birdman…

Posted on Tuesday 24 February 2015

I saw Birdman or (The Unexpected Virtue of Ignorance) Saturday night, one day before the Oscars, and by Sunday night, I was rooting for it to win, even though it was in the running with some other amazing films. In Atlanta, we had [still have] a film series at Emory called Movie Mania, attended by members of the Mental Health Community and trainees at large in the many different programs in the area. It’s only a matter of time before Birdman will be on the screen in one of those discussions – guaranteed. It’s a classic, in the genre and league with One Flew Over the Cuckoo’s Nest, but unlike that film [or A Beautiful Mind, or Shutter Island, or the King of Hearts] – in Birdman, neither Psychosis nor any kind of Mental Health anything is ever mentioned.

As much as I would love to talk on and on about this film, a Blog is no place to ruin a movie for those who haven’t seen it. So I’ll just make a few comments. In the movies, we all cheer for these characters played by Michael Keaton, Jack Nicholson, Russel Crowe, Leonard DiCaprio, and Alan Bates [Martin Scorsese’s Shutter Island may be an exception, but you’ll have to see it to know why]. We all cheer for the protagonists, even with their often tragic endings – everyone in the audience, including the psychiatry residents who then leave the film series to go back to the Emergency room and have to deal with the out of control psychotic people brought by the police, or by distraught family and friends [see this comment on the last post for their dilemma].

The brilliance of Birdman is that it’s not about mental illness, it’s about an aging actor who is searching for an authentic connection with life by adapting a serious drama [by Raymond Carver] about the power of love and connectedness on Broadway. His real success in life had been in his role in a series of popular heroic fantasy films in which he played the caped Birdman - a superhero with superpowers – but he lead something of a meaningless life otherwise with angst and failed relationships. We learn in the opening scene that, in private, he actually has Birdman’s superpowers, hears the voice of the character Birdman, and at times he actually becomes Birdman [again in private] under stress. So Michael Keaton [who was the first film Batman], is a character who contains the psychotic dilemma without anyone medicating him or anyone enthusiasticly aiming him towards recovery. He doesn’t even have a mental illness. He’s just a guy that can’t experience his sense of being in life, and also secretly is a superhero, but doesn’t feel his life in that role either.

I’m about to tell the end of the movie. I don’t think it will interfere with seeing it, but if you hate spoilers, bookmark this post and come back after you’ve seen it. By the way, see it for sure. When you see it, first read the blurb about Raymond Carver’s life. And pay particular attention to the Edward Norton and Emma Stone characters, who, like a Greek Chorus, narrate the dilemma throughout the film in their own lives. ‘I only feel real on the stage, not in my life.’

Keaton’s character achieves authenticity by using a real gun in the ending suicide scene on the opening night of the play. He doesn’t die, but shoots off his nose. While he achieves critical acclaim, it’s a hard act to follow obviously. Looking in the mirror in the hospital, he sees his reconstructed nose which is radically different [looks like a beak]. As a matter of fact, we notice that his bandages look like the Birdman mask. Seeing some birds, he goes to the window and opens it. Later, when his daughter [Emma Stone] comes in the room and sees the open window with him gone, she races to first look at the ground far below with alarm. Then she looks up, and smiles. The end. We smile too. We’re smiling for the Keaton character who seems to have escaped as the Birdman – flying free of the mess on the ground. But what we’ve seen in truth, is a man jumping from the window of a multistory building. That is a dilemma…

When I wrote which side of the street?…, I suppose I hoped I’d be able to focus on Jeffrey Lieberman’s inappropriate and pompous rant on Medscape and avoid the British Psychological Society‘s report. But I can see I’m not going to get away with that. That is, in fact, one of the things that I find so hard about discussing this topic. No matter what I say about psychosis as I see it, I’m seen as taking a side and get hit from some other side as a <something not good>. Mention using neuroleptic medication and I’m a power hungry self-righteous ‘MDeity‘ who loves committing people. Say something about the recovery metaphor, or the down-side of diagnoses, or over-medication, and I’m suddenly a naive 60s type who thinks ‘all you need is love‘ who doesn’t understand trauma. Talk about psychotherapy, and I’m an unrepentant psychoanalyst who way overvalues "talk therapy" and "fanciful theories." At 73, I may have visited each of those pastures along the way, but it was a long time ago and I no longer remember even what they felt like. They didn’t fit for me because each of them relies on a notion of causality, and I don’t know what causes psychosis, or even if it’s a single thing. I tend to use the term Schizophrenia and its traditional subtypes in conversation, but even that has changed for me. Catatonia has been split off in a very helpful way. And there’s no question that in early days, I included cases I would now see as having obvious Manic-Depressive Illness. The ground shifts when you’re without the more solid signatures of my Internist days. But it is what it is.

So I’ll talk about that British Psychological Society‘s report in a bit. And I’ll get back to Birdman [and hope others have thoughts about it too]. First, I guess I’ll have to at least touch on the endless interdisciplinary wars in mental health. But for the moment, there’s something else. This picture is the view from my front porch right now [that has shut down our whole county, closing the clinic I was supposed to work in today], and there are things to be dealt with like logs to bring in from that smaller open shed [I know there’s laughter in Boston, but this ain’t Boston. It’s wimpy Georgia…]:
Mickey @ 12:12 PM

which side of the street?…

Posted on Monday 23 February 2015

the background…
  • The British Psychological Society
    Division of Clinical Psychology

    This report of the British Psychological Society mirrors a widespread reaction against a purely biomedical explanation for psychosis, for Schizophrenia. They propose the alternative possibility that it can be an adaptation to childhood trauma and abuse. They advocate access to psychotherapy for these patients and suggest using neuroleptic medications only when helpful or requested, not as a steady diet. "Many people find that ‘antipsychotic’ medication helps to make the experiences less frequent, intense or distressing. However, there is no evidence that it corrects an underlying biological abnormality. Recent evidence also suggests that it carries significant risks, particularly if taken long term." This report comes from the UK where offering talk therapy to psychotic patients is apparently mandated, but not really available. Something like that.

  • New York Times
    January 18, 2015

    Tanya Luhrman is an Anthropologist at Stanford. Among her books, Of Two Minds is a study of the transformation within psychiatry in the 1980s. In this New York Times piece, she reports favorably on the British Psychological Society’s report above, saying: "The implications are that social experience plays a significant role in who becomes mentally ill, when they fall ill and how their illness unfolds. We should view illness as caused not only by brain deficits but also by abuse, deprivation and inequality, which alter the way brains behave. Illness thus requires social interventions, not just pharmacological ones. One outcome of this rethinking could be that talk therapy will regain some of the importance it lost when the new diagnostic system was young. And we know how to do talk therapy. That doesn’t rule out medication: while there may be problems with the long-term use of antipsychotics, many people find them useful when their symptoms are severe…"

  • New York Times
    January 27, 2015

    Luhrman had mentioned that the NIMH had abandoned the DSM-5 and instituted their RDoC Project. Paul Summergrad, current APA President, offered a short clarifying reply to her NYT piece: "Ms. Luhrmann notes approvingly that the National Institute of Mental Health, in beginning a program called Research Domain Criteria, determined that existing psychiatric diagnoses ‘were neither particularly useful nor accurate for understanding the brain, and would no longer be used to guide research.’ However, she does not mention a joint statement by the institute’s director, Dr. Tom Insel, and the former president of the American Psychiatric Association, Dr. Jeffrey Lieberman, which explained: ‘All medical disciplines advance through research progress in characterizing diseases and disorders. DSM-5 and RDoC [Research Domain Criteria] represent complementary, not competing, frameworks for this goal.’ Precisely."

  • Medscape
    February 18, 2015
the foreground…

In the Medscape article, Jeffrey Lieberman, immediate past President of the American Psychiatric Association, comes out of the gate with:
The article about mental illness was an incredibly unscholarly, misinformed, confused — at worst, unhelpful, and at best, destructive — commentary that will add to the confusion about the diagnosis of mental illness, enhance the stigma, and may lead some patients to doubt the veracity of the diagnoses that they have been given and the treatments that they are receiving. Specifically, Dr Luhrmann was prompted to write this by a report that came from the British Psychological Society, which is a professional organization in the United Kingdom. This report, titled Understanding Psychosis and Schizophrenia, suggested that hearing voices and having feelings of paranoia were common experiences; that they commonly occur in the course of everyday life, particularly in the context of trauma, abuse, or deprivation, and that they shouldn’t be considered symptoms of mental illness and attached to diagnoses because that is only one way of viewing them. Viewing diagnoses as normative mental phenomena has relative advantages and disadvantages. This strikes me as preposterous. It is, at best, phenomenologic relativism, and at worst, simply conflating symptoms with a disorder or a disease… Viewing it this way is, in a way, challenging the veracity of diagnoses and giving people who have symptoms of a mental disorder, license to doubt that they may have an illness and need treatment…
It is not my intent in this blog to defend or oppose the position of the British Psychological Society or Luhrman’s piece. Standards of proof transcend the opinions of any of us. It is, however, my intent to ask, "Who does Jeffrey Lieberman think he is?" "What gives him the right to lambast people who disagree with him with a string of contemptuous invectives like this?" "Does he not realize that if these critics overstate their case, it is at least partly in response to his kind of rigid self-righteousness?" And Tanya Luhrman didn’t write this because of the British report. It’s part of her long held opinion, one that runs as a thread throughout her academic career. But my central point is that Lieberman’s disdainful language and dismissive tone is way out of line no matter what she thinks – conduct unbecoming…
Next, the article addresses the fact that there is no evidence that antipsychotic drugs correct any biologic abnormality, which also is inaccurate. Antipsychotic drugs work through the antagonism or the blocking of dopamine. They may have other downstream and upstream effects with a neural pathway, but the link between dopamine activity and psychotic symptoms is indisputable. After making this point, which essentially equates symptoms with illness, the author says that this is consistent with the view taken by the National Institute of Mental Health [NIMH] Director Tom Insel…
We all know that antipsychotic drugs block dopamine. Neither how that affects psychosis nor whether dopamine is directly involved in the cause of psychosis is any more known now than it was when I first learned about it in the 1970s. Is he missing the point on purpose? To use one of his medical analogies, narcotics are a vital ingredient in treating kidney stones. If you’ve had one, you know what I mean. But kidney stones have nothing to do with opioid receptors. And as for Tom Insel’s blog about the NIMH abandoning the DSM in the run up to the release of the DSM-5, Luhrman’s article is clear that the position of the British Psychological Society is not the same as that of the NIMH. And I expect the joint statement later issued by Lieberman and Insel  came after a few rather steamy phone calls with a rant that rivals this one.
Why would such a report be printed in a widely respected publication such as the New York Times? What other medical specialty would be asked to endure an anthropologist opining on the scientific validity of its diagnoses? None, except psychiatry. Psychiatry has the dubious distinction of being the only medical specialty with an anti-movement. There is an anti-psychiatry movement. You have never heard of an anti-cardiology movement, an anti-dermatology movement, or an anti-orthopedics movement. What would give an anthropologist license to comment on something that is so disciplined, bound in evidence, and scientifically anchored? I can’t imagine how the New York Times editors would think that providing a platform for this would be useful. Maybe they want to be edgy. They want to be provocative and they think this is going to be somewhat controversial and attract readers. It may be interesting reading, but frankly, I think it’s irresponsible.
Besides his apparent misunderstanding of the functions of media, this is a low point. There is, indeed, an antipsychiatry movement, but this isn’t it. That movement is suffused with the same kind of contempt and disdain as his own comments here. If he doesn’t know the difference, I’ll be glad to send him the links that will make the differences immediately apparent. And as for his having to "endure" criticism by an Anthropologist, what does he think Anthropology actually is? Is my discipline is longer than your discipline really an argument he wants to make in an enlightened world? And are his amateur commentary on the motives of the New York Times evidence-based or simply a defensive screed? My vote is clear.
Among her publications are "Understanding the American Evangelical Relationship With God," "Case Studies in Culture and Schizophrenia," "Other Minds: Essays on the Way Mind Understanding Affects Mental Experience," "Of Two Minds: The Growing Disorder in American Psychiatry," and "Persuasions of the Witch’s Craft: Ritual Magic in Modem Culture." This hearkens back to the days when psychiatry had only fanciful theories about the mind and what caused mental illness in people, and also, unfortunately, when it tried to implement ineffective or, at times, harmful and even barbaric treatments. Thankfully, we are well past that. We now have scientifically developed and proven efficacious treatments that are safe and are changing and, in many cases, saving lives.
After thirty-five years of hearing dismissive phrases like "fanciful theories about the mind" about things that have been important to my own and many others understanding of mental illness and mental life, I am probably not the person to rationally even comment on this part, so I’ll pass. But I am a psychiatrist who actually uses the treatments he mentions in that last sentence and keeps up with the science involved. Both the British Psychological Society and Tanya Luhrman recognize the place of medications in treating psychosis, but imply that the medications have been over-used, which they have. They lobby for a place for "talk therapy" in the treatment of psychotic people, which I agree with no matter what one thinks about causality. And while I might generally differ with their contentions about etiology, theirs is a hypothesis to be proven just like any other, not something to mock.
Finally, when I read the article, disappointed and annoyed as I was, I tried to write a serious, responsible, and constructive letter to the editor, which I submitted within 24 hours. Seventy-two hours have elapsed since the article’s publication. I haven’t heard from the Times about their interest in publishing my response, so I assume they won’t publish it. The name that I publish under is my own. My credential is the Chairman of Psychiatry, Columbia University College of Physicians and Surgeons, one of the leading departments of psychiatry in the country, past president of the American Psychiatric Association, and author of the forthcoming book for the lay public called Shrinks: The Untold Story of Psychiatry. Assuming that my letter was not completely uninformed or incoherent, I would think that there would have been reason to accept it, given my credentials and the fact that I made a reasonable point. Let’s see if they print it. If they don’t, that adds further to my dismay over what I consider to be journalistically irresponsible behavior by this once-respected newspaper.
One of the rules about making a diagnosis, particularly in psychiatry, is therapeutic intent – a diagnosis is something you do for a patient, not to them. But Dr. Lieberman should be aware that the temptation in the minds of many readers of this piece with his level of self importance and entitlement is to see him as the object of diagnosis rather than an expert in diagnosis. And equally, one might legitimately ask why Medscape would publish his embarrassing rant.

My own dog in this hunt has to do with an acquired pet peeve. I wrankle when people personify psychiatry as in "psychiatry thinks …" as if psychiatry is a unity all of one mind. I have the same reaction to "psychoanalysis thinks …" for that matter. Because what comes next is usually something I don’t think. But I try to keep my mouth shut because I can see why people do that. He purports to speak for all of us. But I sure don’t think all that Dr. Lieberman says in this piece. And I don’t think what the British Psychological Society or Tanya Luhrman think either, though their general recommendation of more judicious use of medication and access to "talk therapy" have always been part of my own thinking about these patients. Since I don’t know what causes psychosis, I would justify both recommendations on other grounds. There is little question in my mind that the neuroleptic medication can prevent relapse, and in a significant number of cases, that’s an important dilemma added into the mix.

When I arrived on the scene in psychiatry forty years ago, the psychoanalysts were entrenched in the seats of power much as the bio-psychiatrists are now. Some spoke from an arrogant position similar to that taken by Dr. Lieberman here. Even as an immigrating rookie from another specialty, I could sort of smell where that was headed. So it was back then that I learned about what happens when a paradigm flows way beyond its defensible boundaries. And like now, there was money involved – billing medical insurance for long but often optional psychotherapies. A sense of rightness clouded their vision and they missed many opportunities to become right-sized, attacking or becoming defensive when they should’ve been listening and adapting. Sounds familiar. Things were lost in the process.

That epoch is too much a part of my own history for me to feel great comfort in extrapolating it into the present with any certainty, but for what it’s worth, it feels like it’s a pertinent analogy – a time to clean up our side of the street rather than point across the road. I have doubts that Dr. Lieberman is going to be any help at all in that enterprise…

Addendum: An earlier version:
  • by Jeffrey A. Lieberman
    Scientific American
    May 20, 2013
  • by Judy Stone
    Scientific American
    May 24, 2013

    "Conclusion: So many symptoms are now being medicalized, even absurdly, grief. It makes me wonder if there a DSM 5 diagnosis for someone who is self-serving, can’t accept criticism, and believes critics are prejudiced bigots? I was very disappointed to see Dr. Lieberman’s shallow, self-serving and evidence-free diatribe appear in Scientific American as a guest opinion. He failed to reveal important conflicts of interest. He made serious claims for which he presented no evidence. He has made thinly veiled personal attacks on his critics, without offering anything substantive to counter rationally…"

Mickey @ 6:00 PM

legitimately trying…

Posted on Sunday 22 February 2015

This morning’s thermometer says that we’re finally starting to thaw out down here a bit. Time for a real blog with graphs and numbers. Within the few years after the introduction of the Selective Serotonin Reuptake Inhibitor [SSRI] class of antidepressants, their association with suicidal ideation, suicide attempts, or suicides became the question of the hour based on case reports. There was an FDA Hearing in 1991 that didn’t find a signal sufficient for action. But by the next FDA Inquiry in 2004, meta-analysis of Clinical Trials was added to the case reports, and the FDA concluded that a signal justified adding a Black Box Warning to all antidepressants for adolescents, later extended to young adults. Throughout this period, investigators have also attempted to examine large practice databases to clarify this relationship.

No single source tells us all we want to know. Individual Case Reports have no Denominator so we can’t calculate and compare rates. Clinical Trials often have Placebo Controls, but are short duration and are subject to publication and other biases. And the large practice databases have no Placebo Controls for comparison. The study reported here is from  a large UK database that included roughly a quarter of a million patients with analyzable data. There was a disparity in the frequency of the prescribed antidepressants:
by Carol Coupland, Trevor Hill, Richard Morriss, Antony Arthur, Michael Moore, and Julia Hippisley-Cox
British Medical Journal. 2015;350:h51.

Objective: To assess the associations between different antidepressant treatments and the rates of suicide and attempted suicide or self harm in people with depression.
Design: Cohort study. Setting Patients registered with UK general practices contributing data to the QResearch database. Participants 238 963 patients aged 20 to 64 years with a first diagnosis of depression between 1 January 2000 and 31 July 2011, followed up until 1 August 2012.
Exposures: Antidepressant class [tricyclic and related antidepressants, selective serotonin reuptake inhibitors, other antidepressants], dose, and duration of use, and commonly prescribed individual antidepressant drugs. Cox proportional hazards models were used to calculate hazard ratios adjusting for potential confounding variables.
Main outcome measures: Suicide and attempted suicide or self harm during follow-up.
Results: During follow-up, 87.7% [n=209 476] of the cohort received one or more prescriptions for antidepressants. The median duration of treatment was 221 days [interquartile range 79–590 days]. During the first five years of follow-up 198 cases of suicide and 5243 cases of attempted suicide or self harm occurred. The difference in suicide rates during periods of treatment with tricyclic and related antidepressants compared with selective serotonin reuptake inhibitors was not significant [adjusted hazard ratio 0.84, 95% confidence interval 0.47 to 1.50], but the suicide rate was significantly increased during periods of treatment with other antidepressants [2.64, 1.74 to 3.99]. The hazard ratio for suicide was significantly increased for mirtazapine compared with citalopram [3.70, 2.00 to 6.84]. Absolute risks of suicide over one year ranged from 0.02% for amitriptyline to 0.19% for mirtazapine. There was no significant difference in the rate of attempted suicide or self harm with tricyclic antidepressants [0.96, 0.87 to 1.08] compared with selective serotonin reuptake inhibitors, but the rate of attempted suicide or self harm was significantly higher for other antidepressants [1.80, 1.61 to 2.00]. The adjusted hazard ratios for attempted suicide or self harm were significantly increased for three of the most commonly prescribed drugs compared with citalopram: venlafaxine [1.85, 1.61 to 2.13], trazodone [1.73, 1.26 to 2.37], and mirtazapine [1.70, 1.44 to 2.02], and significantly reduced for amitriptyline [0.71, 0.59 to 0.85]. The absolute risks of attempted suicide or self harm over one year ranged from 1.02% for amitriptyline to 2.96% for venlafaxine. Rates were highest in the first 28 days after starting treatment and remained increased in the first 28 days after stopping treatment.
Conclusion: Rates of suicide and attempted suicide or self harm were similar during periods of treatment with selective serotonin reuptake inhibitors and tricyclic and related antidepressants. Mirtazapine, venlafaxine, and trazodone were associated with the highest rates of suicide and attempted suicide or self harm, but the number of suicide events was small leading to imprecise estimates. As this is an observational study the findings may reflect indication biases and residual confounding from severity of depression and differing characteristics of patients prescribed these drugs. The increased rates in the first 28 days of starting and stopping antidepressants emphasize the need for careful monitoring of patients during these periods.

Supplementary Data: «link»

The overall percentages of completed and attempted suicides are shown in this table with significant values shown in red [among classes relative to SSRIs – among drugs relative to Citalopram]:
The main contribution from this study is "when" suicides and suicide attempts occur. The strongest signal is in the first 28 days after starting the antidepressant with a smaller signal in the 28 days after discontinuing the drug:
Here are some of the author’s comments from the full text of the article:
The suicide rates in our study cohort [43 per 100 000 in men and 9 per 100 000 in women] are higher than those in the general population in England [three year average rates of 12.4 per 100 000 in men and 3.7 per 100 000 in women for 2010-12]. Larger differences than this might be expected since our rates are in patients with a diagnosis of depression rather than in the general population. Studies showing greater differences, however, have tended to be in secondary care settings, where patients have more severe depression. These results are consistent with those of our previous cohort study in older people with depression, which found that trazodone, mirtazapine, and venlafaxine were associated with the highest rates of attempted suicide or self harm in people aged 65 or more.

Conclusions:
This study has found that rates of suicide and self harm were similar during periods of treatment with selective serotonin reuptake inhibitors and tricyclic antidepressants, but were higher for the group of other antidepressant drugs, with mirtazapine, venlafaxine, and trazodone being associated with the highest risks. The number of suicide events was small so the results for suicide should be interpreted with caution. Rates tended to be highest in the first 28 days after starting treatment and remained increased in the first 28 days after stopping treatment. These findings are of associations rather than causal effects and are particularly susceptible to confounding by indication, channelling bias, and residual confounding; further research is needed to confirm them. The results of this study indicate that patients taking antidepressant drugs should be carefully monitored, especially during early treatment with antidepressants and when stopping treatment.
In this cohort of almost a quarter of a million patients from general practices in the UK with a diagnosis of depression, 87.7% of them were put on an antidepressant drug [lest we have any question about the ubiquity of the use of antidepressants]. In a population study like this, it’s impossible to directly address whether suicidality can be attributed to the drugs or is related to the depression itself, but in either case, the study supports early treatment and the weeks after coming off the medications as the high risk periods. In the cases of trazodone [Desyrel®], mirtazapine [Remeron®], and venlafaxine [Effexor®], the increased incidence of suicidality does appear drug related [in this and other studies]. 

Why is this article being blogged here? It’s because it’s the first one of these big database studies on this topic that’s legitimately trying to convey something useful to the medical community, and I believe what they say. The others, so far, have just been tricks to undermine the Black Box Warnings.
Mickey @ 8:00 AM

no good deed goes unpunished…

Posted on Friday 20 February 2015

    Society holds our interactions with our customers – healthcare providers and payers – to a higher standard. And it should. Society expects our business to be conducted openly and transparently and in a way that does not create even a perception of inappropriate influence.
    Deirdre Connelly speech January 2010
The quote is from a speech given by then newly appointed CEO of GlaxoSmithKline America, Deirdre Connelly, at the CBI 8th Annual Pharmaceutical Industry Compliance Congress in January 2010. It was a year and a half before GSK agreed to their $3 B settlement, "GSK agreed to plead guilty to a three-count criminal information, including two counts of introducing misbranded drugs, Paxil and Wellbutrin, into interstate commerce and one count of failing to report safety data about the drug Avandia to the Food and Drug Administration." And it was long before GSK’s ChinaGate scandal. When I read this speech back then, I was awed [see “so what went wrong?”…]. I guess I thought that either Connelly was the biggest sociopath on the planet, or she was an angel. I suspected the latter, but felt like I might be being the most gullible naive guy on the planet. I even hoped GSK would confess their sins [Study 329 for example]. But that didn’t happen. Deirdre Connelly, however, did happen. But now…
Pharmalot: WSJ
Feb 17, 2015

In the latest shift at GlaxoSmithKline, Deirdre Connelly, who has run the North American pharmaceuticals business for nearly six years, is retiring, according to a memo distributed yesterday to employees. She will be replaced by Jack Bailey, who most recently headed government affairs, managed markets and the vaccines business in the U.S., according to the memo. The move comes amid an ongoing reorganization at Glaxo, which has promised to cut expenses by $1.6 billion annually through 2017. The drug maker is struggling with declining sales in its key respiratory franchise and an overall sales drop in the U.S., which is its most important market and accounts for roughly one-third of companywide revenue.

“The U.S. healthcare environment is extremely challenging. We are making good progress with payers and early signals are encouraging, but there remains a lot to deliver,’ Abbas Hussain, the president of the Glaxo global pharmaceuticals business, wrote in the e-mail to employees. The memo was first reported by Bloomberg News. “With Jack heading the U.S. business, I feel confident that we have the right experience to steer us through the current environment and deliver our strategy. I’d also like to thank Deirdre for her leadership of the U.S. business these last six years – she is a great leader and a good friend. I’m incredibly grateful for everything she has done to reshape the U.S. business.”

The change comes after a management reshuffling last year in which Connelly, who arrived from Eli Lilly, began reporting to Abbas. Previously, she reported directly to Glaxo chief executive Andrew Witty, who has been under pressure to engineer a rebound not only from declining sales, but also a bribery scandal in China. During her tenure, Connelly, 54, attempted to steer Glaxo through a turbulent period. Last year, sales of respiratory medicines fell 18% in the U.S., due to both lower volume and price reductions. This reflected a 25% drop in Advair, one of its most important medicines [see here]. Two newer products have so far not generated anywhere near the needed sales levels. The Abbas e-mail also noted that Jorge Bartolome, a senior vice president for the respiratory  and medical centre unit, is leaving.

Besides the challenges of growing sales, however, Connelly also implemented a new and closely watched marketing program for sales reps called Patient First. Begun in 2011, this was designed in 2011, before the drug maker paid a $3 billion fine to the U.S. government to settle allegations of improper drug marketing to physicians, among other things. The program was seen as ground breaking because reps are not paid bonuses based on the volume of prescriptions written by doctors. Instead, bonuses have been based on product knowledge, business acumen and understanding needs of patients and physicians, which were assessed in written tests and simulations conducted by third parties. Supervisory observations are also used [details are here]… “The company put a lot of faith and effort in this system working and we are putting patients first,” says a Glaxo sales rep who asked not to be named. “But you wouldn’t go to a car salesman, who just sold some cars, and pay him based on his knowledge of the auto industry instead of commission. Salespeople are in it for sales and they’ve been seeing declines because the motivation isn’t there.”…
Some more from that speech in 2010…
    Doctors don’t need us to teach them how to practice medicine. But doctors do benefit from the very specific and extensive knowledge we have about our medicines and the conditions they treat. After all, it’s hard for health care providers to stay current with all the information available about thousands of medicines – and the new ones coming to market. When our GSK sales representatives talk with doctors, we require that they share the extensive knowledge they have about our drugs – including both who should, and importantly, who should not, take our medicines. This is something that my management team and I set as a fundamental requirement. Employees are trained to inform their customers when our products are not right for their patients. That is just one example of delivering value to the physician that is in the best interest of the patient…
    Deirdre Connelly speech January 2010
My guess would be that Glaxo’s slump is not just from Connelly’s policies, but from many other forces as well. Advair now has some healthy competition. And recall that the off-label promotion of Advair was part of that $3 B settlement against GSK. So falling sales are no surprise:
Off-Label Promotion and Kickbacks: The civil settlement resolves claims set forth in a complaint filed by the United States alleging that, in addition to promoting the drugs Paxil and Wellbutrin for unapproved, non-covered uses, GSK also promoted its asthma drug, Advair, for first-line therapy for mild asthma patients even though it was not approved or medically appropriate under these circumstances. GSK also promoted Advair for chronic obstructive pulmonary disease with misleading claims as to the relevant treatment guidelines…
I may yet be naive and gullible, but I still think Deirdre Connelly was legit. If that’s true, her retirement brings up something fundamental. Can a publicly owned pharmaceutical company survive in a world where a drug isn’t hyped up and sold with aggressive and deceitful marketing? where it’s instead allowed to stand on its actual worth based on efficacy and safety? or will the push for profits, and the dreams of becoming a blockbuster drive the show? Whatever the case, let’s hope that her influence and policies have at least some sticking power. And if she applies to the FDA, let’s give her a long hard look…
Mickey @ 1:51 PM

a non-event…

Posted on Thursday 19 February 2015

Living in the South for a lifetime, one’s tolerance for this kind of cold is an undeveloped skill. People race to the grocery to stock up on things they usually don’t buy as if the Siege of Leningrad is beginning. Schools, clinics, and stores close in the morning [and regret it in the afternoon]. The worst part is the scorn and laughter coming from people who have emigrated here from the North as they watch us slide off the road because we don’t know how to negotiate the icy patches [and they actually own clothes appropriate for this kind of weather]. The dogs lobby constantly to go out, and then lobby constantly to come back in. And the woodpile, planned to be more than adequate for the season, grows smaller at an alarming rate.

It’s not a time conducive to blogging, I must say. If you have a 4-wheel drive Jeep and it’s icy, you suddenly become more popular, sure enough, and there are lots of calls. But it’s more than that. Things just aren’t right, and there’s just a lot busy-ness involved when things just aren’t right. There’s an article that has been open on my computer desk-top for several days. It’s a thoughtful discussion of the DSM-5 and particularly the Major Depressive Disorder category by an academic clinical psychologist [Marco Castiglioni] and an professor in the philosophy of science [Laudisa Federico] – both in Milan, Italy. The abstract is only an outline, but the full text is available on-line and worth reading. The topics are old friends to most of us – biological reductionism; the myth that the DSM-III, -IIIR, -IV, and -5 have been atheoretical; the fatally flawed DSM category of Major Depressive Disorder; and the failure of the DSMs to address subjectivity and relatedness:
by Marco Castiglioni and Federico Laudisa
Department of Human Sciences, University of Milano-Bicocca, Milan, Italy
Frontiers in Psychology. 2014 5:1517.

The aim of this paper is to argue that a strictly reductionist approach to psychiatry represents a theoretical and clinical obstacle to a fruitful synthesis between neurobiological and sociocultural aspects of the sciences of mind. We examine the theoretical and practical motivations underlying this approach, by analyzing the case of depressive disorders, as defined in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders [DSM], and the related removal of the “bereavement exclusion clause.” We first explore the claim that DSM is atheoretical, observing that, far from being atheoretical, DSM adopts an implicit, biologically inspired view of the mind; we show that such a view leads to a sort of circularity in the definition of depressive disorders, in which psychopharmacology seems to play a key role. We then turn to further problems deriving from this position, analyzing the issue of placebo effects in the treatment of depressive disorders and the philosophical question of normative preconditions for psychopathological diagnosis. Finally, we address the issue of subjectivity, which, together with the related aspect of the subject’s relational context, appears to be crucial to any scientific theorizing about mental disorders, despite DSM’s attempt to exclude it. Our defense of a non-reductionist view of mental disorders, however, does not imply that we endorse any sort of metaphysical dualism, or anti-diagnostic or anti-psychiatric positions. On the contrary, we argue that the adoption of a reductionist position actually undermines the theoretical and clinical accuracy in explaining depressive disorders…

But I don’t really buy my it’s too cold to think about it excuse for having nothing to say about this paper. I thought of some lines from my oft-quoted poet:

… And so each venture
Is a new beginning, a raid on the inarticulate
With shabby equipment always deteriorating
In the general mess of imprecision of feeling,
Undisciplined squads of emotion. And what there is to conquer
By strength and submission, has already been discovered
Once or twice, or several times, by men whom one cannot hope
To emulate — but there is no competition —
There is only the fight to recover what has been lost
And found and lost again and again: and now, under conditions
That seem unpropitious.
T.S. Eliot, East Coker 1939

It has all already been said "Once or twice, or several times, by men whom one cannot hope to emulate." I’ve thought all of the things in this paper in one form or another for twenty-plus years. But it’s more than that, because I’ve worked up a full head of steam about these matters many times in the last several years. I hope my torpor reflects something more general. The DSM-5, for all the hoopla, was a non-event. It’s not even a DSM-IV on steroids. It’s a DSM-IV with some quirky changes. Maybe [fingers crossed] it’s back to being a code book where it belongs [and a not-very-good code book at that]. Now they’re publishing a version for patients and the lay public [maybe an attempt to stir up some interest somewhere? amywhere?]. But other than that, it’s not much mentioned.

So I hope my lassitude about the DSM-5 is a barometer to a general lack of interest. But we’ll have to wait until Spring to be sure it’s not the cold when the Sun comes back our way…
Mickey @ 6:56 PM

didn’t get very far…

Posted on Monday 16 February 2015

“If one is given a puzzle to solve one will usually, if it proves to be difficult, ask the owner whether it can be done. Such a question should have a quite definite answer, yes or no, at any rate provided the rules describing what you are allowed to do are perfectly clear. Of course the owner of the puzzle may not know the answer. One might equally ask, ‘How can one tell whether a puzzle is solvable?’, but this cannot be answered so straightforwardly. The fact of the matter is that there is no systematic method of testing puzzles to see whether they are solvable or not. If by this one meant merely that nobody had ever yet found a test which could be applied to any puzzle, there would be nothing at all remarkable in this statement. It would have been a great achievement to have invented such a test, so we can hardly be surprised that it has never be done. But it is not merely that the test has never been found. It has been proved that no such test ever can be found." [referring to Kurt Gödel’s Incompleteness Theorems, 1931]

Last week, I was on a road trip and did some pleasure reading along the way in Seeing Further The Story of Science, Discovery, and the Genius of the Royal Society about the scientists and the science that rates the term ‘genius.’ I also saw the Academy Award nominated The Imitation Game about Alan Turing [speaking of British genius]. Back at home, I watched the older UK Channel 4 movie, Codebreaker [on Netflix], also about Alan Turing – a docudrama that covered his life as seen through the eyes of his psychiatrist. It was as riveting as the recent movie. I even read some of Turing’s papers [at least I saw the words with occasional glimpses of understanding]. The quote above is almost a random sample, just something to let me say, "Who thinks about things like that?" Then I left the geniuses behind and settled back in to my home life. I had obviously wanted to say something about the iSPOT paper [a cul de sac I, II, III, IV…], so I didn’t get around to looking over my usual sites to see what I’d missed last week until this morning. I didn’t get very far…

PsychiatricNews
by Philip R. Muskin, M.D. and Paul Summergrad, M.D.
Feb 12, 2015

APA’s 2015 annual meeting in the cosmopolitan city of Toronto promises to be an unforgettable educational experience. The breadth of the scientific program is impossible to capture in a brief article. The highlights contained here and throughout this issue of PsychiatricNews are but a small sample of what you can expect as we bring together some of the best minds in psychiatry to present compelling clinical, research, and practice-related sessions in one dynamic meeting.
Making the meeting even more timely, Dr. Summergrad has planned a series of presidential symposia to address topics that are particularly relevant. For example, one is ’21st-Century Psychiatry at the Interface of Genetics, Neurobiology, and Clinical Science’ with Charles Nemeroff, M.D., Ph.D., Daniel Weinberger, M.D., Karl Deisseroth, M.D., Ph.D., and David Rubinow, M.D.
One of the meeting’s most popular formats is the interactive sessions, in which meeting attendees can engage directly with experts. This year’s meeting will have 14 interactive sessions, and among their leaders are Dr. Summergrad, Dr. Mayberg, Dr. Nemeroff, Melissa Arbuckle, M.D., Barbara Coffey, M.D., Glen Gabbard, M.D., Otto Kernberg, M.D., Russell Lim, M.D., John Oldham, M.D., Alan Schatzberg, M.D., Nora Volkow, M.D., and Stuart Yudofsky, M.D.
I’ll have to say that after a week of reading about some of the scientific high points in history and the Royal Society, this article felt like a splash of ice water. I’m not in the APA and it’s hardly for me to say how the organization presents itself, but headlining Drs. Nemeroff and Schatzberg seems kind of bizarre. Were I to list entrepreneurial psychiatrists, they’d occupy the top two positions. Both stepped down prematurely from chairmanships [Emory and Stanford] in the wake of Senator Grassley’s Congressional Investigation of undisclosed PHARMA payments [with Dr. Nemeroff moving on to chair in Miami]. Both have been guest authors for a ghost written book and numerous articles – Schatzberg as recently as December [the recommendation?…] and both are part of the Brain Resources iSPOT enterprise [a cul de sac I, II, III, IV…]. They’ve lead the league in industry connections by any measurable dimension, and everybody knows that. So why they’re showcased in this article about this May’s APA meeting is beyond my faculties. Maybe my choice of Turing’s SOLVABLE AND UNSOLVABLE PROBLEMS paper wasn’t so random after all, because I sure don’t have a solution to explain this…
Mickey @ 12:49 PM

a cul de sac IV…

Posted on Sunday 15 February 2015

So in a cul de sac I… and a cul de sac II… I looked at this new? iSPOT paper [The International Study to Predict Optimized Treatment in Depression [iSPOT-D]: Outcomes from the acute phase of antidepressant treatment], but I kept having a nagging feeling, like a déjà vu – like I’d heard it before somewhere. Then looking back into an old post in June 2012 [entrpreneurialism prior to investigation…], I found this that jogged my memory:
NASDAQ
by Zacks Equity Research
June 13, 2012

This will be the catalyst to driving growth of the personalized medicine business, Brain Resource’s major focus and the area that is expected to be the impetus to the company’s long-term revenue and earnings growth. Findings from the iSPOT trial will be used to develop these depression and ADHD biomarkers. iSPOT is the world’s largest clinical trial to predict treatment response in depression and ADHD. iSPOT-D [for depression] has enrolled over 1,700 patients and analysis started on the first 1,000 patients.  Data from iSPOT-D was presented at two major U.S. medical conferences during 2011, including an invitation-only presentation at The American Conference of Neuropsychopharmacology in December and more recently formed a panel of presentations at NCDEU in Arizona…  Brain Resource is planning to submit study outcomes to the FDA for approval [likely via PMA] of a depression and an ADHD test in the near-to-mid term [discussions with the FDA regarding the regulatory approval pathway are ongoing]…
So, as Dr. Carroll hypothesized in his comment, something’s awry. This paper is old news. The 1008 subjects were signed, sealed, and delivered four years ago [2011]. And nosing around the Brain Resources web site, there’s more. For example, on this page, we learn that…
iSPOT-D “Test” cohort (n=1008) complete. First “Replication” cohort (n=700) is locked. 
FDA meeting on first biomarker outcomes from the iSPOT studies. View Report
a report that says…
3 July 2012
FDA meeting on BRC’s Depression Treatment Test
BRC met with the FDA [June 28] t o discuss our Pre-IDE submission in regards to the company’s test to predict optimized treatment for D epression based on our international iSPOT study. This was a positive meeting which addressed the issues previously raised by the FDA. Significantly, the FDA considered a de novo pathway as a possible pathway for our submission. The implication of this being typically less complexity and shorter approval times as compared to a PMA submission . As such, we continue to believe we are on track to develop and obtain FDA marketing clearance in the United States for a personalized predictive test in Depression. Our next steps include filing a Pre-IDE supplement to clarify the pivotal validation study [expected within the next two months], this laying the ground for us to begin working on our final submission.
And here, we learn that Dr. Rush’s publication record is, indeed, part of the grand plan:
iSPOT-D Publication Management Team
The Publication Management Team [PMT] is the administrative body that provides support and structure to ensure a large volume of high caliber papers are produced from the data. The iSPOT-D PMT follows a structured publication plan and has been formed with John Rush, MD as chairman. John Rush, MD was the PI of the first-of-its’ kind STAR*D Depression research study that produced over 120 papers [published across more than 20 peer reviewed journals internationally].
And there have been some changes along the way [from the recent paper]:
  • "Dr. Williams has previously received fees as a consultant for Brain Resource Ltd and in the last 3 years and was a stockholder in Brain Resource Ltd."
  • "iSPOT-D is sponsored by Brain Resource Company Operations Pty Ltd. Dr Williams was the Academic Principal Investigator for iSPOT-D from 2008 to 2013."
  • Dr. Williams is now at Stanford working on the NIMH RDoC, iSPOT, and PTSD…
  • And speaking of a change, Dr. Charlie Nemeroff was a prominent member of the Brain Resources team. However, in the recent paper, first author Radu Saveanu, his Director of Education, represented the University of Miami instead [detoxifying the by-line?].
What does all of this mean? What came of that pivotal validation study? the FDA Submission? John Rush’s  structured publication plan? Why did Williams move to Stanford? or why was this old data published now? Has this commercial venture fizzled? or is there some personalized predictive test in Depression about to come bursting onto the scene?

I haven’t a clue about the answer to any of these questions, but I do know this. This entire personalized medicine scenario has been heavily colored by a quest to find a marketable pick-the-antidepressant test. It has played out among the usual suspects of entrepreneurial psychiatry in high places, spread through the pages of academic peer-reviewed journals, and been nurtured in the departments of psychiatry at some prestigious universities. In fact, this whole story going back to TMAP could be folded into that last sentence – much ado about not very much. Haven’t we explored this cul de sac long enough?

Mickey @ 1:53 PM

a cul de sac III…

Posted on Saturday 14 February 2015

Speaking of cul de sacs, we interrupt this narrative for this utterly brilliant and pertinent commentary from John Oliver…

Mickey @ 8:29 PM

a cul de sac II…

Posted on Saturday 14 February 2015

by Saveanu R, Etkin A, Duchemin AM, Goldstein-Piekarski A, Gyurak A, Debattista C, Schatzberg AF, Sood S, Day CV, Palmer DM, Rekshan WR, Gordon E, Rush AJ, Williams LM.
Journal of Psychiatric Research. 2015 61:1-12.

We aimed to characterize a large international cohort of outpatients with MDD within a practical trial design, in order to identify clinically useful predictors of outcomes with three common antidepressant medications in acute-phase treatment of major depressive disorder [MDD]. The international Study to Predict Optimized Treatment in Depression has presently enrolled 1008 treatment-seeking outpatients [18 – 65 years old] at 17 sites [five countries]. At pre-treatment, we characterized participants by symptoms, clinical history, functional status and comorbidity. Participants were randomized to receive escitalopram, sertraline or venlafaxine-extended release and managed by their physician following usual treatment practices. Symptoms, function, quality of life, and side-effect outcomes were assessed 8 weeks later. The relationship of anxiety to response and remission was assessed by comorbid Axis I diagnosis, presence/absence of anxiety symptoms, and dimensionally by anxiety symptom severity. The sample had moderate-to-severe symptoms, but substantial comorbidity and functional impairment. Of completers at week 8, 62.2% responded and 45.4% reached remission on the 17-item Hamilton Rating Scale for Depression; 53.3% and 37.6%, respectively on the 16-item Quick Inventory of Depressive Symptoms. Functional improvements were seen across all domains. Most participants had side effects that occurred with a frequency of 25% or less and were reported as being in the “none” to minimal/mild range for intensity and burden.

Outcomes did not differ across medication groups. More severe anxiety symptoms at pre-treatment were associated with lower remission rates across all medications, independent of depressive severity, diagnostic comorbidity or side effects. Across medications, we found consistent and similar improvements in symptoms and function, and a dimensional prognostic effect of comorbid anxiety symptoms. These equivalent outcomes across treatments lay the foundation for identifying potential neurobiological and genetic predictors of treatment outcome in this sample.

First, to state the obvious, this is a commercial study funded by Brain Resources. The authors in the by-line in red have received research support from Brain Resources. The ones in blue are employees of or principals in Brain Resources. And the underlined authors are the editor-in-chief and assistant editor of this very journal [Journal of Psychiatric Research]. So at a time when questions of conflict of interest have finally made it to the front page in medical research, these people don’t seem to have gotten the message. There are other anachronisms. Listed author AJ Rush was Director of TMAP and Principle Investigator for STAR*D and CO-MED – studies that notoriously churned out a seemingly endless stream of published papers. This article is, at best, an interim report, likely signalling yet another flood of articles pouring out of this iSPOT enterprise. And medical writer Jon Kilner who has been ghost?/editorial assistant? throughout the studies mentioned in the last post [a cul de sac I…], is still around doing whatever he does once more in this publication.

As to this study itself, it’s bare bones. There’s no placebo control group and neither subject nor rater blinding – just testing on entry and at 8 weeks with phone checkups every couple of weeks for side effects in between. The point was to develop a cohort of responders and remitters to each of three antidepressants [Lexapro, Zoloft, and Effexor XR] while collecting multiple parameters to search for biological predictors of outcome.
… iSPOT-D follows current usual care setting clinical practice in the prescription of antidepressant medications, coupled with collection of a broad range of potential predictor measures [e.g. genetics, neurobiological, psychophysiological etc]. This was done in order to arrive at a battery of tests that can be used in future prospectively-designed validation studies that will test the proposed individual patient-level treatment optimization algorithm built on these predictors.
Although it’s not a standard clinical trial, it’s presented as if that’s what it is. This table shows the results of the primary outcome variables [HRSD17 and QIDS-SR16]. To their credit, they showed their response and remission results in two ways: as the percent of completers, and as the percent of all participants [the latter being what one might see in an office]. Those latter numbers [1/3 respond, 1/4 remit] seem kind of right – remember, that’s with no placebo control:

They were less forthcoming with the side effects, showing only those of completers [which were themselves pretty impressive]:

So here we are three decades after the first SSRI, two decades beyond the hypothesis that there’s some special way these drugs can be used to increase their efficacy looking at a study that says that they’re all the same. And we know what’s coming – a string of studies sifting through all tests neuro looking for something that will point to one or the other drug [with no real rationale that such a test might exist]. We have here a study financed by a commercial firm aiming for a future commercial product, authored by its employees, and published in a journal edited by some of the authors who are also involved with the company. The ticket into a peer reviewed medical journal is presumably the academic credentials of some of those authors.

This article doesn’t answer any questions that haven’t already been answered. It only highlights an ongoing question, "Why is this mis-use of our medical literature for commercial purposes still tolerated?"
Mickey @ 7:30 PM

a cul de sac I…

Posted on Saturday 14 February 2015

by Saveanu R, Etkin A, Duchemin AM, Goldstein-Piekarski A, Gyurak A, Debattista C, Schatzberg AF, Sood S, Day CV, Palmer DM, Rekshan WR, Gordon E, Rush AJ, Williams LM.
Journal of Psychiatric Research. 2015 61:1-12.

We aimed to characterize a large international cohort of outpatients with MDD within a practical trial design, in order to identify clinically useful predictors of outcomes with three common antidepressant medications in acute-phase treatment of major depressive disorder (MDD). The international Study to Predict Optimized Treatment in Depression has presently enrolled 1008 treatment-seeking outpatients [18 – 65 years old] at 17 sites [five countries]. At pre-treatment, we characterized participants by symptoms, clinical history, functional status and comorbidity. Participants were randomized to receive escitalopram, sertraline or venlafaxine-extended release and managed by their physician following usual treatment practices. Symptoms, function, quality of life, and side-effect outcomes were assessed 8 weeks later. The relationship of anxiety to response and remission was assessed by comorbid Axis I diagnosis, presence/absence of anxiety symptoms, and dimensionally by anxiety symptom severity. The sample had moderate-to-severe symptoms, but substantial comorbidity and functional impairment. Of completers at week 8, 62.2% responded and 45.4% reached remission on the 17-item Hamilton Rating Scale for Depression; 53.3% and 37.6%, respectively on the 16-item Quick Inventory of Depressive Symptoms. Functional improvements were seen across all domains. Most participants had side effects that occurred with a frequency of 25% or less and were reported as being in the “none” to minimal/mild range for intensity and burden.

Outcomes did not differ across medication groups. More severe anxiety symptoms at pre-treatment were associated with lower remission rates across all medications, independent of depressive severity, diagnostic comorbidity or side effects. Across medications, we found consistent and similar improvements in symptoms and function, and a dimensional prognostic effect of comorbid anxiety symptoms. These equivalent outcomes across treatments lay the foundation for identifying potential neurobiological and genetic predictors of treatment outcome in this sample.
The third paragraph of the paper says:
    Recent efforts have focused on identifying clinical or laboratory-based measures that help to precisely target treatments for specific patients. While several neurobiological markers have been investigated, none have been of sufficient clinical value to be incorporated into treatment guideline recommendations….

That paragraph deserves a little more introduction:

BACKGROUND

As the decade following the coming of Prozac drew to a close, it was apparent that the new antidepressants were no panacea for symptomatic depression – at least not being prescribed in the chaotic way they were being used. Some thought that we should give the medication in a systematic way, with guidelines, with objective measurement data. This thread is about the some that thought that was the problem. We needed alogorithms for our treatment. Who know the right way to sive these medications? The Experts [the some] – that’s who. So we’ll create algorithms for the drugs used to treat Schizophrenia, Bipolar Disorder, Major Depressive Disorder [MDD], by Expert Consensus for our clinicians to follow as a guide to treatment. And where shall we do this, in the largest public mental health system there is – The State of Texas. Thus, in 1996, the Texas Medical Algorithm Project [TMAP] came into existence – generously supported by Foundations, the State of Texas, and multiple pharmaceutical companies, all coordinated by the psychiatrists of the University of Texas system. The algorithms spread to multiple States, and the Federal Government when the Texas Governor became the US President.

The idea of applying systematic study using clinical  trials of these algorithms appealed to the NIMH, and there followed a period of large acronymed Clinical Trials in Depression, Schizophrenia, Bipolar Disorder, and other disorders.. The largest, STAR*D [Sequenced Treatment Alternatives to Relieve Depression], was run by the TMAP team and had a complex, sequential algorithm in which non-responders were changed to another drug or augmentation scheme. In MDD, there was a side project, IMPACTS [algorithmic psychiatry: the fallacy…] that computerized  the algorithms. It had to be scrapped because the clinicians wouldn’t use it if left to their own devices. Then came COMED which combined multiple antidepressants – no help. I think it’s reasonable for me to say that all of these efforts generated much ado and many papers, spent tons of money, but not much changed in the response rates of MDD to antidepressants [if you’re not up to speed, just look up any acronym using the search box at the bottom of this page]:

That pretty much covers the completed efforts in Recent efforts. Now for the Recent part. Since all of this started, there have been some new kids on the block. Genomics, Proteinomics, Functional Neoroimaging, Cognitive Testing. Well, not new kids, but at least more prominent shiny new objects in neuroscience. And in the rest of medicine, Personalized Medicine [picking specific treatment based on unique biomarkers], had become a hot new area. Well, not a new area, but at least more prominent shiny new object in neuroscience. So Personalized Medicine began to be bandied about as a possible exploratory area for picking an antidepressant – the scientific rationale being «fill in the blank?». And a new character entered the ring – Evian Gordon, a brain training Australian [BrainNet] – and his colleague, Leanne Williams [Brain Resources]. They gathered a who’s who of KOLs [list] for their Personalized Medicine Action Group in D.C. in October 2009 to kick off a campaign to personalize antidepressant treatment [The Mayflower] [which is a must-see to understand this line of thinking].

In the year before this conference [2008], Senator Grassley’s congressional investigation had reshuffled the people he exposed who had unreported PHARMA income. John Rush [of TMAP, STAR*D, and CO-MED] left UT and went to Duke in Singapore. Alan Shatzberg, APA President, stepped down as Chairman at Stanford. Charlie Nemeroff, Boss of Bosses, was removed at Emory and went to Miami as chair. The emptiness of the PHARMA new drugs pipeline was looming. Out of that matrix, two large Personalized Medicine studies came into being. iSpot-D was financed by Evian Gordon’s BrainNet/BrainResources [see personalized medicine: the Brain Resources company II…] and added the Grassley-investigated people to his byline…
by Williams LM, Rush AJ, Koslow SH, Wisniewski SR, Cooper NJ, Nemeroff CB, Schatzberg AF, Gordon E.
Trials. 2011 12:4.
Meanwhile, Dr. Madhukar Trivedi, still at UT Southwestern, started a second Personalized Medicine study, EMBARC [Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care], with a large NIMH grant, mentioning many of the STAR*D veterans as resources in his grant proposals [see the race for biomarkers… and Godzilla vs. Ghidorah…]. This second Clinical Trial is still recruiting.

SCIENCE

The scientific premise behind this line of thinking and series of trials was questionable from the outset. The notion that Major Depressive Disorder as defined represents a distinct clinical entity, a unitary disease entity, was conjecture that has now rapidly moved to the realm of fantasy. The evidence for an over-riding biological etiology was equally scant, and has traveled in the same direction. Likewise, by any ongoing reading of the accumulating information, the therapeutic action of the antidepressant drugs is a non-specific, symptomatic effect – not something determined by the kind of precise or controllable biological mechanisms hypothesized in these studies – certainly nothing tied to etiology.

COMMERCE

The entrepreneurial background in this story should really be considered more a part of the foreground. TMAP was exposed by whistle-blower Allen Jones to be a conduit for PHARMA to introduce in-patent drugs to the public sector without evidence of efficacy justifying their use, facilitated by under-the-counter payoffs to officials. TMAP was shut down and the States have tried to retrieve their considerable losses with varying levels of success. To be fair, the payola was between State employees and PHARMA, not the academics. But the academics in all of these trials have been way too tied into industry across the board. These studies have generated a lot of money for participating universities and centers – over $50 M from the NIMH alone. In Academia, there’s a commerce in published articles and STAR*D probably hit an all time high with well over 100 papers, each with way too many authors [see infectious numerology…]. Then in the iSPOT byline, we see some  legendary psychiatrist entrepreneurs [Nemeroff, Schatzberg, Debattista]. Also, there’s Evian Gordon’s more up front private enterprises hoping to develop commercial tests to screen patients to pick an antidepressant in advance, as in this BrainNet’s pitch [see personalized medicine: beyond blockbusters…]:

Note: this document is now gone from the Internet [see it currently here through the Wayback Machine].

DESIGN

These studies have not been designed like the usual RCTs. For example, none had a placebo group, so the response/remission rates were uncorrected for the usual improvements seen in antidepressant trials from inert treatment [placebo]. As a result, the strength of drug effect [NNT, NNH, Odds Ratios, Effect Size] simply could not be calculated, was an unknown. None of them have followed the usual double-blinding, settling for partial schemes of one sort or another. They were described as "naturalistic" – meaning more like the treatment one might receive in a office situation than a strict controlled trial [and it showed]. They had high drop-out rates and there’s a lot of confusion about the various rating instruments used, particularly with STAR*D [see recalculating…  and still recalculating…]. Thus far, the only completely reported study was CO-MED [a negative trial]. In spite of a flood of offshoot papers, the final report for STAR*D never appeared, and the results that were reported begged credibility.

I started this post intending to comment on the preliminary iSPOT study reported above, but thought I ought to remind us about the history of these two studies [iSPOT and EMBARC] that are part of a quest to find biomarkers that will predict response to antidepressants. What I really wanted to do was describe the rationale for thinking that such biomarkers might exist, but looking back over the literature, I can’t find any rationale. Like the efforts of these investigators in earlier outings that looked at various algorithms and guidelines that explored sequencing, combining, or augmenting antidepressant regimens, scientific rationale is missing. Certainly those outings [TMAP, STAR*D, IMPACTS, and CO-MED] have yielded nothing of note. And yet there are two major ongoing studies with authors familiar to all of us, all hotly pursuing this line of investigation. Perhaps, that’s the more interesting question than the actual studies themselves, Why do they persist in going down this road? Why do they keep trying to find a way to make these drugs more effective than they are, with no scientific clues that it’s possible? Why are these efforts funded?

Maybe I’ll take a shot at those questions, but first I’m going to stick to my guns and report on the iSPOT study in the next post like I planned in this one [before I got wordy with my skepticism], because this report deserves some clarification of its own…
Mickey @ 8:00 AM