Reanalysis of the Randomized Placebo-Controlled Studies of Fluoxetine and Venlafaxine
by Robert D. Gibbons, Hendricks Brown, Kwan Hur, John M. Davis, and J. John Mann
Archives of General Psychiatry. Online February 6, 2012.
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Study questions antidepressant link to suicide in kids
Los Angeles Times By Shari Roan February 06, 2012
In 2004, the Food and Drug Administration announced that antidepressant packages should carry a "black box" warning describing an increased risk of suicide and suicidal thoughts in children and youths up to age 25. The FDA action triggered a significant decline in antidepressant use among children and teens. Now, however, an analysis suggests there is no reason to believe that antidepressants influence suicidal thinking in kids.
The paper, published online Monday in the Archives of General Psychiatry, analyzed data from 41 clinical trials involving more than 9,000 adults and children. The adults were taking either the antidepressant fluoxetine or venlafaxine. The children were taking fluoxetine (Prozac). The study showed that adults had a decreased risk of suicidal thoughts and behaviors while taking an antidepressant. Among children, medications neither increased nor decreased suicidal thoughts or behavior. The new study draws from a larger database than the research performed in 2004 that led to the "black box" warning. However, the data on children are limited to the one medication – fluoxetine. Several important points can be drawn from the new study, said the lead author of the paper, Robert Gibbons, a professor of medicine, health studies and psychiatry at the University of Chicago. It suggests that antidepressants reduce suicide rates by treating the underlying depression. If the treatment does not work, suicide risk remains the same or rises. Moreover, antidepressants appear to affect children differently than adults with regard to suicide. "Maybe children think about suicide in part because of depression, but also maybe due to other reasons not related to depression that are not affected by antidepressants," Gibbons said in a news release. The impact of the "black box" warning, he said, was to reduce antidepressant prescriptions to kids – which was correlated with an increase in suicide rates in subsequent years. "I hope that the warnings will not prevent depressed children and adults from getting treatment for depression," he said. "The greatest cause of suicide is untreated or undiagnosed depression. It’s very important that this condition be recognized and appropriately treated and not discarded because doctors are afraid to be sued." |
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A Fresh Look At Antidepressants Finds Low Risk Of Youth Suicide
National Public Radio by Alix Spiegel February 7, 2012
In 2004, after an extensive review, the Food and Drug Administration issued a strong warning to doctors who prescribed antidepressants to teens and children. Antidepressants, the FDA said, appeared to increase suicide among kids and teens. Doctors needed to be careful. The FDA even mandated that a "black-box warning," the strongest type, be placed on antidepressant packaging. This warning and worries that giving antidepressants to children might cause them to kill themselves was front-page news for weeks and appeared to changed the prescribing behavior of doctors. Fewer doctors used antidepressant medications with their young patients and, according to at least one study, the number of suicides among kids and teens began to rise.
This week the Archives of General Psychiatry published an analysis that finds no increase in suicide among young people taking Prozac. The findings put a new wrinkle in the long-running debate over the safety of the medicines when used to treat depressed young people. The study reviewed detailed data from over 9,000 patients — including 700 youths — who took the antidepressant Prozac and found that the drug didn’t increase suicidality in children at all. It also looked at data for adults taking Effexor. Now, the main author of the study is Robert Gibbons, a statistician at the University of Chicago’s medical school. Gibbons sat on the panel of experts that advised FDA to issue the warnings, but he always felt ambivalent about the panel’s decision. "I worried that what we might end up with was a real epidemic of suicide," Gibbons told Shots. "And the data suggests that that is exactly what happened. Rather than the black-box warning leading to decreases in child suicide rates, they were followed by some of the largest increases in child suicide rates both here in America and around the world." So why did the new study come to such a different conclusion about the risks of suicide in kids? According to Gibbons, the FDA’s findings and his findings are similar in some respects. Both found that when doctors asked their patients about suicidal thoughts and behavior in the context of regularly scheduled checkups there was no difference between the medications and placebos. But when it came to what are called adverse event reports, there was a difference between his study and the review done by the FDA. Adverse event reports occur when patients spontaneously contact their doctors with problems associated with taking a medication. When the FDA looked at these patient reports, they found that patients on antidepressant medications reported 80 percent more suicidal thoughts and behavior than patients on placebos. Gibbons didn’t look at these spontaneous reports in the same way. He only considered them when patients acted on their suicidal thoughts with a suicide attempt. He found that the small number of people who acted on their suicidal thoughts did not affect the overall risk of suicide. The original FDA study also included all antidepressants — not just Prozac. That might account for some of the differences found. Gibbons, who has become a vocal opponent of the black-box warnings since his stint on the committee that advised FDA, says that he hopes this study will reassure clinicians about the safety of the drugs. It’s not clear whether other researchers will agree with him that the new study’s findings present a fundamental challenge to the FDA’s previous conclusions. |
- "I worried that what we might end up with was a real epidemic of suicide," Gibbons told Shots. "And the data suggests that that is exactly what happened. Rather than the black-box warning leading to decreases in child suicide rates, they were followed by some of the largest increases in child suicide rates both here in America and around the world."
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No Link Between Antidepressant and Suicide in Kids
Study Calls FDA Black Box Warning Into Question Medscape by Fran Lowry February 21, 2012
A close look at all randomized, placebo-controlled trials of the antidepressant fluoxetine has failed to find evidence that the drug increases the risk for suicide in youths. And a similar look at all trials of fluoxetine and venlafaxine in adults has concluded that both antidepressants decrease depressive symptoms as well as suicidal thoughts and behavior in adult and geriatric patients. The findings, reported online February 6 in the Archives of General Psychiatry, call into question the wisdom of the US Food and Drug Administration’s 2004 decision to issue a "black box warning" about the purported link between antidepressant use and suicide, lead author Robert D. Gibbons, PhD, from the University of Chicago in Illinois, told Medscape Medical News. Dr. Gibbons, who was on the FDA’s advisory committee that voted in favor of the black box warning, said he was very concerned about the validity of the data that prompted the affirmative vote…
More Harm Than Good "This makes sense if you understand that depression is a major risk factor for suicidal ideation and behavior, and so, by relieving the mental illness, in this case the depression, you remove one of the main drivers of suicidal ideation. This is very important to understand because there’s been considerable concern about whether antidepressant medication might activate suicidal ideation in some people, particularly in young adults. But what he is finding is that the effects of the medication are neutral with respect to suicidal ideation in youth and protective in middle age and older adults." Dr. Reynolds said he often worries that the black box warning has done more harm than good. "The black box warning might have prevented the medically appropriate use of antidepressants in teenagers. I am very happy to see this study come out," he said. |
Synthesis of 6-Week Patient-Level Outcomes From Double-blind Placebo-Controlled Randomized
Trials of Fluoxetine and Venlafaxine
by Robert D. Gibbons; Kwan Hur; C. Hendricks Brown; John M. Davis; and J. John Mann
Archives of General Psychiatry. Published online March 5, 2012.
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Study suggests overall benefit from antidepressants
Reuters By Genevra Pittman March 7, 2012
Despite recent debate about how well antidepressants really work in people with only mild or moderate depression, a new analysis of drug studies suggests they may have some benefit across the board. Researchers found that more patients taking Prozac or Effexor had a substantial improvement in their symptoms than those taking a drug-free placebo pill, regardless of how severe those symptoms were to begin with. "The idea that unless you’re very, very ill, you’re not going to benefit from treatment does not appear to stand up" when looking closely, said the study’s lead author, Robert Gibbons, from the University of Chicago.
Still, not everyone in the studies improved – on average, about five people had to be treated with one of the drugs for one person to feel better, and the benefits seemed to be diminished among some of the oldest patients. What’s more, one researcher not involved in the study said its findings still don’t mean the drugs are any better than non-drug methods of treating depression, such as talk therapy and being more physically active. More adults and kids taking Prozac, known generically as fluoxetine, had at least a 50 percent improvement in scores on depression tests after six weeks compared to those assigned to take a placebo pill. Fifty-five percent of adults on Prozac responded to treatment, compared to 34 percent in the placebo group. In youth, 30 percent on Prozac had significant symptom improvement, compared to just six percent of the comparisons. The benefits were seen regardless of how severe patients’ symptoms were before starting treatment. However, in the elderly the differences between the treatment and placebo groups were much smaller, and the researchers calculated that 17 older patients would have to be treated with Prozac for one to gain from it. "Clearly the efficacy of antidepressants is age-dependent, [and] largest, most interestingly, in youth, which I don’t think would be the mainstream view in psychiatry," Gibbons told Reuters Health… |
More muted, but in it’s way as deceptive as before.
There are many roads to becoming a person who spends a lot of time following the psychopharmacology goings on with an eye out for distortions in the reporting. Some are biological psychiatrists pained by the blatant abuse of the scientific method. Others are people who have been directly impacted by the medications themselves or seen others harmed – the most painful being those who’ve lost loved ones to suicide that was likely medication induced. Then there are the traditional antipsychiatrists whose objections to overmedication have been longstanding. Some are psychiatrists who feel that the psychopharmacologists are destroying psychiatry and psychiatric practice. Others are psychotherapists who have seen their life work maligned or minimized. And some are horrified by the influence of industry and profit-motives in what should be sacrosanct medical decision-making processes.
I could relate somewhat to any one of those, but they’re not what actually brought me out of the woodwork [retirement] – not my real "dog in this hunt." It was two very distinct personal things. The first needs not be repeated again – I left an academic career decades ago when psychiatry was having a biological revolution and I was on the other side of the battlefield. I had a fine life thereafter, if not the one I planned. Three years ago, the chairman of my department, Dr. Charles Nemeroff, was publicly exposed as blatantly corrupt. That woke me up some, but that’s an oft-told story here.
What’s more pertinent was a longstanding love affair I had with the medical literature, almost from the day I discovered it. As an Internist, I read all the journals cover to cover. As a research fellow, I added many others. I read them like people read newspapers, during lunch, in lieu of television. When I changed specialties to psychiatry and later psychoanalysis, it didn’t change. I ate my lunch in the library. I think I was amazed that such a rich dialog was so accessible, and I just didn’t want to miss it. After I left academics, I gradually put the psychiatry literature aside. It wasn’t interesting – kind of like reading a local newspaper in a distant state. I hardly knew what it was about anymore. That was a sad development.
A few years back, I agreed to volunteer at a few charity clinics in the rural place I moved to for my retirement. I knew that was going to be very different from my practice, so I started "catching up" on psychopharmacology. I tried a few textbooks, but they weren’t satisfying, so I started reading the journal articles themselves and was frankly appalled. That’s actually an understatement. Something was terribly wrong. There were tricks of presentation I’d rarely seen, misused statistics, absent essential data, conclusions unsupported by even the data that showed. The major journals had articles that would have only appeared in the "throw-away" literature that haunts doctor’s mailboxes in the past. Dr. Nemeroff’s exposure plus corrupted literature equalled juices flowing in my case. The hallowed literature of my youth had been invaded. That’s how I got here, and that’s why I stayed and will likely stay. The medical psychiatric literature has been perverted from being a place to communicate the leading edge of science to something used for other things – dangerous things – like selling drugs.
Why would a person worry that there would be an “epidemic” of suicides from what that person considers to be an endogenous flaw in the brain? If the rate of suicide had ever dropped precipitously following the introduction of an antidepressant that might be evidence of its efficacy; but one little uptick could be explained by the Werther Effect or chance.
My index of suspicion for a neurotic agenda at work here keeps growing. I ask myself whether those most vocal against the black box warning are trying to ward off anxiety by overcompensating in the direction of being ‘good’ doctors. Being good here means offering a safety net (medication) to everybody assumed to be at risk of suicide. This overvalued idea can result in cognitive biases like those on display here, whereby risks are dismissed or rationalized and data are selectively chosen in service of the neurotic agenda. Sometimes such anxiety arises early in professional training when a suicide does occur on one’s clinical service. The reactions of trainees can include embarrassment, shame, self-doubt, and unless these incidents are worked through professionally they can have lasting neurotic effects. As a former director of residency training, you would know about that, Mickey.
Dr. Gibbons is a different matter. I think he is out of place and out of line making prescriptive professional statements and offering opinionated commentary precisely because he is not a clinician. He should stick to his statistical knitting and, as you have pointed out Mickey, he should try to do it better. His inclusion of the Lilly Study LYAQ (where everyone was also taking Strattera) tells me that he doesn’t know his front end from his rear end when it comes to clinical judgment.
And speaking of clinical judgement, see the next post…
Please consider that not everyone who challenges the “medications first, for everyone and forever” paradigm is an antipsychiatrist. That’s really just about the N-word for the mental health civil rights movement. Did you know about us? You never mention us. Try my site, Corinna West dot com, and The National Empowerment Center for starters.
I do know that not everyone who challenges the “medications first, for everyone and forever†paradigm is an antipsychiatrist because I challenge it too, and I’m a psychiatrist. Nor do I think antipsychiatrist is an N-word, but I take your point and will not use it anymore. In my day, it had a very specific meaning associated with the teachings of Dr. Thomas Szasz, and included a large group who advocated for “medications never, for noone never.” That was a choice, not mine but certainly something available for those who followed that path. My apologies if that word offended you, but I would suggest that a rereading of the paragraph would make it clear that I am hardly in the “medications first, for everyone and forever†set, now or in the past. There are places in the world where psychiatrist is an N-word too. I’ve learned to accept that as simply the way it is…..
Why is Alan Schatzberg still an editor-in-chief of the Journal of Psychiatric Research? What is this guy’s hold on the psychiatric establishment? He must be very charming, or have an excellent wine cellar.
Suggest letters to NPR. If they’re going to wade in the psychiatric waters, they’re going to have to know more about the terrain.
Please please send your stuff to BMJ. They publish things like this, which generate a international attention. Your information deserves that kind of readership.