The Asenapine Chronicles?

I'm not sure what to make of this. A lot of documents have become available on the Shearlings Got Plowed blog, which deal with the new antipsychotic drug asenapine. If I had the time, I'd be burying myself in the documents, as SGP claims that something fishy is going on. I encourage all interested readers to take a good, long look at the documents to see what (if anything) is happening.

Documents such as this one will catch your interest...

Thanks For Your Service, Now Take This Pill

According to a freshly published study, one in five depressed patients receiving services through the VA healthcare system in the United States is taking an antipsychotic. Of those taking antipsychotics, 43% were taking them at high doses (schizophrenia doses rather than lower doses typically used in treating depression). The study, published in the Journal of Clinical Psychiatry, excluded patients with schizophrenia or bipolar diagnoses -- this means that the antipsychotics given to the depressed folks weren't mainly used to treat psychosis or mania. The sample size was over 190,000 patients, so one can't fault the study for not including enough patients. The researchers examined drugs taken within one week of their last antipsychotic prescription and found that 24% of patients were taking multiple antipsychotics at that point.

The most used medication was Seroquel. This is not suprising. Patients seen in mental health speciality clinics were the most likely to receive antipsychotics. So what are the consequences? Well, let's see. There's the high rate of akathisia and medicore efficacy of Abilify. And there's some tricky research involving Risperdal that seemed to suggest the manipulation of the statistics was more impressive than the actual drug in treating depression. Seroquel's unimpressive efficacy and problematic side effects are also not a ball of fun. And so forth. Isn't "progress" beautiful?

I know what some people are thinking, so before you waste your valuable time with a comment, consider this. I'm aware that many of these patients are suffering much more than a simple case of the blues. That doesn't mean we should throw heavy duty antipsychotics at them, particularly at high doses. Certainly there has to be something else. What might that be? Some psychotherapy, some medications, some case management - I ain't saying it'll be easy. But I'm willing to bet that chucking antipsychotics at them en masse is not the solution.

Will Pharma's (Tax) Free Speech Be Limited?

Dan Neil has an absolutely marvelous column in the LA Times about pharma's bitching/moaning regarding increased regulation of its advertising and its potential loss of tax writeoffs associated with drug ads. It's nice to know that when I'm watching a misleading advertisement for, say, Cymbalta or Abilify, pharma is writing off the advertising cost on its tax bill. Big Pharma's legal consultants have weighed in for years on this topic, using such terms as "starkly unconstitutional," "censorship," "plainly violates the First Amendment", and adding that taking away the tax deduction is "Draconian punishment" - see this document from the pharma-friendly Washington Legal Foundation and just try to keep a straight face.

Neil writes that:

Currently in draft form, these [FDA] rules would dramatically raise the legal bar for risk disclosure. Not only would advertisements have to fully explicate serious side effects, the nature of adverse reactions, the risk of dependence, dangerous drug interactions and so on, but all of that would also have to be communicated in the most direct, unambiguous and, if you will, artless form possible.

And, picking some of the low-hanging fruit, Neil goes on to describe two of my most hated ads:

Consider, the current 75-second spot for Abilify, a powerful antipsychotic drug marketed as a potential add-on to antidepressants. At the 33-second mark, the warnings start: "thoughts of suicide," "elderly dementia patients . . . have an increased risk of death or stroke," "uncontrollable muscle movements [that] may become permanent" and so on. The astonishing thing is that Bristol-Myers Squibb spent more than $35 million in the first quarter alone to market this witch's brew.

Seizures, death, trouble swallowing. Jeez, I get depressed just watching the ad. Maybe that's the idea.

Another wonder drug -- as in, I wonder if this will kill me? -- is Wyeth's Pristiq. Again, the potential adverse reactions are alarming: "Antidepressants can increase suicidal thoughts and behaviors in children, teens and young adults," the ad says. "May cause or worsen high blood pressure, high cholesterol and glaucoma."

Scary stuff. And yet, the FDA might say, not scary enough. Because the voice-over rambles on with a litany of potential side effects, some of which is quite hard to follow, the commercial seems to violate the FDA's constraint that advertisements not overwhelm viewers' "cognitive load." On a more prosaic level, the imagery of this suffering woman suddenly redeemed by this medication, so that now she's playing with her family at the park, seems to vastly over-promise relief.

Vastly over-promising relief, indeed. Watching Congress, the FDA, the pharma-funded academic hired guns, and lawyers on these issues will make for an entertaining spectator sport. Not nearly as engrossing as watching the DSM-V drama unfold (1, 2, 3), but still a lot cheaper than going to a Yankees game.

Award Winning Journalism (?)

Erroneous reporting wins prestigious award, starring Charles Nemeroff. Oy. Brought to you courtesy of Health Care Renewal. Read the full story and shake your head. Teaser:

Something about the simultaneously complex and sympathetic nature of mental health reporting is making reputable journalistic organizations and well-meaning reporters sloppy.

New American Psychiatric Association Prez: We Want Money

In a recent speech, incoming American Psychiatric Association president Alan Schatzberg was quoted as saying:

"As the recent attacks on APA and leaders of the profession have occurred, it has struck me that some of the detractors in the press have voiced concern that some folks have earned too good a living, often by doing presentations," he said. "I have heard from colleagues and directly from one reporter asking me about one of my colleagues having too high an annual income. I can assure you these detractors would not ask the same question of a surgeon or radiologist earning 10 times the amount paid our colleagues. None of us do what we do for money. Yet, it is also time for us to realize that our members and residents have never taken vows of poverty, and the complexity of the work deserves to be recognized. We need to ask ourselves how we have contributed to our own devaluation with which others seem to resonate, and we need to reverse the course. The rewards for our dedication should not be limited to a sense of pride, but we are also entitled to be paid commensurate to the challenge.

So Schatzberg must be diving into dumpsters, begging at interstate off-ramps, and the like. Oh, wait a minute. This is the same Alan Schatzberg who in 2007 owned close to 5 million shares of Corcept (which translates into roughly 5 million dollars). I have no idea how many shares he owns currently. Corcept, in case you missed it, has shown its drug mifepristone (aka RU-486: "The Abortion Pill") is ineffective in relieving depression among patients with psychotic depression. Schatzberg, at one time, was the chief scientific officer of Corcept and was also the cofounder of the company. According to Corcept's website, he is still a scientific advisor. Despite the stuides of mifepristone showing negative results, the results were spun in a manner to make them sound as if they were positive (1, 2, 3, 4). In a press release, Schatzberg was quoted as saying that mifepristone "may be the equivalent of shock treatments in a pill." Right, with all of the negative studies, it's definitely shock treatment, meditation, and running a marathon all wrapped together in a capsule. Should he be paid "commensutate to the challenge" of trying to weave positive findings from negative results? I don't know what role, if any, he played in the misleading publications surrounding mifepristone. But in his role as chief of the scientific advisory board, I'd venture a guess that he had some involvement. But worry not, the negative results were not spun into positive findings for the sake of money, but for an altruistic love of patients with depression. I'm touched.

Schatzberg was also busted by yours truly putting his name on a duplicate publication that pimped Cymbalta, Lilly's antidepressant. The study presented data from the same set of patients who were involved in a previously published Cymbalta study. Scientific results are not meant to be published in nearly identical form in two different journals. But that didn't stop Schatzberg and his coauthors. If you've not read the lengthy post on this topic, please feel free to check it out in order to understand my cynicism regarding his recent speech.

Another quote from his talk:

We need to sit down with industry and come up with ways of interacting that are acceptable to both sides and fit with future guidelines. I have pledged to follow up on recent initiatives and work with Dr. Scully [APA's medical director] and our Board of Trustees to effect a new partnership—a partnership we can be proud of for what it contributes to the well-being of our patients and our profession.

I can only wonder what type of mutually agreeable interactions would meet Schatzberg's standards. Duplicate publication, serving as a scientific advisor for a company that writes scientifically dubious papers? And it appears that he's encouraging psychiatrists to be greedy -- take the money and don't feel bad about it. Taking industry money is perfectly acceptable in some instances, but it needs to be transparent, and there are plentiful examples of academics getting paid by industry and slanting science in a sponsor-friendly way.

And the clincher:

"The time has come," he said, "to be proud of what we do and to advocate for what we and our patients justly deserve."

Right, psychiatrists deserve to make as much money as possible bending science for corporate sponsors -- and they should be proud of it too. Am I being too cynical? Maybe. But when a guy with Schatzberg's record starts talking about psychiatrists needing to rake in more money from industry, it makes me think I'm living in Bizarro World. Get ready, APA memebers; it's going to be an interesting ride.

Greedy and Ghostly Scientists

Story one: Zachary Stowe, psychiatrist at Emory University becomes Charles Nemeroff, Jr. Read all about it the Carlat Psychiatry Blog and University Diaries. And check out the WSJ Health Blog as well. The gist is that Stowe apparently did not report all of his external income from his many pharmaceutical industry gigs. Better yet, he was a frequent speaker for GlaxoSmithKline, which had the gall to cancel two of his commercial talks. He then wanted GSK to pay him even though he wasn't going to give the speeches. Read the relevant emails toward the bottom of this document. After reading about Stowe, refresh your memory about Golden Goblet Lifetime Achievement Award Winner, former Chair of Psychiatry at Emory University: Charles Nemeroff. Is there something in the water at Emory? Or is that just how we roll in modern academic psychiatry? Stowe is hereby nominated for a coveted Golden Goblet for his string of emails in which he attempted to shake down GlaxoSmithKline. Sometimes I think that the only thing worse than drug companies are the narcissistic academics who they employ as "key opinion leaders." Not all key opinion leaders are jerks; some are probably even able to reasonably balance their industry cash with being good scientists. But Stowe didn't really portray himself as Mr. Nice Guy in his string of soon to be infamous emails.

Oh, and this little gem:

"Especially disturbing is an email between employees at GSK and a public relations (PR) firm that the GSK hired. The email was titled “For your review/Paxil Breast Milk Press Release” and states:

"[P]lease review the attached press release and forward me any comments/edits.
As you may know, Dr. Stowe is on board for publicity efforts and NAME
REDACTED and I are coordinating time to meet with him next week to arm him
with the key messages for this announcement, which is slated for early February.
We are sending the release for your review at the same time in efforts to secure
distribution on Emory letterhead (as you know, would provide further credibility
to data for the media)."

In his testimony, Dr. Stowe confirmed that the press release was written by the PR
firm and concerned his research on Paxil and its presence in breast milk. He also
explained that placing the press release on Emory letterhead, as opposed to GSK letterhead, would make the data more credible to the public."

If I have this straight, Stowe was willing to place a press release written by a PR firm hired by GSK on official university letterhead to enhance its credibility. Apparently he wasn't concerned about his own credibility. Read the full document of Senator Charles Grassley's investigation of Dr. Stowe.

Part 2: Enter the Ghostwriters

One snippet, then go to Bloomberg for the rest:

Ensuring that medical journal articles presented Zyprexa study results in a positive light was one way for Lilly to reach its sales goal, company officials said in its plan, according to the documents. To do that, Lilly officials hired ghostwriters to prepare submissions to journals such as Progress in Neurology and Psychiatry, according to the unsealed documents. “The paper for the Progress in Neurology and Psychiatry supplement has been completed and sent to the journal for peer review,” Kerrie Mitchell, an employee of the public relations agency Cohn & Wolfe, wrote in a Feb. 23, 2001, e-mail to Michael Sale, a Lilly marketing official. The message was among the unsealed files. “We ‘ghost’ wrote this article and then worked with author Dr. Haddad to work up the final copy,” Mitchell said in the e- mail. Eric Litchfield, a spokesman for Cohn & Wolfe, didn’t immediately return a call requesting comment.

The Bloomberg story is based on a recently released set of internal Lilly documents. That's right -- more Zyprexa documents are on the loose. And the first round of documents provided some good stuff (1, 2, 3), so I can't wait to see what kind of chicanery will be revealed by the latest round. In one sense, it's not exactly news that Lilly ghostwrote Zyprexa papers. We all know that ghostwriting is rampant. How else do key opinion leaders get their names on dozens of papers per year when they are also flying around the country pimping drugs, holding administrative meetings, and doing all sorts of other tasks? But it's nice to have it officially documented that Lilly was playing the ghostwriting game with Zyprexa.

Abilify for Depression: Patients Give it an Oh-For-Three

Abilify for depression: you've seen the ads. You've hopefully read this blog (1, 2) and the excellent series in the LA Times from Melissa Healy. The advantage over placebo is nothing to get particularly excited about. Especially from the patients' point of view. As I have mentioned previously, the two studies that were touted by key opinion leaders are supporting the efficacy of Abilify for depression suffered from a number of problems. Most germane to this post, the patient self-report rating scales did not indicate a significant advantage for Abilify in either study.

Well, yet another Abilify for depression study is out in CNS Spectrums and guess what... Still not a significant advantage over placebo according to patients. So in each of three large studies, Abilify has failed to beat a placebo according to patients' self-report. These three trials are the basis for the massive marketing campaign and an FDA approval. Abilify started off as an also-ran antipsychotic. But times have changed. Bristol-Myers Squibb's CEO prophetically stated in 2004 after Abilify's approval as a treatment for bipolar disorder:

This approval underscores our commitment to delivering innovative solutions that address unmet needs for a broad spectrum of patients with mental illness, as well as their families and health care providers.

He could as easily have stated: "This approval underscores our commitment to rebranding our unpopular antipsychotic as a Swiss Army Knife/broad spectrum psychotropic that treats everything under the sun. If I can get the FDA and the public to believe that this akathisia-inducing bottom feeder can treat depression, then I'll be LOADED, BWAAH, HA HA HA HA!!!"

OK, maybe he didn't actually say any of those things, but his "broad spectrum" comment was literally right on the money. Just don't ask those pesky patients what they think; they might tell you it's no better than a damn sugar pill.

Yes, I'm aware that on some other rating scales, Abilify was rated as superior to a placebo, but I'm thinking that if the patient self-report of depression is consistently not favorable for Abilify, then who are we kidding by calling it an antidepressant?



Robert M. Berman, Maurizio Fava, Michael E. Thase, Madhukar H. Trivedi, René Swanink, Robert D. McQuade, William H. Carson, David Adson, Leslie Taylor, James Hazel, & Ronald N. Marcus (2009). Aripiprazole Augmentation in Major Depressive Disorder: A Double-Blind, Placebo-Controlled Study in Patients with Inadequate Response to Antidepressants CNS Spectrums, 14 (4), 197-206

Pseudoscience, Candy, and Lamar Odom: Brought to you by Daniel Amen

If you follow professional basketball, you've probably noticed that LA Lakers forward Lamar Odom has a well-deserved reputation for inconsistent play. When he's good, he's close to amazing, and when he's bad, he's of little use to his team. So how is this related to mental health? Does he have social anxiety disorder? No, get out of Ricky Williams mode and pay attention...

Odom eats candy. Lots of it. And that's why his play is inconsistent. At least that's the story according to Dr. Daniel Amen, who, according to the Los Angeles Times stated:

Odom freely confesses that he just can't help himself when it comes to the sweet stuff and always keeps a stash on hand of Gummi Bears, Honey Buns, Lifesavers, Hershey's white chocolate, Snickers bars, cookies and more. He eats the sugary snacks morning, noon and night, and even says he sometimes wakes up in the middle of the night, chows down on some treats, then falls back asleep.

This is bad news for the Lakers. I've been telling my patients for years that sugar acts like a drug in the brain. It causes blood sugar levels to spike and then crash, leaving you feeling tired, irritable, foggy and stupid. Eating too much sugar impairs cognitive function, which may explain why Odom doesn't always make the smartest decisions on the court. . . .

As a fan and a physician, it concerns me that our professional sports organizations and players are not more concerned about brain health, which includes nutrition. My advice to Odom and to all sugar addicts is to get your sugar consumption under control. You'll feel so much better and your brain will function better too. And, maybe the Lakers can get their 15th championship and Odom can get his first.

Now, remember that Odom's play is inconsistent, not consistently bad. And if he is eating sugar all the time, shouldn't his play be consistently poor? Oh, and is there any science at all to support the idea that eating sugar impairs athletic performance...? I'll admit to not being a top expert on this, but my brief search of PubMed did not bring up anything to support Dr. Amen's suggestions.

So who is this Amen guy, anyway? He claims that Alzheimer's can be detected early through the use of SPECT brain imaging (single photon emission computed tomography). And he sells vitamins/nutraceuticals on his site which, of course allegedly help to prevent cognitive deterioration. There is sooooooooo much more to read about Amen, and I encourage y'all to head over to Salon to read an excellent debunking of Amen's many pseudoscientific claims.

I've rolled my eyes at this guy for years, but now that he's trying to shoot his witchcraft at the fine sport of basketball, I've hit my breaking point. But what do I know... I mean, Amen apparently wrote that

From the first month that I started to order these (SPECT) scans, I felt that they had a special place in science and that I was led by God to pursue this work

And who am I to argue with a guy who was sent by God to practice medicine. But back to Lamar Odom; he insists that he ate candy for breakfast on the game days in which he played well against the Denver Nuggets. Well, maybe, but I bet a SPECT scan or two would figure out why his performance is inconsistent.

Dr. Amen also has some hot, hot science about the men, sex, and the brain. On The View, of all places. Get ready to cringe.



OK, fine. One more. Dr. Amen can target treatment for ADHD appropriately by... yes, using pricey and unproven brain scans! See below...

Open Up Yer Wallets

Yeah, I know the economy is in very bad shape and possibly getting worse. But for the kind of fantastic investigative journalism we get from the inimitable Philip Dawdy at Furious Seasons, one really should whip out the credit card and make a donation. A summary of his good work is available, and his more recent work on Seroquel is worthy of accolades (1, 2).

Donate here.

Phase V, Abilify, and Vanishing Akathisia

If you've been reading about Abilify for depression on this site, you've probably noticed that I've been down on Abilify for causing akathisia in a frighteningly high percentage of patients. In two recent trials, akathisia occurred in 25% of Abilify patients compared to 4% of placebo patients. What, exactly, is akathisia? That's still a matter of some debate. Let's turn to a recent Journal of Clinical Psychiatry article on the topic. Entitled "Akathisia: An Updated Review Focusing on Second-Generation Antipsychotics," the paper purports to provide "a review of the literature on the incidence of drug-induced akathisia associated with the use of second-generation antipsychotics (SGAs) and first-generation antipsychotics (FGAs)."

It provides a few different characteristics associated with acute akathisia, including:

• "Intense dysphoria
• Awareness of restlessness
• Complex and semipurposeful motor fidgetiness"

It mentions "...suicidal behavior has been described in patients with akathisia in case reports, both in patients receiving antipsychotic medication and in patients receiving selective serotonin reuptake inhibitors (SSRIs)."A couple of descriptions from another journal:

• Increased tenseness, restlessness, insomnia and a feeling of being very uncomfortable
• On the first day of treatment he reacted with marked anxiety and weepiness, on the second day felt so terrible with such marked panic at night that the medication was cancelled

So we can all agree that akathisia does not sound like fun.

Now back to the Journal of Clinical Psychiatry review article. What did the authors conclude? "The comparative incidence of akathisia among the newer antipsychotic agents remains poorly characterized." And "...SGAs are generally associated with a lower propensity for movement disorders compared with their FGA counterparts, an emerging body of comparative literature shows that second-generation medications are not completely free from inducing akathisia."

The authors go through a long list of second-generation antipsychotic medications. The drug that receives the least attention is aripiprazole (Abilify). The authors conclude that "in studies comparing aripiprazole with placebo, akathisia rates in the aripiprazole arm were similar in some studies, and higher in others. As with other SGAs, akathisia rates with aripiprazole were lower than those of FGAs." So Abilify causes less akathisia than older medications and it's unclear if it causes more akathisia than placebo. But, wait, wasn't akathisia related to much higher rates of akathisia than placebo in treating depression? Fortunately, the authors had a little trick to erase that inconvenient piece of evidence; they only examined trials trials involving people diagnosed with schizophrenia or bipolar disorder. So the depression studies -- POOF -- vanished, along with their damning data.

Why would the authors want to censor negative data about Abilify? Well, one author is an employee of Otsuka America Pharmaceutical, Inc., and another is an employee of Bristol-Myers Squibb, companies that market Abilify. And the other authors: All but one of them have a financial relationship with Bristol-Myers Squibb. The best part:

Editorial support provided by Maria Soushko, Ph.D., Phase Five Communications, Inc., New York, N.Y., with funding provided by Bristol-Myers Squibb.

So a paper that excludes the most inconvenient evidence regarding akathisia on Abilify had major parts of the writing done by... a medical writer hired by Bristol-Myers Squibb. If one goes to Phase Five's website , the first animation that pops up says "Spinning Your Science Into Gold." I'd say that this article was indeed 24 karat gold. I hereby nominate all authors of the study for a much coveted Golden Goblet Award.




Citation Below:

Kane, J., Fleischhacker, W., Hansen, L., Perlis, R., Pikalov, A., & Assunção-Talbott, S. (2009). Akathisia: An Updated Review Focusing on Second-Generation Antipsychotics The Journal of Clinical Psychiatry DOI: 10.4088/JCP.08r04210

Update: See a related post at the Carlat Psychiatry Blog. A partial quote:

Publishing an article that was carefully crafted to draw attention away from Abilify's main liability was shameful, and is exactly the kind of deceptive editorial practice that we as a society can no longer tolerate.

Abilify Runs Amok, Runs Stealth Safety Campaign in Medical Journal

Furious Seasons has a rather distressing piece of news from a recent Bristol-Myers Squibb conference call. To sum it up quickly, BMS claims that 10.6% of depressed patients are now receiving atypical antipsychotics. Of those 10.6%, 21.7% are taking Abilify. So that would mean roughly 10-11 in 100 depressed patients are taking antipsychotics and 2 of them are on Abilify. I shudder to think how many are on Seroquel. Or Zyprexa. It made me think of a post I wrote a few weeks ago in which I described the marketing of Abilify for depression. A huge market of depressed people just ripe for the picking.

Going along with this, BMS is pushing back on the issue of akathisa, the side effect that has garnered the drug much bad publicity (at least in the blog world; 1, 2, 3) via a medical journal article that distracts attention from Abilify as an akathisia-inducer. More on that to come soon. Ghostwriters, ignoring contradictory evidence; basically, an attempt to completely obscure the evidence on the topic. It's not the first time BMS has successfully placed a study with major flaws into a medical journal (1, 2). Details will be forthcoming.

David Healy: Marketing, Bipolar, and Biobabble

In an interview with Chrisopher Lane on Psychology Today's blog, David Healy covers the gamut, including the marketing techniques used to pimp Zyprexa, academic spokespersons/key opinion leaders, and bipolar diagnoses run amok. I've been a fan of Healy's work for a long time, but this interview in particular is captivating. Some will claim that Healy is a "bipolar denialist" -- he states that bipolar is overdiagnosed and that the disorder is entirely misunderstood. The fur will continue to fly on bipolarity for years to come, or at least until drug companies run out of products to push for as "mood stabilizers." In the interest of being fair and balanced, Nassir Ghaemi has a rebuttal to Healy's opinion that is also worth reading.

Though I'm tempted to provide a snippet here, I'll instead direct readers to the interview. After a very interesting interview with Philip Dawdy, and now one with David Healy (and other interesting posts), I am really glad the Psychology Today has Christopher Lane on board. I'm sure some people are not pleased with Lane interviewing two of the more prominent critics of modern psychiatry. Giving both of them an outlet to express their views at length runs the risk of Lane being labeled as a Scientologist, as "antipsychiatry," a pharmascold, and as a general rabble-rouser. Good for him. Nice to see that a fairly mainstream publication is willing to step outside the box.

Abilify Marketing Blitz: Atypical Antipsychotics Gone Wild

"The results are extremely unimpressive; they just squeak by," says Massachusetts psychiatrist Daniel Carlat, editor of the respected Carlat Psychiatry Report. For a clinician or a patient's family, the difference between those on Abilify and those who took a placebo "would be hard to actually see," he adds.

Dr. Carlat is referring to the comparison between Abilify and placebo in the treatment of depression, a topic I have discussed in depth previously (1 , 2 , 3, 4). The above quote comes from a Melissa Healy piece in the Los Angeles Times that throws a damper on Abilify's parade through depression.

Another Melissa Healy piece from the LA Times starts off as follows:

About a year ago, patients began trooping into the office of UCLA psychiatrist Andrew Leuchter, asking whether an antipsychotic drug called Abilify "might be right for them." Few appeared to be delusional, plagued by hallucinations or suffering fearsome mood swings. Mostly, they were depressed or anxious, and frustrated by the pace of their recovery.

Leuchter wondered what was up: Depressed patients didn't usually seek out drugs used to quell psychiatry's most disturbing symptoms.

What was up, he soon discovered, was spending on a new advertising campaign touting Abilify as an "add-on" treatment for depression. For the first time since the arrival of a new generation of antipsychotic medications -- six drugs called the "atypicals" because they work differently from the earlier generation of antipsychotic drugs -- the makers of one, Abilify, had been granted the legal right to market to a vast new population of patients beyond those with schizophrenia or bipolar disorder.

Here's Bristol-Myers Squibb's advertisement for the drug:



This is classic. BMS notes that two-thirds of depressed patients who take antidepressants will still have symptoms after a course of antidepressants. And they have a point: Antidepressants ain't exactly miracle pills. So the commercial implies that Abilify must be really helpful... But if patients add Abilify to their treatment regimen, then only about 25% of them experience remission of depressive symptoms. Isn't it a bit strange that Abilify is appealing to the two-thirds of patients who still have depressive symptoms after taking an antidepressant and offering them a treatment that will lead to remission for only one-quarter of them? Of course, no studies have compared adding Abilify to adding another antidepressant, adding psychotherapy, adding an exercise routine, or adding anything except a placebo. Oh, and given that Abilify led to remission of symptoms in about 25% of patients, while placebo led to remission in about 15% of patients, um, that's a pretty small difference. And keep in mind that the studies were designed in a manner that was almost sure to find a benefit for Abilify, as I have noted previously.

If Abilify was generally benign, then a relatively small benefit over placebo is acceptable. But, as I mentioned previously, the side effects are troubling. I took issue with a BMS-funded journal article/puff piece that tried to spin side effect data on Abilify:

The authors note that "adjunctive aripiprazole is relatively well-tolerated in patients with MDD." Relatively? Relative to what -- being hit with a baseball bat repeatedly? They note that akathisia occurred in 25% of patients on Abilify compared to 4% of patients on placebo. Restlessness: 12% vs. 2%; insomnia: 8% vs. 3%; fatigue: 8% vs. 4%; blurred vision: 6% vs 1%. The authors report that akathisia resolved in 52% of patients by the end of the study, which would also mean that for 48% of patients with akathisia, they were stuck with it at the end of the study. But don't worry, it's "relatively well-tolerated."

You gotta like any drug that induces akathisia at the same rate that it induces symptom remission. Psychiatrist Doug Bremner had a similar take on Abilify as showing a poor cost-benefit ratio. For a few descriptions of akathisia, see comments at this post on Furious Seasons.

Given the unimpressive scientific data regarding Abilify for depression on one hand and the drug's exploding sales on the other, I was sure glad to see a big paper such as the LA Times note that there really is a controversy here. And if Seroquel receives official FDA approval as an add-on treatment for depression, get ready for the marketing machine to reach a fever pitch. Viva Zyprexa, anyone? Melissa Healy covers the expansion of atypical antipsychotics from schizophrenia and bipolar disorder into depression in an article that y'all simply must read. I'll close with a sad-but-true quote from Yale psychiatry professor Robert Rosenheck:

The story's pretty clear, and pretty embarrassing for the profession of psychiatry, which has allowed itself to be led by marketing," says Robert Rosenheck, a psychiatrist at Yale University who has studied the effectiveness and expanded use of the atypical antipsychotics. "We know now what these companies' strategies are: The number of people with schizophrenia is limited, so the road to profitability goes through soccer moms. They need to market these drugs to ordinary people who have dissatisfactions in life.

Leading Psychiatrist Slammed in Leading Journal

In the latest American Journal of Psychiatry appears a review of Allison Bass's book Side Effects. As many of my readers undoubtedly recall, the book details the saga of the antidepressant drug paroxetine (Paxil) and the troubled line of "research" used to support its use in children (among other points). The reviewer clearly liked the book, which is not necessarily newsworthy. What is notable is that a book review appearing in perhaps the world's leading psychiatry journal slams a leading member of the psychiatry profession. The reviewer, Dr. Spencer Eth, writes the following:

More recently, psychiatrists have been greeted in the morning with front-page newspaper exposés of huge sums being directed by these same drug companies to the physician leaders of our field. In Side Effects: A Prosecutor, a Whistleblower, and a Bestselling Antidepressant on Trial, journalist Alison Bass has written the powerful story of a leading medication, its manufacturer, and a favored psychiatrist, whose driving force was profit not treatment.

Ouch. Though not naming the psychiatrist directly, it is clearly a reference to Martin Keller, bigwig at Brown University, whose work on one particular study regarding Paxil was the subject of a lengthy prior post. For the collection of my posts related to Dr. Keller, please click here.

Back to the review...

This well-told cautionary lacks the excitement of a novel but instead informs the reader with an actual case study with the real names of psychiatrists we know. We can see exactly how corporate greed, drug-company-sponsored clinical research, and mental health care become a toxic mix that inevitably damages our patients’ well being, our colleagues’ reputations, and our profession’s good name.

It was a refreshing surprise to see Martin Keller's goose get cooked in this review. I don't mean to sound vindictive or meanspirited. Keller has done a lot of work over the course of his career, much of which likely has some redeeming value. That being said, there can be little doubt that some of his "science" is quite dubious. And for a major psychiatry journal to run anything, even a book review, that directly goes after a "key opinion leader" who appears quite culpable in performing bad science -- that's a good sign.

The Vioxx Hit Squad

"We may need to seek them out and destroy them where they live." The words of a Merck employee regarding people who dared to criticize its bestkilling, er, bestselling painkiller/heart attack inducer Vioxx.

According to The Australian , Merck

...made a hit list of doctors who had to be "neutralised" or discredited because they criticised the anti-arthritis drug the pharmaceutical giant produced. Staff at US company Merck & Co emailed each other about the list of doctors - mainly researchers and academics - who had been negative about the drug Vioxx or Merck and a recommended course of action.

The email, which came out in the Federal Court in Melbourne yesterday as part of a class action against the drug company, included the words "neutralise", "neutralised" or "discredit" against some of the doctors' names.

More about this and similar tales of evil at Before You Take That Pill. You might recall that the superhero team in videos used to train Vioxx sales reps was known as the V-Squad. Perhaps the V-Squad was sent out to "destroy them where they live?" Check out the V-Squad videos here and decide for yourself.

APA Monitor: We Don't Need No Stinking Evidence

The American Psychological Association publishes two monthly publications for members, the well-regarded journal American Psychologist, and the APA's newspaper, Monitor on Psychology. I've been having issues with The Monitor for as long as I can remember. At times, I think the magazine makes claims that are not at all substantiated by evidence, which really bothers me. Why? Because psychology is supposed to be a science; it is what separates psychologists from life coaches or snake oil salesmen. I usually skim the Monitor for about 30 seconds per month, but when I saw the cover for this month's issue, my intuition told me to look out for voodoo. The title: Brain imaging: New technologies for research and practice.

So I browsed through the glossy pages, looking for something to catch my eye. Then, on page 36, there it was...

A pacemaker for your brain? Electric brain stimulation may give hope to people with unremitting depression

Oooh. Sounded promising, so I gave it my full attention. Keep in mind that this was in the "Science Watch" section. The article begins:

It's about the size of the letter "o" in this sentence and may have the power to lift deep, unrelenting depression.

OK, there's the attention-grabber. It then goes on to describe deep brain stimulation (DBS). Before long, I ran across:

Since 2005, more than 60 people worldwide have received DBS for treatment-resistant mood disorders. For about 60 percent of them, there's a "striking improvement in their symptoms of depression," says Andres Lozano, MD, PhD, a neuroscientist at the University of Toronto who performs DBS surgery.

Well, that practically screams "valid scientific findings," asking a surgeon if his technique works. What was he gonna say, "Nah, I think DBS is a bunch of hooey. I only do it because it pays really well." I'm willing to bet that physicians who practiced bloodletting were also quite confident that the majority of their patients showed "striking improvement," which is why we conduct controlled trials rather than rely on subjective opinion. Later in the article, the author notes that the results from DBS are "dramatic and promising." The author also notes that

A number of other behavioral and mood disorders might also benefit from DBS. Benjamin Greenberg, MD, PhD, a psychiatrist at Brown University in Providence, R.I., is using DBS to treat obsessive-compulsive disorder, with success rates similar to [Helen] Mayberg's and Lozano's. Also similar is Greenberg's claim that OCD people who've had DBS are then able to tolerate and respond to behavioral therapy.

This broad success leads Mayberg to believe that DBS is establishing itself as an important tool for treating disorders that otherwise won't budge.

OK, so Lozano claims that 60% of people make "striking improvement"; what about others? As mentioned above, Helen Mayberg has done some research on this topic. The article describes one of her studies. Here comes the most convincing evidence I've ever witnessed:

The initial trial included six people who met diagnostic criteria for major depressive disorder. The two researchers and their colleagues implanted electrodes in the white matter adjacent to their patients' subgenual cingulate cortexes and fired up their pacemakers. All the patients, who were awake during the procedure, reported a "sudden calmness or lightness," Mayberg and Lozano reported in the paper.

The researchers followed up with the patients by administering monthly depression scales. After six months, four of the six showed significantly fewer depressive symptoms. To make sure they weren't getting a placebo effect, Mayberg and Lozano secretly switched off the electrodes in their best-responding patient. After about two weeks, the patient's scores began to drop. After about a month, his depressive symptoms had returned. The researchers switched it back on and six weeks later he was back up to non-depressive levels.

So the author of the article, based on the subjective opinion of a psychiatrist and a neurosurgeon, along with and an uncontrolled study of six people concludes that DBS:

• Has shown "broad success"
• "A number of other behavioral and mood disorders might also benefit from DBS"
• "May have the power to lift deep, unrelenting depression"
• Has shown "dramatic and promising" results
  

The author threw in a few caveats about side effects (though he essentially gave it a clean bill of health), and also noted that DBS should be reserved for patients with longstanding depression and who have not shown positive results with other treatments. So it stopped short of being a blanket endorsement of DBS, yet it did really make it sound like a fantastic treatment for longstanding depression despite the very meager evidence cited in its support. I often complain about poorly designed studies, suppression of negative data, or misinterpreted results leading to drugs being touted as unrealistically safe and effective. But this article shows that it doesn't necessarily take drug company involvement to pimp a treatment well beyond the scientific evidence.

For all I know, DBS may turn out to be The Holy Grail in treating depression of all shapes and sizes. I cast no aspersions on the researchers mentioned in the article, as searching for ways to treat seemingly intractable cases of depression is doing God's work. But the writer did a horrendous job of overblowing the evidence in favor of DBS. This kind of article feeds the popular notion that psychologists are a bunch of flakes who know nothing about science. The APA Monitor can do much better than this.

Seroquel, Haldol, and The Full Court Media Press

I was very pleased to have been acknowledged in a recent story in the St. Paul Pioneer Press. The reporter, Jeremy Olson, wrote the following in his story:

An Internet psychiatry blog first raised questions March 2 about the research Schulz presented at the APA conference and why it lacked any of the company's findings."It raises troubling questions when an independent academic author presents results that are in direct opposition to the underlying data," wrote the blogger, an anonymous academic.

He didn't cite my blog by name -- the unwieldy long name which I stupidly chose for the site may be responsible for that -- but I'm nonetheless grateful that my site was acknowledged for its work on this story. He is referencing my post in which I noted that a University of Minnesota psychiatry professor (Charles Schulz) had stated in a press release that Seroquel was "more effective" than Haldol. This was based upon his analysis of data comparing Seroquel to the much older antipsychotic drug Haldol in the treatment of schizophrenia. Yet an internal AstraZeneca analysis found that Haldol was actually more effective than Seroquel. Both the Pioneer Press and the Star Tribune, the two big papers in the Minneapolis-St. Paul area ran stories on the controversy.

When asked about his lavishing of praise on Seroquel in the press release, the Pioneer Press said:

In an interview with the Pioneer Press last week, Schulz defended his research and presentation of Seroquel as accurate and ethical. However, he acknowledged the corporate press release from his APA presentation might have exaggerated in calling Seroquel "significantly superior."

"You know," he said, "I can't disagree with that."

Schulz said the following in the Star Tribune:

In an interview this week, Schulz said the pharmaceutical company never shared its doubts about Seroquel, which went on to become a blockbuster, with annual sales of $4.5 billion today. "I don't recall anybody calling up and saying, oh my goodness, we have this problem," he said. At the same time, Schulz acknowledged that his own study did not really show that Seroquel was more effective than the older drug. "That's a bit of a misunderstanding," he said. "I think the overall message is that it works about the same."

Thanks to a helpful reader, I was able to track down what appears to be Schulz's presentation from 2000. It says "...quetiapine was clearly statistically significantly superior to placebo as well as to haloperidol..." This appears to contradict his statement that Haldol and Seroquel "work about the same." Again, the data from Schulz's presentation don't match AstraZeneca's internal analysis. Schulz is obviously backing away from his earlier praise for Seroquel, for which he deserves some credit. The problem was that Schulz, along with a laundry list of researchers in psychiatry were caught in a tidal wave of unbridled enthusiasm for the atypical antipsychotics, first as wonder drugs for schizophrenia, then as the Next Big Thing in bipolar, then moving into the world of depression and anxiety disorders in the absence of decent supportive evidence.

Interesting sidenote: While Schulz was presenting on the wonders of Seroquel, he was likely quite unaware that AstraZeneca has conducted a study (Study 15) which had found that Seroquel compared unfavorably to Haldol in preventing psychotic relapse among patients with schizophrenia who began the study in full or partial symptom remisison. Furious Seasons has some additional reporting on this study. It is a near certainty that Schulz was not informed about this study's results, as this could have changed his lofty opinion of Seroquel. This points to the problem of researchers relying on data collected by drug companies -- how are researchers to know they are receiving all of the data?

Note to key opinion leaders: If you don't realize it by now, you are pawns. You are being used to place an academic veneer on the marketing of drugs. The drugs that you are marketing as major breakthroughs typically offer little to no benefit over existing treatment and may cause a slew of nasty side effects. Decide if you want to be a scientist or a marketer. Don't try to do both at the same time, because the odds are pretty good that your scientific credentials will end up being tarnished. Just ask this guy. Now that the media are paying much closer attention to the conflicted interests and skewed science that sadly underlie much of psychiatry these days, it would be a good idea to maintain appearances.

Abilify, Depression, and the Memory Hole

The Primary Care Companion to the Journal of Clinical Psychiatry has a piece on Abilify for depression that illustrates many of psychiatry's woes. Full text of the article is here. The journal published an article titled "Examining the efficacy of adjunctive aripiprazole in major depressive disorder: A pooled analysis of two studies." The paper combines data from two previously published studies which examined the addition of Abilify to existing antidepressant treatment (1, 2). One of psychiatry's big-name academics, Michael Thase, signed on as lead author. I'm hoping that he didn't actually write the paper. Actually, there are eleven authors of the paper, which seems a little ridiculous given that the paper is an analysis of data which had already been collected for two previously published clinical trials. Seven of the authors are employees of Bristol-Myers Squibb (BMS) or Otsuka, which both market Abilify. Wait... If you look closely, you can see my favorite disclosure... In the fine print on the first page...

In case you can't read the fine print: In defense of Thase and the other academic authors, they may have not actually written any of the paper. Much or all of the writing appears to be creditable to Ogilvy Healthworld Medical Education. On their site, they note that they perform:

Clinical Development and Publications Management
Experienced medical writers work closely with authors, editors and publishers to provide our clients with a full range of publishing options.

Whatever BMS/Otsuka paid you for this one simply was not enough. Why? Because whomever wrote this thing did an admirable job of focusing on the positive and completely ignoring the negative.

Erasing the Patient's Opinions: Remember, the article's title states that it examines the efficacy of adjunctive Abilify (adding Abilify to existing antidepressant treatment). So you'd think the article would mention all of the relevant depression data from the two relevant studies. Well, no. In the two stuides which are discussed in the article, patients were assessed on depression using the following measures:

• Montgomery Asberg Depression Rating Scale (MADRS)
• Inventory of Depressive Symptoms-Self Report Scale (IDS)
• Quick Inventory of Depressive Symptoms Self-Report Scale (QIDS)

Using the MADRS, the authors conclude that adding Abilify to antidepressant treatment is more effective than adding placebo to antidepressant treatment. OK, fine, though it's not by a particularly huge margin. Mysteriously, the authors do not even mention that the self-report scales (IDS and its subscale, the QIDS) were used in the two trials. And why would they? In both trials, Abilify was not significantly better than placebo on these measures. A letter to the editor pointed out this glaring weakness in Abilify's claims of efficacy, the response to which was weak:

Noting that Abilify did not outperform placebo on the self-report measure in the trial, he wrote that "this may be due to the lower sensitivity" of the measure. So the drug wasn't the failure -- blame the rating scale instead. The people at BMS picked the scale and when it doesn't give results they like, then suddenly it's a poor measurement of depression. I bet Dr. Berman would not have complained about the instrument had it yielded results in favor of Abilify.

In the publications of each of the two clinical trials, the authors tried to downplay the fact that Abilify was no better than placebo according to patient self-reports. Then, when publishing an analysis that combined the results of the two trials, the authors go a step further by not even mentioning that patients completed a self-report. Right down the memory hole. In my opinion, any reasonable academic author writing about such research would want to note the strengths and limitations of Abilify in treating depression. The lack of benefit on patient-rated measures is a major weakness. Yet several big-time academics signed off on this paper despite its complete scrubbing of negative data. For that, I hereby nominate each author for a coveted Golden Goblet Award. And I credit the ghostwriter at Ogilvy with a fantastic job of serving his/her corporate clients. You, sir or ma'am, deserve kudos for a marketing job well-done.

The instructions for authors who submit to the Primary Care Companion to the Journal of Clinical Psychiatry state: "Conclusions should flow logically from the data presented, and methodological flaws and limitations should be acknowledged." Um, does completely scrubbing negative data count as failing to acknowledge limitations? I can see that the peer reviewers and/or editor really paid close attention to this paper.

Safety: The authors note that "adjunctive aripiprazole is relatively well-tolerated in patients with MDD." Relatively? Relative to what -- being hit with a baseball bat repeatedly? They note that akathisia occurred in 25% of patients on Abilify compared to 4% of patients on placebo. Restlessness: 12% vs. 2%; insomnia: 8% vs. 3%; fatigue: 8% vs. 4%; blurred vision: 6% vs 1%. The authors report that akathisia resolved in 52% of patients by the end of the study, which would also mean that for 48% of patients with akathisia, they were stuck with it at the end of the study. But don't worry, it's "relatively well-tolerated."

Overall, another example of a "research" publication being little more than a puff piece in favor of a drug. With big-name academics signed on as authors to add credibilty and just a fine print mention of a ghostwriter.

I thank an anonymous reader for alerting me to this study.

Citation:

Thase ME, Trivedi MH, Nelson JC, Fava M, Swanink R, Tran Q, Pikalov A, Yang H, Carlson BX, Marcus RN, Berman RM (2008). Examining the efficacy of adjunctive aripiprazole in major depressive disorder: A pooled analysis of 2 studies Primary Care Companion to the Journal of Clinical Psychiatry, 10, 440-447

Seroquel, Weight Gain, And the Pursuit of GAD and Depression Indications

Jim Edwards at BNET dug through the Seroquel documents and found many instances of AZ employees noting that Seroquel causes weight gain. Yet the company seemed bent on keeping this information hidden. As I mentioned last week, this sure seems a lot like Zyprexa redux, except with more sex scandals and perhaps more buried data. I suggest that everyone head over to BNET and see the details.

Despite all the bad news, AZ is pressing onward with its application for FDA approval for Seroquel in both generalized anxiety disorder and depression. Yikes. I broke the story earlier this week about the "scientific literature" claiming that Seroquel worked better than Haldol in the treatment of schizophrenia, yet internal company data showed Haldol as superior to Seroquel in reducing schizophrenia symptoms. Between discrepant data, the apparent hiding of negative clinical trials and trying to keep doctors distracted from data indicating that Seroquel caused weight gain, I think that Seroquel's luck may have ran out -- my bet is that the FDA won't approve the drug for depression or GAD. But I've been wrong before; the FDA did approve Abilify as an add-on treatment for depression based on pretty flimsy evidence.

Internal Documents Suggest that Seroquel Data Were Not Presented Accurately

A document dated March 9, 2000 titled "BPRS meta-analysis" shows that AstraZeneca, maker of the antipsychotic drug quetiapine (Seroquel), knew fully that its drug did not relieve schizophrenia symptoms to the same extent as its older, generic competitor haloperidol (Haldol). The document provides results of a meta-analysis, a statistical analysis that combines the results of several individual studies. The authors used the Brief Psychiatric Rating Scale (BPRS) as their main measure of efficacy. The BPRS rates a variety of psychiatric symptoms relevant to schizophrenia. More details on the BPRS can be seen here. A total of ten clinical trials were included in the meta-analysis, which variously compared Seroquel to placebo, Haldol, and several other antipsychotic medications. Four trials compared Seroquel to Haldol. Several subscales of the BPRS were included in the analysis.

When examining the amount of change on the BPRS, Seroquel consistently outperformed placebo, both on the BPRS total score and on several of the BPRS subscales. However, in several analyses, Seroquel was outperformed by Haldol and by risperidone (Risperdal; Janssen's antipsychotic). The document states: "Against 'all doses' of Seroquel, each of the three significant p-values generated was in favour of Haloperidol (Total BPRS, Factor V, and Hostility Cluster). There was no evidence of significant differences between the treatments when Haloperidol was compared to high-dose Seroquel." This is a plain admission that Haldol outperformed Seroquel on several outcomes, but that high dose Seroquel yielded approximately equivalent results to Haldol. Only one trial compared risperidone to quetiapine and the results clearly favored risperidone. The document stated: "Comparisons against Risperidone using all doses of Seroquel showed significant improvements for Risperidone on total BPRS, Factor V scores, and the Hostility Cluster. Against high-dose Seroquel only, the Anxiety item, Factor I, and Mood cluster scores were also significantly in favor of Risperidone." Risperidone beat Seroquel, and did so by a wider margin when a high doses of Seroquel was used.

The author of the document, Rob Hemmings, summarizes the results in a table, which appears below. It is described as such: "The following table is an attempt to simplify the claims that could be obtained from these results. A ✔ is entered for those comparisons where we have a statistically significant benefit, be it with 'all doses' or with high dose Seroquel... A x marks those comparisons where a comparator has demonstrated significant superiority compared to Seroquel."

The table demonstrates that according to an analysis by AstraZeneca employees, Seroquel is only shown to outperform placebo, whereas Seroquel is shown to demonstrate poorer efficacy than several other medications.

Under the heading "Conclusions," the document states, in part:

In terms of generating positive claims for Seroquel, these analyses seem somewhat disappointing. Although some trends in favour of Seroquel were observed in the Factor I and Mood cluster items, there was no evidence in these analyses of a significant benefit for using Seroquel over any of the active agents assessed."

The internal analysis clearly indicates that, based on several clinical trials, Seroquel offered no benefits over the competition in terms of reducing schizophrenia symptoms. Indeed, other drugs tended to outperform Seroquel.

How Can These Data be Managed? Shortly after the internal meta-analysis was completed, AstraZeneca employees discussed how to handle the negative results. An AstraZeneca publications manager, John Tumas, wrote in an email

The data don't look good. I don't know how we can get a paper out of this. My guess is that we all (including Schulz) saw the good stuff, ie the meta-analysis of responder rates that showed we were superior to placebo and haloperidol and then thought further analyses would be supportive and that a paper was in order. What seems to be the case is that we were only highlighting the good stuff and that our own analysis support the "view out there" that we are less effective than haloperidol and our competitors.

It would appear that an earlier analysis provided positive results which did not hold up during the internal meta-analysis. "Schulz" almost certainly refers to Dr. Charles Schulz, a psychiatrist at the University of Minnesota. In a press release from the year 2000, Dr. Schulz was quoted:

I hope that our findings help physicians better understand the dramatic benefits of newer medications like SEROQUEL because, if they do, we may be able to help ensure patients receive these medications first. The data suggest that SEROQUEL is an effective first- choice antipsychotic.

This press release was based on Schulz's presentation at the American Psychiatric Association convention in May 2000. The email from John Tumas discussed earlier noted that a group at AstraZeneca needed to meet soon "because Schulz needs to get a draft ready for APA and he needs any additional analyses we can give him well before then." It is unclear if Schulz ever received the analyses that showed Seroquel was less effective than Haldol. Regardless, in the press release, he was also quoted as saying: "Almost 50 years later, however, many patients are still taking these medications [such as Haldol], even though more effective treatments like Seroquel exist." While he was stumping for Seroquel in a press release, AstraZeneca's internal data painted a completely different picture.

Schulz, in his role as primary author, would typically be expected to demonstrate a solid understanding of the data underlying his presentation. It raises troubling questions when an independent academic author presents results that are in direct opposition to the underlying data. Such issues have been mentioned previously on this site.

The documents regarding Seroquel are available at Furious Seasons. Reporting on other facets of the documents can be found at the St. Petersburg Times, Bloomberg, New York Times, and the Wall Street Journal.