Plavix: Insight into Sticking it to the Consumer

To give a little insight into the greed of our friends in the pharmaceutical industry, consider that it is generally legal for drug manufacturers to pay generic drug manufacturers to not manufacture generic copies of their medications, even as patents set to expire.

From the latest New England Journal of Medicine:

“In August, pharmacies began selling a cheaper, generic version of the blockbuster antiplatelet agent Plavix (clopidogrel). This was good news for patients with cardiac disease or stroke who cannot afford to buy the medication at more than $4 a day. But to Bristol-Myers Squibb and Sanofi-Aventis, who produce and market the drug, it was a financial disaster. Plavix is the world's second-best-selling drug — 48 million Americans use it on a daily basis — and with sales of more than $6 billion last year, it accounts for about 30 percent of Bristol-Myers's total earnings. In an effort to keep the generic version off the market, Bristol-Myers and Sanofi had agreed to pay its Canadian manufacturer, Apotex, $40 million not to release it until 2011. If this agreement fell through because it was deemed unapprovable by government authorities, Bristol-Myers–Sanofi would pay a break-up fee of at least $60 million and they wouldn't take legal action in advance to stop Apotex from releasing the generic. If part of this payoff was late, Apotex would claim "interest at a rate of $20,000 per day," Chief Executive Officer (CEO) Barry Sherman informed a Bristol-Myers executive by e-mail after the companies' pay-off settlement was rejected by government reviewers…”

“…In the case of Plavix, after the authorities rejected the initial settlement between Apotex and Bristol-Myers–Sanofi, the companies reached a second settlement, but by the end of July 2006, it, too, had unravelled in the wake of revelations that the Department of Justice was launching a criminal investigation of the deal. A week later, Apotex began flooding the market with generic clopidogrel, and within days, more than 60% of Plavix prescriptions were being filled with the generic, priced up to 20% lower than the brand-name product. On August 31, Bristol-Myers and Sanofi won an injunction preventing further sales, but by then, Apotex had shipped quantities that industry analysts expected to last until 2007.

The case offers a rare glimpse of the high-stakes arrangements through which pharmaceutical companies delay sales of generics and keep drug prices high — all under the watchful eyes of the Federal Trade Commission (FTC) and the Department of Justice. Though the cash payments at the heart of this deal are shocking, such "reverse payments" from a brand-name drug producer to a generics company are not illegal. What's unusual about the case isn't the millions promised to Apotex, it's that the settlement fell apart and generic clopidogrel was released for sale. In recent years, such settlements have generally stuck, despite federal authorities' efforts to undo them, and generics have been kept off the market.”

The article goes on to describe that these arrangements are relatively common and end up costing consumers a fortune.

For much more on this topic, interested readers can do a quick search on PharmaGossip. There are dozens of relevant posts.

Manic Thinking Improves Mood?

Below I've copied a summary from a study in Psychological Science that cleverly studied the effects of speeded-up thinking on mood.

How 'Manic' Thinking Makes Us Happy, Energized And Self-confident

When people are made to think quickly, they report feeling happier as a result. They also say they are more energetic, more creative, more powerful, and more self-assured. In short, they reported a whole set of experiences associated with being "manic."

Fast thinking, or "racing thoughts," is most commonly known as a symptom of the clinical psychiatric disorder of mania. But, according to Princeton University psychologist Emily Pronin, most healthy people also have experienced racing thoughts at some point in time -- perhaps when they are excited about a new idea they have just learned, or when they are brainstorming with a group of people, or even when they lie in bed unable to fall asleep. Pronin and her Harvard colleague Daniel Wegner decided to explore whether inducing people to think fast might lead them to feel some of the other experiences also associated with the manic experience.

To examine this question, they experimentally manipulated the pace at which participants read a series of statements. Half of participants read the statements at a fast pace (about twice as fast as normal reading speed) and the other half read the statements at a slow pace (about twice as slow as normal reading speed). They then completed a questionnaire assessing their mood, energy level, self-esteem, etc., using standard psychological measures. As an added twist, some of the participants read statements that were very depressing in content (e.g., I want to go to sleep and never wake up) while others read statements that were very elating in content (e.g., Wow! I feel great!).

The researchers found that regardless of the content of the statements, people felt happier, more energetic, more creative, more powerful, and more grandiose when they read the statements at a fast rather than a slow pace. In fact, the effect of thought speed was just as powerful as the effect of the content of the thoughts. In other words, the speed of people's cognitive processing was just as important as what they processed in determining their mood. Even thinking sad thoughts at a fast pace made people relatively happy.

The article, titled "Manic Thinking: Independent Effects of Thought Speed and Thought Content on Mood" appears in the September issue of Psychological Science, and was co-authored by Emily Pronin of Princeton University and Daniel Wegner of Harvard University.

The reported effect of fast thinking on mood could have important applications in both clinical (psychiatric) and normal populations. The authors note that simple manipulations of thought speed could perhaps be used to improve individuals' mood, self-esteem, feelings of creativity, feelings of power, and energy level. Such manipulations could be useful in everyday situations, where people would like a quick mood, energy, or self-esteem boost on a day they are feeling tired or downcast. Manipulations of thought speed might also prove useful as part of treating depression, which is characterized by slow thinking, and also by the absence of things like positive mood, energy, feelings of power, and self-esteem.

The authors note that: "The results of our experiment suggest the intriguing possibility that even during moments when people feel stuck having depressed thoughts, interventions that accelerate the speed of such thoughts may serve to boost feelings of positive affect and energy."

Source: Association for Psychological Science

Hat tip: Robert Karl Stonjek

Venturing into Politics Briefly

I try to leave politics out of this blog, though I suppose some may label me a pinko for pointing out problems within the drug industry.

But, that being said, rushing through legislation that enables arbitrary (entirely at the president's discretion) detention, defines torture in a rather Oliver North sort of way, and gives the rubber stamp to kangaroo court proceedings brings two issues to mind:

1) It is a brilliant move by the Republican party, which can run this sort of rally around the flag balderdash to improve support among their base because…

2) Democrats already only nominal opposition to the Republicans has essentially vanished entirely. “Oh my God, they’ll say we’re terrorist sympathizers if we openly oppose this Stalinist legislation – and then we won’t regain control of the House and Senate.” News flash, you morons: You’re not going to gain control of anything if you never take a stand. When something is wrong, by God, explain why it is wrong and perhaps people will see you as something more than the party that sits around with dumb looks on their faces while the Republican Party is raping our Dear Republic in the name of Patriotism.

I will do my best to post nothing else on politics anytime soon. See the New York Times for a timely editorial on the topic (registration likely required).

Review of Doughnuts for Doctors

Doughnuts for the Doctors: Moynihan and Cassels on the pimping of antidepressants…

I was very much looking forward to their book, Selling Sickness, as I’ve been favorably impressed with much of Moynihan’s earlier work on disease mongering. The authors discuss depression in a chapter titled Doughnuts for the Doctors, in 18 short pages, which is unfortunately far too brief for the weighty topics tackled within. They point out that physicians are certainly influenced by contacts with drug reps, and that there are a litany of problems with SSRI’s (suicidality, small advantage over placebo, significant side effects such as sexual dysfunction, etc.), but the attention given to these points is unfortunately too brief.

I was more impressed with their description of the American Psychiatric Association’s convention, where the virtual orgy of drug promotion disguised as education (industry-sponsored symposia and those slick looking booths staffed by likely remarkable attractive cheerleaders, er, drug reps) was discussed again too briefly, but in a captivating manner. Loren Mosher, who quit the APA a few years ago in disgust, along with David Healy are discussed in passing. For Healy, especially, this is short shrift.

More interesting was the debate on the prevalence of mental disorders, including depression, which focused on the differing findings of Kessler versus Narrow in their estimates of the aforementioned problems. Certainly, Narrow found a lower prevalence for mental disorders than did Kessler, and the discussion is important and timely for all mental health practitioners and researchers.

My favorite line in the chapter is in the context of the finding that half of people receiving treatment for mental disorders were “either noncases or mild cases.” The authors opine cleverly, “The global obsession with “unmet need” – a notion that is constantly pushed by doctors and drug companies as the justification for aggressive drug marketing – may well be helping to create a strange new phenomenon: ‘met un-need.’” A great point when one considers how much energy (some of it indeed justified) goes into campaigns to get more people into treatment because [insert mental disorder here] is undertreated in the community. The authors then discuss a screening test from our friends at Bristol Myers Squibb which found that 49% of individuals had a “mental disorder." Later research showed, unsurprisingly that this test was a poor assessment of mental health. More (but still not enough) on marketing depression follows after this point.

A little more on the well-tread territory of antidepressant use in children follows, in which their insights are spot-on. What I found more interesting was the discussion of “thought leaders” and their development by the drug industry. Another great quote follows:

“Promising prospects might be singled out by a detailer as a potential thought-leader, and then given some small speaking engagement to test them out. Later, if they’ve proven their worth, they might be paid to speak regularly in small local settings about the latest new drug in the pipeline. With a bit of luck the thought-leader could eventually find themselves on a drug company’s ‘speaker’s bureau’ earning thousands of dollars for making presentations to their international peers about the latest new disease, at high-profile events like the APA congress in New York.”

More good stuff follows on “thought leaders," though yet again I wanted more.

Overall: If I had to assign stars, I’d give this chapter 4 of 5. Great source of references for the interested reader. The writing was solid and interesting, but it just went too quickly from topic to topic. Nonetheless, it is hard to disagree with their implicit conclusions that antidepressants are much more a miracle of marketing than science.

Hopefully time will arise for a brief synopsis of the ADHD chapter as well.

Merck: Only the Little People Pay Taxes

Ahhhh... Nothing like Merck getting caught evading taxes to start off the day. Pharmagossip has a summary of the story in the Wall Street Journal which details Merck's tricky accounting procedures related to this scandal.

"Thirteen years ago, Merck set up a subsidiary with an address in tax-friendly Bermuda, in partnership with a British bank. Merck quietly transferred patents underlying the blockbuster drugs to the new subsidiary, according to documents and people familiar with the transaction. Merck then paid the subsidiary for use of the patents.

The arrangement in effect allowed some of the profits to disappear into a kind of Bermuda triangle between different tax jurisdictions. The setup helped Merck slash $1.5 billion off its federal tax bills over roughly the next 10 years."

Check out the story on PharmaGossip or over at the Wall Street Journal.

Coming Soon... Selling Sickness Review

No time today. Hopefully on Thursday, I'll post my review of a couple of chapters from Selling Sickness by Ray Moynihan and Alan Cassels. I'll discuss the chapters on depression and ADHD in sticking with the psychiatry/psychology theme of the site.

Check out Rost's Site

If you haven't been following Peter Rost's trials and tribulations, this is a great time to start. There is something so refeshing about a whistleblower at a pharmaceutical company. I think everybody will enjoy his site.

Nemeroff: Another Lesson in Reviewing Literature

OK, OK. Enough about poor Charles Nemeroff already! Maybe he made a little mistake on the VNS thing. But, what if a similar problem occurred in another venue?

It did. Nemeroff & Owens were reviewing several treatments in the journal Nature Neuroscience (2002) and they came to the conclusion that both mifepristone and a transdermal lithium patch were likely solid treatment options for mood disorders.

Let’s start with mifepristone. To quote the review: “impressive studies [indicate] that the glucocorticoid receptor antagonist mifepristone is very effective in the treatment of psychotic depression.” The authors cite one study (not “studies”) to back up this claim. In this study, mifepristone was tested on five (yes, FIVE) individuals. So based on a study of five patients, Nemeroff and Owens state that the medication is “very effective.” That, my friends, is bad science! Oh, and incidentally (and not mentioned by the authors), mifepristone is better known as “the abortion pill.” I don’t know, but I think I might mention that in my review of mifepristone.

More on mifepristone/RU-486, the antidepressant: How about – It’s not an antidepressant. In a study of over 200 patients, mifepristone was found to be somewhat (mild to moderate effect size) more efficacious in alleviating psychotic symptoms of psychotic depression, but no more effective at alleviating depressive symptoms than a placebo. Granted, that was published years after Nemeroff and Owens’ dubious statement about its efficacy, but I thought readers may be interested to know that their statement on efficacy was quite overblown and has not been supported in a much larger study.

The rub: Nemeroff was reportedly a member of the scientific advisory board for Corcept Therapeutics, which was (and perhaps still is) developing mifepristone.

Now, about that lithium patch. The authors say “Changing the pharmacokinetic profiles of existing drugs has also proven beneficial. For example, controlled or sustained-release preparations of venlafaxine, buropion and paroxetine are now available, and methods to deliver a monoamine oxidase inhibitor and lithium via patch technology have been developed. These methods improve tolerability of the drug, as well as patient compliance.”

Sounds good, eh? The lithium patch improves tolerability and compliance, except that the authors provide not a single source to back these claims. When writing a review article, the point is to summarize scientific evidence, which is generally done through providing sources! Who needs a source, though, when you stand to profit handsomely from the use of the lithium patch. After all, Nemeroff is the co-patent holder for the device!

A related post on Nemeroff is available from the Alliance for Human Research Protection here.

VNS, Chuck, and Conflicts of Interest

Nemeroff Part 2

Suppose you are the paid chairman of the “Mechanism of Action Advisory Board” for a company that markets a device (vagus nerve stimulation or VNS) which treats depression. Is it ethical to slap your name on a very favorable journal article related to VNS without indicating that you (and several of your coauthors) have a substantial conflict of interest?

How about having a ghostwriter make substantial contributions to the aforementioned paper? And what do you think about making sure that this “scientific review” of VNS overlaps carefully with the marketing used for the device? At this point, I’ll quote directly from Health Care Renewal’s excellent post:

“There is no discernible difference between the corporation's press releases and the text of the review article on these topics. The review did not address the controversy surrounding the FDA approval process. In these respects, the review has the hallmarks of a ghostwritten article. As described by Leemon McHenry, who has written on conflict of interest issues in medicine, "I have ... seen contracts between the pharmaceutical companies and the ghostwriting companies with the plan of production and the budget. What is particularly interesting about these is the fact that it is clear that the company owns the manuscript until it is released to the "authors." The company's legal department reviews the manuscript and releases it at the end of the process. The first draft isn't even reviewed by the "authors." This is all internal until the second draft." It appears very likely that the VNS review was carefully screened by the corporation to ensure that the first draft was "on message" before being released to the "authors" for them to strengthen the hard science surrounding the stealth infomercial.”

Should your allegedly detached and scientific review skirt around any issues about the controversy of the device’s FDA approval for treating depression? To quote the NY Times: “…in the most carefully controlled trial, a group that had the device implanted but not turned on fared nearly as well as the group being stimulated. Critics also pointed out that long-term results indicated that 30 percent of the patients reported worsening depression similar to Ms. Coram’s, creating unanswered questions about potential harm.” Yeah, certainly don't mention any controversy!

As the lead author of the study, should you bother to mention that you are the chair of the Advisory Board for the corporation?

Better yet, should you publish this article in the journal where you are editor in chief? To top it off, make sure to be quoted in a press release by the VNS manufacturer, in which you describe how the latest article shows VNS is super-duper wonderful:

"After reviewing all the available data, taken together, it is clear that VNS Therapy is a promising treatment for patients living with TRD. Given the nature of TRD, it is exceptional that the antidepressant effect of VNS Therapy has been shown to improve over time and is sustained long-term for patients with TRD. Results of ongoing clinical and imaging studies will be critical to increasing our understanding of the mechanisms of action that mediate the beneficial effects of VNS Therapy for TRD.”

So, to summarize, a ghostwriter hired by Cyberonics pens a draft of an article (or at least writes quite a bit of an initial working draft) favorable to VNS therapy for depression. Eight academics, including Nemeroff, sign their names to it after perhaps adding some substantive content. The article is then sent to Neuropsychopharmacology, where Nemeroff is editor in chief, resulting in likely disproportionately favorable reviews and a relatively easy publication. In this publication, the financial conflict of interest of Nemeroff and colleagues is not mentioned. To celebrate this great triumph of marketing, er, science, Cyberonics issues a press release discussing how this “peer-reviewed” article provides support for their product. To top it off, Cyberonics reportedly ordered 10,000 reprints of this so-called study. Friendly representatives will be visiting a psychiatrist near you with this ironclad evidence of efficacy!

For more details, read Health Care Renewal’s post on the topic.

Is this a fluke for Dr. Nemeroff, a one-time occurrence. We’ll see…

Is Chuck Using a Ghostwriter?

There have been enough interesting stories about Charles Nemeroff, professor of psychiatry at Emory University, that I’m sure they warrant a posting or two.

Let’s start with ghostwriting and then move on to David Healy and then to conflicts of interest.

It is mentioned on Nemeroff's website that he has published “more than 750 research reports and reviews,” which is one impressive feat. In a quick Medline search, I turned up his earliest publication date as 1975. So, that’s about 30 years of publishing, putting him at 25 publications per year. I’m not saying the man is not legitimately prolific, but given his administrative responsibilities, major travel obligations (research and paid lectures across the country), and his time apparently spent trying to discredit David Healy (more on that coming soon), I wonder if he really had a legitimate role in 750-plus articles.

It appears that I’m not the only wondering if all of these publications are legit. Chuck had a recent publication in Neuropsychopharmacology where the wonders of vagus nerve stimulation were discussed. Let’s quote from Health Care Renewal’s great post on this subject:

“…the article acknowledged "editorial support" from a professional writer, who acknowledged to the Wall Street Journal that she was employed by the corporation for the task of writing a first draft. Although the authors claimed they provided substantive input after the first draft, it is ethically dubious to use a hired writer for a first draft.”

In other words, a ghostwriter wrote much (perhaps all) of the first draft, then Nemeroff and company added their pieces (or not) to the final draft. Who knows how many of the other 750-plus Nemeroff publications were, um, “assisted” by a ghostwriter? I’d have to defer to David Healy on that point.

So Junk Food is Bad for You??

This is bloody great! The British Heart Foundation has opted to run some rather inflammatory ads on the ingredients in junk food. The food industry is calling this a "scare tactic." The ad to the right features the caption "what goes into chips goes into you" -- brilliant!

Maybe you should be scared, making scare tactics the appropriate choice.

The story on BBC here.

Of course, you could just gain the weight, then take Xenical to lose the pounds if you are one of a trendy group of psychologists who favor a pharmacological approach to weight management, right?

Increasing Availability of Condoms on College Campuses

Oh no, the next thing you know, safe sex will be everywhere! A very interesting (and brief) read over at Effect Measure. One quote follows to pique your interest...

"So with condom manufacturers eager to mine a ready market, and with administrators happy to receive free or discounted products that will keep students healthy, condom distribution at many colleges around the country has become as fundamental to freshman orientation as buying textbooks and finding the dining hall."

How about we distribute SSRI's to increase the duration of these frisky college sexual encounters? See my post on that, um, interesting idea here.

Link to the Effect Measure post on condoms here.

Is a 3% Safety Recall Rate Acceptable?

The chronically excellent Pharma Marketing Blog has a great post on the drug industry’s reaction to an Institute of Medicine report calling for serious reforms. It is noted that 3% of drugs are recalled post-approval for safety reasons. Here’s Pharma Marketing’s take:

“Is a 3% Recall Rate Really "Good"?
The drug industry, through its trade association PhRMA, considers a 3% drug failure rate "good." Obviously, the IOM doesn't think a 3% failure rate represents a "good" system. In any other industry a 3% recall rate due to safety issues would be "bad."

In the airline industry, for example, if 3% of airline flights ended in fatal crashes, there would be no airline industry. The actual rate of "fatal events" in the airline industry ranges from 0.00 to 1.92 per million flights."

Much more over at the Pharma Marketing blog, where the posts have been especially interesting lately.

Hat Tip...

For the TADS post (next post down), I should mention that Dr. Robert Foltz had an interestng article in Ethical Human Psychology and Psychiatry in the Summer 2006 issue that helped to aptly point out some of the concerns with the TADS study.

Drugs or Therapy for Adolescent Depression? TADS...

Admittedly, this post gets an ‘F’ for timeliness, since the study was published in 2004! However, since this site is relatively new, I ask for your forgiveness.

The Treatment for Adolescents With Depression Study examined depressed adolescents who were assigned to one of four groups: fluoxetine (Prozac) alone, placebo, cognitive-behavior therapy (CBT), or pill placebo.

Treatment lasted for 12 weeks. At first glance, the results seem clear. The CBT + fluoxetine group had the best outcomes, improving to a statistically significantly greater degree than each of the other conditions. Further, fluoxetine alone was significantly more effective than CBT alone, which was not more effective than a placebo. Case closed – right?

Not exactly. First of all, people who were receiving fluoxetine alone had the lowest rate of comorbidity (i.e., having additional psychiatric diagnoses) – their rate of comorbidity was 43.1% compared to 58% for CBT alone, 51% for placebo, and 55.6% for CBT + fluoxetine. Additionally, those on fluoxetine had the lowest rate of dysthymia, a longstanding mild to moderate form of depression, (5.5%) compared to the other conditions – CBT alone (15.5%), placebo (10.7% ), CBT + fluoxetine (10.3%). Thus, one could argue that the fluoxetine group was the easiest to treat, as their overall psychiatric condition appeared to be somewhat less severe than that of participants in the other treatment groups.

Treatment was not always blind. Those receiving fluoxetine + CBT were fully aware that they were receiving mediation whereas those on CBT were fully aware that they were not taking medication. This is a huge confound given that it is quite clear that the placebo effect in depression is huge. Simply put, the placebo effect likely put fluoxetine + CBT at a substantial advantage over CBT alone.

Safety. Harm-related adverse events occurred in 11.9% of the fluoxetine group, 8.4% of the fluoxetine + CBT group, 4.5% of CBT participants, and 5.4% of placebo-treated patients. The relative risk of greater than 2 when comparing fluoxetine to CBT suggests that psychotherapy is notably safer than SSRI treatment. Comparing SSRI treated patients to non-SSRI treated patients indicated a significant difference in the direction of SSRIs being more likely to induce harm-related adverse events. Nobody committed suicide in the study, but let’s keep in mind that these patients are likely monitored much more carefully (thus, protecting from actual suicide) compared to patients in the real world. In addition, there was one psychiatric (non-harm related) adverse event in the CBT group, 16 in the CBT + fluoxetine group, and 23 in the fluoxetine alone group. ‘Nuff said on safety.

My View: This study was generally well-done but the confounding issues described above leave one to wonder about its results. Evidence shows that, considering both safety and effectiveness, psychotherapy is not much better than a placebo for adolescent depression and that medication is problematic at best.

Oh, and one more thing. The press release from the National Institute of Mental Health indicated that TADS was a $17 million study. Good study, but it sounds like the researchers were getting paid on one of those infamous Halliburton contracts!

The American Psychological Association and Drugs for Kids

The American Psychological Association released a gargantuan 246 page report on the use of psychotherapy and pharmacotherapy for children and adolescents. It's nice to see that the organization that is so devoted to getting psychologists to prescribe medication is actually, on the other hand, also releasing a report that points out many of the evidence gaps in treating children with psychotropic medications. The majority of child psychiatry practice relies on clinical folklore rather than evidence, unfortunately. However, psychological interventions for many disorders also haven't shown a lot more efficacy than placebo interventions (but at least they seem quite a bit safer than meds). I've not had the time to read the report in its entirety, but I did like one section of text quite a bit:

"It is ironic that the specific advantages of available treatments, whether psychosocial or psychopharmacological, for depressed youth are small compared with the “nonspecific” effects of placebo and other supportive comparison treatments. It could be argued that more resources are warranted to investigate and train practitioners in the “nonspecifics” of the therapeutic alliance, support, exposure, and problem-solving skills that seem to cut across many treatments. It could also be argued that “watchful waiting” may be appropriate for some youth who present with milder symptoms of depression (pg. 117)."

Full text here and a press release summarizing the findings here.

Interview with a Drug Rep

I'm never sure how PharmaGossip finds stories like this! In any case, excerpts from an interview with a former drug rep follow below...

When you’re talking about trips and that sort of thing, it’s interesting. The industry did put in, over time, some self-imposed regulations. There were certain things you were not allowed to do, but in the end, it really didn’t matter. Maybe the really overt tactics of flying a doctor and his whole family out to the Bahamas for a weekend might have pulled back a little bit, but it was made up in other ways. Instead of just calling them trips it was called continuing education, or continuing medical education. That’s how they got around it from a PR perspective. Now we’re going on the trip, but we’re tying it to a lecture so we can call it continuing education. It takes on a lot of different forms.

Now, maybe what they’ll do is look at the top prescribers within the country. They’ll categorize those doctors as opinion leaders, go after those people and stroke their egos. They’ll say things like: “Because you’re such an opinion leader in the area of antidepressants and you’re leading the country in your use or your philosophy on this, we’d like you to come on board and be a consultant for our firm.”

So basically, we would hire them to be a consultant, which meant as a consultant, they’re now being paid and have a financial relationship to that company. With being a consultant, there were oftentimes trips because they’d have these think tank or brainstorming meetings. All that changed was how it was handled.

There were other things that went on like free samples, which was a very interesting way that the company would manipulate doctors. Doctors, unfortunately, would often see samples as the one act of benevolence that the industry provides. Really, the samples were a huge marketing tool. I was evaluated as a rep by how many samples I could push through my territory. There was a direct correlation between the number of samples you moved, and the number of prescriptions written for that drug. If you could get a doctor comfortable enough to hand out free samples, that doctor is now comfortable enough to pull up a prescription pad and write. It just makes really darn good business sense. Yeah, give out a week’s worth or a month’s worth of this antidepressant or this cholesterol-lowering medicine, because you know what, that patient oftentimes is now going to be on these drugs for a year, two years and in some cases a lifetime. We would even go to some doctors who had free clinics to give out these samples. We knew that if they became comfortable handing them out to the indigent patient population, that they’d come back to their private practice and then write prescriptions for those drugs.

Again, this is something I think people need to be aware of. Those samples often are for the most expensive and least tried and true drugs on the market. There’s a reason they’re giving them out for free. They want you to get hooked on them. They want you to take them.

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In the next clip, she talks about off-label drug use, which as we all know is a HUGE part of psychiatric prescriptions, especially for children and adolescents...
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Well, legally we were never supposed to be able to push them for off-label use. But again, there are certain tactics around that, because certainly with some of these drugs, the vast majority of the things that they’re prescribed for are not for the specific thing that they’re indicated. Physicians also have that liberty to be able to use drugs for purposes that they see fit.

We were often told in training sessions exactly what all the off-label uses were. It was always prefaced by, “We’re never supposed to talk about these things” – half wink wink – “But here are all the other ways that doctors are finding success with our drug.” We’d also get updates in terms of the studies or articles that were done on off-label use. Again, wink wink. You’re not supposed to use any of these in the field when you’re talking to physicians, or if you are talking to them you have to heavily preface it by, “Dr. Smith, this Drug A is not indicated for X, Y or Z, but I just thought you might find this article interesting.” You knew darn well that Dr. Smith is now going to read that article, because maybe it’s a patient type he’s struggling with, or whatever the case is, and that’s going to plant that seed in Dr. Smith’s mind.

So although you always had to be careful how you worded it, it was certainly known, I think, industry-wide that there were ways of planting those seeds. This is how the industry became so amazing at marketing their drugs. I mean that in a scary sort of way, because they use physicians to help them promote their drugs.

One of the key ways in terms of off-label use would be to find a doctor in a certain territory who was actually having a lot of success using a drug in an off-label sort of way. Then it was a matter of stroking that doctor, grooming him as an opinion leader, giving him the ego boost, asking him to come on board and be a consultant and then having that doctor hold round-table discussions with other doctors within the territory to talk about that specific drug, and the things that it’s indicated for. Since it’s peer to peer, that doctor is then going to bring up all the other ways he or she is using that drug and having success. And now, because they’re hearing it from another doctor, those ideas spread, and the other doctors are much more likely to take action.

Maybe you hold a dinner program where a doctor is giving a presentation on a drug or a disease state. You invite the doctor who’s using it for off-label use to come to that talk, and then maybe raise that use during a Q and A where he shares how he’s using it for all these other things. There were specific legalities, or specific guidelines that were in place, of things companies could or could not do. They were very, very effective at legally skirting those issues in many ways, because they were getting other people to talk about it.

Much other juicy inside gossip can be found in the full text of the interview here.

If this makes you think of how Neurontin was marketed illegally for off-label purposes, feel free to see my post here.

Plagiarism: How Large a Problem?

Good question. Iain Chalmers discusses what should be done to researchers who plagiarize. He says Name 'Em and Shame 'Em. I say that's a good start. Here's what he says in the latest BMJ...

During a search for studies that might be eligible for inclusion in a systematic review of controlled trials of epidural analgesia in labour in the late 1980s, I identified a paper by Asim Kurjak and John Beazley published in Acta Medica Iugoslavica. Well over half of the text and some of the data in this paper were identical to material in an unacknowledged paper published three years earlier by other authors in the Journal of Obstetrics and Gynaecology of the British Commonwealth. In correspondence, I learnt that these authors had not been contacted by Professors Kurjak or Beazley.

Professors Kurjak and Beazley had both worked at Queen Charlotte's Hospital in London, but the paper purported to be a report of a clinical trial done in Croatia. I first wrote to the British author, Professor Beazley. In a letter sent to me on 25 February 1991 Professor Beazley expressed his surprise and dismay because he had never seen the paper bearing his name. He requested an explanation from Professor Kurjak, now professor of obstetrics at the University of Zagreb, who wrote to me on 26 February 1991 confirming that Professor Beazley had not been involved in the paper. Professor Kurjak's letter to me made no comment on his obviously plagiarised text.

In the report of our systematic review of epidural analgesia in labour, my coauthor and I stated that we had excluded the Kurjak and Beazley article "because it contained long passages of text, and some data, which were identical to material published three years previously in an unacknowledged article by different authors."

…

Because Professor Kurjak had failed to explain the plagiarism, I reported our findings to those whom I thought should investigate it. The editor in chief of Acta Medica Iugoslavica, Nikola Pers, writing from the Croatian Academy, concluded his letter to me:

As a colleague and psychiatrist I believe that the stated problem should be solved in the way which would not harm (the) professional and scientific reputation and respect which Prof. Kurjak has earned in 16 years since the problem paper has been published. (10 June 1991).

I wrote to Stojan Kneceviz, Professor Persic's successor as editor of Acta Medica Iugoslavica (now renamed Acta Medica Croatica), requesting a copy of any notice placed in the journal to draw attention to the plagiarism, but I have never received any response to my request.

…

Four years ago it was discovered5 that Professor Kurjak had plagiarised material from a Norwegian PhD thesis6 and published it as a book chapter coauthored with a Croatian colleague.7 A copy of the thesis had been given to Professor Kurjak two years previously by its author (H-G Blaas, personal communication). After the publishers of the book had been informed of the plagiarism, they stopped distribution of the book and republished it without Professor Kurjak's chapter. Professor Kurjak and his coauthor did not deny the accusations of plagiarism but tried to play down their "errors of judgment" (H-G Blaas, personal communication).

The plagiarised Norwegian author and his PhD supervisor (Blaas and Eik-Nes) informed the executive committee of the International Society for Ultrasound in Obstetrics and Gynecology, which decided that Professor Kurjak and his coauthor would be "ineligible for membership of the Society and associated benefits for a further three years" (Karel Marsál, personal communication). The Norwegian investigators also reported Kurjak's plagiarism to the then dean of the medical school at the University of Zagreb, Boris Labar, in March 2002 but they have not so far received any response.

The example of Professor Kurjak's plagiarism that I identified occurred more than a quarter of a century ago. Thanks to an astute referee of an earlier draft of this article, the plagiarism turns out to have been even more blatant than I had thought. In his comments, the referee, Jim Neilson observed:

The 1974 Acta Med Iug paper...is clearly an amalgam of two papers—one of which is, as pointed out by Iain Chalmers, the 1971 paper by Noble et al in J Obstet Gynaecol Br Cwlth 78: 559-63. I have done a little detective work and the maternal acid-base work has been lifted from Pearson and Davies, J Obstet Gynaecol Br Cwlth 1973;80: 218-24.[ISI][Medline] As with the Noble paper, large parts of the text have been used verbatim, with little modification, and with no acknowledgement of the Pearson and Davies paper...The figures in the tables have been modified slightly from both original papers, in the Kurjak and Beazley paper—so this is not only plagiarism, it is also scientific fraud."

Link to the full text of Chalmers’ investigation here.

It would be nice to see more serious discipline on the part of universities. If your faculty are repeatedly plagiarizing or engaging in other forms of gross scientific misconduct, you should FIRE the offending parties. An accidental swiping of a sentence here or there -- oops, a little mistake. But cases like the above call for much harsher discipline. Of course, if someone is bringing in the grant money, what university will have the intestinal fortitude to give a corrupt researcher the boot?

Medical Journal Editors: The Drug Industry Stinks!

When I saw that Richard Smith was publishing a book, I knew it would contain a lot of good stuff. For those of you unfamiliar with his work, I've excerpted from one of his articles in the British Medical Journal below, in which Dr. Smith discusses some of the problems that occur in drug industry sponsored research. Please tell me that the academic psychiatrists and psychologists who conduct trials are paying attention!

Seeding and switching trials—Sometimes companies will conduct trials simply to get doctors to prescribe their drug. These "seeding trials" are often scientifically meaningless. They have no clear question and no controls. But they are conducted on a large scale, and "investigators" (often ordinary doctors, not researchers) are paid substantial sums to enter patients into the trial. A variant is a "switching trial" in which a doctor is paid to switch patients from their usual treatment to the new treatment. These sorts of trials will rarely make it into major journals, but many may be published somewhere—and then used to promote the drug with doctors, most of whom are scientifically naive.

Postmarketing surveillance—Yet another variant—with perhaps more scientific justification—is postmarketing surveillance. Many adverse effects of drugs do not emerge until after they are on the market, so it makes scientific sense to gather data on patients taking new drugs, but it can also make marketing sense as a way of getting doctors to prescribe the drug. Again doctors may be paid substantial sums "for expenses." My guess is that they rarely explain this to patients. Instead, patients may be flattered to think that they are getting the newest (with a false implication of best) treatment. These trials will often be published, sometimes in major journals—because they give important data on adverse effects.

Placebo controlled trials—Pharmaceutical companies are usually required to conduct a trial of their new drug against a placebo to get a licence for the drug. This requirement may conflict with the Declaration of Helsinki, which deems it unethical to give patients a placebo if an evidence based treatment is available. As most new drugs are not completely new but "me toos," this conflict arises often. What patients and doctors want to know is whether the new drug is better than existing treatments. But pharmaceutical companies have a horror of "head to head" trials, where treatments are tested against each other in trials that are big enough to give a clear answer. A clear but unfavourable answer would be dreadful for a company that had spent hundreds of millions of dollars bringing the drug to market and tens of millions on trials.

DeAngelis, Smith, Angell, who's next? The list of medical journal editors who are noticing that something smells fishy is growing...

Corruption and Fraud in Medical Journals

Richard Smith, ex-editor of the British Medical Journal, has just published a book titled The Trouble with Medical Journals in which he blasts for their lax oversight. The following is an excerpt from PharmaGossip's nice summary.

He said: "It is increasingly apparent that many of the studies journals contain are fraudulent, and the scientific community has not responded adequately to the problem of fraud."He added: "I went away to Venice to write this book and I was rather taken aback by how negatively it turned out. When I put together all the evidence on journals I was surprised by the extent of the problems."

Dr Smith went on: "Medical journals have increasingly become creatures of the drug industry. The authors of studies in journals have often had little do with the work they are reporting."The use of ghost writers by pharmaceutical companies is rampant and many studies have conflicts of interest that are not declared."

I've not had the good fortune of reading Dr. Smith's book, but it's officially added to my to-do list!

DTC Advertising: How Widespread is its Influence?

An interesting look from an FDA survey of physicians...

"One question the FDA survey asked was:

"Think about the most recent interaction you've had with a patient ... Can you think of a patient who initiated a discussion about a prescription drug they saw advertised?"

And 92% of surveyed physicians said YES!

Follow the link to see a more thorough writeup from the always thoughtful Pharma Marketing Blog.

IE Problems Fixed

This blog now shows much better in Internet Explorer than last week. Thanks to the good folks at Scientific Misconduct Blog for the help. Not only a great site on misconduct in research, but knowledgeable about .html -- that's what I call one stop shopping!

Friday: Research Misconduct Links

For two GREAT links to in-depth stories on research miscondict, check out the following:

1) Bloomberg News coverage of Big Pharma's Shameful Secret.

2) Aubrey Blumsohn's blog on Scientific Misconduct.

I've followed research misdeeds for quite a while, and I'd give these my highest endorsement.

Increasing Prescribing by Psychologists: Progress or Just Flatulence?

Well, here’s some good news if you are an enterprising psychologist: An article in the latest Journal of Clinical Psychology advocates that psychologists should not just be satisfied with the honor of prescribing psychotropic meds. The constant advocacy of the American Psychological Association has, of course, set the psychotropic train in motion by convincing legislatures in New Mexico, Louisiana, and Guam to allow psychologists psychotropic prescription privileges under varied degrees of supervision. That can of worms is beyond the scope of this latest article, which states that psychologists should carve out a bigger slice of market share through wider prescription privileges. All for the patients’ sake, of course.

The authors discuss the success of their mainly behavioral weight management program, which indeed sounds somewhat encouraging. They mention that, however, pharmacological treatments (they emphasize orlistat/Xenical), are effective in enhancing weight loss and then keeping the weight off, though they provide little data to back this assertion. My relatively brief review of trials on orlistat indicated that the effects are often relatively small relative to placebo In fact, a meta-analysis found that “for patients taking orlistat, weight loss was 2.2 kg greater than those on placebo at 4 years."

Oh, and let’s not forget the side effects, which I’ll quote from the authors: “oily spotting, flatus with discharge, fecal urgency, and oily stool.” Let’s face it: part of the joy of losing weight is that one becomes more appealing to members of the opposite (and in some cases the same) sex. When one is feeling joyous about losing 65 pounds, and is on a hot date, yet is emitting discharge-laden flatulence, this likely eliminates the romance of the evening rather quickly.

I’ll gladly agree when the authors say “Psychology practice is necessarily altered as one begins to prescribe medicine (p. 1217).” Take a look over at psychiatry over the last 40 years and see how well that worked out…

“Prescribing psychologists have additional responsibilities in physical health care management. The patient encounter involves areas of physical health status not usually covered in the general psychology appointment. Conducting a review of systems, inquiring about common side effects, and collecting biological markers (blood pressure, fasting glucose, lipid profile, etc.) are required parts of a standard patient encounter. To do this requires an adequate understanding of physical processes and the terminology needed to appropriately manage and document the patient status in ways not normally used in the mental health arena (p.1217).” Yep, more training, indeed. Like the kind you could get if you trained as a nurse practitioner or a physician.

“Any physical conditions that psychologists treat currently, such as nicotine dependence, sleep disorders, and chronic pain, are opportunities for psychologists to prescribe. Bupropion sustained-release, nicotine patches, nonbenzodiazepine hypnotics, selective serotonin reuptake inhibitors (SSRIs), non-steroidal anti-inflammatory drugs and other pain medications are all agents that psychologists, with proper training and experience, can prescribe safely and effectively (p. 1218).”

My take: Great economic opportunity for psychologists. However, the outcomes for patients are likely to be compromised as we become focused on treating more patients in less time. How will we develop relationships with patients and deliver the psychotherapeutic interventions that we know are as effective in the short term and generally more effective in the long-term than medications? Never underestimate the corrupting power of cash. Never.

Window Dressing at Stanford

Stanford's New Conflict of Interest Policy: No Coffee Mugs and Pens, But Consulting Contracts, Directorships, and Stock Options are Fine

I'd like to take credit for the above headline and related story, but I can't. The credit goes to Health Care Renewal for the story on Stanford's much ballyhooed PR campaign, er, new prohibitions on interactions between affiliated physicians and the drug industry.

With much fanfare, as reported by the New York Times, Stanford University announced it will "prohibit its physicians from accepting even small gifts like pens and mugs from pharmaceutical sales representatives under a new policy intended to limit industry influence on patient care and doctor education." Also prohibited will be "accepting free drug samples and from publishing articles in medical journals that are ghost-written by industry contractors. The policy would also apply to sales representatives from makers of medical devices and other companies, not just pharmaceutical companies. Company representatives would be barred from areas where patient treatment and doctor education occur...."

But...

"On the other hand, " The new policy does not cover consulting agreements between faculty members and companies aimed at developing drugs or medical devices. Those are governed by an existing conflict-of-interest policy."

Interested readers should follow the link to HCR's site for the full story.

IE Problems

For some reason, the blog is looking good on Firefox but not so hot on Internet Explorer. I'll have to put my extremely limited .html skills to work. Feel free to provide advice!

Paxil and Suicide: Is GSK Lying?

“GSK’s analysis of suicidality left out two attempted suicides and two completed suicides on Paxil, and exaggerated the number of suicidal acts on placebo.”

A quote from Peter Breggin in his latest report on the allegedly hidden side effects of paroxetine (Paxil). Below are summaries of information from his two so-called Special Reports on the hidden side effects of Paxil. Both are published in Ethical Human Psychology and Psychiatry, and both are somewhere on his website (I didn't have time to track them down)

He documents the quote on top in his Special Report Part 1. The mysteriously vanishing suicide attempts and completed suicides are described well enough to be convincing, though without having access to the data (which very few individuals have), I suppose one could maintain skepticism.

Breggin also notes that two attempted suicides and two completed suicides which occurred during the placebo run-in were added inappropriately into the adverse events for placebo database. “Adverse drug effects are never reported from the placebo wash-out phase. This is because all study patients receive a placebo for a short time before some of them receive the drug and some stay on placebo. Thus, while it is tragic that these events occurred on placebo, they did not occur in the phase of the trial that compared placebo to active medication. It is the equivalent of having a football team’s preseason losses count against them in their regular season record and an absolute joke. I recall that David Healy found similar shenanigans in his peeks at company raw data for SSRI’s, though I am failing to remember which medications he examined.

Breggin goes on to note that GSK researchers in US sites listed not a single incident of akathisia, which is rather odd considering how frequently agitation/hostility/motor symptoms are reported as side effects for paroxetine. Instead, the terms agitation, anxiety, and nervousness were sometimes labeled as paroxetine side effect in GSK sponsored research, and Breggin claims these were frequently euphemisms for akathisia.

Breggin notes that in the five suicide cases during which participants were taking Paxil, their adverse drug reactions were listed as:
1. Severe insomnia
2. light-headedness, drowsiness, malaise
3. “restlessness (agitation)”
4. vertigo
5. motor akathisia. “mild hyperkinesia”

This, of course, relates to akathisia serving as a potential cause for some suicides, which is discussed eloquently by David Healy in many publications, including here. See my coverage of his latest work here.

Overall Take on Breggin: Yes, I realize that Breggin is an iconoclast. Some of his statements over the years have been overblown. He relies quite a bit on case studies, and one can of course find a case to fit any supposed problem or solution. But, his criticism of the sloppy FDA approval of Prozac in Talking Back to Prozac was right on as has been much (though certainly not all) of his subsequent work.

My View: Again, not a smoking gun, but disturbing nonetheless. Finding that industry is overestimating placebo-related serious side effects and underestimating them for medication is a BIG problem that likely happens more than we imagine. Remember Vioxx and the New England Journal of Medicine, anyone?

David Graham Speaks

You may at first think this has nothing to do with Clinical Psychology or Psychiatry, but let's keep in mind that this says a lot about the FDA's oversight capabilities.

On PharmaGossip, there is a link and excerpt from David Graham's editorial in the latest JAMA. Graham is one of the few (meaning approximately two) people at FDA who have stepped up to the plate to discuss the risks of certain medications (like the COX-2 inhibitors and antidepressants, especially the COX-2's).

"In a recently reported meta-analysis of 138 randomized trials covering all NSAIDs, Kearney et al²⁷ found that for 37 trials with rofecoxib (85% at 25 mg/d), acute MI risk was increased (RR, 1.73; 95% CI, 1.09-2.82) compared with placebo. With celecoxib (41 trials), the RR was 2.70 (95% CI, 1.30-6.29), which was driven by 21 studies at doses of 400 mg/d or higher. Combined vascular event risk (primarily MI) compared with placebo was also increased for diclofenac (RR, 1.63; 95% CI, 1.12-2.37) and approached statistical significance for ibuprofen (RR, 1.51; 95% CI, 0.96-2.37).²⁷ Risk was not increased with naproxen (RR, 0.92; 95% CI, 0.67-1.26).²⁷

What does this all mean? First, rofecoxib increases the risk of acute MI at low and high doses. This risk begins early in therapy, probably with the first dose. There is no initial 18-month period of immunity from risk.^{17-19,21, 26} Celecoxib also increases risk at doses higher than 200 mg/d; at lower doses, the potential risk is less clear. Several other NSAIDs increase risk, including the COX-2 selective NSAIDs diclofenac and meloxicam, and the nonselective NSAID indomethacin, and probably ibuprofen. Meta-analyses of randomized clinical trials and observational studies agree that naproxen is neutral for MI risk."

PharmaGossip has a better quote from Graham that I won't steal, so I'd encourage you to check it out.

Link to Graham's editorial here.

Yet More New Research on Antidepressants and Suicide

Uh-oh. David Healy is at it again.

Not good news for SmithKlineBeecham, the manufacturer of paroxetine (Paxil).


Healy and colleagues utilized data from a few sources in their latest article in PLoS Medicine:


1. The data submitted by GlaxoSmithKline on paroxetine for review by the Committee on Safety of Medicines Expert Working Group

2. Data from United Kingdom Drug Safety Research Unit (DSRU) prescription-event monitoring studies on paroxetine and fluoxetine

3. Legal cases in which the authors have given evidence. This is admittedly a little shakier, though still of interest.

4. E-mails from 1,374 patients in response to a BBC programme on paroxetine broadcast in 2002.

What did they find? Let's focus on data type 1 for this post...

*In clinical trial data provided by the manufacturer, participants taking Paxil were significantly more likely to show hostility (Odds Ratio = 2.10).


*The following data comes from trials NOT included in the previous bullet point: "In data from sertraline paediatric trials submitted by Pfizer, aggression was the joint commonest cause for discontinuation from the two sertraline placebo-controlled trials in depressed children. In these trials, eight of 189 patients randomised to sertraline discontinued for aggression, agitation, or hyperkinesis (a coding term for akathisia), compared with no dropouts for these reasons in 184 patients on placebo (95% CI, 1.72–infinity). When discontinuations for any manifestation of treatment induced activation (suicidal ideation or attempts, aggression, agitation, hyperkinesis, or aggravated depression) were considered, there were 15 discontinuations on sertraline compared with two on placebo, a relative risk of 7.3 (95% CI, 1.70–31.5; p = 0.0015) (p. e373)."


*Very limited data on healthy volunteers suggests increased hostility among people taking paroxetine.


*The link between akathisia (which is induced on occasion by antidepressants) and aggression as well as suicide is explored


Summary: There is certainly much more in the article than I can describe now (like data from the other three sources). It admittedly falls well short of a smoking gun, but it nicely summarizes research on the topic with a close eye on paroxetine. The evidence continues to slowly trickle down and it has often been inconsistent, but there is certainly enough data to suggest that at the very least we should insist on full disclosure of data from clinical trials, warn about possible aggression/suicidality side effects, and monitor patients for aggression/suicidality quite closely. Oh, and we should use psychotherapy first -- better results in the long term with many fewer side effects.

The full text of the article is here.

Drugs for Alzheimer's Equal Better Outcomes?

Pharmawatch has a very interesting article on the use of the modestly cognitively enhancing cholinesterase inhibitors in dementia care. Memory clinics are increasingly offering these medications but, according to research, may be missing other key aspects of care. Below is an extract from the article in the British Medical Journal to which Pharmawatch is referring:

"Specialist memory clinics do not offer care in the community to their patients as they decline.^{9 14} This means that the clinics are confining themselves to the easy parts of the management of neurodegenerative disorders. Patients are assessed and then discharged or else reviewed until cognitive deterioration and behavioural disturbances become problematic. They are then referred to ordinary old age psychiatry teams, which have to arrange proper management plans; this sometimes involves undoing what has been done by clinicians who lack experience with long term care of people with dementia. The task is not made easier when potential members of the multidisciplinary team have been recruited to memory clinics."

This should interest anyone interested in the geriatric population.

Fraud or Scapegoating?

PharmaGossip has links (most recent and older, but still relevant) to what, at the very least, is an interesting mudslinging match between a controversial psychiatry "professor" (it's murky whether he is actually a professor, apparently) and Big Pharma. Dr. Sharma is accused of fraud and falsifying his academic credentials. He has, among other things, conducted trials involving antipsychotic medications and has apparently served as an investigator for several drug companies. He denies allegations and claims he is being scapegoated for drug industry failures.

A news story in the Observer from late May is also relevant and interesting.

Antidepressants. Efficacy and Safety Issues: Part 1

ACNP Report: Efficacy -- A Closer Look

To begin the series on Antidepressants: Efficacy/Safety, which at this point will focus predominantly on youth (but that can change at any time), let’s begin with the American College of Neuropsychopharmcology Report, focusing primarily on its conclusions and commentary surrounding the efficacy of antidepressants for depressed youth.

The ACNP Report. As evidence mounted suggesting that SSRI’s were linked to suicidal ideation in youth, the ACNP decided to analyze the data on the issue and provide a report on both the efficacy and safety of these medications in treating depression in children and adolescents. As many of you may have seen, the ACNP issued a preliminary report in 2004 followed by a final report in March 2006, which you can access here if you’d like. They concluded that fluoxetine (Prozac) is a safe and efficacious treatment for youth depression. There is indeed some evidence to support this idea, such as the TADS study (discussed later), though this study has serious methodological shortcomings that weaken its conclusions. However, it is indeed curious that fluoxetine would be the lone medication to show efficacy for youth depression, given its strong chemical similarity to other SSRIs.

A curious conclusion: The ACNP authors believe that the data “…suggest that it is the SSRI action combined with the absence of other pharmacologic effects such as on the noradrenergic system that it crucial for an antidepressant effect in children and adolescents. Tricylcic antidepressants and other new-generation non-SSRI antidepressants are therefore not recommended as a first-line treatment for depressed youth. (p. 478).”

Why this is curious: Let me get this straight. Data show that the SSRIs sertraline (Zoloft), citalopram (Celexa), and paroxetine (Paxil) all yield responses that range from slightly superior to placebo to not superior to a placebo. So somehow it must be the specific “SSRI action” that is doing the trick? WHAT TRICK? The medications are no more efficacious than a placebo, so why are the authors trying to describe WHY SSRI’s are more effective than a placebo?

Conflicts of interest: Well, fortunately, I think I have an answer! The initial ACNP report (2004) was ghostwritten – hat tip to Timothy Scott on this one (Ethical Human Psychology & Psychiatry Summer 2006) – by an agency called GYMR. The final report does not acknowledge the use of the firm (which of course does not mean the firm did not assist in its preparation). Instead it acknowledges the help of Miriam Davis, who is indeed an accomplished medical writer, and like virtually all of the authors of the task force report appears to have received significant funding from pharmaceutical companies at various times. Across the board, the conflicts of interest are mammoth. Ten of eleven authors reported receiving funding from pharmaceutical companies.

Explanation of failed studies: At one point in the ACNP Report, the authors attempt to explain away studies that compared a medication to placebo and found no significant advantage for the medication. “A negative study without an effective comparator [i.e., a study comparing drug to placebo], which fails to prove the effectiveness of the test medication, cannot prove that the drug is not effective… Without an active comparator, it is not possible to determine whether the study failed because (1) the drug is ineffective, or (2) the study sample was treatment resistant, or placebo responsive or the depression transient, or (3) the study design was not optimal in terms of the dose, duration of treatment, the primary outcome measure, or, most commonly, the sample size was too small to detect an effect. (p. 475).”

Why the above arguments are fallacious: The logic is that you can show a drug is effective if it is significantly superior to a placebo, but that you cannot show it is ineffective if it is not significantly superior to a placebo. Sounds like two different sets of rules to me – I’m throwing the bullshit flag! Beside the ridiculous double standard just mentioned, let’s go point by point…

1) Treatment resistant: If a drug is effective, it should effectively treat people with depression who are “treatment resistant.” When the drug is approved, is it marketed for only “non treatment resistant depression?” Of course not. It is true that some samples may be more difficult than others, but one cannot simply claim “Oh, those people were too difficult – it was the patients’ fault it didn’t work!”

2) Placebo responsive: Planet Earth to ACNP… The news is that depression, in general, is quite placebo responsive! Look at the meta-analyses by Kirsch et al (1998, (2002) if you are in need of confirmation that the vast majority of the antidepressant drug effect is replicated by placebo. The small amount of improvement in drug-treatment patients that remains after accounting for the placebo effect may be explained by medication side effects tipping trial participants to the fact that they are on medication, which thus enhances their response (Moncrieff, 2002).

3) The depression was transient: OK, so on one hand, we can excuse a failure of the treatment because the sample was treatment resistant, and on the other hand, we can say that their depression was not serious enough, that it was “transient.” So, if the drug is no more efficacious than a placebo, then the sample was either too chronic/resistant or not depressed seriously enough. Well, that’s certainly having your cake and eating it too!

4) Dose or duration: If there were solid evidence tying dose to response for SSRI’s in depression, then this would be a fair argument. In the absence of such evidence, this is a meager excuse. Granted, a three week study seems a bit short, but all studies mentioned in the ACNP Report were of 8-12 weeks. Shouldn’t we reasonably expect a medication to outshine an inert placebo within two to three months?

5) Primary outcome measure: Fortunately, one of the ACNP’ers, Graham Emslie, would be an expert on this topic! When fluoxetine was submitted for FDA approval for pediatric depression, there was an interesting flip-flop on the primary outcome measure. Emslie, mind you, was the lead author on one of the studies submitted to FDA for approval.

A quote from the FDA’s review: “In the responder analysis based on Dr. Emslie’s original primary efficacy variable (i.e., recovery rate…), the result was not significant (29% for Fluoxetine-treated group and 19% for placebo, p = .339). The analysis based on remission was also not significant (p=.238). But the result was significant based on the percent responder defined by CGI-Improvement scores (p=.040). Note that in Dr. Emslie’s ’97 paper, the percent responders defined by CGI-Improvement was presented as the primary result (p. 8, my emphases in bold).”

So Emslie’s team submitted to the FDA a primary outcome measure for their study, and when fluoxetine showed no superiority on that variable, they simply fished for a variable that reached significance and proclaimed it the primary outcome variable.

I will agree in principle that all measures should be examined and considered, but I find it more than ironic that the ACNP has decided to play the primary outcome measure card when one of their report authors have been caught altering the primary outcome variable.

6) Small sample size. OK, finally, a fair point is made. However, let’s keep in mind that this is the point of meta-analyses and review articles – to examine findings across studies to indicate what a body of literature has to say about a certain topic. Fortunately, a rather excellent meta-analysis has been done on this topic, finding no significant benefit for medication over placebo for depressed youth (full text here of Jureidini et al, 2004). Another good meta-analysis by Whittington and colleagues suggested a moderate benefit for fluoxetine only (e.g., all other SSRI’s were found to be ineffective), though this clearly should be weighed with a possibility of increased suicidality.

More will be forthcoming on this topic. Part 2 should be up in a day or two...

Physicians (Like Everyone Else) are Poor at Self-Assessment

The most recent JAMA has a literature review on how well physicians’ self-assessments compare with external ratings/outcomes of various sorts. The sad but apparently true answer: Not very well. Of course, if you’ve been reading psychological research by the likes of Dunning and colleagues, this will surprise you very little.

Summary: A minority of studies found a positive relationship between self-assessment and external ratings, but most found no relationship or a negative relationship. An analysis based on a small subset of studies found that the physicians who rated themselves highest on self-assessments actually showed the poorest performance on varied external criteria.

In other words, the accuracy of self-assessment is generally poor, but even more so among people who are the most confident. Check out the abstract here.

“Taken together, these conclusions prompt reflection on the use of self-rated assessment and its role in lifelong learning and value in regulation and patient care” (p. 1100).

My advice: Watch out for cockiness amongst yourselves and your peers and seek to find ways of validating your self-assessments.

Antidepressants and Suicide in Kids... Coming Soon

There has admittedly been quite a bit of discussion on this topic. However, I will soon (read: Tuesday) describe some issues, in detail, that should give us all even greater cause for concern.

Busy Day

It's a rather busy day today, but I've got a good story or two in mind for later today or, at worst, tomorrow.

Interview with Dr. Peter Rost

Keep an eye on this story

Peter Rost, ex Big Pharma executive, has been raising Cain lately. Check out an interview with him on PharmaGosssip here.

Client Expectations Are Important...

The latest article in the October Clinical Psychology Review by Roger Greenberg and pals -- Are patient expectations still relevant for psychotherapy process and outcome -- is worth your time.

Client expectations are indeed a huge and oft-overlooked factor. While many academics are jousting their various theories against one another in clinical trials and nearly always finding no difference between various theoretical orientations in their ability to induce symptom reduction, client expectations are at work across therapies of all types. A thoughtful piece that clinicians and academics should check out.

Abstract provided below with a link if you'd rather go to the publisher's site:

"Patient expectations have been regarded as a variable affecting the course of psychotherapy for more than 50 years. Yet, even though expectations are often considered a factor common to most psychotherapy systems, their importance may be undervalued. This paper places the expectancy issue in a historical context, discusses the varied definitions of expectancy, and reviews the extant expectancy research literature. Discussion of results affirms the continuing relevance of patient expectations, suggests that they may be even more vital to the psychotherapy process than is often acknowledged, highlights research strengths and weaknesses, and calls attention to areas on which clinicians and researchers might focus to improve treatment effectiveness."

Link to the abstract.