developmental problems, anxiety and sleep disorders, and Tourette Syndrome, and I am always grateful for any expert advice once they do eventually see a psychiatrist.

Being exposed to media criticism of generalists prescribing for mental health problems is more likely to make the public unnecessarily angst-ridden about accepting care from their primary-care physicians and could prolong the duration of family and school crises caused by these disorders being undertreated.

Nora E. Hanke, M.B., Ch.B.
Easthampton, Mass.

My response:

Letters to the Editor:
As a parent you testified at the FDA hearing on antidepressants of February 2nd I feel the necessity of responding to the two letters you published yesterday on “Detecting Suicide Before it Happens” (April 7). I agree that practitioners and family members of patients at risk need far better training in recognizing suicide potential. However, what Dr. Quinnett fails to acknowledge, is that these pills are triggering the onset of suicidal symptoms in some patients who were not at all suicidal at the time their treatment commenced. This was true for my daughter, for many of the victims described at the hearing, and may well be the case for the healthy volunteer who recently died at Eli Lilly’s clinical trial facility. My daughter was being treated by a psychiatrist at one of the best teaching hospitals on the West Coast for anxiety, but no one dreamed she was suicidal. And she was even seen on the last day of her life and still no one perceived her as suicidal; her doctor had no idea what she was witnessing because she had not been properly trained to recognize the onset of akathisia or more importantly what to do about it which is to taper the antidepressant and administer a concomitant sedative. She indicated the sedative was optional; it most certainly was not. From the autopsy we learned my daughter had not been metabolizing the antidepressant.
Frankly I am sick and tired of hearing the refrain we are “frightening” depressed patients from seeking treatment. I think people should be frightened of antidepressants and know that these are powerful drugs with known adverse effects, not the least of which is exacerbation and even triggering of mania and psychosis by their stimulant properties. Neither psychiatrists nor general practitioners have been made adequately aware of the dangers of these drugs or of what to do about adverse symptoms when they arise. They themselves are unfortunately the victims of duplicitous cover-up by both pharmaceutical companies and regulatory agencies who, for well over a decade, have been suppressing and failing to publish “inconvenient” results of clinical trials in order not to "frighten" doctors from prescribing these pills. No medical professional should be working in the dark whether they are a psychiatrist or a general practitioner; if the full truth is published then doctors and patients alike can make their choices with the facts they need.