The Eli Lilly documents I mentioned in the last post [foul…] have quite a history indeed. Little wonder I said, "I got really lost following the timeline and their exact path from sealed documents into the public domain, and promise to try to get that in order soon." Dr. Peter Breggin had the first shot at them as an expert witness "Dr. Breggin originally found, examined and evaluated each of these documents in the early 1990s when he was the plaintiffs’ medical and scientific expert for the combined Multi-District Litigation [MDL] concerning Prozac." He’s written up their subsequent history which I couldn’t possibly summarize [An Examination of Eli Lilly and Company’s Contentions that the BMJ Prozac Documents were Never Missing and Have No Significance], but it sounds like a plot in a John le Carré novel and is worth reading over. As he tells it, as the dicuments appeared in recurrent suits against Lilly. The suits would be settled privately and the documents would be sealed and then disappear. Finally they were leaked to the British Medical Journal who forwarded them to the FDA and a member of Congress. Lilly denies involvement in their disappearance.
As for the characters mentioned in the emails, they were high-ups in Lilly at the time, in Europe and in the US. I’ve added links to the info I could find [Further links and information on David Healy’s Let them Eat Prozac site and on AHRP]:
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This is message #1 from: BOUCHY CLAUDE
November 13, 1990 10:49
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Interlude: I find myself with that déjà vu feeling again. I’m a late comer to all of this pharmaceutical business, having spent my life in another corner of the psychiatric world, and just when I think I’m finally getting caught up, I run into some new thing like "329" or "TMAP" or "STAR*D" and I start nosing around and there’s some huge saga laying in wait behind a tree. So after I clicked on Pharmagossip’s links to those Lilly emails this weekend, I found myself today falling down another rabbit hole into an alternative universe that a lot of you know all about, but I didn’t even it know was there.
Here’s just a piece of the story. It’s from a legal brief kindly forwarded by Leehmon McHenry from the Baum Hedlund law firm. It tells the story of Prozac being turned down by the BGA [Germany’s FDA] and why:
| ADDITIONAL PROPOSED FINDINGS OF FACTS | |
| 39. | German regulators expressed concerns about Prozac and an increased risk of suicidality in the early 1980’s, before Prozac was approved for marketing. |
| 40. | According to a May 25, 1984 internal memorandum from Eli Lilly and Company (“Lilly”) regarding Lilly’s efforts to obtain registration of Prozac in Germany: “During the treatment with the preparation [fluoxetine/Prozac] 16 suicide attempts were made, 2 of these with success. As patients with a risk of suicide were excluded from the studies, it is probable that this high proportion can be attributed to an action of the preparation in the sence (sic) of an deterioration of the clinical condition, which reached its lowest point.” |
| 41. | According to a June 26, 1984 Lilly memorandum, item # 10: “The BGA [German equivalent of FDA] suspects fluoxetine [Prozac] to be a stimulating/activating drug (side-effect profile, suicides, suicide attempts).” Item # 14 states: “This is a very serious issue in the opinion of the BGA. It might well be that we will have to recommend concomitant tranquilizer intake for the first 2 or 3 weeks in the package literature.” |
| 42. | A January 29, 1985 memo states: “Two major concerns [regarding the Prozac application] seem to be the reason that the registration [in Germany] was not accepted,” “efficacy questioned” and “suicidal risk.” |
| 43. | On February 26, 1985, the German Regulatory Authority told Lilly “we intend to refuse the registration of [Prozac] for the following reasons.” 2.1 states: “The use of [Prozac] seems objectionable, as the increase in agitating effect occurs earlier than the mood elevating effect and therefore an increased risk of suicide exists.” |
| 44. | A March 29, 1985 Preliminary Report of Benefit/Risk Considerations concerning Prozac written by Professor Herrmann, a professor in Germany who was hired by Eli Lilly to help the company obtain approval of Prozac in Germany, stated:“The BGA are making the objection that initially activation and agitation occur before the drug works antidepressively, and that a higher rate of suicides might result from this.” The report further states: “Overall it holds true that the higher incidence rate, for which an explanation must be found, remains in the initial phase as well as in view of the entire duration of treatment, in looking at all patients as well as patients of controlled studies. If an explanation cannot be found for this, this fact will remain a significant obstacle to approval in the Federal Republic of Germany.”. “The fact that suicide attempts are more frequent with Prozac than with imipramine [an older, comparison antidepressant] remains to be explained.” “The benefits vs. risks consideration for [Prozac] currently does not fall clearly in favor of the benefits. Therefore it is of greatest importance that it be determined whether there is a particular subgroup of patients who respond better to Prozac than to imipramine, so that the higher incidence of suicide attempts may be tolerable.” |
| 45. | According to an April 1, 1986 memorandum of a meeting with Professor Herrmann: “Still not resolved is the fact that suicide attempts have been observed more frequently on fluoxetine as compared to imipramine…. According to the today’s knowledge [fluoxetine’s ‘favourable’ side effect spectrum] is negatively affected by the increased suicidal risk.” |
| 46. | According to a December 8, 1987 FDA memo, the FDA had asked Lilly for an explanation of Germany’s concerns about Prozac. The memo, written by Dr. Richard Kapit states: “On December 4, 1987, [Lilly sent a letter to the FDA]…. regarding comments made by the German regulatory authority (the BGA) on the safety of Prozac…. The letter asserted that the German authorities never defined or documented the phrase … ‘unacceptable damaging effects’… The company asserts that all information made available to the BGA has been made available to the FDA, and to their knowledge, the FDA has used more sophisticated analyses in reviewing the data…. Conclusion: The BGA comments do not appear to reflect clinical events, since no such events have been reported to the FDA, and according to the company, we have received all information submitted to the BGA. Recommendation: The comments by the BGA should not affect FDA’s conclusion that [Prozac] NDA 18-936 is approvable.” |
| 47. | However, the February 26, 1985 memo described above did explain Germany’s concerns that “the increase in agitating [over-stimulating] effect occurs earlier than the mood elevating effect and therefore an increased risk of suicide exists.” |
| 48. | In April 1988, Lilly received “a bad surprise … an official letter from the BGA officially rejecting our application for registration!” |
| 49. | Lilly continued to pursue its application for approval of Prozac in Germany and in an August 30, 1989 memo, Lilly received feedback from the “Commission A” (an expert working/consultant group to BGA), stating that a “counterindication [for Prozac] because of acute suicidality should become a warning whereby the physicians should be advised that in the absence of sedation, the risk of higher suicidality should be taken into account.” |
| 50. | Lilly eventually gained BGA approval in 1989, but agreed to include in the German prescribing guidelines for Prozac a warning that the use of sedatives may be necessary to counteract Prozac’s activating side effects. |
Prozac was turned down in Germany in 1985 because of the akathisia and suicidality [43]. That report that says “The benefits vs. risks consideration for [Prozac] currently does not fall clearly in favor of the benefits” came from, Professor Herrmann, a consultant hired by Eli Lilly [44] – their own consultant! When the FDA asked Lilly why they were being turned down in Germany, Lilly lied outright, saying that the BGA didn’t say. When the BGA finally did approve Prozac, they required a warning [49][50]. There’s an online petition from a group called SSRI-Crusaders that has a very good narrative, including where those emails in the last post fit.
Eli Lilly has known Prozac (fluoxetine) causes akathisia, defined as an extreme subjective feeling of inner restlessness. This condition has long been known to be caused by antipsychotic drugs and recognized as leading to suicidal and homicidal-suicidal feelings. Lilly’s own internal documents show the condition was identified in association with Prozac as early as 1978. August 2, 1978, when only three trials were underway, minutes of a meeting of the Fluoxetine (Prozac) Project Team read: "There have been a fairly large number of reports of adverse reactions… Another depressed patient developed psychosis… Akathisia and restlessness were reported in some patients." A similar meeting held 10 days earlier stated, "some patients have converted from severe depression to agitation within a few days; in one case the agitation was marked and the patient had to be taken off [the] drug." The minutes further state, "in future studies the use of benzodiazepines to control the agitation will be permitted. From that point on, Lilly’s trial subjects were put on tranquillizers to get them over the akathisia experienced by some in the early days on the drug. Those who developed akathisia or who had any suicidal tendencies were excluded from the trial data on the basis that they would otherwise obscure the results of the drug’s success in treating depression.
and yet here in 2013, we still spend no small amount of time dealing with studies by Martin Keller [2001] or Robert Gibbons [2012] who try to deny what was known all those years ago. And Prozac is the index drug, the one that started this whole avalanche of the me-too drugs that poured from the pipeline aided by the widespread pharmaceutical-academic alliances that have made swiss cheese out of psychiatry for over three decades. Lewis Carroll and Alice didn’t have anything on us…
The ugly picture of big pharma companies cherrypicking data, manipulations, streams of lies, scientific fraud, the abhorrent spectacle of greedy vultures feeding on vulnerable people is out and in the public domain.
Slowly, painstakingly, thanks to individual patients, bereaved parents, scientific truth seekers as you are – we know. And the landscape of health care is being transformed, slowly maybe, but the monopoly of knowing the facts has been breeched.
The daily Svenska Dagbladet has just published its investigation of class-differences in medicating children, which accords with the known socio-economic map of Stockholm. Less educated parents, smaller family income, more pscych drugging of children… and I just received an invitation from Helsedirektoratet, the Norwegian NIH, for a national conference on medication-free treatments of psychic problems. The initiativ came originally from users, survivors and family members, and has taken a few years, like any political case of great importance to ordinary people, we, the majority on this beautiful, fragile earth. Thanks for your illuminating blog!
The memo written by Claude Bouchy November 13, 1990, reproduced here and in your previous post, went to Sidney Taurel, among others. At that time Sidney Taurel was based in London as vice president of Lilly European operations. From 1998 to 2008 he was CEO of Eli Lilly and Company. In 2006 plus 2007 Mr. Taurel’s salary at Lilly was over $20 million. Mr. Taurel has no training in medicine or pharmacology. He is now retired from Lilly and moves in high level business consulting and advisory circles.
When confronted with the ethical question posed by Claude Bouchy, Mr. Taurel had the option to give firm direction to his employees that they should not tamper with the adverse event reports coming in from the field. Did he choose that option? You be the judge.
One person after another is registering on my site with accounts of initial adverse reactions to antidepressants along the lines of hyperalerting, akathisia, etc. which their doctors deal with by prescribing benzos, thus compounding a situation of chronic adverse drug reactions.
This is so common as to have been addressed, in a sideways way, by clinician Jim Phelps in this paper http://www.medical-hypotheses.com/article/S0306-9877%2812%2900252-6/abstract
In personal correspondence, Dr. Phelps says he sees the combination of an antidepressant and a benzo as a red flag. Patients having difficulty withdrawing from the combination poses a daily challenge to him in his clinic work.
“In personal correspondence, Dr. Phelps says he sees the combination of an antidepressant and a benzo as a red flag. Patients having difficulty withdrawing from the combination poses a daily challenge to him in his clinic work.”
Yeah, and guess who is doing this stupid crap more and more these days and then dumping it on psychiatrists? Hint in that last sentence, if they are dumping it ON psychiatrists, it ain’t psychiatrists. I just love all this hostile verbage at mental health sites attacking us, when it is non psychiatrists doing this stuff with the reckless abandon that is destroying what little responsible credibility some psychiatrists still practice.
But, not so easy to spew venom at “Doctors” as a generality, is it?
Oh, and not at the growing numbers of patients who demand meds at moment one, because you can’t spew venom at “the public” either.
Nice to have scapegoats, when the mirror is just a turn away.
Mickey,
You write brilliantly.
There are many that already know about the Prozac debacle but there are more who don’t.
By writing a piece in layman’s terms you are introducing those that don’t know into a whole new world of underhand shenanigans.
I read a lot of Grisham, in fact I think I only need to read two more of his books and I’m up to speed on his vast work. Much of what he writes is fiction but he writes based on his research and experience.
You are so right about this all being like a John le Carré novel – only trouble is… many turn a blind eye to the obvious because when one becomes embroiled in all of this one finds it’s been going on for years, worse still, it’s still going on.
Lilly baked a cake and added some nice sugary icing. The rest came along and just made that cake more appealing to those who thought they were starving of a chemical imbalance.
Lilly’s lawyers are a piece of work too. I highly recommend, ‘The Power to Harm: Mind, Medicine, and Murder on Trial’ – I wrote a review for it here – http://fiddaman.blogspot.co.nz/2010/05/power-to-harm-mind-medicine-and-murder.html
SO on balance: HAVE ANTIDEPRESSANTS DONE MORE HARM THAN GOOD?
How many lives have been saved or turned around b/c of them – v. not?
What is this rally against the biological psychiatry? You can dig up as much crap as you want. (actually you can do it in any field.) But unless you can address the above, all you’ve got going here is a morality play in SSRI-landia.
I have every respect for people who demand that corporations be ethical. Our lives depend on this. However, why are the stinky Lilly-gate emails so shocking? Intellectually speaking: people across the board “suck.” Why would anyone ever want to spend life parsing the good people from the bad? Well, I suppose it could be considered a worthy personal existential study. One finger forwards, three back.
Both the science and the anecdotes tell a compelling story. If you are one of the <<1% of the general population with authentic severe MDD you are screwed. In fact: you are so screwed that you are either so slowed down or restless/agitated – in either case – that you are off the charts/tabulations. I know this by science and by anecdote – "on balance these medications work spectacularly for some authentic patients." As I said before – if you or your loved ones are bothered by side effects then, you or they are the rare outliers – or hardly depressed at all. And maybe that is from where the guilt and anger issues. These medications, despite what marketeer hucksters say, are not a panacea for the misery of LIFE.
PROZAC makes some depressed people motorically restless, emotionally agitated, and some after taking it – kill themselves. Yet, in 1977 before the world became vaccinated with SSRIs, we were cautioned that depressed patients needed to be monitored carefully at about 3.weeks after starting sedating Tricyclic antidepressants (i.e., sedating as compared today w/ SSRIs) . We were told that It was about then, people w/ MDD might become "activated"; might have the energy to put suicidal musings into action; just prior to feeling better. So yes. SSRIs caught on; MDD came out of the closet; and every Tom-Dick-Harry who suffered from "LIFE" jumped on the bandwagon. Compared with the TCAs, SSRIs were marketed as candy. Makes you wonder why they were not dispensed in PEZ containers.
So, how do you all see the following?
GLYX-13, an NMDA Receptor Glycine-Site Functional Partial Agonist, Induces Antidepressant-Like Effects Without Ketamine-Like Side Effects
Jeffrey Burgdorf1, Xiao-lei Zhang2, Katherine L Nicholson3, Robert L Balster3, J David Leander1, Patric K Stanton2, Amanda L Gross1, Roger A Kroes1 and Joseph R Moskal1
1Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, McCormick School of Engineering and Applied Sciences, Northwestern University, Evanston, IL, USA
2Department of Cell Biology & Anatomy, New York Medical College, Valhalla, NY, USA
3Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA
Correspondence: Dr JR Moskal, Director, Falk Center for Molecular Therapeutics, Northwestern University, Department of Biomedical Engineering, 1801 Maple Ave, Suite 4300, Evanston, IL, 60201, USA, Tel: (847) 491-4802, Fax: (847) 491-4810, E-mail: j-moskal@northwestern.edu
Received 1 November 2012; Accepted 8 November 2012
Accepted article preview online 3 December 2012
Top of page
Abstract
Recent human clinical studies with the NMDA receptor (NMDAR) antagonist ketamine have revealed profound and long-lasting antidepressant effects with rapid onset in several clinical trials, but antidepressant effects were preceded by dissociative side effects. Here we show that GLYX-13, a novel NMDA receptor glycine-site functional partial agonist, produces an antidepressant-like effect in the Porsolt, novelty induced hypophagia, and learned helplessness tests in rats without exhibiting substance abuse-related, gating, and sedative side effects of ketamine in the drug discrimination, conditioned place preference, pre-pulse inhibition and open field tests. Like ketamine, the GLYX-13-induced antidepressant-like effects required AMPA/ kainate receptor activation as evidenced by the ability of NBQX to abolish the antidepressant-like effect. Both GLYX-13 and ketamine persistently (24 hr) enhanced the induction of long-term potentiation of synaptic transmission and the magnitude of NMDAR-NR2B conductance at rat Schaffer collateral-CA1 synapses in vitro. Cell surface biotinylation studies showed that both GLYX-13 and ketamine led to increases in both NR2B and GluR1 protein levels as measured by Western analysis, whereas no changes were seen in mRNA expression (microarray and qRT-PCR). GLYX-13, unlike ketamine, produced its antidepressant-like effect when injected directly into the medial prefrontal cortex (MPFC). These results suggest that GLYX-13 produces an antidepressant-like effect without the side effects seen with ketamine at least in part by directly modulating NR2B-containing NMDARs in the MPFC. Furthermore, the enhancement of ‘metaplasticity’ by both GLYX-13 and ketamine may help explain the long-lasting antidepressant effects of these NMDAR modulators. GLYX-13 is currently in a Phase II clinical development program for treatment-resistant depression.
Keywords: NMDA Receptor; GLYX-13; Ketamine; Depression; Medial Prefrontal Cortex.
Context is everything. Just how sucky/stinky are Burgdorf, Zhang, Nicholson, Balster, Leander, Stanton, Gross, Kroes and Moskal?
Regards,
Mark
Yes. I am aware that some here have lost mentally ill loved ones . And for this my field has failed you – but not for the reasons you might think.
LIFE sucks, except when it does not.
FWIW I am a fan of Healy: e.g., from a CNN report:
“Healy noted that when data surfaced showing a link between antidepressant use and risk of suicide in children, the APA issued a statement proclaiming that “we believe that antidepressants save lives.”
“What I believe they should have said is that the APA believes that psychiatrists can save lives because it takes expertise to manage the risks of risky pills,” he said; if psychiatrists’ only role were to dole out drugs, then less trained physician’s assistants could easily replace them, he noted.
But when a questioner, claiming himself “speechless” in the face of Healy’s arguments, asked whether he should just stop prescribing antidepressants, Healy said no. Healy prescribes them himself, but believes that the role of the doctor is to manage risks, not view drugs as harmless. “Medical treatment is poison, and the art of medicine is trying to find the right dose,” he said.
As for what could be done to disentangle medicine from industry, Healy wasn’t entirely pessimistic.
“The key issue in the short term is access to data. We have to insist on that,” he said. “We let industry come to our meetings and let them talk in our programs. I don’t think it’s huge problem that they get paid. The big problem is that if you ask for data, they can’t give it to you. That’s not science, that’s marketing masquerading as science.”
Mark K hits it on the head, which is why many at sites are so frustrated and rage: the issue, like most in our culture, is gray, or grey, how ironic even the word had two equivalent spellings. People benefit, people detriment, and people just tread water with medication. But in the end, illness is multifactorial, and so is treatment.
If 70% of surgery was done today by people who went to the ACME school of surgery and created more screw ups post operatively, would you blame surgeons for the problems? Unfortunately, I think many would! Again, part of scapegoating is targeting people who care enough to react to the accusations.
Gives the accusers an extra kick in their attacks.
Not that there aren’t enough psychiatrists out there who practice like they went to an ACME school of psychiatry. When medicine embraced the business model of practice, thus was born the spawn of evil!
Just my opinion.
Dr. Hassman,
I understand your position about non psychiatrists who prescribe 75% of psych medication. One of them tried to bully me into taking some.
However, it was one of your colleagues who put me on Prozac and Ritalin several years ago. When I became suicidal, my dose was doubled and of course, I got worse. I was then cold turkeyed off of the meds which led my descent into what I call psych med hell for several years.
I don’t think my story is unusual. Psychiatry’s answer when patients have adverse reactions is to blame it on mental illness and give them more of the meds that are poisoning them.
And in some cases like a friend of mine, who complained about an adverse reaction to an antipsychotic, this person was forcibly committed against her will. Her crime was to get understandably belligerent when the bleeping psychiatrist blamed her complaint on her mental illness.
I know it is painful as a psychiatrist who obviously cares about doing the right thing to read blog entries like this. But you’re doing nothing to further the discussion by accusing people of various venom, particularly when so many people like myself have been injured by psychiatry.
Mickey, these blog entries are painful to read as someone who experienced suicidal ideation on Prozac. But I thank you profusely for the service yo are providing in telling the truth about what happened.
Anger comes in all shades. Mine is cold, determined. I will do what I can to educate myself and my world to the dangers of blindly accepting “expert advice”. It’s all too often laden with vested interests. It’s limited, often selfconstricting.
I’ve had to bury a young son. He died in his sleep from what I did not know then, but know now, influence on every organ and the heart of neuroleptic medication, and the carelessness of the medical staff who did not inquire about known irregularities of hearts of family members.
When grief subsides, anger gives new energy. It may be a life force. Honest professonals have reason to be angry and defend medicine as art, as a cooperative undertaking and as politics – in order to lessen suffering, not just make piles of money.
There’s much to be angry about. We’d better use that force as wisely as we can. Mickey Nardo is on a good track, in my opinion. I thank him from my heart..
In bleak moments I’m still blaming myself for having trusted the local shrink. I did not even know there were creatures called “thought leaders” in medicine. He was. He still is. There’s work to be done.
Is it psychiatrists or GPs who are publishing dishonest articles misrepresenting the benefits and risks of psychiatric drugs?
Mark, your comment, “Yes. I am aware that some here have lost mentally ill loved ones .”
Are you suggesting that those that have suicided were mentally ill and it had nothing to do with the medication.
Many of the suicides that have occurred on these meds were by patients given the drug/s for such things as insomnia, school examination jitters, relationship breakdowns – Are any of these three mental disorders? In some instances patients have had their diagnosis deferred, been prescribed psychiatric meds then gone on to complete suicide – were these group of patients mentally ill too?
Be interested in your thoughts without any kind of personal spat.