1 Boring Old Man

In musings…, the thing I was musing about wasn’t, apparently, clearly stated based on some emails and tweets that came my way. Here’s another shot. I work as a volunteer in a local charity clinic. There are several reasons, but one of the main ones is that the local primary care physicians and my colleagues in the clinic don’t know much about psychiatric medications and treat them as if they are like the symptomatic medications in the rest of medicine. So if a person is depressed, the give an antidepressant. And if the patient returns saying I’m still depressed, then they add another, or some other psychiatric medication like an atypical antipsychotic that’s advertised for depression. And so patients are walking around taking hands full of pills, and if they stop, they have withdrawal symptoms. It’s a mess. So as much as I’d like to get a lot of them medication free, at least I can slowly bring things down to something rational – to levels that meet some kind of conventional standard. And with patients with psychotic illnesses, I can lower doses, trim the polypharmacy, monitor for TD etc. There’s a lot more that can be done as a glorified social worker, and I find that very rewarding having gotten a pretty good feel for the resources in the community. And then there’s crisis intervention, and some limited psychotherapy. We have three volunteer "therapists" and so when I find a person who badly needs counseling, I can refer them.

This was foreign soil to me, but I enjoy it enough and feel like it’s helpful enough to keep at it. But I can’t help but make some observations working there. As I said, one of the observations is that a lot of the pressure to medicate comes from the patients themselves. They’d be glad for me to give out Xanax like people did in the past. It’s a major drug of abuse in these parts in spite of the hypervigilance of pharmacists, DEA, and Georgia Narcotics Bureau. I use those drugs in acute crises, in some patients with panic disorders, and in psychotic people as a way of minimizing antipsychotics – pretty standard fare. But saying "no" to requests for benzos is a major activity of every clinic day. There’s another surprising pressure from patients – antidepressants. Like everywhere, there are large numbers of people on SSRIs, and they both complain that the drugs aren’t enough and insist on continuing to take them. I’ve read all the explanations for that: television ads; withdrawal if they stop; pressure from doctors; hopes for a panacea; etc. and I’ve seen a lot of every one of those. But that’s not the whole story. They sure aren’t pressured by me. And I find that people with false hopes aren’t that hard to wean off the drugs if one is careful and have some alternative ways to improve their lives available. But I’m personally convinced that a lot of people take them for a reason that is related to drug effect. And a lot of people who stop them, come back later asking for them – even knowing the negative effects that caused them to stop in the first place. In spite of their negative effects, they get something from taking them. The question is what? not if? in my mind.

So, if I’m right, what is it? and is it good for them? I’ve never bought that the antidepressants are specific antidotes for depression, even though it’s clear that they help some people with depressed affect. They help other people too – patients with OCD, patients with anxiety disorders and panic attacks, women with bad PMS symptoms. They often work better in those conditions than in depressed people. And the notion that the antidepressant properties and the side effects can be separated is a fantasy of chemists, not a reality that I’ve seen. So I’ve assumed that the therapeutic benefit [when there is one] is part of the same complex of effects as the downside side effects. That’s why I jumped on that NZ study, because the incidence and quality of the side effects they reported feels right. And the cohort they describe is reporting a double edged sword, a compromise. That’s what I see from these drugs myself. And since I don’t think these medications are specific antidepressants, I wonder what they are actually doing.

The universe isn’t very helpful with that question. The pharmaceutical industry and a whole generation of psychiatric KOLs preach the gospel of ANTIDEPRESSANTS as if they should work specifically for all depression. If they don’t, the patient has TREATMENT RESISTANT DEPRESSION and drugs are changed, combined, augmented, the patient is genetically screened, etc. There’s even a move to have a diagnostic scheme that fits the drug’s effects [RDoC] rather than the clinical symptoms. I don’t find that line of thinking at all helpful. On the other side of the coin, there are people who point to the same things I point to on this blog – the academic-pharmaceutical alliance, the experimercials, the KOL class in psychiatry, the bio-bio-bio rhetoric, the myth of chemical imbalances, the dreams of neuroscience, the DTC television ads, etc. In their view, these drugs are all hype, created by entrepreneurs, charlatans – a mass hypnosis. All of those things happen and are real. I don’t like them either. But they don’t address the fact of the patients I see that would answer the questions exactly like the cohort in New Zealand – these medications are a double edged sword, a compromise that they prefer to the alternative.

How do psychiatric drugs work?

by Joanna Moncrieff and David Cohen

British Medical Journal. 2009 338:b1963.

[full text on-line]

Drugs for psychiatric problems are prescribed on the assumption that they mostly act against neurochemical substrates of disorders or symptoms. In this article we question that assumption, proposing that drugs’ action be viewed rather as producing altered, drug induced states, a view we have called the drug centred model of action. We believe that this view accords better with the available evidence. It may also allow patients to exercise more control over decisions about the value of pharmacotherapy, helping to move mental health treatment in a more collaborative direction.

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I don’t mean to trivialize her work by saying this, because she has lots of important things to say, but for this post, that slide says it all clearly and simply [in spite of the mispelling – just kidding]. In my way of thinking, her drug centered model has to be correct in this instance. I know of nothing that suggests the antidepressants are specific anti-depressants [a possible exception is that sometimes, the Tricyclics reverse endogeous depression in dramatic fashion – emphasis on sometimes]. From where I sit, the SSRIs create a syndrome that is perceived as helpful by some depressed people. I say that they "turn down emotions" and use words like "blunting" or "dampening." Others say that in a more perjorative way – "numbing." That would explain their effects in GAD and OCD. I don’t know how refine that further. As I mentioned, I discovered after the fact that the place where I had prescribed them most often was in patients in therapy for PTSD who had hard emotional times along the way. I think I was trying to help "dampen" their emotions, but I wouldn’t have known to say that at the time.

Well, next weekend, the American Psychiatric Association Board of Trustees meets in Arlington, VA. This will be their first meeting since APA Speaker Dr. Mindy Young’s letter to the Trustees was published about what has been called the Kupfer Affair [or for that matter, since my Open Letter to the Board of Trustees]. I doubt you need any reminders about what the Kupfer Affair is all about. But if you do need a  refresher, you’ve come to the right place:

Dr. Kupfer should have disclosed to APA his interest in PAI in 2012. Dr. Kupfer’s interest in PAI, which came after the decision had been made to include dimensional measures in DSM-5, did not influence DSM-5’s inclusion of dimensional measures for further study in Section 3. Interest in inclusion of these measures in DSM-5 began with conferences starting in 2003. If and when PAI develops a commercial product with CAT, it will not have any greater advantage than the dozens of dimensional measures currently being marketed by others.

Wednesday, I was writing about the NZ survey of patients’ experience taking antidepressants [a surprising finding…] titled Adverse emotional and interpersonal effects reported by 1829 New Zealanders while taking antidepressants. From the title and references, one can assume that the authors were honing in on the more subtle and understudied "emotional and interpersonal effects" of these drugs, so widely prescribed and taken, often for long periods of time. There’s a paradox in the study. In spite of the heavy side effect burden reported by the  respondents, they took them for a long time and reported positively on the results – at least more positively than many might’ve expected. Several commenters thought that was a placebo effect of some kind rather than an outcome from the drugs themselves. I’m not so sure I know the answer to that, but I was intrigued by the results. I emailed the authors, John Read, Claire Cartwright, and Kerry Gibson, at the University of Auckland and asked if we could take a look at their questionnaire, and had a pleasant exchange with Dr. Read the same day.

Following ethics approval from the University of Auckland, the anonymous questionnaire was placed online. A google webpage advertising the study was established [http://www.viewsonantidepressants.co.nz]. This webpage provided participant information and a link to the online questionnaire. The study was publicized in the New Zealand media via media releases, interviews with the researchers and advertisements.

But as for the questionnaire itself, again it seemed straightforward. The paper well documents the heavy "emotional and interpersonal" side effect burden of these drugs and made it clear that the way to find out these things is simple – ask the patients who take them. The survey confirmed the high incidence of suicidal feelings and aggressiveness [attributed to the antidepressants, not the depression itself], and higher incidence of these symptoms in younger patients. But in spite of these negative findings, over half of the respondents had continued taking the medications for over three years, and their general report on the quality of life was surprisingly positive:

The chart on the right is in response to this question: While taking anti-depressants my quality of life was: Greatly improved… Slightly improved… Unchanged… Slightly worse… A lot worse… Those of us who follow this story on the use of antidepressantss in modern psychiatry and the dramatic prescription rate over the last twenty-five years come to the table from a variety of directions. I got here when I left my cloistered practice and discovered how many people were on such bizarre combinations of drugs, and I stayed when I began to look at the psychopharmacology literature and saw how it had been invaded [and corrupted] by industry and complicit KOLs. Others are former patients who suffered unannounced side effects or unacknowledged withdrawal symptoms. Some were offended by the "medicalization" of human mental life and the assumptions about underlying biology. That’s only a few. But no matter how we got here or where we point our fingers, we share an outrage at the takover by PHARMA with the complicity of many higher-ups in psychiatry, the corruption and commercialization, and the resulting rampant prescription of psychiatric medications in both psychiatry and primary care. So a report like this can be a Rorschach for any of us to project our preconceptions onto – mine included.

I had several thoughts about the survey. First, I thought it was a great idea. While it lacks the scientific rigor of a randomized, placebo controlled, double-blind clinical trial, it goes straight to the heart of the matter – What do the patients say? It’s like David Healy’s Rxisk web site which I also like. We ought to be doing this kind of survey on all the medications, over and over. It’s what both  prescribers and patients alike need to know. By listing the side effects explicitly, the authors bias may show, but how else are we going to find out if we don’t ask? And frankly, their findings with a few exceptions are what I might have predicted having prescribed these medications in my new post-retirement role as a "clinic doc" in a charity clinic staffed by volunteers. But the article speaks to some open questions I have in my own mind working in that setting. These are my speculations, not those of the authors.

I would never qualify as a bio-bio-bio psychiatrist. In my natural state, I’d clearly fit more into the bio·psycho·social category. So I’ve had to retool for the clinic where I work [and, for that matter, for this blog as well]. I’m able to use more of my psycho· skills there than I would’ve thought, but in an abbreviated and modified way. My social· has been flexed beyond my imagination, since much of what I do a lot of is classic social work. And the bio· is a major player. I take my comfort in doing it rationally, which isn’t what my colleagues and the local docs do, and people on meds are definitely bludgeoned with my warnings and instructions. But I have to compromise more than I’d like, because the patients just go elsewhere and get medicated up to the hilt. But there are some observations from the clinic that relate to this survey.

There’s an enormous pressure to medicate coming from the patients. I expected it from the "druggies" that haunt such clinics, but I was surprised to find that it was from almost all comers. As I mentioned, most of my practice before was with treatment failures, people who had already given up on a medicine cure/treatment. The other thing is that the patients in the clinic come in thinking that all I want to hear about is their symptoms and the intensity thereof. I have to ask, even prod, to hear about their lives. I wasn’t used to that. And there’s something else that seemed peculiar to me. There’s the frequent refrain that the drugs are not working "enough" or have "stopped" working. But suggesting discontinuing altogether is not well received, and best mentioned after you get to know the patient well enough to be trusted. So it’s not just that they expect medications, they want them – even the patients dissatisfied with the results. I think that must be why each new drug that comes along has a waiting following. As long as I’m blathering about odd things, I was taught and actually think of most depressions as time limited, but the patients in the clinic don’t seem to think that way. Plenty stop them on their own all along the way, but a surprising number see them as an ongoing need. And it’s certainly not because I push that idea on them. Quite the opposite.

I can generate psychological and conspiracy theories galore about all of these things – a symbolic attachment, placebo effects, acknowledgement, etc. and have seen examples of each new theory, but what I really think is that the paradox in this NZ survey is accurate – many patients are enduring the downside in return for an upside that’s hard to quantify, one that shows up in the answer to "my quality of life." Recently, a friend who was struggling with the task of taking care of a new incapacitating illness in her husband had been put on an antidepressant. She said something I’ve heard many times, "Yeah, it really helped. Nothing was different, but I just didn’t care as much." And she was visibly "better." After a couple of months, she stopped it and seems fine. I believe her, and the patients in the clinic, and the results of this survey. There’s a real reason that many take antidepressants, and keep taking them, in spite of the adverse effect burden. That said, there are many that take them because they’ll take anything just in the hope of feeling better, even if they don’t work. And there are too many that take them just because they’ve been prescribed.

• Emails point to ‘troubling’ relationship between drug firms, regulators.
  Milwaukee Journal Sentinal, October 6, 2013
• Pharmaceutical firms paid to attend meetings of panel that advises FDA.
  Washington Post, October 6, 2013
• FDA and Pharma: Emails Raise Pay-for-Play Concerns.
  MedpageToday, October 7, 2014
• Why Did the F.D.A. Approve a New Pain Drug?
  New York Times, December 3, 2013
  hat tip to George Dawson…

• I’m personally a chronic back pain person with a back full of hardware. After my first back event, I was sent home with a bottle of Percocet – "two every six hours as needed for pain" it said. I sure had pain, so I took two, and reached the following conclusion. There was never going to be a minute for the rest of my days when a couple of those wouldn’t feel like a fine idea. So I threw them away. They were too good. My point is that their addictive potential is impressive.
• Later in life, I had some pain situations where I simply had to take something [after a couple of back surgeries, for a dental abscess or two, etc]. I learned that when you have big time pain, they are mostly pain pills. The euphoric effects aren’t so noticable then. But for lesser pain, they become happy pills too. I learned that with an excruciating dental abscess. The first pill after it began to get better was when I got that "uh-oh" feeling and tapered off.
• After using narcotics for more than two days, I think it’s best to assume physical dependence and taper rather than stop. My assumption, by the way, is that anyone can become addicted to narcotics. It’s an equal opportunity drug.

Bob Rappaport, the director of the F.D.A’s Division of Anesthesia, Analgesia, and Addiction Products, observed at the meeting that it was reasonable to anticipate that a single-entity hydrocodone product “will contribute to the already critical public-health problem of prescription opioid abuse and misuse.” But he also chastised the expert panel for some of their more pointedly critical remarks about Zohydro ER, observing that they were “punishing this company and this drug because of the sins of the previous developers and their products” and that “from a regulatory standpoint, that’s not something we can do.” He explained that as long as the drug met F.D.A. requirements, it ought to pass muster; Zohydro ER could not be scapegoated simply by virtue of being an opioid. “We are obligated at the agency to operate within the regulatory framework,” he said, “and that includes providing a level playing field for industry. We don’t have a choice by that. It’s the law.” 

This opens a very large can of worms, one that comes up frequently. The FDA deals primarily with the pharmaceutical industry, and in capitalist USA, the consideration of the industry needs is often on the front burner. Make restrictions too tight, and industry fails. In our world, industry develops the drugs. Make them too loose, and commerce carries the day – and people can get hurt or killed.

Without a system like this, there’s no incentive to develop drugs and we stagnate. With such a system, double binds like this are inevitable. Rarely do we see a new drug that doesn’t have something about it that throws a monkey wrench into the equation. But the issue with Zohydro™ER seems to me to transcend the argument put forward by Bob Rapaport above. It has to do with a hierarchy of values. Zohydro™ER is not a "me too" drug. It’s a "me too much" drug.

Hydrocodone generally comes in 5.0 mg, 7.5 mg, and 10.0 mg pills. Zohydro™ER comes in capsules. "Each Zohydro ER capsule contains either 10, 15, 20, 30, 40, or 50 mg of hydrocodone bitartrate USP." Its assets are that it doesn’t have Acetaminophen and one doesn’t have to take as many pills or take them as often. The downside is that some of those pills could easily be lethal to people who are not tolerant or to children.  They will be worth a mint on the street where bigger is better. I expect the drug culture people see them as something like a new iPhone – a potential blockbuster. The risk/benefit ratio is much higher than the pills on the market already. And in the hierarchy of values, surely "do no harm" trumps convenience every time.

If you work in the medical field, you know that prescription narcotics have become a major drug of abuse in the US. When I started working in a charity clinic in Appalachia, I was stunned by the number of people on Narcotics and how many times I was asked for a refill. When I renewed my DEA license last time, I relinquished my certification for the opioids altogether. So now when asked, I can simply say, "I am not licensed to prescribe those drugs." There must be a grapevine, because after a couple of months, they stopped asking. While doing that helped my mental health, it didn’t do much for drug abuse in the county since I never prescribed them anyway. Up here, illicit drug use is almost a cultural phenomenon [replacing the moonshine made in these mountains a generation ago]. The main drug here was Methamphetamine when I first came a decade ago, but a new Sheriff seems to have shut down most of the meth labs. Now it’s prescription pills. I don’t know where they come from exactly – bad doctors? pain clinics? Mexico? other points south? Thefts? Wherever it is, they’re plenty available.

• Critics Question FDA’s Approval Of Zohydro
• New pain pill’s approval: ‘Genuinely frightening’
• Zohydro: Is This Painkiller FDA’s Fatal Mistake?
• FDA approves pain killer 10 times stronger than Vicodin
• Zohydro: The FDA-Approved Prescription for Addiction

Feb. 26, 2014

Dozens of Groups, Experts Call on FDA to Withdraw Its Approval of Zohydro, Supercharged Opioid

WASHINGTON, D.C. – More than 40 consumer organizations, health care agencies, addiction treatment providers, and community-based drug and alcohol prevention programs today called on the U.S. Food and Drug Administration (FDA) to revoke its approval of Zohydro, an opioid so powerful that a single dose could kill a child. The FDA approved the drug in October against the advice of its own advisory committee, which voted 11-2 against allowing Zohydro, made by Zogenix and Alkermes, to be sold. It is the first single-ingredient hydrocodone drug ever to be approved. Other drugs, such as Vicodin, combine hydrocodone and acetaminophen. Zohydro is scheduled to be available in March.

Earlier this month, three U.S. senators raised concerns about the drug and asked the FDA to explain how it will prevent misuse. Writing on behalf of “groups on the front-line of the nation’s opioid addiction epidemic,” the organizations said there is no need for another high-dose opioid. “Too many people have already become addicted to similar opioid medications and too many lives have been lost,” said Andrew Kolodny, president of Physicians for Responsible Opioid Prescribing. “The FDA should exercise its responsibility to protect the public’s health by reversing its approval of Zohydro.”

“I’m worried about their plan to market the drug for back pain and other common problems,” said Judy Rummler, chair of the FED UP! Coalition and president of the Steve Rummler Hope Foundation.  Judy’s son Steve died of a drug overdose in 2011.  He had become addicted to the painkillers that were prescribed to him for his chronic back pain. Opioid prescriptions have skyrocketed in recent years. The U.S. has just 5 percent of the world’s population but is consuming more than 99 percent of the world’s hydrocodone. Opioid addiction and overdose deaths have increased commensurately.

“The capsules will contain a whopping dose of hydrocodone,” said Pete Jackson, president of Advocates for the Reform of Prescription Opioids. Jackson lost his 18-year-old daughter to a single dose of OxyContin. “It’s crazy to let this drug go on the market as it undoubtedly will become the next OxyContin that will fuel the opioid addiction epidemic.” Added Dr. Michael Carome, director of Public Citizen’s Health Research Group, “I’m amazed that the FDA would approve a dangerous new opioid over the strong objection of its advisory panel. In the midst of a severe epidemic of opioid addiction and overdose deaths, this is the last thing we need.” 

The letter is available at http://www.citizen.org/hrg2185.

LAURA SULLIVAN, BYLINE: When Zohydro is released next month, it will be one of the most powerful prescription painkillers on the market. It’s highest dosage will contain five to 10 times as much hydrocodone as the widely used Vicodin. The drug company’s literature says an adult could overdose on two capsules. A child could die from swallowing just one pill.

DR. MICHAEL CAROME: People are going to die from this drug.

SULLIVAN: Dr. Michael Carome is the director of Health Research for Public Citizen.

CAROME: We are in the midst of a public health crisis. There is an epidemic of opioid addiction resulting in thousands of deaths. And the last thing we need now is another high-potent, high-dose, long-acting opioid drug, Zohydro, that will simply feed the epidemic.

SULLIVAN: Overdose deaths and addiction rates from prescription painkillers similar to Zohydro have grown dramatically in recent years. Carome and 41 other healthcare advocates are asking the FDA to remove its approval of the drug. Zohydro is a crushable pill. That means it’s snortable and, some experts say, more prone to abuse than other drugs like the new versions of Oxycontin, which are no longer crushable. The drug company Zogenix is marketing the drug.

DR. BRAD GALER: There’s a lot of misinformation being put out there by people who don’t have all the facts.

SULLIVAN: Dr. Brad Galer is the company’s chief medical officer. He says they will introduce a non-crushable version of Zohydro in three years. And the company will closely monitor prescription transfer abuse. But he says millions legitimately need this drug.

GALER: We’re talking about patients that are in bed, depressed, can’t sleep, can’t work, can’t interact with their loved ones – it’s a very significant medical health problem that is being ignored.

SULLIVAN: That argument isn’t sitting will with public health advocates. Dr. Andrew Kolodny is chief medical officer at the Phoenix House Foundation.

DR. ANDREW KOLODNY: We have many opiate formulations on the market. There’s absolutely no need for a new opioid formulation.

SULLIVAN: FDA’s own advisory panels seem to agree. The panel voted 11-to-2 not to approve the drug. Then in November, top FDA officials overruled that panel. And that’s where things get complicated. Last fall, a series of emails were made public from a Freedom of Information Act request. They were emails between two professors who had, for a decade, organized private meetings between FDA officials and drug companies who make pain medicine. The drug companies pay the professors thousands of dollars to attend. And here’s what has critics concerned. One of those companies was Zohydro’s original manufacturer, Elan Corporation. Zogenix wasn’t in the picture yet but went on to partner with Elan.

Dr. Kolodny of Phoenix House Foundation.

KOLODNY: When those emails surfaced, I think for many of us there was a sense of a-ha.

SULLIVAN: Elan has a new owner and the company did not respond to requests for comment. In a statement, the FDA said the meetings did not address specific drugs and that the FDA took part to develop better research methods. The statement says those research methods may have benefitted companies making pain drugs but that they also benefitted patients. Zohydro’s Dr. Galer attended the meetings when he worked for another drug company.

GALER: Those actually were looking at old studies to improve patient care.

SULLIVAN: So I asked him: But if the drug manufacturers are sitting in a room with FDA officials talking about pain drugs, and they’re there because they spent 20 to 30 thousand dollars to be in the room, and some of the other advocates aren’t allowed in that room at the same time, does that raise any concerns for you that that could be a conflict of interest?

GALER: Well, again, I’m here as chief medical officer for Zogenix. Zogenix was not involved whatsoever. All I can say is that this medication, Zohydro ER, will benefit many patients…

Adverse emotional and interpersonal effects reported by 1829 New Zealanders while taking antidepressants

Psychiatry Research

by John Read, Claire Cartwright, and Kerry Gibson

3 February 2014

Background: In the context of rapidly increasing antidepressant use internationally, and recent reviews raising concerns about efficacy and adverse effects, this study aimed to survey the largest sample of AD recipients to date.

Methods: An online questionnaire about experiences with, and beliefs about, antidepressants was completed by 1829 adults who had been prescribed antidepressants in the last five years (53% were first prescribed them between 2000 and 2009, and 52% reported taking them for more than three years).

Results: Eight of the 20 adverse effects studied were reported by over half the participants; most frequently Sexual Difficulties (62%) and Feeling Emotionally Numb (60%). Percentages for other effects included: Feeling Not Like Myself – 52%, Reduction In Positive Feelings – 42%, Caring Less About Others – 39%, Suicidality – 39%, and Withdrawal Effects – 55%. Total Adverse Effect scores were related to younger age, lower education and income, and type of antidepressant, but not to level of depression prior to taking antidepressants.

Conclusions: The adverse effects of antidepressants may be more frequent than previously reported, and include emotional and interpersonal effects.

see also:

• Are the Side Effects of Antidepressants Underestimated
• Psychological side-effects of anti-depressants worse than thought

The history is well known to us. When these drugs were first introduced, we were lead to believe that the sexual side effects were occasional. And as it became apparent that was untrue, the drug-makers fought that truth tooth and toenail. When the issue of suicidality was first on the table, the same fight ensued. It’s still going on with the endless attempts to disprove the black box warning put in place in 2004 using population statistics. Well this article uses population statistics in the right way, they asked the question directly and the results are right there in black and white. The main findings are in the abstract above. Here’s the breakdown by specific drug:

In my own musings about these medications since they came out, I’ve wondered how they work. I don’t think I ever thought that they had a primary effect on depression per se, nor did I ever think they were acting at some fundamental level on the cause of depression. When it became apparent how common the sexual side effects were and I started hearing about those first four symptoms in the table, I wondered if they were working by dampening down the emotional system in some global way, and the fact that some people with anxiety disorders are so responsive seemed confirmatory. Some patients complained about those first four symptoms and stopped the drugs. Others seemed to welcome them, saying something like "I need to be turned down." But the main observation I can add to that was something I noticed when I left practice.

My practice was primarily a psychotherapy practice with patients who were treatment failures from other therapies. I was a rare medication user: short term Benzodiazepines for crises; stimulants for some adult patients with undiagnosed ADD; some time limited Inderal for people with performance anxiety.  When I retired, I went over every case I’d seen as sort of an exit exercise, and the surprise to me had to do with SSRIs. I’d used them here and there along the way, but in retrospect, every case I had with significant PTSD was on SSRIs. And I came to think think that was because those patients are hypervigilant, have affect storms, and actually do better with the volume turned down. I was surprised that I hadn’t noticed that along the way, but I didn’t.

I wasn’t surprised by this next part either. Most SSRIs are prescribed by Primary Care Physicians and people take them for a long time. Lots of people I see are reticent to "give them up," however people who’ve been on them for a long time frequently feel better when they’re off of them – "I feel my life."

But I’ll have to admit that this next part was a surprise:

83% improvement? With this?

Boehringer Kept Pradaxa Analysis From FDA, Records Show

Bloomberg

By Jef Feeley and Michelle Fay Cortez

Feb 25, 2014

Boehringer Ingelheim GmbH didn’t disclose a data analysis to U.S. regulators that indicated the blood-thinner Pradaxa may have caused more fatal bleeding after it was cleared for sale than the drug did in a study used to win approval, unsealed court filings show. Boehringer gave U.S. regulators one analysis of data gathered after the drug’s October 2010 approval that showed the number of people who died from bleeding was less than expected, according to internal documents made public in lawsuits over the product. The company didn’t share a second analysis showing a higher death rate, the documents show. The Food and Drug Administration was reviewing the bleeding as part of a safety check spurred by results seen in adverse incident reports sent to the agency. Andreas Clemens, an executive who oversees Pradaxa, acknowledged the Ingelheim, Germany-based company shared only one of the analyses and said he couldn’t say why, according to the unsealed court filings.

“Having run an analysis in several ways, there is no good reason not to disclose all the results,” said Harlan Krumholz, a Yale University cardiologist in New Haven, Connecticut, who is leading an effort to get companies and researchers to share their findings fully. Boehringer gave the FDA the underlying data and provided an analysis using what the drugmaker considered to be the most appropriate comparison, said Marjorie Moeling, a company spokeswoman, in an e-mailed response to questions. “The company is completely confident that all of the facts will show that Boehringer Ingelheim acted appropriately and responsibly.”

A company filing this month said Boehringer faces more than 2,000 suits involving Pradaxa, a treatment used to prevent strokes in patients who suffer from atrial fibrillation, a heart-rhythm disorder. Regulators cleared the drug, which generated $1.4 billion in 2012 sales, as the first alternative to warfarin, a product sold by Bristol-Myers Squibb Co. under the brand name Coumadin that’s been used for 50 years to avert strokes caused by blood clots. Patient lawsuits contend Boehringer knew the drug posed a deadly risk when it won FDA approval. While warfarin offers a way to counteract excessive bleeding, there’s no approved antidote available yet for those on Pradaxa. In November, the company released data from the first human study of an antidote in 145 healthy volunteers. Boehringer’s decision to provide only one analysis on Pradaxa’s use after the drug’s approval may complicate the company’s defense as it prepares to face the first trial of claims that it hid the medication’s health risks.

“It is important to resist selective presentation of results, especially when the finding depends on which analysis is done,” said Krumholz, who isn’t involved in any of the Pradaxa lawsuits, by telephone. “The fact that different analyses of the same data can yield different conclusions makes it imperative that we promote an opportunity for independent analyses through data sharing so that these issues will be out in the open”…

hat tip to pharmagossip…

Back at the end of January, when I read J&J chooses Yale to review requests for clinical drug data, I wrote a placemarker… vowing to keep an eye open on what happened. I’m suspicious of these independent panels to oversee Data Transparency. And after some experience with Martin Keller at Brown [Paxil Study 329] and Joseph Biederman at Harvard [childhood bipolar disease], the Ivy League thing has lost its former glow. So when Harlan Krumholz at Yale wrote Give the Data to the People, about his  Yale University Open Data Access [YODA] program being chosen as the overseer of J&J’s clinical data, I was suspicious, and said so [reassure us…] – sending my post to Dr. Krumholz himself. He was offended, and as it turned out, he had every right to be offended [a patch of blue…]. I was the one in the wrong [thus my foot-in-mouth title and picture]. He had been involved in the Vioxx story in the rightest of ways and he directly reassured me without the usual evasions about the J&J panel deal. Harlan Krumholz is a white hat guy, and I hadn’t done enough homework to know that. While I come by my distrust honestly, I’ve obviously become paranoid and went off half-cocked. Like most of us, I don’t like admitting I was wrong, but I was.

The proof will be if the American College of Cardiology jumps on this Pradaxa thing and gets to the bottom of it. Academic/Organized psychiatry has not done that through all of our exposes and scandals. They’re either silent or worse, part of the defense. I think that’s why the Pradaxa story caught my eye. I realized that my expectation was that Medicine proper would get involved in an active way. Psychiatry hasn’t done that.

"I’m a kind of paranoiac in reverse. I suspect people of plotting to make me happy."
Raise High the Roof Beam, Carpenters [1955], J. D. Salinger

GlaxoChinaGate contd. – Enter the British Serious Fraud Office Dragon

Pharmagossip

by Jack Friday

02/24/2014

Britain’s Serious Fraud Office plans to prosecute or fine some companies for engaging in bribery overseas, and analysts said some cases might involve mainland China, with GlaxoSmithKline and Rolls-Royce as likely targets. "We have a number of cases in mind but need to look at all the facts," a spokesman with the fraud office told the South China Morning Post.

The Bribery Act seeks to punish Britain-linked firms for bribery overseas, and a new policy by the office announced this month could make it easier to deal with such cases efficiently. The timing of the prosecutions and fines would depend on the circumstances of individual cases, the spokesman said.

In a speech in November quoting Chinese President Xi Jinping’s anti-corruption slogan "Striking tigers as well as flies", Ben Morgan, the joint head of bribery and corruption at the office, said: "We are investigating the types of cases that risk being overlooked as too difficult or too sensitive."

Rob Elvin, a Britain-based managing partner of law firm Squire Sanders, said: " We assume this includes GlaxoSmithKline and Rolls-Royce." Beijing is probing GSK, the largest British drug firm, for alleged bribery in mainland China…

Which brings us to the concept of sin. I didn’t grow up Catholic, but if your Dad’s family immigrated from Italy, about half your relatives are Catholic. My same aged cousin delighted in telling me what I was missing by not going to parochial school, and we had endless talks about purgatory, limbo, papal infallibility, confession, transfiguration, and the like in those days long before Vatican II. But the abiding concern for any two little boys was, of course, sin – venial and mortal. My cousin was obsessed with the difference, and every time we got together, he gave me an exposition on his updated research on those differences, as he planned how to keep his sins on the sunny side of the street [an interest we shared].

Analysts said the office’s new deferred prosecution agreement policy would speed up prosecution of corruption cases. From Monday, these agreements for economic crimes would be available to British prosecutors, the office said last week. A deferred prosecution agreement is one between the prosecutor and a company that allows prosecution to be suspended for a period of time, provided the firm meets certain conditions.

The fraud office’s director David Green said such an agreement sought to avoid damaging the company too much, which would hurt employees and shareholders. The new policy was significant as it provided additional tools for prosecutors, said Andrew Dale, a partner at law firm Orrick, Herrington & Sutcliffe. These agreements would potentially enable the fraud office to resolve more investigations more efficiently, said Keith Williamson, head of forensic and dispute services for Asia at Alvarez & Marsal, an international professional services firm. "We may see a [spate] of resolutions, either settlements or prosecutions," he said.

Deferred prosecution agreements would encourage companies to voluntarily report corruption within their ranks to the fraud office, Williamson said. Elvin said: "[These] agreements are most certainly significant. They allow commercial organisations to settle allegations of criminal economic activity without being prosecuted and without any formal admission of guilt. [They] provide a cost-efficient and quick means of addressing financial crime by corporates."

However, British authorities were likely to still prosecute the most serious economic crimes, he said.

When I first read that second part, I felt outraged. Protect the company’s reputation? Clean up the court docket? Keep the shareholders and employees from getting hurt? What about the patients? the sick people who are getting gouged or hurt! How in the hell does that help them? And what about the doctors who are given false information? that they’ve passed on? I doubt  that any of the actual injured parties would think very much of these deferred prosecution agreements. It’s just more of the venial sin malarkey that my cousin was incorporating into his life planning. But then it occurred to me that maybe they were onto something back in the day with their venial versus mortal distinctions.

However, British authorities were likely to still prosecute the most serious economic crimes, he said.

In Medicine, the term "malpractice" used to cover all medical sins. But recently, criminal prosecutions have become more common. The standards for the differences aren’t totally clear at this point, riding still on a case to case basis. The ones with mens rea [guilty mind] are the clearest as in the usual criminal cases. The confusing ones are where the levels of negligence are on the table. But my point is that the law is beginning to approach the issue my cousin called the difference between mortal and venial sins when it comes to physicians. It seems to me that rather than continue to complain about the penalties for the sins of pharmaceutical companies, we ought the spend our time looking into the situations where those sins are mortal [and committed by a person or persons]. We have plenty of examples to draw on in our deliberations. Maybe we could help them along the road to doing the right thing by defining the domain.

This post has nothing to do with psychiatry, but everything to do with the pharmaceutical world. It’s about the so-called blood thinners, anticoagulants taken to decrease clotting in conditions like atrial fibrillation, a heart rhythm abnormality associated with clot formation that can lead to stroke. The standard drug, Warfarin, has been in use since the 1950s. It interferes with the Vitamin K dependent factors in clotting, so it’s effect can be reversed with Vitamin K. Obviously, the main problem is abnormal bleeding, and so clotting has to be checked frequently.

Comes now Pradaxa®, a new drug that acts on a different part of the clotting mechanism. It doesn’t require the frequent blood tests like Warfarin, at least that’s how it was introduced. Abnormal bleeding is less than Warfarin for certain kinds of bleeding, but perhaps more for gastrointestinal bleeding. There are no simple blood tests to monitor it, and it can’t be rapidly reversed.

New York Times:
• Study of Drug for Blood Clots Caused a Stir, Records Show
• New Emails in Pradaxa Case Show Concern Over Profit
Healthcare Renewal:
• "Can’t This be Avoided?" – How Corporate Marketers Manipulated a Clinical Research Report to Avoid "Undermining" Marketing Messages
Hooked: Ethics, Medicine, and Pharma
• Pradaxa: More Evidence of Drug Firms Manipulating Science

It’s patients suing the drug firm over Pradaxa-related harm that led to the articles in the Times. The judge ordered release of some documents related to the case that include internal company e-mails about a research study coordinated by a company scientist, Paul A. Reilly. Reilly’s study showed that a part of the safety problem with Pradaxa was that some patients had too high a blood level and some patients too low [sound familiar?]. He concluded that a blood test that measured drug levels could be helpful for at least some patients in avoiding dangerous reactions. [Such a blood test is available now in Europe but not the U.S.]

A draft of Reilly’s paper that included these findings unleashed a storm of e-mails from other company scientists and officials. They argued that publishing a paper with these conclusions would undermine the company’s primary marketing point in favor of Pradaxa, the result of a fine-tuned marketing effort going back a decade. Moreover, some feared that if the paper were published, it would be that much harder to get the government regulators to hold off demanding blood tests. The end result was that the paper was published recently but with many of the offending details removed.

Boehringer Ingelheim insists that this was a simple matter of scientific review and refinement. A draft was circulated, others chimed in with appropriate criticisms, and in the end the final paper was suitably modified to better present the actual facts. Nobody here but us scientists, boss…

Is it really wanted to publish this exposure event paper of RELY?

I cannot believe that for a decade a drug was developed with the clearly defined target of no monitoring needs, a prospective trial without plasma level monitoring was performed generating the RELY study results, that we promote 2 fixed doses without monitoring, defend continuously to Health Authorities that individual patient characteristics do not allow a dose translation based on plasma levels only and then finally release a publication where exposure event relationships which was neither prospectively defined nor adequately conducted are described to define an effective and safe plasma level range…

This will make any defense of no monitoring to HA extremely difficult [ie Health Canada, TGA] and undermine our efforts to compete with other NOACs.

As I am not empowered to release or stop any publications I would like to ask you to check once again whether this is really wanted.

"Unless we can find a solution to the commercial incompetence problem, we have to recognize that the pharmaceutical industry has an irreducible conflict of interest in relation to the way it represents its drugs, in science and in marketing. And unless we can resolve this in a way that is more in the public interest and in patients’ interest, I would argue that drug companies should not be allowed to evaluate their own products."

I love the Olympics. It’s always the same. It starts with great conflict in the air – the Ukraine, Terrorists, discrimination, not-ready hotel rooms, who was that lady sitting with Putin?, etc. And then things settle down and you worry about the US atheletes for a while, crestfallen when the heros lose. And by the end, you’re watching some crazy sport like Biatholon or Parallel-Ski-Cross and rooting for athletes from places you’ve never even heard of before. And you find out that the lady with Putin at the opening ceremony wasn’t some mistress. She was a Russian athlete who was disabled for life in a Bob-Sled accident 5 years ago. And then there was the segment about the Russian hockey team, Lokomotiv, who all died in a plane crash two years ago, and how their city recovered.

I’ve been to two Olympics – Munich in 1972 and Atlanta in 1996. It was the same scenario – even with the craziness with the Terrorists. By the last night, we were in a hanger on an isolated military base at midnight being strip searched along with a crowd of people who spoke other languages. But we were all great pals and uniformly relieved the Germans were being so careful. The first days in Atlanta were snafu filled, and let’s face it, Atlanta isn’t Barcelona [and we heard about that]. But by the end, it was great in spite of the bombing. The Olympics always puts me in a good mood about people and the world, something hard to feel if you watch the evening news very much.

• Psychiatry Gone Astray by Peter Gøtzsche on David Healy’s blog
• An Obvious Response to "Psychiatry Gone Astray" by George Dawson on Real Psychiatry
• Get Real: Peter Gøtzsche Responds by Peter Gøtzsche on David Healy’s blog
• The Proud Critics of Psychiatry by George Dawson on Real Psychiatry

I respect every one of the people listed here. I read their  blogs, and their books. I think each of them has taught me something valuable along the way. Psycritic is a thoughtful, introspective child psychiatrist. Altostrata taught me about the withdrawal syndromes from psychoactive medications, something I didn’t know about. David Healy taught us all about akathisia and suicidality on antidepressants. He parsed the peculiar history of the FDA and explained why the system is so odd like no other has even tried to do. Peter Gøtzsche and the others at Cochrane taught us how to compare studies, how to detect missing data, how to think critically about the ubiquitous clinical trials, how to see corruption. Dr. Carroll has taught me more than I even knew there was to learn about biological psychiatry. And I appreciate both David Allen and Sandy Steingard having the ability to maintain a balanced perspective on matters psychiatric in today’s way too contentious environment. Usually I find George Dawson’s posts acerbic, but I have respected his standing up to many of the spurious criticisms of psychiatry [though the post above wasn’t his best outing].

So I kept deleting what I wrote and starting over. Finally, I came back after watching a 30 mile cross country ski event and erased my musings for the last time. I guess I’m having an Olympic Spirit moment, and not really in the mood to comment on the ad hominems when all the players are people I respect, even if they take pot-shots at each other. In spite of the the differences, Psycritic was right. There are lots of high-quality comments in both the posts and in the comment section. I pass on the links for those. Otherwise, I’m obviously too conflicted to comment, so I’ll just hold my comments for another day…