New York Timesby Robert Gibbons and J. John MannOctober 7, 2014The changes in treatment and attitude brought on by Prozac prompted two colliding points of view. One was that antidepressants were overprescribed and people were encouraged to turn to a pill to solve all their problems. Another viewpoint was that major depression was one of the most debilitating illnesses in the world and was mostly untreated or undertreated, and even though we were now prescribing a lot of antidepressants there were still too many people with moderate to severe depression that remained untreated.
A third claim intruded into this debate, namely that the efficacy of antidepressant medications is overstated and the best evidence of effectiveness was in only the most severely ill patients. In an effort to shed light on this question, we obtained much of the world’s complete longitudinal data on randomized controlled trials of the antidepressants fluoxetine [Prozac] and venlafaxine [Effexor] in depressed patients conducted by Lilly, Wyeth and the National Institute of Mental Health. We included studies regardless of whether they demonstrated the medications were effective in order to get the clearest picture possible of the efficacy of these widely used antidepressants.
From the statistical model that synthesized these data across all studies separately for each age category, we computed estimated response and remission rates. We found an improvement in depression regardless of age in both medications relative to a placebo pill. Interestingly, the greatest benefit in terms of response and remission rates was seen in children, followed by adults, and then by more modest effects in the elderly. There was no evidence that severity of depression made a difference to how well the antidepressant medication worked. Based on these findings we concluded that antidepressants work across the lifespan, in patients with moderate or severe depression.
In a recent blog post, I reviewed Dr. Gibbons’ most recent paper, yet another assault on the Black Box Warning, this time using commercial databases [gibbons everlasting…] and cataloged his many previous attempts to cast doubt on the 2004 FDA Black Box Warning. He has made similar attempts to debunk the warnings on Neurontin® and Chantix® [very monotonous…].. This recent NYT comment is based on his 2012 articles with the same intent. I had offered a strong criticism at the time of those 2012 articles [an anatomy of a deceit 1… etc.], as did many others. But in gibbons everlasting…, I left out something important, something mentioned by Dr. Bernard Carroll both in his comment here and to the New York Times. So I thought I’d just run it around again:
by Gibbons RD, Coca Perraillon M, Hur K, Conti RM, Valuck RJ, and Brent DAPharmacoepidemiologic Drug Safety. 2014 Sep 29. doi: 10.1002/pds.3713. [Epub ahead of print]
PURPOSE: In the 2004, FDA placed a black box warning on antidepressants for risk of suicidal thoughts and behavior in children and adolescents. The purpose of this paper is to examine the risk of suicide attempt and self-inflicted injury in depressed children ages 5-17 treated with antidepressants in two large observational datasets taking account time-varying confounding.METHODS: We analyzed two large US medical claims databases (MarketScan and LifeLink) containing 221,028 youth (ages 5-17) with new episodes of depression, with and without antidepressant treatment during the period of 2004-2009. Subjects were followed for up to 180 days. Marginal structural models were used to adjust for time-dependent confounding.RESULTS: For both datasets, significantly increased risk of suicide attempts and self-inflicted injury were seen during antidepressant treatment episodes in the unadjusted and simple covariate adjusted analyses. Marginal structural models revealed that the majority of the association is produced by dynamic confounding in the treatment selection process; estimated odds ratios were close to 1.0 consistent with the unadjusted and simple covariate adjusted association being a product of chance alone.CONCLUSIONS: Our analysis suggests antidepressant treatment selection is a product of both static and dynamic patient characteristics. Lack of adjustment for treatment selection based on dynamic patient characteristics can lead to the appearance of an association between antidepressant treatment and suicide attempts and self-inflicted injury among youths in unadjusted and simple covariate adjusted analyses. Marginal structural models can be used to adjust for static and dynamic treatment selection processes such as that likely encountered in observational studies of associations between antidepressant treatment selection, suicide and related behaviors in youth.
In gibbons everlasting… I listed Dr. Gibbons previous articles on this topic since the Black Box Warning was issued by the FDA in 2004. While the FDA meta-analysis supported the case that suicidality is an uncommon but dangerous side effect of the use of SSRIs in adolescents, it was the case reports heard by the panel that lead them to append the warning. Dr. Gibbons statistical analyses have chased disproving the warning all over the map – from multi-country comparisons, the CDC statistics, proprietary databases, VAH statistics, drug company clinical trials, etc. always chasing the same hypothesis, the same one recently espoused by Lu et al [all databases are not created equal…]:
The Hypothesis [my version]:
The Black Box Warning is wrong. It scared doctors who prescribe fewer antidepressants to adolescents, depriving them of needed treatment, thereby increasing the incidence of suicidality.
In his previous outings, over the last decade, Gibbons has stuck to attempts at using population meta-analyses to show that antidepressants don’t increase the incidence of suicidality. His articles are difficult because they can’t be vetted [not enough information] and they involve complicated statistical analyses that he describes, but does not show. They are invariable followed by media reports, The ones mentioned in the NYT above were followed by a media blitz [the campaign…]. Invariably he finds no evidence of suicidality in adolescence on SSRIs. There are several points to make about these papers:
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There is no strong evidence that SSRIs are even effective in adolescent depression. Only Prozac was approved, and that was early on before these questions were raised. So the notion that effective treatment is being withheld is unsubstantiatable.
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This syndrome is not common, but once you see it, you have no question of causality [at least I didn’t]. It’s not a population study thing, it’s a case report thing. And there are plenty of cases of completed suicides among those reports. I don’t even treat adolescents, but I personally know of several such cases. The cases are substantiatable.
Now to the most recent paper and Dr. Carroll’s point. After a decade of trying to prove it doesn’t happen, in this new study, it seems that it does happen after all:
"For both datasets, significantly increased risk of suicide attempts and self-inflicted injury were seen during antidepressant treatment episodes in the unadjusted and simple covariate adjusted analyses."
And then Dr. Gibbons undoes it with some kind of factor analysis that is opaquely described and unintelligible to any physician no matter how statistically sophisticated. Carroll calls it "voodoo statistical hand waving," but even that is forgiving because Gibbons’ presentation is effete and insulting to the reader. So the question really comes down to Why do these recurrent articles against the Black Box Warning keep coming? with each study more questionable and convoluted than the last. They are presented as being in the service of child advocacy – hardly likely. One hint about their persistence is in looking at the authorship:
by Nemeroff CB, Kalali A, Keller MB, Charney DS, Lenderts SE, Cascade EF, Stephenson H, and Schatzberg AF.Archives of General Psychiatry. 2007 64[4]:466-72.
Three authors on Senator Grassley’s list, chairmen who lost their chairs in the following years; four customers of Sally Laden, notorious ghost-writer; and the medical director and emplyees of Quintiles, a major CRO. Then:
News coverage of FDA warnings on pediatric antidepressant use and suicidalityby Barry CL and Busch SH.Pediatrics. 2010 125[1]:88-95.
These studies were financed by the National Bureau of Economic Research, a think tank founded by a member of the Eli Lilly Board at the time [see pretty loud coi…, the NBER study, and tortured numbers…]. Then there are the numerous studies of Dr. Gibbons who has testified for Pfizer in the cases involving SSRIs, Chantix, and Neurontin. Throw in the recent study by Lu et al [see all databases are not created equal…], employed by Harvard’s Managed Care conglomerate. There are others, but nowhere among them are the expected child psychiatrists or psychologists. This is pretty much an industry effort all the way through.
This is a strange story about an unlikely collection of people diligently pursuing the debunking of a clear, if uncommon, adverse effect of a class of medications when given to youth – a potentially fatal complication. It proposes to be advocacy for teens being denied effective treatment, yet even the evidence for its effectiveness is decidedly underwhelming. The people producing these studies are not from the community of people actively involved in treating the populations studied, and the evidence they present is at some distance removed from the actual patients [claims databases, population statistics, etc.], invariably connected with some industry [PHARMA, Managed Care, etc.], and generally accompanied by some kind of prominent media coverage like the NYT piece I started with above. The important question is Why? Why do they keep at it? Of course we can’t truly know their motives, but it’s a pretty good guess that it’s not what the articles say. And though unprovable, we can easily hypothesize for ourselves what drives this campaign. Almost anyone reading this could come up with a set of motives, but I want to say a few of them out loud:
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PHARMA: Depressed adolescents are common – a lucrative market for the sale of antidepressants.
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PHARMA: The suicidality Adverse Event was downplayed in the original reports – a litigation liability.
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Managed Care: The cost of delivering care other than drugs to depressed teens would be expensive.
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Psychiatry: The KOL psychiatrists have based their reason d’etre on the effectiveness of the SSRI drugs, talking about ‘depression’ as if it’s a ‘disease entity’ and the SSRIs as the ‘treatment’ for that ‘disease entity’. They essentially define psychiatry by this disease/treatment dyad.
In my mind, this is an affront to the biological psychiatrists who have given us effective treatments for the subset of depressed people who have the depressions that fit the disease model – eg Manic Depressive Illness, Melancholia. It is an affront to the psychotherapists from a variety of disciplines who work with adolescents who present with depression. It is an affront to psychiatrists who don’t subscribe to the neoKraepelinian dictum that all mental illness is biological. And it is an affront to the scientists who adhere to the scientific method and use its tools carefully – hypervigilant to the introduction of bias, including their own. But first and foremost, it is a betrayal of the trust of the depressed adolescents, their parents, and the practitioners who treat them…
Mickey, I agree with pretty much everything you wrote above, but I’d like to point out that escitalopram is FDA approved for MDD in adolescents aged 12-17. I know you’ve had previous written about a study of Lexapro in adolescents, but I’m not sure if the one you wrote about was one of the ones used to obtain FDA approval.
If the NYT article was not ghostwritten by PHARMA I will stop posting on medical blogs for a week. That was pure sales nonsense.
Then comes the question of proving a nonevent. Children are depressed and not being treated. Where is the science behind this and how does this reconcile with the noted work of psychiatrist of all types.
We once again see sales trumping science, and as so well stated, ultimately after all the care providers it is the patient being harmed, all for a few pieces of silver.
Steve Lucas
Of all the things that can contribute to low moods in adolescents, shouldn’t an endogenous depression be the last consideration? High school may be the number one cause of “depression” among teenagers.
This is a direct quote from the NYT article:
“There was no evidence that severity of depression made a difference to how well the antidepressant medication worked. Based on these findings we concluded that antidepressants work across the lifespan, in patients with moderate or severe depression.”
That’s actually contradictory because they omitted “mild”. This means it doesn’t work as well in mild depression as moderate to severe. So therefore the severity does matter. So it shouldn’t be given or really even tested for drug trials in mild depression (therapy, sleep hygiene and exercise seem to be fine). And there are plenty of studies to indicate TCAs and MAOIs work better in severe depression.
This article was as reassuring to me as the CDC’s latest Ebola press conference.
I happen to think SSRIs and SNRIs work but not all that well. Certainly patients who have benefitted from them should not discontinue based on skepticism.
But every time the experts try to bolster the case for them, they paradoxically create more doubt in my mind.
Anyone try Emsam lately?
MAOIs work especially well in people who have a lot of anxiety and who eat too much and sleep too much when they get depressed (as opposed to having insomnia and losing appetite).
Hmm. That’s what I did when I suffered my “retarded depression” that was severe anemia. I stayed at my cousin’s house and started eating meat again. My depression lifted, but I didn’t have enough information to challenge my bipolar II diagnosis and had been convinced that I was broken. It was a decade later when I suffered that depression again, but found out that it was anemia and was cured with high doses of iron and vitamin C, that I got it. Prior to learning that, I did not believe that I could survive another “depression” and so submitted myself to a decade of rotating drug cocktails. Sometimes, I wish I could experience bitterness on my own behalf; but it’s obvious to me now that I have never suffered an endogenous depression, and can’t help but suspect that a whole lot of people labeled with depression also have not.
I suffered from PTSD, as well and, I think, made the mistake of thinking that the grief and exhaustion of drawn out episodes of PTSD symptoms were depression. As is the nature of the beast, there’s a tendency to underestimate the impact of struggling with it and to deny the impact of triggers and trigger avoidance.
There is really good research being done on PTSD. After my only psychotic episode, I found some studies linking war veterans and immigrants who were tortured in their home countries with a psychosis thought to be linked to PTSD. Now it appears to be common knowledge.
http://ptsd.about.com/od/relatedconditions/a/Psychosis.htm
I’ve wandered off again, I think PTSD, among other things should be explored before taking a ten question inventory and deciding that someone is depressed due to some chemical malfunctioning in their brain that is specific to psychiatry and “comorbid” with other psychiatric disorders.
But this new patch, bypasses the stomach so that patients don’t have to follow dietary restrictions for MAOIs and tricyclics that I just read about or the first time in an article selling Emsam on CNN. Not a bad reason to develop a patch, I suppose. I had no idea that tyramine was such a threat.
But I feel it would be imprudent not to be suspicious of all claims made by “experts” and the drug industry on just about anything, these days.
http://www.cnn.com/2011/HEALTH/expert.q.a/02/15/older.antidepressant.emsam.raison/index.html?eref=rss_latest
Just curious, what MAOI did you take back then? Must have been either Nardil or Parnate or Marplan (unlikely).
I haven’t taken MAOIs. Now I’m kind of curious about why, sense I’ve been prescribed just about everything else. I’ve just read enough about antidepressants that it surprises me that I haven’t heard about dietary restrictions and MAOIs.
For whatever that’s worth. I can’t remember what medication is responsible for the fact that I’ve cut grapefruit out of my diet. I should look it up again— I love grapefruit.
Psychiatry committed covert suicide when the following went unchallenged:
Managed care dictated care interventions.
Pharma sold that better living through chemistry was the treatment of choice.
Social workers dumbed down therapy, oh, and cheapened it too.
Mental health administration focused on profit margins in CMHCs
Hospitals agreed to keep patients for short stays and band aided care.
Psychologists chipped away at dumbing down the needs of prescribing.
Oh, and psychiatry as a whole agreed to the above.
So, everyone is complicit, and everyone can shut the f— up and not complain because no one is innocent nor a victim.
Keep railin’ away about Big Pharma, they are not front and center now, no, it is us continuing to do nothing for responsible, appropriate, needed change to even remotely try to fix the system. Having to listen to patients tell me my attitude and approach to advising good interventions is either very appreciated, or just rudely dismissed, well, it kills me inch by inch every day.
I honestly and wholeheartedly look forward to reading about the class action suit against a sizeable group of psychiatry, be it an institution or group of doctors who have been caught ruining lives and can be successfully sued, hopefully criminally as much as civily, that finally makes the cowards and silent supporters of appropriate care sit up and realize, “damn, that could be me next!”
Maybe some innocents taken down too will rally the responsible troops.
Nah, doubt it, greed, power, and sheer arrogance rules the majority of this profession, and too many of you just can’t admit it!
Grapefruit is involved with something called cytochrome 3A4 which breaks down drugs like Buspar but about 85 other drugs. So maybe that was it. Maybe a sleeper.
Buspar is another drug in my opinion that ought to be on the questionable efficacy list.
@psycritic: escitalopram has been approved by the FDA for MDD in adolescents (12-18 yrs). The strange thing about this approval, is that it was based on only 1 positive escitalopram study in adolescents, and an “extrapolation” from 1 positive racemic citalopram study. The FDA monograph mentions that 1 other escitalopram study and 1 other citalopram study were negative (http://www.drugs.com/pro/lexapro.html#s123). I find this approval procedure strange, and contrary to usual FDA standards. Also, using the same logic, racemic citalopram should have also been approved, and it wasn’t. Anyone with inside information about this?
Gad, Psycritic,
See A Review of Escitalopram and Citalopram in Child and Adolescent Depression and the next post…
The reason these KOLs persist is because they have staked out a domain of expertise and now defend their intellectual legacies.
Pfizer, FDA Square Off on Chantix Psych Risk
http://www.medpagetoday.com/PrimaryCare/Smoking/48096
These KOLs exist because no one, NO ONE will stop attending the false seminars and symposiums, no one will stop reading the free CME courses these liars run, and, no one will tell the APA to go to that rather hot place where only the slime should reside.
And, very few, albeit not no one, will stop listening to these scam pharma reps who somehow still troll the halls of offices. However, again, the issue is NOT the drugs as of 2014, it is the fallout from what people have done after the decades of the lies the drugs set up, as noted in my earlier comment.
You can’t stop the train, but, you could dislodge some of the rail cars from being dragged to the canyon ahead where there is no bridge to cross it. Where are those who want to pound away at those rail car connectors?
Pay attention to the deeds, not words of the alleged dissenters and what they are doing in their offices and in their own halls of influence. Not a swipe at Dr Nardo here, but, perhaps at some of the commenters?
No one to my knowledge can accuse me of being a hypocrite in my travels across the lands of outpatient care these past 15 years. And to have to face the possibility of doing inpatient care as a Locum upcoming, ugh.
No, the better ending to that last sentence is ARGHHHHHH!
I’m old enough to remember when scientists and even psychiatrists enjoyed a good intellectual tussle in a Socratic not Powerpoint teaching environment and could get into it without all the name calling and ridicule. Now it’s all about “settled science” (thank you very much AGW fanatics who never read Karl Popper) and “consensus opinion” and appeal to authority. Kind of like Soviet science or psychiatry in the 1950s.