Flashback: Zyprexa 2008, WSJ Alaska Settlement Article

By 
• AVERY JOHNSON

Eli Lilly & Co. struck a $15 million settlement with the State of Alaska that closes the book on a potentially costly trial over the antipsychotic medicine Zyprexa.

Zyprexa, which notched $4.8 billion in sales last year, is approved by the Food & Drug Administration to treat schizophrenia and bipolar disorder. Thousands of product-liability suits have been filed against Lilly, alleging the company didn't adequately disclose information about Zyprexa's links to weight gain and diabetes. Other suits claim Lilly pushed the drug for unapproved purposes, causing state Medicaid programs and third-party payers to bear unwarranted costs.

Lilly already has reached a $1.2 billion settlement with 31,000 plaintiffs. It still faces nine cases filed by other state attorneys general, 1,600 by individual plaintiffs, and others by shareholders and third-party payers such as insurers.

In addition, Lilly is in talks with the U.S. attorney for the eastern district of Pennsylvania to resolve a probe into the Indianapolis drug maker's marketing practices.

The central issue in Alaska's suit, which sought $5,000 for each of the roughly 200,000 Zyprexa prescriptions written for state residents, was whether Alaska's consumers were deceived because Lilly failed to adequately warn about a link to diabetes.

Before Tuesday night's settlement ended the three-week trial, closing arguments had been set to begin as early as Friday.

Lilly didn't admit any wrongdoing and said it settled to avoid having the trial drag on. "This represented, from the company's perspective, a very good way to resolve this matter and get back to business," said Nina Gussack of Pepper Hamilton LLP, a law firm representing Lilly.

Alaska Assistant Attorney General Ed Sniffen said the state took the deal because damages would be difficult to prove and the certainty that Lilly would appeal an unfavorable verdict made a final outcome uncertain. He said $200 million would have been the "best-case scenario," but added that, "at the end of the day, our original estimates kept getting refined, and as the trial went on it became clear that we could take some money now or risk more later."

Anchorage Superior Court Judge Mark Rindner bolstered the state's position last week when he said the FDA has proven incapable of policing drug regulation, according to an Associated Press report.

But both Lilly and the state also were anticipating a U.S. Supreme Court ruling this fall on whether FDA approval pre-empts state claims regarding drug defects. A decision in favor of pre-emption could have made moot any judgment in Alaska's favor.

While the $15 million is a fraction of the penalties the state sought, it is a substantial sum relative to Alaska's population of 670,000. The attorneys general for other states that have sued -- as well as those for the roughly 30 states with Zyprexa probes under way -- could use their larger populations to multiply any claims based on the Alaska settlement, says Edward Sherman, a specialist in complex litigation at Tulane University Law School in New Orleans.

A clause built into Tuesday's deal requires the company to pay Alaska more per capita if any other state gets a better deal.

Ms. Gussack said Lilly would consider each claim separately and that $15 million wouldn't be a benchmark. She said "the reason the number is so small is because Lilly's defense was so good," not because Alaska's population is small.

Connecticut Attorney General Richard Blumenthal, who filed suit against Lilly March 11, said he was "highly encouraged" by the Alaska settlement.

Write to Avery Johnson at avery.johnson@WSJ.com

Endocrine Today: Antipsychotic Drug Warnings Indicate Need for Better Communication Between Endocrinologists, Psychiatrists

Endocrine Today, June 2010
by Angelo Milone
In January, the FDA issued a warning about adverse metabolic effects for adolescents taking the second-generation antipsychotic drug olanzapine. The revised labeling for olanzapine, which is FDA-approved for the treatment of schizophrenia and bipolar disorder in adolescents and adults, states that clinicians should consider the increased potential for weight gain, hyperlipidemia and long-term adverse effects for adolescents.

In 2003, the FDA issued a warning for second-generation antipsychotics, including olanzapine (Zyprexa, Eli Lilly) and risperidone (Risperdal, Janssen), among others, citing an increased risk for diabetes and hyperglycemia. The FDA stated that glucose levels should be monitored in patients with diabetes, at risk for diabetes or with symptoms of hyperglycemia.

Concurrently, the American Diabetes Association and American Psychiatric Association recommended glucose and lipid testing for all patients started on second-generation antipsychotics.

Now, the latest FDA warning adds to the issue surrounding metabolic risks associated with these drugs.

“The adverse effects caused by these new second-generation antipsychotic drugs are without a doubt problematic,” Daniel Hartung, PharmD, MPH, assistant professor of pharmacoeconomics at Oregon State University, told Endocrine Today.

Such warnings and recent data indicate a greater need for communication between endocrinologists and psychiatrists in monitoring weight gain, glucose and other lipid levels, experts said.

“Communication between endocrinologists and psychiatrists — and among all physicians — is critical in the management of a patient’s psychiatric disorders and the adverse effects of their medication,” said Howard R. Belkin, MD, DDS, JD, a psychiatrist at Beaumont Hospital, Royal Oak, Mich.

Elaine Morrato, DrPH, MPH, found that the FDA warning for second-generation antipsychotics did not increase metabolic screening rates.

Endocrine Today interviewed leading researchers in the field to discuss the results of recent studies, potential issues with the current FDA advisory system and methods to improve communication between endocrinologists and psychiatrists.

Metabolic risks ignored

Despite warnings, recent study results have indicated that physicians may not be screening users of second-generation antipsychotics for elevated glucose and cholesterol levels.

Elaine Morrato, DrPH, MPH, assistant professor in the department of health systems, management and policy at the University of Colorado, Denver, and colleagues conducted two studies “to see to what degree the 2003 FDA warnings were adopted.”

In a study published in Archives of Pediatric and Adolescent Medicine in April, Morrato and colleagues concluded that more effort is needed to ensure that patients who receive second-generation antipsychotics are screened for diabetes and dyslipidemia and monitored for adverse drug effects.

They analyzed Medicaid claims data from California, Missouri and Oregon on 5,370 children aged 6 to 17 years without diabetes who were taking second-generation antipsychotics and 15,000 children without diabetes who were taking albuterol but no antipsychotics.

Glucose screening was performed in 31.6% of children treated with second-generation antipsychotics vs. 12.6% treated with albuterol. Lipid testing was performed in 13.4% of children taking antipsychotics vs. 3.1% taking albuterol. The case incidence of glucose and lipid disorders was higher in children treated with antipsychotics vs. albuterol (8.9 per 1,000 children vs. 4.9 per 1,000 children and 9.7 per 1,000 children vs. 4.6 per 1,000 children).

Their findings reflect clinical practice patterns one year after recommendations from the ADA and American Psychiatric Association called for metabolic screening of patients receiving second-generation antipsychotics regardless of age or underlying diagnosis.

“The results suggest that work is still needed to improve metabolic monitoring of children receiving antipsychotic medication,” Morrato told Endocrine Today.

A study published in Archives of General Psychiatry in January also examined laboratory claims data from Medicaid programs in California, Oregon and Missouri between 2002 and 2005 — before and after the 2003 FDA warning. Morrato and colleagues compared glucose and lipid monitoring trends in 109,451 patients receiving second-generation antipsychotics with a control cohort of 203,527 patients receiving albuterol but no antipsychotics.

Again, they found that the FDA warning was not associated with an increase in blood glucose and cholesterol screening (1.7%; P=.02). Initial testing rates for patients using antipsychotics were low; glucose testing was at 27% and lipid testing was at 10%.

Although new prescriptions for olanzapine declined during the warning period (annual share decline, 19.9%; P<.001), the researchers found that prescriptions of the lower-risk drug aripiprazole increased (share increase, 12.1%; P<.001). This may be attributed to the elimination of prior authorization in California during the same time frame, according to the researchers.

“I suspect that it is easier, and therefore faster, to switch prescribing practices following a drug warning, particularly if safer alternatives are available, than it is to increase complexity in medical care by adding extra monitoring,” Morrato said.

 According to Hartung, also a researcher for this study, “the results demonstrate that the way we communicate risk information to clinicians needs to be re-evaluated for some types of messages.”

The conclusion does not necessarily indicate that physicians are ignoring governmental and industry recommendations, Belkin said, adding that the data were four- to eight-years-old when the study was published.

“During those intervening years, the knowledge among psychiatrists that there is a relationship between the use of second-generation antipsychotics and weight gain, hyperlipidemia and increases in blood sugar, anecdotally, has become common knowledge,” Belkin said.

“Clinical experience with these medications, discussions with patients, other psychiatrists and physicians seem to have made the use of screening and monitoring tests for the adverse effects of these medications relatively common. It appears, from discussions with physicians, that screening and monitoring tests are now routinely performed prior to and during the administration of second-generation antipsychotics,” he said.

Warning, revised labeling

The FDA warning and revised labeling for olanzapine states that clinicians should consider the increased potential for weight gain, lipid disorders and potential long-term effects.

Eli Lilly, the manufacturer of Zyprexa, sent a letter to physicians in January detailing the amount of weight gain associated with the drug. The proportion of study participants reporting significant weight gain was greater in adolescents compared with adults.

After 24 weeks of treatment with olanzapine, the percentage of adults who gained at least 7% of their baseline body weight was 89%. Further, 55% of adolescents gained at least 15% of their baseline body weight and 29% gained at least 25% during long-term exposure to olanzapine, according to information provided in the letter.

The letter further stated that clinically significant elevations in triglycerides have been observed in adolescents taking olanzapine. These elevations are reportedly as high as 500 mg/dL, which is “extremely high,” according to Belkin.

 “These weight gains are clearly clinically significant and undesirable,” he said. “Physicians are urged to consider these long-term risks to adolescents and consider alternative treatments before prescribing olanzapine.”

Second-generation antipsychotics are a heterogeneous class of drugs and that extends to efficacy and adverse effects, according to Hartung.

“Not only do some of these agents have the propensity to exacerbate metabolic profiles, they can also lead to potentially life-threatening arrhythmias and have been linked to an increased risk for death in elderly patients,” Hartung said. “Some of these risks are manageable and can be acceptable when treating certain serious chronic mental illnesses, such as schizophrenia; however, when the drugs are used for conditions in which the effectiveness is uncertain or unlikely to be positive, the risk-benefit equation becomes unacceptable.”

The FDA warning also states that the safety and efficacy of olanzapine has not been established in children aged younger than 13 years.

However, Morrato and colleagues found that one-quarter of new prescriptions for second-generation antipsychotics were filled for children, according to data from the aforementioned study published in Archives of General Psychiatry. Although olanzapine was not the most commonly prescribed antipsychotic among children in the study, the numbers were still “considerable,” Morrato said. Among children initiating antipsychotic therapy, the most commonly prescribed antipsychotic was risperidone (50.5%). New prescriptions for children aged 6 to 12 years totaled 60.7%, and new prescriptions for adolescents aged 13 to 17 years totaled 39.1%.

“I was struck by the number of children who are using these medications,” Morrato said. “Many psychiatrists and primary care physicians would not necessarily think about screening a 14-year-old for diabetes. Yet, there are studies coming out that suggest these younger patients experience the same metabolic adverse effects as adults. This is a vulnerable group, and the long-term consequences of second-generation antipsychotics in children and adolescents are unknown.”

Targeting the warnings

A study published in the January issue of Archives of Internal Medicine examined the effect of an FDA warning about antipsychotics in elderly patients with dementia and behavioral disturbance. The FDA issued an advisory warning in 2005, citing an increased risk for death in this patient population taking antipsychotics.

Data show a small decline — about 20% — in atypical usage among elderly patients with dementia, according to Ray Dorsey, MD, assistant professor of neurology at the University of Rochester Medical Center. However, Dorsey and colleagues noted that the study raised larger issues about communication between patients and providers and appropriate prescribing.

“We found that the FDA advisory did lead to a substantial decline in atypical use among the elderly with dementia, although tens of thousands of patients continue to receive these agents despite little evidence of their efficacy and substantial safety concerns,” G. Caleb Alexander, MD, assistant professor of medicine at the University of Chicago and a researcher for the study, said in an interview.

Alexander and Dorsey said given the reliance on FDA advisories to communicate new information about drug safety, more systematic research is needed to understand the effect of advisories.

“We suggest that the specificity and impact of warnings could be enhanced by targeting the warnings to physicians such as geriatricians and psychiatrists, in this case, and patients and potentially caregivers who are most likely to be affected by the warning,” Dorsey told Endocrine Today.

Moreover, the approach should be akin to the ways in which pharmaceutical companies target physicians who are most likely to prescribe and patients who are most likely to use or benefit from a drug. The same approach could be used to communicate safety information and risks, Dorsey said.

Other means of communicating risk beyond “Dear Provider” letters and posting of advisories on the FDA’s website may be needed. In addition, Dorsey said, the target audience should be expanded beyond prescribers to patients directly.

“Pharmaceutical firms could be responsible, including financially, for communicating safety risks that emerge after a drug is approved, and regulators could ensure and assess the effectiveness of such communications,” Dorsey said.

Inadequate testing

This is not the first time that adherence of the FDA guidelines regarding metabolic testing and antipsychotic drugs has been called into question.

A small study published in the June 2007 issue of BMC Psychiatry examined monitoring practices in primary and secondary care to determine how often patients treated with antipsychotics were having their BMI, glucose and lipids checked.

Paul Mackin, MD, PhD, a National Institute of Health Research clinician scientist and psychiatrist at Newcastle General Hospital, England, examined the burden of cardiovascular risks in patients with severe mental illness taking second-generation antipsychotics. Despite clear recommendations about monitoring this patient group, the results were not positive, he said.

“We found that monitoring was inadequate, despite the generally poor metabolic status of these patients,” Mackin said.

Of the 106 community-treated psychiatric patients from across northeast England, 53% had hypertriglyceridemia and 31% had hypercholesterolemia — but only 7% received lipid-lowering therapy. Recording of measures of adiposity occurred in 0% of patients, and less than 50% of patients had neither blood glucose nor lipids monitored during the follow-up period.

“It’s difficult to be certain about the reasons for these findings, but it would appear that lack of awareness on the part of the clinicians may be a key issue. Who should be responsible for monitoring is also an unresolved problem. Should it be the general practitioner or the psychiatrist?” Mackin said.

With robust evidence to show that some of these drugs carry serious metabolic adverse effects, there should be no excuse for lack of monitoring, he said.

“However, I do not think that doctors are willfully ignoring warnings such as these,” Mackin said.

There is a need for better communication between primary and secondary care to ensure that clinicians and patients know who is taking responsibility for checking for the emergence of metabolic adverse effects associated with second-generation antipsychotics, he said.
“We are getting better at this, but there is still a long way to go,” Mackin said.

Increased need for communication

Endocrine Today interviewed experts who said communication between endocrinologists and physicians is critical to manage a patient’s medication for psychiatric disorders.

Ned M. Weiss, MD, an endocrinologist at Abington Memorial Hospital, Pennsylvania, said discussion between the two specialties is essential, and endocrinologists have a responsibility to guide their colleagues in psychiatry to recognize the metabolic abnormalities associated with these medications and guide patients to the appropriate settings for therapy and follow-up.

“The endocrinology community should be proactive in this effort,” Weiss said.

“Clinical trials of various lifestyle interventions may help some of these patients avoid the serious sequelae of the metabolic syndrome. I have had some success using meal replacements in these patients as a way to help them control their body weight. However, my sample size is small and follow-up is difficult. Nevertheless, this approach, as well as others, is needed in larger settings so that we can have more outcomes data that can help drive clinical decisions in the office setting,” he said.

Morrato said the current data highlight the challenges between cross-consulting and collaboration.

“This is a case in which psychiatrists may not typically be trained to monitor for diabetes and endocrinologists may not typically be trained to monitor for mental health disorders,” Morrato said. “For patients taking antipsychotics, it is important that both health care professionals are involved in patient care decision-making. However, unless there is well-integrated care, it can place more ownership and burden on patient to manage information between the different specialties.”

Some experts said second-generation antipsychotics are beginning to be prescribed for other psychiatric disorders, such as severe anxiety, obsessive-compulsive disorder, depression and sleep disorders.

Moving forward

Sun H. Kim, MD, an assistant professor of endocrinology, gerontology and metabolism at Stanford University School of Medicine, said when analyzing these studies it may not be fair to say many doctors “ignore” the FDA warnings.
“Many doctors, especially psychiatrists, are aware and concerned about the side effect profile of antipsychotic medications,” Kim said.

The main issue, according to Kim, is that patients who are treated with antipsychotic medications are primarily seen by psychiatrists who feel more comfortable, and rightly so, with managing psychiatric problems than metabolic problems such as high glucose and cholesterol levels.

“Therefore, there might be some hesitance to order these tests,” Kim said, adding that these issues are somewhat unfortunate, as emerging evidence suggests that individuals with psychiatric problems are more at risk for metabolic/medical problems regardless of their antipsychotic therapy.

“I would love to see a model in which patients with psychiatric problems are taken care of in a system where both psychiatric and medical issues are addressed in one clinic by a team of physicians,” Kim said.

As far as the current FDA advisory system, Alexander said he would not characterize it as “broken.”
“
Nevertheless, there are a number of ways that the advisory system might be strengthened. These include more sophisticated efforts to reach high-volume prescribers of the therapies in question, as well as greater efforts to systematically measure the effect of advisories on a number of outcomes,” Alexander said.
“
Ultimately, the advisory system is all about trying to improve drug safety, and yet we know relatively little about the true impact that advisories have,” he said.

A Bitter Pill to Swallow:Zyprexa: (Un)Informed Consent

Stay Puft, indeed. Thanks, Zyprexa.

I’ve written before about my growing frustration at my failure to lose weight in the many months after being hospitalized and treated for my anxiety, depression, OCD, and most of all, chronic insomnia, with a “drug cocktail” containing  the atypical anti-psychotic Olanzapine (Zyprexa).  

By the time I finally weened myself off of Zyprexa (more than a year ago), I'd socked on 80 pounds of ugly Syndrome-X type fat, and have stubbornly maintained this ponderous girth – the heaviest weight I’ve been.

I’ve been heavy and slim before through various phases of my life, but now that my weight homeostasis has been reset at an alarming, elephantine level -- I can’t lose much -- and have been unable to keep even any modest temporary weight losses off.

My guess is it has to do with a change in body chemistry/function due to the drug -- perhaps due to insulin resistance or other unidentified hormone-like dysregulation.

I originally balked at taking this atypical antipsychotic for an “off-label” use – due mainly to fear over the horrible movement disorder tarditive dyskensia. 

In order to allay my fears, and convince me to take my medicine, the nurses provided "informed consent" printouts (required by law) for each psych med I was prescribed.

I saved my original “informed consent” printout from the CareNotes System from Texas Health Resources (dated 11-28-10) and pulled it out of files the other day.

On the second page of all the dire warnings for:

Olanzipine (by mouth).

Treats psychotic mental disorders, such as schizophrenia or bipolar disorder (manic-depressive illness)

We find:

Possible Side Effects While Using This Medicine:

Call your doctor right away if you notice any of these side effects:

Allergic reaction; Itching or hives, swelling in your hands,, swelling or tingling in your mouth or throat, chest tightness, trouble breathing.

Blurred or other changes in vision.

Change in how much or how often you urinate.

Fast or uneven heartbeat.

Fever, sweating, confusion, or muscle stiffness

Increased restlessness or excessive movements.

Jerky muscle movement you cannot control (often in your face, tongue, or jaw).

Lightheadedness or fainting.

Numbness or weakness in your arm or leg, or on one side of your body.

Severe sleepiness, slurred speech, or trouble with breathing.

Shakiness, problems with balance or walking.

Swelling in your hands, ankles or feet.

Swollen breasts, or liquid discharge from your nipples (men or women).

Trouble swallowing.

Then:

If you notice these less serious side effects, talk with your doctor:

Back pain.

Constipation, upset stomach.

Dry mouth, increased thirst, or watering of the mouth.

Increased appetite.

Missed menstral period.

Redness or swelling in your eye.

Sleepiness or unusal drowsiness.

Stuffy or runny nose.

Trouble with sleeping.

Weakness.

…And finally, at the very, very bottom of all these warnings, only then do we find my bete noire:

Weight gain.

As I now know from OCD-powered research on various internet and magazine exposes, serious big-time weight gain is a very common problem with Zyprexa, and this side-effect was suppressed by its Big Pharma manufacturer, Eli Lilly.

The side effects of long-term use are reportedly so significant that class-action lawsuits against the manufacturer of the medication are ongoing. Problems associated with use of this drug include development of blood sugar disorders, movement disorder and weight gain. For those that suffer the slings and arrows of our fat-prejudiced society every day (even leaving aside the serious health problems of diabetes) it’s in no way a “less serious side effect.”

 The bottom-of the list “weight gain” side effect warning could be more accurately relabeled “May lead to near-permanent, impossible to shed insulin-resistant weight gain.”

 See my other blog posts about Zyprexa for more on all that.  

With the well-known food labeling, the ingredients are listed in descending order by weight. I would/should think that “informed consent” forms would/should similarly list adverse drug side effects in descending order from most common to least common. Are they? Clearly, no. Using such a common-sense standard, “weight gain” would land at the top of any list, not the bottom.

And statistically -- is the weight gain really “near-permanent weight gain?” In my case, the weight did not budge after I stopped the medication. I’d politic for some serious, public studies done on this alarming reality.

Anecdotally, many of the bipolar folks I’ve met in my group therapy sessions have ballooned up due to their meds, and many have had to resort to bariatric surgery to shed the weight. I’d hate to see it come to that for us uninformed “off-label” atypical antipsychotic users.

So much for the “informed consent.” Thank you, too g*d- d#mned much, Eli Lilly. Perhaps the time to contact a lawyer and join in on the class-action lawsuits is here.

In any case, other “off-label” patients need to be forewarned.

Eli Lilly’s Zyprexa: Profit Outweighs Patient Risk?

Here’s a few alarming notes gleaned from “Bitter Pill,” the February 5, 2009 Rolling Stone expose, written by Ben Wallace-Wells, about Elli Lilly’s “atypical antipsychotic” (or AA) blockbuster drug,  Zyprexa (olanzapine).

The Perils of Aggressive Marketing

In 2001 when Eli Lilly’s patent on their blockbuster antidepressant drug Prozac (which produced nearly a third of the company’s total revenues) was set to expire, Lilly “bet the farm” that Zyprexa would prove to be their next blockbuster product. It was hoped that this new “atypical antipsychotic” Zyprexa would match or top the success of clozapine in treating schizophrenia, while mitigating those chemicals that caused the devastating extrapyramidal movement disorders of the older antipsychotics.

On September 30^th, 1996 the FDA approved Zyprexa for the treatment of schizophrenia, making it the fastest “drug to market” in history. The drug label did little to warn doctors and consumers of a sizeable risk for severe weight gain or hyperglycemia, even though internal Lilly documents raised concerns about these side effects. It would be nine years before a comprehensive government study would reverse claims of a safer “side effect” efficacy that surrounded Zyprexa and the other AAs, and raise disturbing questions about hidden risks.

Due to aggressive “off-label” marketing campaigns, AAs as a class swelled beyond their original “marked territory” (estimated at $170 million for schizoprenia), far exceeding the country’s supply of schizophrenic brains, with sales zooming past $2 billion, all the way to $16 billion by the 1990s.

A Lilly company memo stressed, “The ability of Eli Lilly to remain independent and emerge as the fastest-growing pharma company of the decade depends solely on our ability to achieve world-class commercialization of Zyprexa.” The sales problem was there simply weren’t enough schizophrenics in the world as such to save Lilly’s bottom line.

Even as studies slowly emerged that criticized the side effects, Zyprexa continued to win market share.

As  Zyprexa and AAs expanded their marketing campaigns to treat “off-label” conditions beyond schizophrenia, by 2006 they were so successful that nearly 1 in 5 children who visited a psychiatrist’s office left with a prescription for the drugs. Meanwhile, there was little evidence that Zyprexa really did any good for these off-label uses. Even so, this lack of science didn’t deter doctors from prescribing them to children.

By 2001, more than 20 million people had taken Zyprexa. In 2007, the drug generated $4.78 billion, 25% of Lilly’s total revenue.

A Terrible Side Effect Emerges -- Risky Weight Gain

Some medical researchers say the AA drugs may eventually be responsible for tens of thousands of cases of diabetes and other potentially fatal diseases.

While the extrapyramidal movement disorders seemed to be diminished as hoped,  Zyprexa caused a startling amount of weight gain. By the end of just one week, physicians often noted dramatic weight gain, and by the end of a year, some of the patients had gained up to 125 pounds.

In an Indiana University study, a group of male students were given 10 mg/day to test the side effects. Within two weeks the students had gained 5 pounds more than those in a control group. Taking 10 mg was the equivalent of eating 1500 additional calories every day. Some students gained 15 pounds in two weeks.

While Eli Lilly’s experts concluded from their own studies that Zyprexa only caused an average weight of 24 pounds a year, other clinical trials later found 1 in 6 patients gained more than 66 pounds in a year. Such a staggering side effect could raise a patient’s blood sugar – an indication the drug could cause diabetes.

However, relying on conflicting studies provided by Eli Lilly, the FDA instead concluded that patients would only have an average weight gain of 11 pounds.

It was later found that kids prescribed the drug have gained as much as 35 pounds, in as little as 8 weeks, and also have seen their cholesterol and insulin levels rise.

Upon the point of reaching 5,000,000 users, a senior Lilly scientist estimated that Zyprexa had caused as many as 100,000 (2%) of those users to gain 90 pounds. The health risks of that kind of weight gain are profound. Internally, Lilly’s own experts were criticizing the company for covering up the link between Zyprexa and diabetes.

Lilly has agreed to pay a $2.6 billion fee to settle charges (without admitting guilt) that it built the market first by concealing its side effects, and then by marketing it “off label” for diseases for which it had not been approved by the FDA.

Mindfulness at 3:00 AM: Cultivate Compassion

So there I was at 3:00AM last night -- suddenly fully awake and quite angry about my dreadful weight gain, and the failure to lose any significant weight despite all attempts over at least a year. I was frustrated and ruminating about that @##$$ Zyprexa -- not a proper mood for quickly dropping back into restorative sleep and facing the next workday.

I briefly considered taking a "hypnotic" drug (otherwise known as a sleeping pill), but then I decided instead to practice converting the turbulent waves of anger into a serene surface of compassion a la Zen mindfulness.

Instead of continuing to feel outraged about my present state, I redirected my thoughts towards a transforming learning experience -- to feel more outward understanding and compassion for all those other overweight folks who are suffering and unkindly discriminated against.

It took and time some practice, but I was able to accomplish compassion, dissipate the ruminations, and doze off. So that's my new mission -- to convert any obsessive feelings of anger into compassion whenever I can.

Here's an article from the web for those that also may want to cultivate compassion.

Compassion: An Antidote to Anger?

by Elisha Goldstein, Ph.D.

Mindfulness teacher and author Thich Nhat Hanh writes:

The nectar of compassion is so wonderful. If you are committed to keeping it alive, then you are protected. What the other person says will not touch off the anger and irritation in you, because compassion is the real antidote for anger.

There’s often misinterpretation between the words anger and aggression. Anger by itself is not an issue. It is important to be able to notice when we are getting angry, frustrated, irritated, or annoyed because it is often a signal that something is amiss. With that awareness we have the ability to choose what we want to do with it. It is the behavior of aggression and hostility that put people on the defense and cause problems.

When we cultivate compassion, we begin to soften the reactivity of aggression and hostility that often stems from anger.

What is compassion?

Compassion is a quality of awareness that combines identifying with another’s feelings (i.e., empathy) while understanding the position the other is in.

Inherent in the definition of mindfulness is non-judgment and another quality of it is “kind attention.” So as we cultivate a practice of nonjudgmentally placing kind attention on our own experience, we naturally begin to elicit feelings of self-compassion which then begins to flow outwards to others.

To cultivate compassion for another, try this: Allow yourself to imagine the sorrows and pains that the other person holds. During this life they have certainly had disappointments, failures, losses and wounds so deep they may not feel safe to share. Imagine them as your own child, feeling frightened and in pain, and how you may want to comfort them.

Sometimes, through practice, we come to understand that compassion may very well be the greatest antidote to the reactivity that can stem from anger and a pathway toward constructive-anger.

No Do-Over: A Medication I Wished I'd Refused -- Zyprexa

From the Alliance For Human Research Protection website:

http://www.ahrp.org/cms/content/view/513/56/

A Web Review/Commentary on Rolling Stone - "Marketing a Phony 'Miracle' Drug"     
Sunday, 15 February 2009 

Read it and weep, now on order from eBay.

“Bitter Pill” by Ben Wallace-Wells in the current issue of Rolling Stone is an excellent, informative, in-depth article providing an overview into the pharmaceutical industry’s immensely successful—albeit illegal—aggressive marketing tactics, for selling a particularly unsafe, dangerous class of drugs—the antipsychotics, Zyprexa in particular.


The article is long, it covers a sizable territory: early enthusiasm for the promise the new antipsychotic drugs held, against the (by then) acknowledged intolerable effects of existing neuroleptic / antipsychotic drugs; the failure of science to this day, to answer basic questions about schizophrenia; Eli Lilly’s frantic effort to replace Prozac (which was going off patent); the aggressive sales pitch of Lilly’s reps; growing disillusion about the drugs among prominent psychiatrists at Yale and Harvard; the TMAP algorithm scam and Allen Jones, the whistleblower whose testimony led two public officials to lose their jobs—Steven Fiorello, Pennsylvania pharmacist who was convicted of a felony, and Dr. Steven Shon, medical director of the Texas Mental Health department who was forced to resign; Lilly’s aggressive off-label marketing campaign; the erosion of FDA power under the Bush administration, and Eli Lilly’s ties to the Bush family; the lawsuits which are absorbed as the cost of doing business; finally, the inescapable contrast between how much better people with schizophrenia fare in the developing world—with minimal access to drugs—compared with patients in the West whose treatment is centered on the drugs.

For almost a decade only “a few figures on the fringe of the medical profession” noted the dichotomy between the claimed efficacy of Zyprexa, and the demonstrable harm produced in patients.

Now mainstream professors at Yale and Harvard are acknowledging the marketing success of antipsychotics are not justified by the evidence. None of the drugs used to treat schizophrenia work very well—and they all produce debilitating irreversible physical and neurological damage. The drugs’ failure is related to the lack of understanding about schizophrenia. Scientists acknowledge, “We actually have a profound ignorance of the specific molecular mechanism of schizophrenia.”

“We tend to think of drugs as solving discrete problems — penicillin to eliminate bacteria, insulin to modify diabetes — but the antipsychotics are shooting at an invisible target. With schizophrenia,” says Dr. William Eaton, chairman of Johns Hopkins, Department of Mental Health, "we don't know what the hell is going on."

It is well to remember that effective drugs, such as antibiotics, don’t need multi-million marketing campaigns.

Wells sought to understand how, Zyprexa, a drug created to treat schizophrenia—in a very tiny population mostly inhabiting county jails and state prisons—wound up being used on depressed moms and misbehaving kids—and how Eli Lilly turned a flawed and dangerous drug into a $16 billion a year bonanza.

The development of Zyprexa and the other antipsychotics in its class (‘atypical’) affords a window into the interaction of key institutions--academic psychiatry, professional organizations, consumer advocates, the FDA, and the media—which came under the influence of the pharmaceutical industry.

Wells writes: “The most vivid models we have of corporate deception come from the tobacco industry, where scientists working in company labs, behind sealed walls, conducted misleading experiments out of public view and then told the wider world they had found things they hadn't.

But the pharmaceutical industry is immune to this kind of conspiracy. The size of clinical trials and the federal regulations that govern them mean that a company can never develop and study a molecule in-house; it relies on a platoon of contracted researchers, specialists at academic institutions, who test the molecules and then publish their findings in academic journals.”

But when those who conduct the trials sell their professional integrity, signing secret confidentiality agreements which prevent them from publishing the actual research findings; and when influential academics pen their name to industry-sponsored ghostwritten reports in those journals; and when prominent physicians are recruited to promote the drugs as “safe and effective” for unapproved uses -- thereby broadening the number of patients exposed to the drugs’ harmful effects; the result is even worse than the deception by the tobacco industry. After all, smokers were not urged to “ask your doctor” if smoking is right for you… Prominent doctors with impressive academic credentials did not serve as paid consultants helping tobacco companies to promote smoking.

To accomplish the extraordinary marketing feat and generating “irrational exuberance” among clinicians, drug manufacturers took control of the drug testing process—including data analysis, authorship (penned by prominent academic psychiatrists), publication placement in key journals—and key academic psychiatrists were recruited for their professional influence to persuade clinicians and public policy officials that a class of drugs—the new ‘atypical’ antipsychotics—were better and safer than the old drugs, despite evidence contradicting such claims. FDA’s impotence vis-à-vis this powerful industry was accomplished after the Reagan administration made it a policy to gut the FDA: “Simply put, the FDA was no longer in a position to independently evaluate the effectiveness — and risks — of a drug like Zyprexa.”

It is understandable that well-meaning psychiatrists who treated patients with schizophrenia, sought better treatment without the debilitating side effects of the older drugs which they by then recognized as so painful that patients simply stopped taking them, were excited by the promise of an alternative. However, the marketing hype did not make sense from the very beginning: a top Lilly executive announced that its new schizophrenia drug, Zyprexa, has "the potential to be a billion-dollar-a-year drug." Dr. William Wirshing, a psychiatrist at UCLA, is quoted saying: "I almost pulled off the road and crashed into the side rail." At the time, the entire market for atypical antipsychotics was only $170 million. "How the hell do you make $1 billion? I mean, who are we gonna give it to? It's not like we're making any more schizophrenic brains."

And then there were the early red flags about dangerous adverse effects: “Wirshing saw very quickly, however, that Lilly had a problem: Many of his patients taking Zyprexa were gaining a startling amount of weight. The pattern was as sudden as it was consistent. For the first few days they were on the drug, you weren't aware of any palpable difference. But by the end of the week, you could see the weight gain, almost in real time. Bellies and thighs started spreading, faces started puffing out. By the end of a year, the results were stunning. Some of his patients had gained more than 125 pounds.”

When Dr. Wirshing brought his concerns about Zyprexa to executives at the company, they tried to dismiss the evidence. “First they told him that it was just the skinny schizophrenics who were getting fat. Wirshing re-examined his data; it wasn't true. Then they told him that it was the schizophrenia itself that was causing the weight gain, rather than the drug. Wirshing was apoplectic: "If schizophrenia causes that much weight gain, how come I've been working with schizophrenics for 20 years and didn't know that?"

But how did the FDA fail to notice the obvious dangers? “In 1995, as the company was preparing to submit Zyprexa for approval to the Food and Drug Administration, Lilly convened a panel of experts to review the results of its largest study. The specialists concluded that Zyprexa produced an average weight gain of 24 pounds in a single year. One in six patients, clinical trials later revealed, gained more than 66 pounds. Such a staggering side effect, doctors knew, could elevate a patient's blood-sugar levels — an indication that the drug could cause diabetes.”

“The data Lilly submitted in its application to the FDA that same year led the agency to draw a far less alarming picture of the drug. Relying on a database of 51 separate and conflicting studies provided by the company, the FDA concluded that patients taking Zyprexa for one year would have an average weight gain of only 11 pounds. "It's akin to the guys from the cigarette companies going, 'Well, it doesn't cause cancer,'” Wirshing says. "It's just plain not true."

It would be nine years before a comprehensive government study (CATIE) would reverse many of the claims that surrounded Zyprexa and other atypical antipsychotics, and raise disturbing questions about their risks. And nine years, in the pharmaceutical industry, is a lifetime.

The pharmaceutical industry and the federal government have always had an unusually intimate relationship — the government is industry's biggest customer and ostensibly its watchdog.

The FDA regulates the development of a drug and, at least in theory, the marketing that follows its release. However, the FDA, the National Institute of Health, and the IRS receive hundreds of millions of dollars in user fees, grants, and taxes. Because Medicaid and Medicare buy such a large portion of drugs — particularly in the case of the antipsychotics, since virtually no schizophrenics can afford private insurance — the companies lobby those agencies, and their state subsidiaries, to try to win preferences for their own medications.”

To ensure that their more expensive antipsychotics and antidepressants were the recommended treatment of choice for which the government will pay for, drug companies initiated and paid-for the TMAP Algorithm formulary, signed off by a “consensus” panel of “expert” academic psychiatrists. TMAP is the most lucrative scam in medicine.

An influential player missing from the Rolling Stones article, is Steven Hyman MD PhD, the Director of the National Institutes of Mental Health, a leading neuroscientist, and a Harvard Professor whose enthusiastic endorsement of both the SSRI antidepressants and atypical antipsychotics, was expressed in widely publicized 1998 letter to the Director of the Center for Medicaid State Operations at HCFA, in which he expressed concern that the high cost of the atypical antipsychotics might constrain their use:

‘In some parts of the country, we understand that health care systems will not routinely allow new patients to be started on atypical antipsychotic medications until they have failed a course of the standard (less expensive generic) antipsychotic medications. We see no scientific justification for such a practice and consider it particularly ill advised. . . This is a situation in which HCFA and the NIH institutes working in concert can have a substantial beneficial effect on the health care of the American people.”
But in 2002, Allen Jones, an investigator in the Pennsylvania inspector general's office, became convinced that government officials had been enrolled in marketing the drugs.

Jones uncovered evidence showing that TMAP promoters included not only prominent psychiatrists, but government officials who set state mental health policies. These officials served as paid “experts” declaring the new antipsychotics “superior.” Though contradicted by the scientific evidence, their opinions had the mantle of government authority, thus ensuring a market and a continuing flow of sales.

TMAP is an epic fraudulent scheme not unlike Bernard Madoff’s $50 billion Ponzi scheme, which SEC investigators failed to detect for over a decade. Harry Markopolos, a financial expert recognized that Maddoff’s claimed investment return rates were implausible in 1999.

They were, therefore, fraudulent. He recently testified at a Congressional hearing how Maddoff relied on 14 “feeder” funds that funneled investor funds to Madoff for a commission. 

Allen Jones recognized “a big red flag” when he observed that TMAP promoters claimed Zyprexa and the other new antipsychotics were better than the old drugs. But they relied on biased research by industry-paid doctors, “a practice so commonplace that for most medical professionals, it barely registers — it's just part of the background noise.”

However, “independent science, minus the drug-industry money, had come to a different conclusion." Underscoring the scope and magnitude of the TMAP fraud, 18 states adopted TMAP or TMAP versions. What's amazing is how well and for how long both of these fraudulent schemes worked.

Those involved in crafting and promoting TMAP, and those who helped Eli Lilly promote the expansive marketing of Zyprexa were not only collaborators in fraud—they were instrumental in causing severe harm to tens (if not hundreds) of thousands of people—including children and the elderly—some of whom have been killed by the drug.

“Indeed, internal documents show that Lilly's own experts were criticizing the company for covering up the link between Zyprexa and diabetes: "I do believe they made a very strong point that unless we come clean on this, it could get much more serious than we might anticipate," one Lilly executive warned in an internal e-mail in October 2000.

But in hospitals and doctor's offices, the company's sales force continued to push Zyprexa as a wonder drug. In a common industry practice, Lilly persuaded leading psychiatric experts to endorse the drug and then paid them to tout it to doctors, who had little expertise when it came to antipsychotics.”

Former Lilly Zyprexa sales rep, Ahari was struck by how perfectly the strategy worked: Most doctors, pressed for time, did not "approach the education they were getting from the industry with any skepticism at all."

The visible physical harm produced by Zyprexa, confirmed by internal company documents, could not have gone unnoticed by treating clinicians: “The weight gain was visible and striking. "You'd see it from one visit to the next," says Dr. John Abramson, a clinical instructor at Harvard Medical School who has studied the atypicals. "They'd come back, and they'd look like a different person. It looked like someone stuck an inflation needle in them and pumped them full of air." There were other effects, too. Patients got dizzy; they got tired; some saw their blood-sugar and cholesterol levels spike.”

“Between 2000 and 2004, the deaths of 45 children were linked to the atypicals. Some were strikingly young. An eight-year-old boy died of cardiac arrest. A four-year-old boy died of complications from diabetes. Perhaps most vivid of all was the case of a 15-year-old boy in South Florida referred to by social workers as a "runner," a kid who kept fleeing his exasperated foster parents to return to his birth mother.

Admitted to a psychiatric hospital by a judge, the boy was tethered to a chair and pumped full of atypical antipsychotics, presumably to calm him. When his lawyer came to visit him, she found the boy not only sedated, but suffering from another acknowledged side effect of the atypicals: His breasts had become engorged and started to leak milk. The boy was lactating.”

“Visiting the most celebrated mental-health centers in the United States, it is hard to conclude that, even after the innovation of the atypicals, the drugs make a decisive difference in care.” It is difficult, therefore, to brush off the profession’s failure to recognize the disparity between clinical evidence and marketing hype as “overbright enthusiasm” or “irrational exuberance” or to accept the excuse offered by prominent psychiatrists such as, Dr. Peter Tyrer, Imperial College in London: “Almost the whole scientific community was conned into thinking — as a consequence of good marketing — that this was a different and better set of drugs. The evidence, as it's all added up, has shown this to be untrue."

If the whole scientific community was “conned,” they should hand in their license as they do not merit the status of “learned intermediaries.” Furthermore, leading psychiatrists who concealed their significant conflicts of interest, serving as industry’s consultants and promoters, who conducted rigged clinical trials and penned their name to fraudulent reports—reports that have polluted the scientific literature—continue to hold sway as prominent leaders within the profession. Shame on the psychiatric establishment for its failure to say, enough of the lies, enough corruption!

The devastating consequences of deregulation--which gave free rein to predatory profit seekers—is demonstrated in both, the economic meltdown and the transformation of medicine from its therapeutic mission into an accomplice for Big Pharma. The dire consequences of predatory market manipulation are borne by American consumers and taxpayers.

Time magazine has named 25 People to Blame for the Financial Crisis (24 men and one woman). Who will name the names in the medical community who are to blame for the drug-induced mental health crisis?

Time Blog: David Healy: Beware of Big Pharma and Conflicts of Interest

by Maia Szalavitz, Oct. 05, 2012

British psychiatrist and Big Pharma gadfly David Healy is so controversial amongst his colleagues that some have tried to have his medical license revoked — but there he was on Thursday, speaking at the American Psychiatric Association’s (APA) second largest annual meeting at a well-attended session on conflicts of interest.

“It’s a miracle that I was asked along to give a talk [here], and I’m extremely grateful,” Healy said.

His disquisition was perhaps less humble. Arguing that his profession is “committing professional suicide” by failing to address its dangerously close relationship with the pharmaceutical industry, he likened psychiatry’s attitude toward its faltering legitimacy to the Vatican’s widely derided response to its child-sex-abuse scandal by priests — essentially that psychiatry is brushing off justifiable concerns as hype instead of dealing with the source of the problem.

Few experts believe that psychiatry’s relationship with the drug industry is healthy. While several speakers at the session pointed out that other specialties are similarly entangled with industry, “everyone does it” is generally not a valid defense where conflicts of interest are concerned.

(MORE: Antipsychotic Prescriptions in Children Have Skyrocketed: Study)

The conflicts throughout medicine — not just in psychiatry — are clear. In 2004 alone, pharmaceutical companies spent about $58 billion on marketing, 87% of which was aimed squarely at the roughly 800,000 Americans with the power to prescribe drugs. The money was spent mainly on free drug samples and sales visits to doctors’ offices; studies find that both free samples and sales calls increase prescribing of brand-name drugs and raise medical costs without improving care.

Moreover, nearly half of all continuing medical-education classes are sponsored by industry. By their third year of medical school, 94% of psychiatrists in training have already accepted a “small noneducational gift or lunch” from a drug company, according to Dr. Paul Appelbaum, a past president of the APA and director of Columbia University’s Division of Law, Ethics and Psychiatry, who spoke on the panel with Healy.

And while only 34% psychiatrists believe that receiving food or gifts affects their own prescribing patterns, 53% believe that it influences that of their colleagues, according to a study cited by Appelbaum. Research shows that this type of thinking — “Everyone else is prone to biases and social factors, but not me!” — is common and confounds attempts to address conflicts. “At least some of our colleagues are wrong,” Appelbaum said drily of the study.
Healy’s jeremiad was more severe and sharply worded, but it seemed to be well received by the psychiatrists assembled in the audience. Many even asked questions that suggested they too were troubled by the status quo.

“I’m going to argue that we need you to be biased. We want you to be biased by treatments that work,” Healy told his colleagues. “I don’t mind if you’re my doctor and you’ve given talks for industry. My concern is not that you’ve been paid by industry, but that you’ve been fooled by industry. The key conflict is whether people are hiding data from you.”

(MORE: Top 10 Drug Company Settlements)

Healy went on to discuss how drug companies have repeatedly concealed important information about the risks of their medications, whether by hiring ghostwriters to spin the results of scientific studies and then getting renowned experts to put their names on the published papers; by employing tricks in clinical trials like using inadequate doses of comparison medications to make the company’s own drug look better; or by simply keeping unfavorable data out of the public domain.

Healy himself has also been targeted directly by drug companies that haven’t been happy with his critiques. In fact, he’s widely believed to have lost an academic job offer at the University of Toronto as a result of one such critical lecture. At the session on Thursday, one slide in his presentation contained information he sought via a Freedom of Information Act request detailing drugmaker Eli Lilly’s strategy for shutting Healy down. To counter his public insistence that drug companies reveal hidden drug data, Eli Lilly proposed doing things like planting confederates in the audience of his presentations to ask questions that support industry’s view.

Healy also described how in his own attempts to publish formerly hidden data — which all now reside in the public domain — he encountered legal issues with journals, which ultimately resulted in rejection of publication. The clinical-trial data in question in this case showed a greater risk of suicidal acts associated with antidepressants than had previously been revealed.

Healy also referenced hidden data from trials of the antipsychotic drug Zyprexa. “None of them mentioned [that the drug could cause] diabetes or [had] the highest suicide rate in clinical-trial history,” he said. Although drug companies are now required by medical journals to register all of their clinical trials with the National Institutes of Health if they wish to publish them — including those that never end up being published — this is not a legal requirement.

They can still hide relevant data from the Food and Drug Administration by not disclosing trials that they never attempt to submit to a journal.

Healy noted further that when data surfaced showing a link between antidepressant use and risk of suicide in children, the APA issued a statement proclaiming that “we believe that antidepressants save lives.”
“
What I believe they should have said is that the APA believes that psychiatrists can save lives because it takes expertise to manage the risks of risky pills,” he said; if psychiatrists’ only role were to dole out drugs, then less trained physician’s assistants could easily replace them, he noted.

(MORE: A Doctor’s Dilemma: When Crucial New-Drug Data Is Hidden)

But when a questioner, claiming himself “speechless” in the face of Healy’s arguments, asked whether he should just stop prescribing antidepressants, Healy said no. Healy prescribes them himself, but believes that the role of the doctor is to manage risks, not view drugs as harmless. “Medical treatment is poison, and the art of medicine is trying to find the right dose,” he said.

As for what could be done to disentangle medicine from industry, Healy wasn’t entirely pessimistic. “The key issue in the short term is access to data. We have to insist on that,” he said. “We let industry come to our meetings and let them talk in our programs. I don’t think it’s huge problem that they get paid. The big problem is that if you ask for data, they can’t give it to you. That’s not science, that’s marketing masquerading as science.”

But what of the issue of doctors being visited by paid-industry types — or being paid by industry themselves? The panel’s organizer, Dr. Daniel Carlat, director of the Pew Prescription Project, noted a new disclosure law, passed as part of President Obama’s health-reform bill in 2010. Under the legislation, drug companies must reveal which doctors have taken any payment or gift from them worth more than $10, and describe the exact amounts taken and the purpose for them on a publicly available website. (Unfortunately that website will not be up and running until 2014 at the earliest.) All of the panelists agreed, however, that while public disclosure is good, it is not enough.

Dr. Roy Perlis, who heads the Center for Experimental Drugs and Diagnostics at Massachusetts General Hospital, cited research showing that disclosure can actually backfire in unexpected ways. In one study, for example, people were asked to estimate the number of coins in a jar and provided an “adviser” to help them guess. Unbeknownst to them, the adviser had been paid to try to push people to make higher estimates than they otherwise might.

In one condition of the trial, participants were told in advance that the adviser had this bias, but that made matters worse. Under this circumstance, the adviser encouraged participants to make even higher estimates than in the situation without disclosure.

(MORE: How a Study of a Failed Antidepressant Shows That the Drugs Really Work)

“There are two different mechanisms” to explain the phenomenon, says Perlis. “One is strategic exaggeration: ‘I know you’re going to discount what I say, so I deliberately will be more effusive and tell you a higher number.’ The other is so-called moral licensing: ‘I’ve disclosed my conflict, therefore I’m allowed to be biased.’ This very thing may well also play out when disclosing conflicts of interest in medicine.”

Maran Woolston, a woman with multiple sclerosis, also spoke on the panel about how betrayed she felt when she learned her doctor had referred much of her care to a drug-company subsidiary, but had not revealed it to her — and had also taken $300,000 in funding from various drugmakers.

“In my opinion, transparency isn’t a silver bullet,” she said. “My ideal solution — and this may be naive — is that [doctors should] accept no payments whatsoever because then there can be no conflict of interest.”

Read more: http://healthland.time.com/2012/10/05/psychiatrist-contends-the-field-is-committing-professional-suicide/#ixzz2DdF4cY1r