Zyprexa: Lilly Admits Guilt, But Also Blame Physicians

In February 2007, I wrote a post in which I described evidence that Lilly's antipsychotic olanzapine (Zyprexa) was marketed off-label for dementia. The evidence I discussed was based on documents generously and bravely hosted at Furious Seasons. At the time, I was careful to avoid labeling the practices as illegal -- they were definitely unethical but I couldn't really say for sure what if a law was broken. However, a law firm known to represent Lilly was regularly visiting my website at the time, which made me think that Lilly was seriously concerned about legal troubles. I suppose they had good reason to be worried.

I can now officially say that the off-label marketing of Zyprexa for dementia was criminal. Lilly just admitted to committing a crime in the off-label marketing of the drug for dementia and settled legal charges for a cool $1.4 billion. And there are more cases still on the books.

For a really interesting take on this situation, listen to New York Times reporter Gardiner Harris. You can find his talk embedded in the New York Times story from January 14, 2009, which is linked here. The plea agreement in the latest case is available here.

It is important to remember that pimping Zyprexa for dementia is far from a victimless crime. Antipsychotics, including Zyprexa, have been linked to an increased rate of death in elderly patients and have also been shown to be of little to no more benefit than a placebo in reducing dementia-related symptoms (1, 2). For a disturbing account of the widespread inappropriate use of such medications, read this post and weep.

This is truly a case where lust for profits likely led to the early demise of who-knows-how-many patients. And we're just talking about dementia, not the other cases where Lilly went berzerk with marketing Zyprexa (1, 2).

Blame the Physicians Too: While much of the blame for the overuse of antipsychotics in the elderly can be placed on corporations such as Lilly, it is also true that Lilly does not directly administer the drugs. Physicians need to understand that prescribing drugs which have been found to offer little benefit but are linked to killing patients -- how is that legitimately practicing medicine? First, do no harm?? Yes, I know that dementia is a hell of a difficult condition to handle. But does that mean we should be doling out ineffective and potentially deadly treatments to "manage" persons with dementia. Yes, reps from Lilly (and likely others) wined and dined physicians, "educating" them about the benefits of Zyprexa and other antipsychotics. That's their job -- to positively spin their products. No different than a used car salesperson except that drug reps are typically much better looking.

Doctors need to use critical thinking skills -- you don't just listen to a drug rep or skim a drug-company provided journal article reprint then jump on the Zyprexa bandwagon. How about learning how to evaluate evidence so that junky marketing disguised as science does not persuade you to write inappropriate scripts? Yes, we can be outraged that Lilly and others pimp ineffective and dangerous treatments, but the physicians are the most important link. If they cannot be better educated to understand clinical trial results, and cannot take time to critically review the scientific literature, then this pattern will repeat itself over and over again. It takes tricky pharmaceutical marketing in combination with an audience that is unwilling to think critically for this type of tragedy to occur. And occur again, it will.

Unfortunately, the published scientific literature is quite biased, as negative studies tend to vanish rather than grace the pages of our journals. But it's still a much better idea for prescribers to actually read journals and critically examine their findings, as opposed to relying on marketing alone. Better yet would be for research data on medications (negative and positive) to be available for all to see.

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.

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.

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.

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.

Demented Marketing of Zyprexa?

Background: There has been prior mention of how Zyprexa was allegedly marketed off-label as a treatment for dementia, including writing by Alex Berenson. This post will provide more details regarding this issue, especially about the hypothetical case of “Martha,” a case used by Lilly sales representatives in their meetings with physicians.

Before reading this piece, please note that Lilly has denied that it markets its products off label.

Martha’s symptoms have been described as much more strongly resembling dementia than either schizophrenia or bipolar, the only two indications for which Zyprexa is FDA approved. According to Alex Berenson, Martha was described as

a widow with adult children "who lives independently and has been your patient for some time." Martha was described as being agitated and having disturbed sleep, but without the symptoms of paranoia or mania that typically marked a person with schizophrenia or bipolar disorder.

Berenson noted that a Lilly spokesperson said that Martha was intended to represent a patient with schizophrenia.

More on Martha: Here is more on Martha, perhaps from the same document examined by Berenson. This document is titled Zyprexa® (olanzapine) Primary Care Q3 Implementation Guide, and it is dated June 2001.

This is Martha. Martha is a widow who lives independently and has been your patient for some time. She is becoming more complicated to manage, and you note increasing agitation. Her sleep is disturbed; she dozes during the day and is up most of the night. Her family has shared their concerns with you, saying, “She thinks we’re trying to take advantage of her.”

Martha’s family doesn’t want to send her to a nursing home, but her agitation and confusion must be addressed. Your goals of treatment for Martha may include reducing her behavioral disturbances without impairing her cognitive functioning.

Does Martha Have Schizophrenia? Upon checking the Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria for schizophrenia, it appears that Martha does not meet the diagnostic criteria for schizophrenia, despite Lilly’s claims that Martha was intended to represent a patient with schizophrenia.

Later, the same document discusses possible Zyprexa dosage for Martha.

…a starting dose of 5mg – or even 2.5 mg – at bedtime is appropriate.

In schizophrenia trials, Zyprexa is typically dosed at 10-20 mg, not 2.5 mg-5 mg. This also apparently contradicts Lilly’s claim that it was intending Martha to represent a patient with schizophrenia, as it would make little sense for Lilly to recommend a subtherapeutic dose of Zyprexa to physicians.

Under the heading of Back Cover/Close, it is stated:

In summary, doctor, prescribing ZYPREXA is a safe, proven solution for patients like Martha/Michael/Kelly who suffer with mood, thought, and behavioral disturbances. It’s easy to use, and it works [emphasis in original].

Again, note the broad terminology. Rather than discussing bipolar disorder or schizophrenia, for which Zyprexa is indicated, the language of “mood, thought, and behavioral disturbances” is in place, which suggests much a broader application of Zyprexa.

In the same document, a potential question that reps may receive from doctors is mentioned:

With Martha I would just prescribe a cholinesterase inhibitor, such as Aricept. They are supposed to be pretty good with agitation.

Rep: …Why not prescribe ZYPREXA, which has proven efficacy for agitation and related behavioral disturbances [my emphasis], has been on the market for more than 4 years, and has helped over 6 million patients with symptoms just like Martha’s?

In the case of Martha, note again that schizophrenia is not mentioned; instead, “agitation and related behavioral disturbances” are brought to the fore.

FDA Indication for Dementia? In the same document, under the heading of “Helpful Hints,” subheading titled “Martha Spread,” it is stated that

…You will note that on the right-hand side of the spread under the cognition information is a space that has been intentionally left open. Upon launch of the IM [intramuscular] formulation of ZYPREXA, we will be placing a sticker in this spot to announce the new formulation and new indication (agitation associated with dementia) [my emphasis].

Zyprexa was never approved by the FDA for the treatment of dementia, though it would appear from the above quote that Lilly was expecting such approval.

Email Message: To shed further light on the possible off-label promotion of Zyprexa for dementia, further documents were reviewed, including an email issued to “Area Zyprexa Champions,”

Since the diagnosis of our 3 patients in the Zyprexa core message piece are: Martha – dementia,[my emphasis]…can you enlighten us a little more about dementia. We know that we are to describe the symptoms and stay away from diagnoses, but for our own background, can you elaborate on dementia…We are getting a little grief from some of our docs about promoting Zyprexa for dementia [my emphasis], but according to the slides in the audioconference set, there is no FDA approved drug for dementia.

This email clearly indicates that at least some individuals at Lilly were seeing Martha as a case of dementia and that some doctors seemed upset about Zyprexa being promoted for dementia.

Martha’s Symptoms Increase as She Ages: Another document, titled Zyprexa Retail Implementation Guide states under the heading Sales Call, subheading Patient Profile

Martha is a widow you’ve known and treated for several years. As she’s aged, she’s become more complicated to manage – clinically, and at home. These are comments you hear from her family (read testimonials from profile). Your main goal of treatment is to treat her illness and reduce her behavioral disturbances. Do you see patients like Martha?

The comment of her “becoming more complicated to manage” as she’s grown older sounds much more reminiscent of dementia than of schizophrenia, as with schizophrenia, symptom severity is often rather clear at a relatively young age (twenties and thirties) and does not necessarily worsen over time.

Summary: All told, the documents I reviewed appear to paint a picture of Martha being described as a patient with dementia. Her case was then apparently to be described to physicians in primary care settings in an attempt to open their minds to prescribing Zyprexa. Martha’s symptoms do not seem related to schizophrenia; rather, they seem to more strongly resemble symptoms of dementia. In addition, an email indicated that at least some Lilly employees thought of Martha as a patient with dementia and that some physicians were upset that they perceived Zyprexa was being marketed for dementia.

For more on the story of Zyprexa’s marketing, please see the following (1, 2, 3, 4)

Disclaimer: Please note that I am not equipped to state whether Lilly’s marketing practices regarding Zyprexa were illegal, as the law seems to be pretty unclear on this point.

Of course, whether a practice is legal and whether it is ethical are two different things.