come rest a while I… »
« those infernal drums…
red alert…

Posted on Sunday 4 March 2012

 What’s the point about blogging about the pharmaceutical intrusion into the psychiatric literature? If it’s just to decry it, it’s something of a wasted effort. The point is to try to make transparent the things that went on unobserved and created the mess we are now faced with. Early detection is in my mind the key to any possibility of success in changing things. It is in that spirit that I’m recurrently posting about the Robert Gibbons article published on-line in last month. This post is further background information that I think might be pertinent. Here’s the abstract of his article as a reminder:
Suicidal Thoughts and Behavior With Antidepressant Treatment
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.
[full text on-line]

Context: The US Food and Drug Administration issued a black box warning for antidepressants and suicidal thoughts and behavior in children and young adults.
Objective: To determine the short-term safety of antidepressants by standard assessments of suicidal thoughts and behavior in youth, adult, and geriatric populations and the mediating effect of changes in depressive symptoms.
Data Sources: All intent-to-treat person-level longitudinal data of major depressive disorder from 12 adult, 4 geriatric, and 4 youth randomized controlled trials of fluoxetine hydrochloride and 21 adult trials of venlafaxine hydrochloride.
Study Selection: All sponsor-conducted randomized controlled trials of fluoxetine and venlafaxine. Data Extraction: The suicide items from the Children’s Depression Rating Scale–Revised and the Hamilton Depression Rating Scale as well as adverse event reports of suicide attempts and suicide during active treatment were analyzed in 9185 patients (fluoxetine: 2635 adults, 960 geriatric patients, 708 youths; venlafaxine: 2421 adults with immediate-release venlafaxine and 2461 adults with extended-release venlafaxine) for a total of 53 260 person-week observations.
Data Synthesis: Suicidal thoughts and behavior decreased over time for adult and geriatric patients randomized to fluoxetine or venlafaxine compared with placebo, but no differences were found for youths. In adults, reduction in suicide ideation and attempts occurred through a reduction in depressive symptoms. In all age groups, severity of depression improved with medication and was significantly related to suicide ideation or behavior.
Conclusions: Fluoxetine and venlafaxine decreased suicidal thoughts and behavior for adult and geriatric patients. This protective effect is mediated by decreases in depressive symptoms with treatment. For youths, no significant effects of treatment on suicidal thoughts and behavior were found, although depression responded to treatment. No evidence of increased suicide risk was observed in youths receiving active medication. To our knowledge, this is the first research synthesis of suicidal thoughts and behavior in depressed patients treated with antidepressants that examined the mediating role of depressive symptoms using complete longitudinal person level data from a large set of published and unpublished studies.
I’ve already had a lot to say about it in these earlier posts:
Why am I so stirred up about this article? First, Dr. Gibbons, a Biostatistician, has been stirred up about the black box warning about suicidal thoughts with antidepressants since 2004 when it became required on the SSRI drug labeling with various angles of attack – covered in earlier posts. Second, this article  was published without data, with unintelligible tables, yet makes definite conclusions widely covered [Medscape, Lancet, Press]: Here are a few of Dr. Gibbons’ comments in these interviews:
    • "The adverse event reports for suicidal thoughts and behavior showed a fairly small signal in children, but the prospective measurements showed no effect of treatment whatsoever. As a statistician, I put more weight in prospective data than these retrospective reports," he said. "The vote was 15 to 8, so some of the members of the committee, myself included, were not persuaded by those reports and felt that the black box warning was not warranted."
    • 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.
    • "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."
Here’s an article that cannot be vetted because its data is inaccessible, with a strong conclusion, one the author has been out to prove for six years, a conclusion he’s given as an expert  legal witness, and a conclusion that would be favorable to pharmaceutical manufacturers. Which ones? The ones with in-patent antidepressants on the market today. The two main ones are Eli Lilly [Cymbalta] and Pfizer [Pristiq]. And which drugs did Dr. Gibbons study [from Medscape]?
    "We were interested initially in looking into the efficacy of antidepressants, so we approached Eli Lilly to see if they would part with all of their longitudinal data from their randomized, placebo-controlled trials, and remarkably, they said ‘yes,’ " said Dr. Gibbons. "We said that we were going to analyze all the data and write a paper and were not even going to show it to them, and they said ‘fine’." Next, the researchers approached Wyeth with the same request and got the same reply. "All of a sudden we had an awful lot of placebo-controlled, randomized clinical trial data, complete longitudinal records for every subject, and we were able to ask questions about the efficacy of antidepressants and whether or not that efficacy is moderated by the severity of illness of the patient and also whether or not there are changes over time in suicidal thoughts and behavior, whether or not those are the same in adults and the elderly and children, and whether or not any changes in suicidal thoughts and behavior are related to changes in depressive severity," Dr. Gibbons said.
[Wyeth is now part of Pfizer]. So added to his strong opinions, and his having personally testified about those opinions as an expert witness, we have him studying older drugs made by the very two companies with current drugs on the market. So I then looked to see if those two manufacturers were aiming to try to get these new drugs approved for kids [from clinicaltrials.gov]:

PFIZER [WYETH]
ELI LILLY
From the look of things, these seem like the kind of studies one does when winding up for an FDA appproval. They are particularly focusing on suicidal thought in the ones where their primary outcome is shown. They’ve been criticized  for using items on the HAM-D or CDRS-S to assess suicidal thought, so they seem to be migrating to specific rating scales, in particular, the Columbia–Suicide Severity Rating Scale [C-SSRS] which is in the process of being validated. It’s a clinician rated scale [even being developed for a phone in system]. Note that the last author on the Gibbons article [February 2011] and on the CSSR-S article [December 2011] are the same – John J. Mann:
    J. John Mann MD, is The Paul Janssen Professor of Translational Neuroscience (in Psychiatry and in Radiology) and Vice Chair for Research in the Department of Psychiatry at Columbia University. He is Director of Research and Director of Molecular Imaging and the Neuropathology Division at the New York State Psychiatric Institute. Dr. Mann is trained in Psychiatry and Internal Medicine and has a Doctorate in Neurochemistry. His research employs functional brain imaging, neurochemistry and molecular genetics to probe the causes of depression and suicide. Dr. Mann is the Director of the NIMH Conte Center for the Neuroscience of Mental Disorders, and Past President of the International Academy of Suicide Research. Dr. Mann has published 458 papers and edited 10 books on the subjects of the biology and treatment of mood disorders, suicidal behavior and other psychiatric disorders. In private practice he specializes in the treatment of mood disorders.
Here’s the CSSR-S article recently published and the Columbia Video of the scale [proprietary]. It’s the scale used in the Emslie article on Lexapro reviewed earlier – the one I called a clinically insignificant study…:
The Columbia–Suicide Severity Rating Scale: Initial Validity and Internal Consistency Findings From Three Multisite Studies With Adolescents and Adults
by Kelly Posner, Ph.D.; Gregory K. Brown, Ph.D.; Barbara Stanley, Ph.D.; David A. Brent, M.D.; Kseniya V. Yershova, Ph.D.; Maria A. Oquendo, M.D.; Glenn W. Currier, M.D., M.P.H.; Glenn A. Melvin, Ph.D.; Laurence Greenhill, M.D.; Sa Shen, Ph.D.; and J. John Mann, M.D.
American Journal of Psychiatry 2011 168:1266-1277.

Objective: Research on suicide prevention and interventions requires a standard method for assessing both suicidal ideation and behavior to identify those at risk and to track treatment response. The Columbia–Suicide Severity Rating Scale [C-SSRS] was designed to quantify the severity of suicidal ideation and behavior. The authors examined the psychometric properties of the scale.
Method: The CSSR-S’s validity relative to other measures of suicidal ideation and behavior and the internal consistency of its intensity of ideation subscale were analyzed in three multisite studies: a treatment study of adolescent suicide attempters [N=124]; a medication efficacy trial with depressed adolescents [N=312]; and a study of adults presenting to an emergency department for psychiatric reasons [N=237].
Results: The C-SSRS demonstrated good convergent and divergent validity with other multi-informant suicidal ideation and behavior scales and had high sensitivity and specificity for suicidal behavior classifications compared with another behavior scale and an independent suicide evaluation board. Both the ideation and behavior subscales were sensitive to change over time. The intensity of ideation subscale demonstrated moderate to strong internal consistency. In the adolescent suicide attempters study, worst-point lifetime suicidal ideation on the CSSR-S predicted suicide attempts during the study, whereas the Scale for Suicide Ideation did not. Participants with the two highest levels of ideation severity [intent or intent with plan] at baseline had higher odds for attempting suicide during the study.
Conclusions: These findings suggest that the C-SSRS is suitable for assessment of suicidal ideation and behavior in clinical and research settings.

I have no question that these antidepressants can cause an agitated state called akasthisia that can be associated with exaggerated aggression and lethal thought. I’ve seen it happen myself. It’s uncommon but a big deal when it occurs. I am suspicious when someone tries to convince us that it doesn’t happen at all because the secondary gain is enormous – a huge pharmaceutical market. The other reason for my suspicion is obvious, I’ve seen akathisia occur in several adults and an adolescent with my very own eyes. I know Dr. Gibbons hasn’t seen it. He doesn’t see patients. I’m very suspicious of Clinical Trials as a way to study it, because the people who run them and write them up don’t see the patients either. They might be spread out all around the world [and the studies are funded by people who gain if it’s not seen]. I don’t even know if akathisia occurs at a rate that would appear in a statistical study.

So what is my conclusion? I don’t have one yet, but I have a high level of suspicion that the forces at work here are being driven rather than just serendipity. I’m suspicious that Dr. Gibbons fervor has a cause. I see two drug companies that stand to gain a lot by either pediatric approval or a lifting of the warning. I see a new suicidality scale being introduced and used in these studies, shepherded by the same author writing with Dr. Gibbons. I read the comments of a Biostatistician talking about physician motives and what needs to be done for patients – odd. And given the track record of this industry, in this specialty, in this time, I say that there’s enough here to try to keep this issue on the very front burner. On the other side of the coin, I don’t see a lot of evidence that these drugs are very effective in kids and adolescents in the published studies [tuning the quartet…, clinically insignificant study…] or in my own experience treating kids. Yes, I do use them. Yes I have seen them help, primarily in kids with an obsessive compulsive diathesis, but also at times with depression. But the idea that being careful with antidepressants in kids is depriving them of some kind of vital treatment is patently absurd from where I sit. Their effectiveness is such that one is glad when they do work [some], and hardly surprised when they don’t.

I’m comfortable with the advice from Dr. David Healy who has been at the forefront of this issue from the beginning:
    This is not an argument for not using Prozac. As I also mentioned in the 1991 letter to the BMJ:  “The significance of the emergence of suicidality.. is that it can be anticipated and forestalled by warning patients.”
Every time I give an antidepressant to a young person I warn them, warn those around them, and give them my home phone number. It’s never a casual prescription. And as for Dr. Gibbons next installment due out any day, I’ll be reading it very carefully. This whole scenario has the feel of pharmaceutical sheenanigans to me…
  1.  
    jamzo
    March 5, 2012 | 9:41 AM
     

    how is it that the “archives of general psychiatry” provides a free full-text view of the gibbons article?

    other articles are not accorded this status

    is someone paying for this “free full-text view”?

  2.  
    Mickey
    March 5, 2012 | 9:45 AM
     

    Excellent point! It’s very unusual as best I can tell. I had the same suspicions…

  3.  
    wiley
    March 5, 2012 | 4:42 PM
     

    I’ve been reading a lot of your posts. As a person who has been labelled as “bipolar” over a reaction to a drug, who discovered after years of useless and worse polypharmacy that the “depression” I was so afraid of having again was pernicious anemia, it gives me comfort to see someone who understands the numbers to say what I’ve been thinking for a long time.

    When I last started feeling unexplained fatigue, I did not go to a psychiatrist and describe myself as depressed and I’m glad of it. That fatigue eventually proved itself to be one of the effects of Multiple Sclerosis. I have no doubt that had I subjected myself to the psychiatric industry I would have been prescribed one cocktail after another and would have been described as “treatment resistant”.

    After my traumatic experience in nuclear forces the most twisting and damaging force I’ve dealt with is psychiatry. their labels, their dark prognostications, and their drugs.

    I did work out a lot of childhood issues with therapy before therapists started asserting in the first meeting that they wanted to put me on an antidepressant to make therapy “easier”. I find it unaffordable, if not impossible to get any kind of talk therapy that is more about listening than imposing a school of therapeutic tactics. It offends me that so many mental health professionals make so much for doing so little for their patients, especially those with MDs who appear to believe that once a person has been diagnosed with a mental disorder EVERYTHING is in the patient’s head.

  4.  
    Altostrata
    March 5, 2012 | 5:33 PM
     

    Why are the Archives of General Psychiatry and American Journal of Psychiatry etc. publishing articles with unintelligible charts and statistics? Isn’t this something the editorial board is supposed to review?

  5.  
    Peggi
    March 5, 2012 | 7:46 PM
     

    so what is the job of an editor? Especially for a professional journal?

Sorry, the comment form is closed at this time.