Antipsychotics for Dementia: A Psychiatrist Speaks

A recent comment was left by a reader (Steve B MD) who claims to be a psychiatrist. I only say "claims to be" because, hey, this is the internet, and you never know who people really are. His comment was regarding a rather lengthy post on antipsychotics for dementia. I found his comment thoughtful enough to merit its own post. Here is the second part of his comment, with my emphasis added because I could not agree with him more...

Regarding your comment that "...it takes time, effort, and using one's training in mental health," that just speaks to how the mental health profession (particularly psychiatry), despite its stated interest in improving the lives of patients, is too focused on the immediate effect on a patient's behavior than in long-term outcomes. As a psychiatrist, I am sometimes appalled at how my colleagues focus on the short-term benefit afforded by an unproven medication and ignore any consideration of the long-term side effects or, more importantly, other ways that the patient may learn to change his/her behavior for the better.

We have indeed been hijacked by drugs. I wouldn't entirely blame the drug companies, though, because psychiatrists have every right not to use meds in this way. It's just that our profession's knee-jerk reaction to a psychiatric symptom is to medicate, and not to help a person through his/her struggle in a more compassionate and productive way.

Amen, brother.

Effexor, Marketing, and Dr. Drug Rep

Great job by Dr. Daniel Carlat. Read his piece in the New York Times Magazine regarding his stint as Dr. Drug Rep, when he stumped for Wyeth's antidepressant Effexor for a cool $30k in one year. Not bad work if you can get it. It is a fascinating account of a common industry practice -- train doctors to give speeches to other doctors in which certain treatment is pushed hard. Overplay efficacy and downplay negative effects. Drug companies state, with a straight face, that this is "educating" physicians -- buying them fancy dinners and having one of their colleagues read company-produced marketing slides on their product.

Carlat's blog is also a great source of information.

Will the Antipsychotic Coverup Continue?

At this point, there are a slew of lawsuits facing manufacturers of atypical antipsychotics, from individual suits ranging to suits brought by state governments. Allegations of fraudulent marketing, kickbacks, and hiding research results are among the claims made in such suits. For example, Arkansas recently filed a lawsuit. Read it here and read my take here.

The most important thing that could come from these suits in the long run is not the money that various drug companies may have to shell out in fines. No, the important piece is the information, the internal documents that I am nearly certain document numerous instances demonstrating bad science, covering up negative data, and detailing ludicrous marketing campaigns. Check out the documents on Zyprexa over at Furious Seasons and you'll get a taste for what I mean. I've written about them on a few occasions (1, 2, 3) as have others, with one monster post from Furious Seasons serving as an excellent example. If such documents from all companies who have engaged in such ethically dubious practices were to become public information, the PR hit would be enormous. Hell, the media may even wake up and run numerous stories on this issue. Imagine: 60 Minutes, Panorama, NPR, Frontline, Now, and other news programs hitting this one hard on multiple occasions. And the complicity of academic psychiatry makes the story yet more fascinating.

As I mentioned recently:

Without academics pimping these treatments well beyond what was scientifically justifiable, these medications would never have achieved such huge success, but now this rather dangerous group of medicines is used for virtually every psychiatric disorder under the sun. These uses include "bipolar disorder" in infants, ADHD, and dementia. Let's put the most vulnerable individuals on the riskiest treatments despite no clear evidence that they work particularly well. There is indeed some evidence for the efficacy of these medications in the short-term treatment of schizophrenia and bipolar disorder, and in a small number of trials, even some long-term evidence of efficacy. But their indiscriminant use across the board for virtually every condition brings great shame upon psychiatry as a profession, on Big Pharma for its slick marketing strategies (1, 2), and most especially upon academic psychiatry for its morally bankrupt role as a group of salespeople who have misrepresented scientific findings to help promote drugs (1, 2, 3, 4, 5, 6, 7, 8).

But such hopes may well be fleeting. The various offending companies may just decide to settle these cases, which nearly always means that they get to keep their dirty laundry private. Here is a sad possibility mentioned by Furious Seasons:

Risperdal goes off patent in about one month--except for some extra and short-lived pediatric indications--so I'm not sure that Janssen/J&J has a huge incentive to fight Arkansas and the other states that are suing it in order to protect what is soon to be a generic product. It's likely much cheaper for the companies to settle the case (liability insurance will cover much of the cost), write an agreement in which they admit no fault and manage to deep six any documents and other evidence of bad behavior, and move onto Invega.

Zyprexa goes off-patent in 2011 and Seroquel is off-patent the same year as well (not sure about patents on Seroquel XR), so one wonders how much incentive those companies have to fight the state suits, or whether they will just settle the cases and move onto whatever is next for them.

Maybe I am a bit too cynical, but it wouldn't shock me if that's how things played out. After all, Lilly has already settled about $1.3 billion in lawsuits over Zyprexa. Why stop now?

Unfortunately, his prognostication is likely correct. Of course, if some insider at AstraZeneca, Janssen, Bristol-Myers Squibb, or Lilly (or Pfizer --though it seems Geodon has not received much legal attention) decides to leak aforementioned documents, then we're on to something. Consider this an open call to the insiders at said companies. Email me or Peter Rost or Philip Dawdy or Ed Silverman or Jack Friday (Pharmagossip). We're all currently accepting insider documents regarding such matters...

Arkansas Unleashes The Razorbacks on Risperdal

As documented at Furious Seasons, the state of Arkansas has leveled some very serious allegations at Johnson & Johnson, manufacturer of Risperdal via its subsidiary Janssen. Furious Seasons was kind enough to post a copy of the lawsuit. Here's a partial listing of the allegations:

• J & J hid the extrapyramidal side effects of the medication through conducting scientifically bogus studies which covered up the risks of Risperdal
• J & J marketed Risperdal off-label for such conditions as ADHD, depression, anxiety, and aggression associated with dementia
  
• J & J falsely represented Risperdal as cheaper and more effective than older antipsychotics
• J & J did not represent their own knowledge that Risperdal is associated with weight gain
• J & J offered kickbacks to physicians to prescribe Risperdal for "non-medically necessary" uses

The lawsuit makes for interesting and inflammatory reading. Keep a couple of things in mind when considering these charges

• Zyprexa was clearly marketed off-label for various conditions (1, 2, 3)
  
• It seems that Lilly was involved in hiding the risks associated with Zyprexa (1, 2)
  
• Bristol-Myers Squibb just settled a large lawsuit, partially regarding claims that it promoted Abilify off-label
• Take a look at a couple studies (1, 2) that were designed to encourage off-label prescription of antipsychotics as well as a "scientific review" of relevant literature on antipsychotic off-label use.
• And of course, there are several states (I've lost count of exactly how many) that are suing Lilly for its promotion of Zyprexa and its alleged concealment of risks associated with the drug.
  

I don't know about you, but I think I'm seeing a pattern emerging here. And while we're talking about weight gain, diabetes and the like, I hope you all have a fantastic Thanksgiving.

Atypical Antipsychotics for the Elderly: A Booming Business

A recent report in the St. Petersburg Times has indicated that between 20-26% of atypical antipsychotic prescriptions are for elderly people. The drugs are typically given in order to help calm patients. This is interesting because the data supporting their efficacy is very weak (1, 2, 3). While the article in the Times is interesting and discusses the problems with the drugs in terms of side effects, it, along with other media coverage with which I am familiar, is missing a major point: Atypical antipsychotics show minimal effects over the benefit given by a placebo. They are also linked to an increased risk of death. So you are increasing the odds of your patients dying, but you are, according to clinical trial research, providing minimal clinical benefit.

Here's a shocking snippet from the article:

Testifying at a congressional hearing, Dr. David Graham, a prominent FDA drug safety expert, was asked if he had issues with any medications already on the market.

"I would pay careful attention to antipsychotic medications. ... The problem with these drugs are that we know that they are being used extensively off-label in nursing homes to sedate elderly patients with dementia and other types of disorders. ...

"But the fact is, is that it increases mortality perhaps by 100 percent. It doubles mortality. So I did a back-of-the-envelope calculation on this and you have probably got 15,000 elderly people in nursing homes dying each year from the off-label use of antipsychotic medications. ...

"With every pill that gets dispensed in a nursing home, the drug company is laughing all the way to the bank."

Granted, this is a back of the envelope calculation that may be inaccurate. But nobody disputes that these medications are linked to increased odds of dying for the elderly, and someone needs to get the science writers to read the research (cited above) that these medications don't work very well. It is hard to think of a bigger scam -- works as well as a sugar pill but increases your odds of dying. The public outrage won't start until people in the media gets rid of headlines that read:

Dementia relief, with a huge side effect: The off-label use of some drugs is helping elderly patients, but may be killing thousands.

Again, the data do not support that these drugs are much more helpful than a placebo, making the headline misleading. Please incorporate the actual research findings regarding atypical antipsychotics into the story and let's try again...

Newer antipsychotic medications offer little to no benefit over placebo, and are killing thousands of elderly patients.

Doctors talk about the risk-benefit ratio with various treatments, which makes sense. When a class of drugs seems to have little benefit and a high cost, both financially and in terms of side effects (including death), shouldn't we try something else? The media create the outrage and then the change occurs. What about the academic experts who have participated in studying these drugs? They should be the most aware of the small at best benefits and the high side effect burden. Yet instead, some of them are churning out tripe such as the latest study pimping Abilify for dementia. If academics are asleep at the wheel, then it is up to the media to start the outrage. I generally like this St. Pete Times article, but if even the most skeptical writers are still claiming the drugs work, it is not a good sign.

But What Else Can Be Done? It is true that elderly patients with dementia can be difficult to manage and that giving them a chemical restraint such as Zyprexa may slow a person down. But how about the following crazy idea, again taken from the St. Pete Times piece...

There are other options, but they take time, money and effort.

At the Cobble Hill Health Center in Brooklyn, Dr. Louis Mudannayake decided to try to change the thinking at his 400-bed nursing home.

Ignoring naysayers and the doomsday predictions of senior nurses, 18 months ago he put together a team of pharmacists, social workers and recreational therapists to review every atypical prescription.

If a new roommate caused agitation, room assignments were changed. If a new aide was hit while dressing a patient, the aide was given special training on that patient's preferences and routine.

Though the nursing home's resources were initially stretched, Mudannayake said the quality of patients' lives improved. "Ultimately, I'm convinced financial expenditures will be diminished, because it's easier to manage a patient who is calm," he said.

Atypical use at Cobble Hill has been cut from about 25 percent of patients to about 10 percent, he said. Almost 40 percent of patients were taken off the drugs completely; 75 percent of those still on the drugs have had their dosage reduced.

"We instituted a cultural change. That's what's required to bring the numbers down," said Mudannayake, who said psychiatric hospitalizations did not increase as medication dropped.

"You'll always have doctors say there's nothing else to use but atypicals, and I agree there are a small minority of patients where you need to use these drugs. But not in the numbers we are using them."

I see, so you can do something else besides dole out Zyprexa and its siblings like candy. But it takes time, effort, and using one's training in mental health. You'd think that psychologists and/or other mental health professionals could easily be hired as consultants to devise such plans. Of course, it is a lot easier to just attempt to sedate chemically over and over again. But are we supposed to do what is easy, even if it is not in the best interest of the patient?

Shame, Shame, Shame. In my humble opinion, this phase atypical antipsychotic mania will be associated with gigantic shame on the psychiatric profession. Just wait a few years. The amazing part is how few "leading lights" within the field have stepped up to the plate and pointed out the problems associated with these medications. When they were first released, all sorts of "key opinion leaders" happily pushed them as a huge improvement over older antipsychotics in terms of treating schizophrenia. Turns out that was mostly hype. Then the atypicals for bipolar rush hit full force, again with the help of "key opinion leaders."

Without academics pimping these treatments well beyond what was scientifically justifiable, these medications would never have achieved such huge success, but now this rather dangerous group of medicines is used for virtually every psychiatric disorder under the sun. These uses include "bipolar disorder" in infants, ADHD, and dementia. Let's put the most vulnerable individuals on the riskiest treatments despite no clear evidence that they work particularly well. There is indeed some evidence for the efficacy of these medications in the short-term treatment of schizophrenia and bipolar disorder, and in a small number of trials, even some long-term evidence of efficacy. But their indiscriminant use across the board for virtually every condition brings great shame upon psychiatry as a profession, on Big Pharma for its slick marketing strategies (1, 2), and most especially upon academic psychiatry for its morally bankrupt role as a group of salespeople who have misrepresented scientific findings to help promote drugs (1, 2, 3, 4, 5, 6, 7, 8).

Update: I forgot to publicly tip my hat to Furious Seasons, where I first saw the link to St. Pete Times piece. Philip Dawdy also added some spot-on commentary, as is the norm at Furious Seasons.

Sex, Psychiatric Drugs, and the Honor System

I had briefly alluded to Dr. David Linden in an earlier post. You may recall that he is the psychiatrist who had his license suspended by the State of Oklahoma because, through sexual contact, he gave genital herpes to two patients. I had never known why Oklahoma was called the Sooner State, but now it makes sense. If you have sex with, and give herpes to your patients, you get your license back sooner than anyone would reasonably expect. To be specific, his license was suspended for a grand total of three months for such misconduct. Can you say slap on the wrist with a wet noodle?

So who is this guy? Let's find out.

License. A link to his Oklahoma physician profile can be seen here. Remember, two cases of herpes transmitted to patients = three months suspension of Oklahoma medical license. I find it more than a bit confusing that his Nevada license is still active. It would appear that in the state which houses Sin City, one can have all the sex with patients that one wants and not be subject to disciplinary action. So give herpes to two patients through sex, and the consequences are having a license suspended for three months in one state and no consequences in another state. Very interesting. Perhaps his transgressions occurred in Oklahoma, so Nevada figures it is out of their jurisdiction. But, if a doctor has sex with patients in one state, I'm going to go out on a limb here and say that his license should be suspended (or, maybe, just maybe, permanently rescinded) in all states.

Imprisonment of Study Participants. That's what the FDA found in their investigation of Dr. Linden. One woman wished to participate in a study in Linden's inpatient facility. She agreed to participate in a study and then changed her mind. She was not allowed to discontinue the study for four days, and only after the involvement of an attorney. What part of "you can discontinue the study at any time" did Linden fail to comprehend?

Patients Without Consent. Two patients did not sign informed consent forms to participate in studies. This is a gigantic no-no. Participants absolutely must provide consent to participate in studies, particularly when they involve taking medications. On six additional occasions, participants signed the incorrect consent form.

Unlicensed Hospital Stays. In one study, patients were placed in an unlicensed hospital for at least two weeks. The study protocol called for patients to be placed in a licensed hospital. Oops.

Drug Dosing. Patients were given incorrect doses of study medication on multiple occasions in one study. I'll quote the FDA report regarding drug dosing in another study:

The amount of study drugs dispensed to, and returned by, subjects 002, 005, 008, 015, and 020 cannot be determined.

Adverse Events? What Adverse Events? Two participants who were placed under emergency inpatient detention during their participation in studies -- their extreme mental instability was not reported as a serious adverse event. Seem to me like it would be rather important to report all serious adverse events that occur in a study. Unless, of course, one was either sloppy or wanted to bury negative data.

And there is more, believe it or not. The FDA investigation only examined two trials. All of the above problems and more based on two studies. Impressive. And then he collects data which is the foundation of the "science" that supports various medications.

Who Would Hire This Guy? Well, let's see. According to his research webpage, he has done clinical trial research for the following:

• AstraZeneca
• Bristol-Myers Squibb
• Boehringer Ingelheim
• Eli Lilly
• GlaxoSmithKline
• Janssen
• Johnson & Johnson
• Novartis
• McNeil
• Pfizer
• Shire

And, to quote his site: "The following Contract Research Organizations have greatly contributed to our success"

• I 3 Research
• INC Research
• Parexel
• PPD Development
• Quintiles
• Rho Inc.

Want to sign up for one of his trials? It appears that his research organization is recruiting patients with the following conditions:

• Alzheimer's
• Dementia
• Depression
• Schizophrenia
• Bipolar Disorder
• Insomnia

On the Stump. Given his impeccable research and ethical credentials, it is no wonder that Dr. Linden...

...is also recognized as a leader in his community and he is a member of several Speakers Bureaus including: Wyeth Pharmaceuticals, Pfizer Pharmaceuticals, Bristol Myers Squibb and others.

Time For Bad Jokes. I can't help myself. Here are a couple of quotes from his site.

Our P.I. is Actively Involved in Trials
David E. Linden, M.D., our Principal Investigator, is actively involved in the research we conduct. As a result, you directly benefit from his years of experience and expertise.

Yes, he has a very hand-on approach. Wink-wink. Also feel free to insert your own punchline. One more...

Dr. Linden has an extensive and prestigious portfolio in Clinical Psychiatry.

Again, I'll leave the punchline to you. It would appear that drug companies have rather lax standards regarding their investigators, would it not? It would seem that imprisoning your patients, having sex with them, playing all sorts of sloppy with data, and other misdeeds would disqualify a person from engaging in clinical trial research. I understand that there will be occasional data errors in research; one can never rule out human error and I accept that. But this is well past slight mistakes due to occasionally poor oversight. And is this what we would like our "science" to based on?

I've written about a similar situation (minus the sex/herpes part) in an earlier post. After reading this post and my prior post, as well as the links contained in both posts, does it not make one wonder the extent to which psychiatric drug research is based on sloppy and/or fraudulent data? I'm not throwing out a number here. I really have no idea. Perhaps these are rare occurrences. But given that FDA oversight of research is close to nonexistent, much of what happens in research is essentially done on the honor system. Unfortunately, it appears that there is enough dishonor in the current honor system to strongly suggest that we need a lot more oversight.

Upcoming Features

Two upcoming stories will both titillate and enrage.

1) How a certain company hid risks of a medication. And I have the documentation to prove it. Of course, "independent" academics make a special appearance.
2) A researcher with an impressive record. It is unlikely that any researcher has given sexually transmitted diseases to more patients than this person. Holding patients captive? Yes. Running clinical trial sites that provide strange data? Yes. And more.

All coming, hopefully soon, from your humble correspondent. Readers, please continue to send tips.

In the meantime, several blogs have been absolutely ablaze lately, including the following. Do yourself a favor and check them out.

• Scientific Misconduct Blog
• Health Care Renewal
• Furious Seasons

Absolutely Smashing Indictment of Big Pharma

Okay, we all know by now that Pharma Giles is the premier site for cutting parody on the pharma industry, bar none. On occasion, he steps away from vicious satire and issues a dead-on, incisive rant. One such rant was recently posted and I think everyone should read it. Teaser follows:

Drugs like Vioxx, Oxycontin and possibly Avandia have all recently been launched onto an unsuspecting public in the quest for billion dollar profits, and have gone on to harm tens of thousands, even though there is evidence to suggest that the companies behind them had a pretty good inkling of the potentially lethal hazards and side-effects from data they chose to selectively ignore during trials.

People have needlessly suffered or died, at best because of complacency and at worst because of corporate greed, and as a result public trust in the pharmaceutical industry has never been lower. And because of public mistrust, the regulatory environment has become so tight that it is now much harder to launch new medicines of any sort – a situation which is a constant cause of whining by the pharma CEOs who are, ironically, ultimately responsible for creating the hostile regulatory climate in the first place!

Pharma industry wonks talk about the “risk/benefit” of new drugs, and yet it seems that these days it’s the public who take the risks and the CEOs and shareholders who get the most benefit.

Executives hide behind the line that they cannot be aware of every little thing that goes on their companies and therefore cannot be responsible for any illegal actions of their underlings. Sorry, guys, but just what do you get paid six, seven or even eight figure "compensation packages" for? By and large, it certainly isn’t for your personalities or good looks, is it?

Howard Udell is certainly now trying to suggest that, well, sure he pleaded guilty, but only because he was the boss and not because he was actually personally responsible for any wrong-doing. Sorry, pal, that may well be true but I think the buck stops with you. If you or your fellow execs weren’t aware of any wrong-doing THEN YOU DAMN WELL SHOULD HAVE BEEN.

Mr. Udell is still employed in his capacity as Chief Counsel for Purdue, Ms. Skolek points out to me.

Slam dunk. I'd also add the atypical antipsychotics into the mix as well. Take a look at recent data regarding their performance in dementia, for example (1, 2). Shockingly poor. And who is accountable when these medications are marketed to bury risks and make false statements regarding a drug's efficacy? Apparently, nobody. Sure, a fine may be levied, but that's just a drop in the bucket. You don't think accountants and lawyers are busy figuring out, as I type, how much money can be lost in lawsuits versus how much can be made from B.S. marketing campaigns that overstate benefits and hide risks? It's all a risk-benefit calculation: How much financial risk do we take by hiding data versus how much can we benefit from aggressively marketing the product?

Latest Abilify for Alzheimer's Study is a Complete Joke: Here's Why

A trial has recently appeared in the American Journal of Geriatric Psychiatry. This study claims that aripiprazole (Abilify) is safe and effective in treating Alzheimer’s patients who presented signs of psychosis. As I will demonstrate, anyone with an ounce of common sense and certainly anyone who passed a basic statistics course can see these claims (especially the claims regarding efficacy) are bordering on hilarious.

Efficacy: Here’s what the authors said…

Apripiprazole 10 mg/day was efficacious, and safe for psychosis associated with AD, significantly improving psychotic symptoms, agitation, and clinical global impression.

Quickie stats lesson. In determining if there is a “statistically significant difference” between two groups, a large factor is the size of the sample. Just because a difference is “statistically significant” does not imply that the difference actually means anything of value. With a large sample size (as was seen in the present study), very small effects can become “statistically significant.”

Next, let's discuss the size of these treatment effects -- how helpful was Abilify? Mean change on the Neuopsychiatric Inventory – Nursing Home Version was 17.6 points for the 10 mg/day Abilify group and 13.0 points for the placebo group. With the knowledge of the mean change and the standard deviations from both groups, one can easily calculate the effect size, which indicates the magnitude of the treatment effect (i.e., did people get a little better or a lot better?). The effect size (using Cohen’s d) was .14. The general guideline is that d = .20 is a small effect, so less than small – I guess you could call it miniscule.

How about other measures used in the study? Here are a few...

• Neuropsychiatric Inventory – Nursing Home Version Psychosis subscale: Effect size = .19
• Clinical Global Impressions – Severity: Effect size = .12
• Clinical Global Impressions – Improvement: Effect size = .10
• Brief Psychiatric Rating Scale: Effect size = .15
• Cohen-Mansfield Agitation Inventory: Effect size = .17

No matter how you slice it, the effects were all very small. Let’s also do a common sense test. The Clinical Global Impressions – Improvement Scale asks one question. The wording may vary slightly across studies, but one example is:

Rate total improvement whether or not in your judgment it is due entirely to drug treatment. Compared to his/her condition at admission to the project, how much has he/she changed?

In the current Abilify study, the average advantage for people taking Abilify 10 mg/day versus placebo was 0.3 points. There are seven points on the rating scale. For example, at one point on the rating scale is minimally improved and the next point is moderately improved. So the average patient on Abilify was 0.3 points closer to moderately improved compared to minimally improved relative to someone on a placebo. Can you say ooooh, big deal?

Anyone who has taken a basic course in statistics should be either laughing or crying (your choice) at this point. What makes this particularly egregious is that the first two authors are academic researchers who absolutely must have received this lesson dozens of times during their research training, so there is no pleading ignorance on their part.

Statistical Significance: Okay, maybe this is a smaller point. But when I plug their numbers (means, SD, N) into a t-test, I find that some of the differences they labeled as statistically significant are no longer statistically significant. Yes, they used a different statistic, which was apparently useful to them, but I thought I’d at least mention that if someone chose to use a different analysis, the data may have turned out as not statistically significant. In any case, the benefits of Abilify as shown in this study are minimal at best.

Safety: Okay, so Abilify does not work very well, but at least it won’t kill you, right? 18 people died across the course of the study, including 3% of the placebo group and 7% of the Abilify 10 mg/day group. Cerebrovascular adverse events were reported for four patients in the 10/mg Abilify group and zero people in the placebo group. As has become nearly an essential disclaimer in studies these days, the authors write: “Eighteen deaths occurred during the study, none of which were considered to be related to study medication. [my emphasis]” Of course not. The study is funded by a Bristol-Myers Squibb, and the company and its “independent” academic investigators determine if the drug could have caused any deaths. The fox is policing the henhouse.

Discussion: The best part of any article is the discussion, because it is a marketing exhibit.

The results of this placebo-controlled fixed-dose study indicate that aripiprazole impacts beneficially on psychotic symptoms in institutionalized patients suffering from psychosis associated with AD; this is the first such study to report improvement in both primary and secondary outcome measures in this patient population...

Aripiprazole also produced significant improvement in other aspects of psychological and behavioral symptoms, as evident from changes in secondary outcome scores...

Thus, the results indicate that the use of aripiprazole cannot only alleviate the specific symptoms of psychosis, but can also reduce the overall psychological and behavioral burden of AD...

Interestingly, the 5 and 10 mg/day doses of aripiprazole show robust efficacy to improve the CMAI scores from baseline to endpoint, reinforcing the evidence that atypical antipsychotics are efficacious in the treatment of agitation. [Apparently “robust efficacy” means having a miniscule impact relative to placebo.]

Again, see above commentary about the extremely small extent to which Abilify “impacts beneficially” upon participants in this study.

To the authors’ credit, they mention that

Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo.

Right, kind of like what happened in this study, at least for the patients who took 10 mg of Abilify. I realize it may have been a chance occurrence that the Abilify 10 mg patients died at a higher rate, but when you combine minimal treatment benefit with doubling the risk of death, why the hell would anyone choose to prescribe Abilify based on results from this study?

Believe it or not, there are a couple of other points about the study that I could prattle on about, but I think the point has been made.

Journal Policies: If you wander over to the American Journal of Geriatric Psychiatry’s Instructions for Authors, you can see the following:

Provide measures of effect size liberally. Give cautions when statistical significance has doubtful clinical or practical significance.

What I have done in this post is provide the measures of effect size since the authors did not provide a single measure of effect size. Not a single one. But wait, if this paper clearly violates one of the main principles listed under “Statistic Guidelines” for the Instructions to Authors, how did it get published? Good question. And that takes me right back to my earlier posts on peer review and how the “experts” who review papers sometimes do so in a slipshod, lazy, biased, and/or incompetent fashion (1, 2, 3, 4). And the editor? Did he even skim this manuscript to see if it conformed to the guidelines of the journal?

So a paper that flouts the journal’s own policies is published, a paper in which statements regarding a product’s efficacy are far overblown. Perhaps drug reps will be disseminating this wonderful piece of science nationwide or even internationally to help get patients onto Abilify because now their marketing is based on "science." Will physicians see through this sort of ruse and laugh the reps out of the office, or will they briefly scan the abstract, conclude the drug is effective, and then whip out their prescription pads? You tell me.

Last, but not least, I present a Golden Goblet Award to the academic authors of the study as well as to the coauthors at Bristol-Myers Squibb. Your ability to present teeny treatment effects as "robust" and get away with it is notable. Great work. You deserve a good cut of however many $$$ are added to BMS's coffers from unneeded prescriptions of Abilify for dementia.

Ari-Pimp-Razole: Science and Marketing Collide

Wow. I've recently seen a study on aripiprazole (Abilify) that boggled my mind. It was in the category of godawful. I'll be writing more about it, likely within the next few days. Stay tuned. It goes to show that Bristol Myers Squibb will stop at nothing to market their product, but I suppose their recent large settlement for naughty marketing of Abilify already indicated they had no qualms in how they pimped their product.

The atypical antipsychotics keep taking a beating on this site (1, 2) -- lots of hype for these medications treating, um, everything, yet little supporting data.

NIMH Gets Dunce Journalism Award

I have pilloried the study published in the American Journal of Psychiatry in September 2007 that purported to show that fewer SSRI prescriptions for kids in the USA was associated with an increase in the youth suicide rate for American youth. I quote from my earlier post below:

Look closely at the above graphs (click to enlarge) from the article. Note that the decrease in SSRI prescriptions from 2003 to 2004 was very slight across the 0-10, 11-14, and 15-19 age groups, which is the timeframe in which suicide rates for those aged 5-19 increased notably. The larger declines in SSRI prescribing for youth occurred from 2004-2005, which happens to be when the suicide rate for those aged 15-24 appears to have decreased from 10.3 per 100,000 (see Table 9; page 28 here) to 9.8 per 100,000 (see Table 7 here). Yes, I know I am comparing data for ages 15-24 to data on ages 5-19, but I think this makes sense when one considers that the suicide rate for those 14 and under is much lower than for those aged 15-24. Actually, grouping suicide data for ages 5-19 makes little sense to me given the vast differences in suicide rate within this age group.

It is important to note that the authors of the paper did not have data from 2005, but there is nothing from the 2003-2004 U.S. SSRI prescription data cited in their paper that even suggests a relationship between decreased SSRI use in youth and an increased suicide rate, as the decrease in prescriptions was minimal. Pay close attention: The authors ran a total of zero statistical analyses to examine the relationship between SSRI prescription rates and suicide rates in the United States. That’s right, zero. So they put up a couple of figures without a single shred of statistical evidence, then claim that declining SSRI prescriptions are associated with an increase in suicide rates. Any peer reviewer who was not drunk or on a high dose of Seroquel should have noticed this gigantic flaw.

Various newspapers and websites dumbly ran with this story using descriptions such as:

Warnings that antidepressants may increase teen suicides appear to have backfired, a new study suggests...

Suicide rates for preteens and teenagers increased sharply when the Food and Drug Administration slapped a "black box" warning on anti-depressants and doctors started writing fewer prescriptions for young people, according to federal data released Thursday

...and others. Please read my earlier post regarding idiotic media coverage of this article for details.

Enter NIMH: In a story datelined September 19, 2007, Jules Asher wrote a story for the NIMH website. As of today, it is still available. It mentions that

...based on mathematical models using previous years' data, the authors predicted an 18 percent increase in youth suicides between 2003 and 2005.

And, as mentioned above, this prediction turned out to be incorrect. Youth suicide rates in 2005 showed little change from 2004. Perhaps the NIMH writing staff could throw that little tidbit of information into an updated version of the article? Earlier in the piece, it is mentioned that

NIMH grantees Robert Gibbons, Ph.D., University of Illinois at Chicago and J. John Mann, M.D., Columbia University, and colleagues, make a case for a possible link between changes in prescription patterns, regulatory warnings and suicide rates in the September, 2007 issue of the American Journal of Psychiatry.

Again, note that they did not make much of a case in that the only statistical analysis they presented was from the Netherlands, yet they apparently believe such data generalized to the US as well. And remember that their own graphs contradict their argument and that the 2005 preliminary data on suicides also contradicts their arguments. The reason I am ranting/raving here is because I expect better from an allegedly nonpartisan organization that is dedicated to science. Why publish a story on the NIMH website pushing results from a study that is so full of holes that I could drive a fleet of Mack Trucks through it? Did the NIMH run stories publicizing findings of more credible research showing a link between SSRIs and increased suicide attempts? Nope. Kind of makes one wonder to what extent NIMH is an objective organization dedicated solely to advancing science, doesn't it?

Major hat tip to an anonymous reader who passed along the link to this wonderful article.

Thanks for the Tips

I'm lucky enough to have many smart readers who send along excellent tips, which are greatly appreciated. In fact, I am currently working on a couple of posts that began with generous leads from my readers. Thanks to everyone who has passed along various stories in need of public documentation and attention. Continue to pass along your tips. The email link is in the right column. I'll be waiting...

The Slap Heard 'Round the World: Atypical Antipsychotics for Alzheimer's

Atypical antipsychotics just got slapped hard. A new study in the Archives of General Psychiatry delivered sizable blow to these medications by finding that they yielded no clinical benefit over "watchful waiting" (placebo) in treating dementia, while all atypical antipsychotics studies were associated with higher costs.

Olanzapine (Zyprexa) did particularly poorly. Patients taking Zyprexa had higher costs, yet their activities of daily living (personal care, doing chores, household activities, etc.) score was significantly worse than patients taking placebo. Patients taking risperidone (Risperdal) and quetiapine (Seroquel) also scored worse than patients receiving placebo on this measure, though Zyprexa patients had the lowest overall scores. In addition, Zyprexa patients were rated as significantly more dependent by their caregivers than patients taking placebo. Here's what the authors said:

The secondary finding that patients taking olanzapine scored worse on the activities of daily living measure than patients treated with watchful waiting most likely represents the greater level or combination of sedation, gait disturbances, and behaviorally inhibiting adverse effects with this drug.

Ouch. You may recall that this class of medications was marketed off-label for dementia. For example, see a prior post, complete with links to documentaton of how Lilly pushed Zyprexa for dementia/Alzheimer's. Let's not forget that antipsychotic meds are linked to that teeny little side effect known as death in older patients with dementia as well.

Let's see if I have this straight: A large number of dementia patients are placed on expensive drugs that have scant evidence of efficacy, and are linked to an increased rate of death. Uh, does this strike anybody else as W-R-O-N-G?

What Do Academics Say? Surely, academic psychiatrists are aware of the fact that atypical antipsychotics are poorly supported in treating dementia. After all, they are highly educated, objective scientists and they will pass along the objective evidence to the world. That's why they write things like this in the journal Current Psychiatry:

SGAs [atypical antipsychotics] remain the first therapeutic option for psychosis and agitation in Alzheimer’s patients.

Phew, good thing people can turn to objective, unbiased scientists for a realistic appraisal of the research literature, right? I think a Golden Goblet nomination can safely be issued to the authors of the above piece in Current Psychiatry -- you really should read my earlier post on the topic -- the article is mind-bogglingly bad.

Risperdal, er, Invega for Depression?

A new study (published in the Annals of Internal Medicine ) demonstrated that risperidone (Risperdal) was effective in reducing depressive symptoms in people who had not responded to a prior course of antidepressant treatment. But how effective? What is the marketing angle? How does this tie in with Invega? Let's find out...

What is Effective? People who were not responding to their current antidepressant were assigned to receive risperidone or placebo as an add-on to their current antidepressant treatment. On average, people taking Risperdal improved by 2.8 points on the Hamilton Depression Rating Scale (HAM-D) relative to people taking placebo. Look over the scale and tell me if you think 2.8 points is a very meaningful difference. Decide for yourself. Yes, the difference was statistically significant, and when a sample size contains 268 people spilt between two groups, it is common for a small difference to be statistically significant. Similarly small (in some cases moderate), but statistically significant, differences were found on other measures assessing overall mental health, disability, and life satisfaction. Results in terms of response to treatment (i.e., getting 50% better or more) and remission (no significant symptoms of depression) were a little more encouraging, but not overwhelmingly so. In sum, risperidone worked better than placebo as an add-on to antidepressant treatment by a small to moderate margin. So far, so good.

Lies, Damned Lies, and Statistics: Here's two quotes from the discussion section:

In our study, risperidone augmentation offered statistically significant benefit on multiple measures within 1 week, and the magnitude of benefit appeared to increase steadily throughout the study...

Our findings suggest that risperidone augmentation is well tolerated and has beneficial effects early in the course of treatment among patients who do not respond to initial therapy. Investigators have reported that early symptom improvement (during the first week of therapy) may predict eventualremission, a key ultimate treatment objective...

Not to be a stickler for details, but at the end of Week 1, the average patient on Risperdal was 1.5 points better off on the HAM-D (see above) compared to the average patient on placebo. Yes, it's statistically significant, but it's pretty close to meaningless. Oh, and at week 2, the difference had shrunk to 1.2 points and was no longer statistically significant. So how did "the magnitude of benefit appear to increase steadily throughout the study" when the benefit decreased from week 1 to week 2? The benefit of risperidone over placebo did improve from a measly 1.9 points on the HAM-D at week 4 to a questionably meaningful 2.8 points at week 6 -- not sure that is a steadily increasing benefit worthy of much mention.

Enter Invega: Here's another piece from the discussion...

Although not evaluated in this trial, a new medication closely related to risperidone, extended-release paliperidone, has hypothetical advantages related to its metabolism and delivery system, including reduced serum fluctuation, reduced peak exposure, and fewer cytochrome P450–related drug–drug interactionswith widely used antidepressants.

Awesome! I was hoping they'd mention Invega (paliperidone), the Son of Risperdal and I was not disappointed. As you likely know, Invega is the patent extender for Janssen, as generic risperidone will soon make branded Risperdal into a has-been. This is clearly an attempt to link the present study's modestly positive results to Invega. You can bet your life savings that Janssen reps will be pounding down doors attempting to convince docs that Invega is just like Risperdal but better because of some trumped-up advantages, which will include some of the "hypothetical advantages" mentioned above. So the study, published in a highly respected journal, goes to show that a product just like Invega works as an antidepressant, but Invega gives you the efficacy of Risperdal in a new, improved formulation.

Note to Peer Reviewers: You're not actually obligated to run marketing tripe for Janssen. There was not a single reference cited to support the "hypothetical advantages" of Invega. Not one. In the future, I think such statements that lack supporting data should be excluded from your journal. This is supposed to be about science, not marketing, right?

Where did the Key Opinion Leaders Go? A previous trial examined risperidone as an antidepressant, generally finding the drug ineffective, though one had to look closely to notice the use of tricky statistics (1, 2) in the trial. The prior trial was also noteworthy for its authorship line, which apparently included people whose contributions to the study seemed minimal. In addition, the order of the authors switched around in suspicious ways as the data moved around from being presented at conferences to being published (3, 4).

In the present study, key opinion leaders are nowhere to be found in the authorship line. I know that people at Janssen read my prior posts regarding the prior study -- perhaps they have learned that someone is watching them and that adding authors for the sake of marketing (lending a veneer of "independence" and credibility to an industry funded study) may well become public knowledge, making them look like used car salespeople. In any case, I appreciate that there were no academic authors thrown on the authorship line as a means of boosting the credibility of the present study.

Now I'm off to snort a couple of Seroquel to deal with all of this marketing trickery. Rumor has it that Seroquel can be a pretty good high...

Paxil's "Advantages"

Paxil and its advantages. Yeah, that's what this blog is about. I just recently retitled the blog; it was formerly known as the Paxil Pimp's Paradise. What am I talking about? I received an email a couple of days ago, to which I will reply in this post. Don't worry. In sticking with my informal confidentiality policy, I'll not reveal the identity of the person or his/her employer. Here is the email:

Respected Sir / Madam,

I read your review on website, please if you can provide me the the reviews for Advantages of Paroxetine for depression & anxiety. It would be more interesting if it would consist of recent data i.e. in year 2007.

I expect you [sic] early reply

Thank You.

Yes, this person works for a drug company. That's all I will reveal about the author of the email. Here is my reply...

Dear Sir/Madam,

Please see the following posts for a detailed explanation of the "advantages" of paroxetine (Paxil/Seroxat) as discussed previously on my site...

• Advantage 1: Increases suicide attempts in patients.
  
• Advantage 2: Potentially increases obesity in patients, though research is preliminary.
• Advantage 3: Increase in birth defects for children whose mothers were taking Paxil while pregnant.
• Advantage 4: Excellent marketing, both for social phobia and depression. Excellent use of misleading writing in so-called scientific journals when writing about the "advantages" of Paxil, including using euphemisms for unpleasantries like suicide attempts.
• Advantage 5: Major discontinuation symptoms. Take Paxil for a while, try to stop and let me know what "advantage" you notice. See references at bottom of this post for a start. There are many more studies documenting clearly the difficulties with paroxetine withdrawal.
  
• Advantage 6: Those wonderful sexual side effects. And they might last for a long time even after one stops taking the medication.

I hope you find this information useful in your search for the advantages of Paxil. I am flattered by your interest in my opinion on this matter. For additional information on paroxetine, you may want to consult Martin Keller, who has a somewhat different take than myself, but who is a potential recipient of the prestigious Golden Goblet Award for his excellent scientific work on paroxetine. Karen Wagner, another Golden Goblet Nominee, may also be an excellent source. You may also wish to consult the following websites:

• Seroxat Secrets
• Seroxat Sufferers

Should I be able to assist further, please let me know. There are other sources with which you will want to be familiar. You may also want to contact Philip Dawdy regarding the advantages of atypical antipsychotics, and please see Aubrey Blumsohn regarding the advantages of Actonel in treating osteoporosis. Also, I hope you contact Jack Friday, Ed Silverman, or Peter Rost to provide industry cheerleading. For any questions regarding the excellent Rozerem advertising campaign, please see John Mack. Last but absolutely not least, for any advice regarding how to outsource your scientists, fake your clinical trials, and abuse your employees, please take advice from the sage Pharma Giles.

Sincerely Yours,

Paxil Pee-Yimp #1

Handing Out Props

The bipolar disorder diagnosis explosion, the torturous American Psychological Association and more... Posts you must read include the following:

• Bipolar rates are increasing as long as you're willing to call everything bipolar and defy God's will. That's the title of the post over at The Last Psychiatrist. And you need to read it. Now. While you're there, you'll want to check out an excellent read on what "borderline personality disorder" actually means.
  
• Both Furious Seasons and Psych Central have hammered on the latest revelations about antipsychotics being doled out for 0-5 year olds in Florida. Yes, I said 0-5 year olds, often diagnosed with ADHD. Who needs Ritalin when you can dole out Zyprexa? Better yet, how about combining the two and adding a couple more psych meds just for fun. The report into antipsychotic use among kids in Florida's Medicaid program is here.
  
• The joke that is continuing medical education just got funnier, in a tragic sort of way. Read all about it at the Carlat Psychiatry Report.
• The Scientific Misconduct Blog continues to document atrocities in the world of science at a breakneck rate. Every single post on the site is worth a read, and I was particularly drawn to the post about the great Prozac coverup.
• Dr. John Grohol notes that while it is easy to bash psychiatry as a profession, psychologists can hardly be smug about their own field. And he just so happened to hit on the exact two issues that drive me most crazy about the American Psychological Association: 1) APA is pushing as hard as it possibly can to get psychologists "prescription privileges." Can you say "psychology losing its identity?" 2) APA's stance on psychologists serving as, um, "consultants" to the U.S. military regarding the interrogation/torture of detainees has enraged a good chunk of its membership. Nice call, John! After reading Grohol's post, you can find more reading on psychologists and torture here, here and here (among many places). Note that the American Medical Association and American Psychiatric Association clearly forbid their members from any involvement whatsoever in interrogations. But the APA allows its members to participate because it (allegedly) helps to avoid abuses. Yeah, that has worked out really well so far. I can't think of any abuses. Nope. Not a single one.