This little brief was out recently in The Onion and I thought I'd pass it along for whomever might get a chuckle out of it.
"A new study published in The Journal Of Pediatric Medicine found that a shocking 98 percent of all infants suffer from bipolar disorder. 'The majority of our subjects, regardless of size, sex, or race, exhibited extreme mood swings, often crying one minute and then giggling playfully the next,' the study's author Dr. Steven Gregory told reporters. 'Additionally we found that most babies had trouble concentrating during the day, often struggled to sleep at night, and could not be counted on to take care of themselves—all classic symptoms of manic depression.' Gregory added that nearly 100 percent of infants appear to suffer from the poor motor skills and impaired speech associated with Parkinson's disease."
Given that there are documented cases of antipsychotics being prescribed to infants (for what specific affliction I've never been able to find out) and documented cases of toddlers diagnosed with alleged child bipolar disorder, this piece isn't nearly as far removed from reality as some of the Onion's other satires on mental health issues.
Seriously.
A fine article in the St. Petersburg Times the other day details how the State of Florida last year began requiring approval for doctors wishing to give antipsychotics to kids younger than 6 in the state's Medicaid program. The review process went through the state program and even though it usually approved most doctor requests to use the dangerous drugs on kids, many doctors decided against going through the process and treated the kids with something else.
As a result of the approval process, prescriptions of atypicals in this population decreased by 75 percent last year and 40 percent fewer doctors even wrote prescriptions for the drugs at all. Shall we say that quite a few docs were being indiscriminate in the use of these drugs?
As I reported here in 2007, many of the prescriptions of atypicals in the Florida Medicaid system were for kids with ADHD and here's the confirmation that that's what was going on:
"He [a reviewer of some approvals] understands doctors might want to use an atypical to sedate an uncontrollable child with ADHD, one of the most frequent diagnoses reported. But he rejects the request unless a recent evaluation shows the child is violently aggressive. Bengtson also wants proof the physician has first tried other medications with fewer side effects. And if the request is for an inappropriately high dosage, the answer is no."On the other hand, kids who are autistic and aggressive are routinely approved for Risperdal, even if they're younger than the FDA age guidelines. 'At least we have some safety data for autism,' Bengtson said."
Some small kids still get the drugs despite the review process, apparently because there are a small minority of cases where there use is merited.
You've got to wonder what would happen if this approval process were implemented in other states.
BTW, the paper's article notes that there were 23 infants under 1 year of age who were given antipsychotics in 2007. Last year, there were none.
This falls under the category of "One of the weirdest stories I've ever seen": Investigators for HHS created a bogus product and an obviously bogus clinical trials protocol for the same and submitted it to three institutional review boards and one of the boards actually approved the trial. IRBs, as they are known, are roughly the same thing as human subjects committees at medical centers and they are supposed to evaluate protocols for trials of drugs and devices that will be used on patients in clinical trials shops.
The trial called for a full liter of a fictitious liquid to be poured into a woman's stomach after surgery (which I've never heard of before) and while two IRBs rejected the protocol, one--namely, Coast IRB, LLC., of Colorado Springs--approved the protocol, calling it "probably very safe," according to the AP.
The HHS investigators also created a fake IRB and was contacted by at least one research coordinator looking for quick turnaround of a protocol approval.
All of this shows how easily the IRB process can be manipulated.
The allegedly influential U.S. Preventive Services Task Force, which sets guidelines for doctors on a host of health issues, is now recommending that all US teens be screened for depression once a year by a doctor. The recommendation is even to be applied to teens who show no signs of depression symptoms.
"Calonge stressed that the panel does not want its advice to lead to drug treatment alone, particularly antidepressants that have been linked with increased risks for suicidal thoughts. Routine depression testing should only occur if psychotherapy is also readily available, the panel said. Calonge said screening once yearly likely would be enough."The recommendations come at a pivotal time for treatment of depression and other mental health problems in children.
"Recently passed federal mental health equity legislation mandates equal coverage for mental and physical ailments in insurance plans offering both. The law is expected to prompt many more adults and children to seek mental health care.
"Yet at the same time psychiatrists specializing in treating children and teens are scarce. A separate report, also released Monday in the Pediatrics journal, says primary care doctors including pediatricians and family physicians will need to get more involved in mental health care."
This is simply stunning stuff. While I'm not a depression denier--I know all about teen depression from personal experience--I am simply stunned that an allegedly reputable group of doctors would recommend such wholesale screening when they know damn well that psychotherapy is often inaccessible (for a number of reasons) and that doctors, with zero expertise in mental health care, will simply steer kids towards anti-depressants which have very rocky track records in terms of efficacy and safety. It's one thing to recommend screening for kids at-risk of depression, but this is just so over-the-top that I almost don't know what to say.
But whatever. This is the new America where sadness of any kind is unacceptable and where we will all soon be, to rip off Jello Biafra, jogging for the master race. It's all very good new for the pharma companies, however.
Ironically, I happened to talk with a friend of mine last night who is a pediatric nurse and he said, "Doctors have become drug pushers."
I sadly agreed with him.
Over the weekend, news came out that Eli Lilly's compound LY2140023, also known as mGlu2/3, failed to outperform placebo in a major phase 2 clinical trial, marking a major setback for the drug.
That's discouraging news for Lilly, as the drug had shown some promise in an earlier trial of about 200 patients and had gotten a ton of press attention as being a new way to address psychosis without larding the pounds onto patients. The drug works on glutamate receptors instead of the usual antipsychotic target of dopamine receptors.
"In the latest trial, however, the results fell short of the mark. Lilly tested the drug on 393 patients for four weeks. The drug failed to outperform Zyprexa. More surprisingly, Lilly said the drug did not outperform a placebo. The response of patients to the placebo was approximately double that normally seen in schizophrenia clinical trials."
It's interesting that there was such a large placebo response in the trial, especially since placebo response in trials involving patients with psychosis generally runs around a 10 percent to 20 percent response rate (at least in trials I'm familiar with).
It's also interesting that placebo performed roughly as well as Zyprexa.
In a press release, the company noted:
"A higher-than-expected placebo response was observed (14.6 points improvement) as measured by the Positive and Negative Syndrome Scale (PANSS) total score. The primary analyses did not demonstrate that any of the four LY2140023 monohydrate doses (5, 20, 40 and 80 mg taken twice daily) separated from placebo. Similarly, olanzapine at 15mg once daily also did not separate from placebo."
Lilly plans more clinical trials of LY2140023.
On Friday, Joseph Heyman, the AMA's board chair issued a statement in response to the Alliance for Human Research Protection's call for an investigation of a recent fracas involving a Lexapro study and unreported conflicts of interest by one of the study authors. The basic story is that JAMA's editor in chief and a deputy editor went gangster on a separate researcher who brought the matter to JAMA's attention. Heyman's statement reads:
"The American Medical Association is owner and publisher of the Journal of the American Medical Association (JAMA) and its specialty Archives journals. While we are ultimately responsible for these publications, as most in the medical and journalism professions are aware, these journals are editorially independent of AMA. That means we do not review or interfere in what is printed in these journals."Recently, concerns have been raised over how JAMA editors addressed a conflict of interest issue brought to light by Professor Jonathan Leo. As owner and publisher of JAMA, we take these concerns very seriously.
"In accordance with the Editorial Governance Plan for JAMA, this entire matter is being formally referred to the Journal Oversight Committee (JOC). The AMA is requesting that the JOC examine the concerns related to Professor Leo’s inquiry and upon completion present its findings to the AMA Board of Trustees. The AMA Board will give careful consideration to whatever is reported to it by the JOC."
It sure sounds like JAMA's editor in chief, Catherine DeAngelis, created a ton of trouble for herself when she lashed out at Leo. There's background on all this here and here.
I generally don't post on weekends, but news is just out that controversial Harvard child psychiatrist Joseph Biederman and his colleagues Tim Wilens and Thomas Spencer were named in a federal subpoena yesterday. The trio have all pulled in millions from pharma companies while also doing federally-funded research, a potentially illegal conflict of interest which was allegedly improperly reported. They are all being investigated by their university and NIH.
The subpoena, issued by the US Attorney for Eastern Massachusetts, was served on Fletch Trammel, an attorney representing various states attorneys general and other plaintiffs in cases against pharma companies over pushing antipsychotics for use in children and adults. Apparently, the feds want whatever documents and depositions Trammel has gathered on the three.
I have no idea where this is going or what, but it sure is getting serious.
A fine article is out in the Washington Post today (the link is to page 2 since the WashPo site is being odd today), detailing a cat fight between researchers over how to interpret results of a long-term study of kids getting ADHD meds and kids getting therapy only. Read the article for the debate.
Meanwhile, the raw results of the study are far more interesting.
"In August 2007, the MTA researchers reported the first follow-up data, which by then no longer showed differences in behavior between children who were medicated and those who were not. But the data did show that children who took the drugs for 36 months were about an inch shorter and six pounds lighter than those who did not...."With the MTA having followed the children for eight years, the latest data have confirmed that there are no long-term differences between children who were continuously medicated and those who were never medicated. Some of the data were published online yesterday in the Journal of the American Academy of Child and Adolescent Psychiatry...."
"The subgroup analysis found that children in homes that were socially and economically stable did the same in the long term with or without medication. Children from troubled or deprived backgrounds slid backward as soon as the intensive therapy stopped and they went back to their communities. About one-third -- those with the least impairment to begin with -- continued to improve over the long term."
So much for Ritalin and Adderall. I'll have more on this after I get a hold of the study.
The following is my written testimony which I submitted yesterday to the FDA's Psychopharmacology Advisory Committee. On April 8, the committee will hold a hearing on AstraZeneca's applications to have Seroquel approved for three different depression indications as well as for anxiety.
Dear Members of the FDA Psychopharmacology Advisory Committee:
I am writing to you to encourage you to NOT recommend approval to the FDA of Seroquel XR for any of three depression indications and generalized anxiety disorder for which AstraZeneca is seeking FDA approval.
I base my recommendation upon having taken Seroquel for depression and agitation for 14 months in 2004 and 2005. It caused me to experience rapid weight gain of over 10 percent of my body weight (a quality of this drug that I was not warned about in advance), tightened muscles in my legs and back, gave me tardive dyskinesia, gave me jerking spasms in my legs, gave me horrific nightmares and didn't do much to treat my depression. Some of these side effects continue to this day.
What I experienced is not unusual among patients given this drug. There are 20,797 adverse events in the FDA's adverse events database related to Seroquel, including 2,016 where the reported outcome is death. It is a nasty drug in my opinion.
Seroquel is well-known to cause diabetes and explosive weight gain in some patients and for this drug to be approved to treat depression and anxiety could well result in the FDA creating a new public health problem (diabetes) in order to address depression and anxiety. That would make no sense.
Perhaps there is data in AstraZeneca's submissions of clinical trials for the depression and anxiety indications to argue against other evidence of diabetes and weight gain and other problems with the drug, but if it exists then the company hasn't made it available to the public. In my own view, unless the clinical trials data show Seroquel to be a profoundly powerful anti-depressant and anti-anxiety drug, then the committee should recommend against its approval based upon its unsafe safety profile.
As it stands, AstraZeneca was cited by the FDA in December 2008 for off-label marketing of Seroquel for depression and the company has successfully gotten doctors to prescribe the drug to patients off-label for several years. After Seroquel was approved for bipolar depression in October 2006, sales of the drug exploded and it wasn't because of bipolar disorder (a market AZ had already saturated) but because of depression. Sales of Seroquel in 2005 were $2.76 billion. In 2008, sales reached $4.45 billion, 62 percent growth in less than four years.
Another feature of Seroquel you need to consider is that the drug is now a reported drug of abuse, in prisons and on the streets. This is documented in the academic literature and there are numerous documented arrests of people for illegal Seroquel possession. On the street, Seroquel is known as "Susie Q" and "Quell" and can even be made into a "Q Ball" (a combination of cocaine and melted Seroquel, then injected). On the streets, Seroquel is crushed and snorted and produces a knock-out downer effect akin to heroin and snorted opioids such as OxyContin. This isn't AstraZeneca's fault of course, but it is the social reality of its molecule.
Approval of this drug for depression and anxiety would lead to even more Seroquel being diverted into the street drugs market, due to its increased use and availability above ground.
Not approving Seroquel for depression and anxiety would not keep a single patient from being prescribed the drug by their doctor (it's already widely prescribed off-label), but it would save America from an inevitably aggressive DTC marketing campaign. I certainly don't want to turn on my TV and see an advertisement for a drug that injured me and many thousands of other patients.
If, however, you choose to recommend the drug for approval for any of the four indications under review, then do so only with the provision that the FDA strengthen warnings about the drug's side effects on its labeling. For example, the current warnings about diabetes, hyperglycemia and weight gain are buried many pages down in the drug's prescribing information. In my opinion, these warnings should be upgraded to black box warnings, in order to properly alert prescribers and patients.
As I first reported two weeks ago, the editor in chief of JAMA, Catherine DeAngelis, basically engaged in thug tactics in going after Jonathan Leo, a neuroanatomy prof at Lincoln Memorial University, who had brought an unreported conflict of interest in a journal article to JAMA's attention. DeAngelis and another editor went batty on Leo and the whole thing made its way to the Wall Street Journal's Health blog. DeAngelis reportedly called Leo a "nobody and a nothing" to the Journal's reporter, but she later claimed in JAMA that the WSJ lied.
Now, the Alliance for Human Research Protection is calling for the AMA's board of directors to suspend the two editors, and more:
"We are deeply concerned about the unbecoming and unethical conduct of the Editor-in-chief and Executive Deputy Editor of the Journal of the American Medical Association, who were reported to have used unprofessional and intimidating tactics against a conscientious academic, Dr. Jonathan Leo. Their behavior undermines the integrity of the JAMA peer review process, first, by failing to properly vet a manuscript for the accuracy of scientific reporting and for author conflict of interest and bias and, second, by launching an ad hominem attack on the scientist who was attempting to correct the record....""Accordingly, the Alliance for Human Research Protection calls for a public apology to Dr. Jonathan Leo by the American Medical Association, the immediate suspension from duty of the two editors involved in this matter, a thorough investigation by the AMA board of directors, and a commitment to reviewing, clarifying and publishing JAMA's editorial policies to protect against future violations of standards for professional conduct."
This is the tastiest little contretemps in ages, but it's also quite serious that DeAngelis went after Leo in such a fashion. It'll be interesting and very telling to see how the AMA's board responds to AHRP's letter.
Separately, The Economist now has an account of this lovely square dance and opines, in part:
"The JAMA editorial explains that the new policy arises from a desire to 'ensure a fair process of investigation and above all, to protect the integrity of science and the reputation of JAMA.' The first two goals are laudable, but the rule of silence seems designed with the third, rather more self-serving, goal in mind. If JAMA is not careful how it implements its new policy, that may yet work against the first two goals."
What with the attention the JAMA editors have stirred up with their sophomoric behavior, you have to wonder how the board will address this.
Seriously, folks, the Rubicon has now been crossed. IMS Health reports that in 2008, sales in the US of antipsychotics (used for absolutely every alleged mental disorder under the sun) in 2008 reached $14.6 billion, topping lipid regulators (ie, statins, etc.) which hit $14.5 billion in US sales. Follow the above link and click on "top therapeutic classes by US sales.
Lipid regulators are usually the top revenue producers in the US, so this is big news and tells you a whole lot abotu how successful the off-label marketing campaigns of makers of the atypical antipsychotics have been. US sales of antipsychotics in 2004 amounted to $9.6 billion, marking 52 percent growth in four years.
I can assure one and all that America didn't suddenly develop millions of more people with psychotic disorders. These drugs are being used for depression now and that's where I bet the sales boost came from. America is no longer "Prozac Nation." It's not "Atypical Nation." And that ain't good.
It'll be interesting--and discouraging--to see how many new cases of diabetes and neuroleptic malignant syndrome crop up as a result.
Anti-depressant sales were $9.6 billion, up a bit from 2007's $9.4 billion. That's kind of impressive growth considering that most anti-depressants are now available in generic forms.
Five major US water systems have so many pharma products in their water supplies that fish are picking it up, and anti-depressants and meds for bipolar disorder, presumably anti-seizure drugs, are showing up in the fish. The cities are Chicago, Dallas, Phoenix, Philadelphia and Orlando, Fla.
"Fish caught near wastewater treatment plants serving five major U.S. cities had residues of pharmaceuticals in them, including medicines used to treat high cholesterol, allergies, high blood pressure, bipolar disorder and depression, researchers reported Wednesday."
I've dubbed this phenomenon "pharmawater."
Researchers noted that the concentrations weren't high enough to practically affect humans, but that none of this is good for the fish. I noted last year that researchers had found that Prozac in rivers made fish swim oddly and not eat. I can't imagine that any of this is good for humans either.
Last year, the AP reported that psych meds were showing up in water supplies around the US and, this year, that pharma manufacturing facilities in India were polluting rivers there with all manner of meds.
I'm sure most of you have seen those ads all over the 'Net beckoning one and all to click to find out their "real age." Clicking through takes you to realage.com where you can fill out various surveys, be told an approximation of your age and so on and then you start getting all manner of emails, tailored to what your alleged health concerns are or should be. It turns out, according to this New York Times article, that the website is in league with the Devil, meaning that people who sign up end up getting loads of email from pharma companies, some of which push them to particular products or make suggestive diagnostic inferences about the person. Seriously. And people who sign up don't know about any of this.
It's all about finding out if you are older or younger than your calendar age. Wow, neato!
It's got a connection to the Oprah Winfrey show, because her in-house TV doctor, Dr. Oz, helps market RealAge. RealAge is owned by Heart Digital Media, which is part of the Hearst Corporation which of course shut down the Seattle Post-Intelligencer last week, putting actual friends and colleagues out of work. Hearst, I love you so much!
"They are asked throughout the test if they would like a free RealAge membership. If people answer yes to any of the prompts, they become RealAge members, and their test results go into a marketing database."RealAge allows drug companies to send e-mail messages based on those test results. It acts as a clearinghouse for drug companies, including Pfizer, Novartis and GlaxoSmithKline, allowing them to use almost any combination of answers from the test to find people to market to, including whether someone is taking antidepressants, how sexually active they are and even if their marriage is happy.
"RealAge sends the selected recipients a series of e-mail messages about a condition they might have, usually sponsored by a drug company that sells a medication for that condition.
"'Our primary product is an e-mail newsletter series focused on the undiagnosed at-risk patient, so we know the risk factors if someone is prehypertensive, or for osteoarthritis,' said Andy Mikulak, the vice president for marketing at RealAge. 'At the end of the day, if you want to reach males over 60 that are high blood pressure sufferers in northwest Buffalo with under $50,000 household income that also have a high risk of diabetes, you could,' he said."
I simply love how invasive big pharma has gotten in our lives, so I'm going to sign up myself and see what kind of BS pharma sends me.
OK, so I filled out the test using a fictitious profile and checking off all the questions about worry and mental health diagnoses. My alleged real age came in at two years older than my profile's real calendar age. Ohhhh, I'm so scared. Here's what's ruining my life, according to the test:
"Older Not knowing your cholesterol levelsOlder Worrying too much
Older Not taking a daily aspirin
Older Having depression
Older Not knowing your blood pressure
Older Not flossing enough
Older Being a smoker
Older Not designating a driver
Older Driving too fast
Older Not sleeping enough
Older Not having air bags
Older Facing a lot of stress
Older Not getting enough vitamin C
Older Not eating enough whole grains
Older Not getting enough vitamin E
Older Not eating breakfast every day
Older Not getting enough calcium
Older Not eating your veggies
Older Not getting enough folic acid
Older Eating too much red meat
Older Not eating enough fruits
Older Not getting enough potassium
Older Needing to review your eating habits
Older Having a high BMI
Older Doing only the bare minimum
Older Neglecting your muscles"
Wow, that was fun. Now, let's see what super meds ads Big Pharma sends me, 'cuz I know they just want to help me. Yay!
Apparently, one thing making me younger, according to the test, is "Not taking any meds."
How much you want to bet that I get lots of suggestive material pushing me towards meds?
News came out yesterday via the WSJ's Health blog that the National Institute of Mental Health has announced that it's gotten $60 million from the federal stimulus package and is directing it to "Research to Address the Heterogeneity in Autism Spectrum Disorders," according to NIMH.
"Examples of research topics include developing and testing diagnostic screening tools for different populations; assessing risk from prenatal or early life exposures; initiating clinical trials to test early interventions; or adapting existing, effective pediatric treatments for older children, teens, and adults with ASD."
I'm all in favor of researching the hell out of autism spectrum disorders, but does anyone seriously believe that this $60 million will create new jobs and stimulate the economy? I don't. If anything, it'll redeploy already-well-paid researchers and their staffs from other projects into autism research projects defined by NIMH. I fail to see how that creates new jobs. I'm not hearing about mass layoffs of researchers.
I guess it falls into line with my initial suspicions when I first saw details of the stimulus plan a ways back--and that is that a fair amount of the $500 billion or so in spending (and borrowing from China) would go to priorities that can't create new jobs. For example, paying a portion of laid-odd peoples' COBRA. That won't suddenly create new health care jobs and won't create a job for the laid-off person, so it kind of defeats the stated purpose of President Obama's stimulus package (or Congress' or whomever's it is), which is to create jobs, and that bugs me.
Don't read into this that I am hostile to autism research. I'm not. I simply think it's something more properly addressed through the regular budget cycle.
I am a bit suspicious, however, of adapting "effective pediatric treatments" to older youngsters and adults. While I suppose some of that might go to various behavioral and learning therapies, I fear that a good chunk of it will go to researchers studying Risperdal--the lone approved autism medication for kids--and how to adapt that to adults. Wouldn't there already be plenty of evidence of its use off-label? Here's a 1998 study.
Perhaps I am too much of a skeptic, but there's something here that I just don't trust beyond the jobs issue. Then again, perhaps my suspicions are utterly misplaced.
At any rate, it will be interesting to see which proposals NIMH funds and if said fundage creates any new jobs.
Fascinating piece in the New York Times yesterday, which detailed a new study asserting that a significant thinning of the brain's right cortex is either a marker for depression or indicates a vulnerability to depression.
"The scientists conducted brain imaging of 131 individuals, including children and adults ages 6 to 54, about half of whom were considered at high risk for depression because of their family history and half of whom were in a low-risk group. Maps of cortical thickness showed significant thinning of 28 percent on average across broad expanses of the right cerebral hemisphere in the high-risk group, compared with the low-risk group, the paper reported."The cerebral cortex is the region of the brain centrally involved in reasoning, planning and mood, and thinning of the cortex may affect an individual’s ability to pay attention to and interpret social and emotional cues, scientists suggested."
Whether this thinning has a one-to-one relationship to depression isn't clear (and probably still wouldn't entirely supersede environmental factors) and it's not clear what the treatment implications would be since I don't think anti-depressants re-thicken a cortex. So where all of this leads is a bit beyond me, but it is an interesting bit of research.
I heard back from Forest Labs' outside PR person this morning and she provided me with citations for published studies of Lexapro and Celexa in adolescents that were used as the basis for approving Lexapro for major depression in 12 to 17 year olds.
One study appeared in the American Journal of Psychiatry in June 2004 and measured the effectiveness of Celexa not Lexapro. The study found:
"Additionally, at endpoint more citalopram-treated patients (36%) met the prospectively defined criterion for response than did placebo-treated patients (24%), a difference that was statistically significant."
That's not particularly impressive performance and probably barely crosses the threshold of statistical significance. What's more, the Celexa arm of the study involved only 44 adolescents, so this claimed efficacy and response was only achieved by 16 patients. That strikes me as a very small population upon which to hang, in part, a drug's approval.
A positive study of Lexapro in treating adolescent depression remains unpublished in a medical journal (so it's not gone through peer review yet), but was presented last year at the American Psychiatric Association's annual meeting as a poster. You can view the poster here.
Poster presentations are generally slim on details and this one is no exception. In it, the authors reported that the mean score (meaning average) on the Children’s Depression Rating Scale improved by 18.4 points in the placebo group and by 22.4 points in the Lexapro group. The poster contains no details on what percentage of patients in each group responded to placebo or Lexapro, so it's not possible to say what the effect size is for the drug, at least not until the full study goes through peer review and is published.
Here are the two failed studies, failed meaning that the drug did not outperform placebo:
Journal of the American Academy of Child and Adolescent Psychiatry, March 2006
Journal of Clinical Psychopharmacology, June 2006
So we have two failed studies and a positive study of Celexa with a very small effect size plus a poster presentation of Lexapro and that's what the FDA based its approval of Lexapro for teens upon. My guess is that this drug just barely squeaked through the approval gate, but that's one of those things the FDA will never tell the public. It's pretty clear that Lexapro/Celexa for teen depression sure don't have a ton of efficacy.
No matter where any of you stand on the pro-meds/anti-meds divide, I suspect that all of you are interested in drugs going through appropriate clinical trials for real psychological diagnoses, being appropriately and consistently vetted by the FDA, and, if approved, being labeled with appropriate warnings about side effects, as well as having clinical studies published in medical journals where one and all can assess the results. That sort of process has, in my opinion, broken down at the FDA, most recently with regard to the agency's recent approval of Lexapro for major depression in adolescents aged 12 to 17. I'm utterly baffled by the FDA's approval process for the drug.
First, I need to let you know that I reached out to both the FDA and Forest Labs' outside PR person (they don't have their own PR shop apparently), but got no answer from either. Classic. Then again, the FDA still owes me all kinds of answers to all kinds of questions.
Second, the FDA has once again gone and approved a drug for use in kids with only one positive clinical trial, a trial that remains unpublished (unless PubMed is fibbing), despite the FDA's longstanding policy of requiring two positive clinical trials of a drug for approval. Both the FDA and Forest might claim there were two positive studies, but only the first study referred to on the drug's package insert was of Lexapro. The second was of Celexa. Yes, the FDA is now letting pharma companies obtain approval of drug's using data from other, similar drugs.
Even worse, Lexapro had at least two failed clinical trials in adolescents. More on that in a bit.
Here's how the insert describes the first study (download it here; the relevant text is on pages 22 and 23):
"The efficacy of Lexapro as an acute treatment for major depressive disorder in adolescent patients was established in an 8-week, flexible-dose, placebo-controlled study that compared Lexapro 10-20 mg/day to placebo in outpatients 12 to 17 years of age inclusive who met DSM-IV criteria for major depressive disorder. The primary outcome was change from baseline to endpoint in the Children’s Depression Rating Scale - Revised (CDRS-R). In this study, Lexapro showed statistically significant greater mean improvement compared to placebo on the CDRS-R."
I cannot find this study published anywhere. Forest didn't respond to a request to provide information about where it's published. So it's unclear how many teens were involved in the study and exactly how much efficacy Lexapro had over placebo. What's more, there's no way for clinicians, teens and their parents to evaluate the drug's safety and side effect profiles, which strikes me as being necessary information.
Here's how the insert describes the second study:
"The efficacy of Lexapro in the acute treatment of major depressive disorder in adolescents was established, in part, on the basis of extrapolation from the 8-week, flexible-dose, placebo-controlled study with racemic citalopram 20-40 mg/day. In this outpatient study in children and adolescents 7 to 17 years of age who met DSM-IV criteria for major depressive disorder, citalopram treatment showed statistically significant greater mean improvement from baseline, compared to placebo, on the CDRS-R; the positive results for this trial largely came from the adolescent subgroup."
Citalopram is Celexa, which is also made by Forest. I'm not a pharmacologist, but from what I understand Celexa and Lexapro are quite similar compounds ("me too" anti-depressants as some have called them), although they were different enough for each to receive a patent. Why the FDA would approve a drug based upon extrapolated data from a different compound is beyond me. The FDA didn't respond to my request for comment. I've not been able to find where this study is published and Forest didn't respond to my request for information.
Here's how the insert describes the failed studies:
"Two additional flexible-dose, placebo-controlled MDD studies (one Lexapro study in patients ages 7 to 17 and one citalopram study in adolescents) did not demonstrate efficacy."
Well, at least, the FDA got Forest to note this in the insert.
So we've got a drug now approved for teen depression but only one of the four studies was actually able to establish the efficacy of Lexapro in teens, that study is unpublished (as far as I know) and this approval really calls into doubt the FDA approval process. Risperdal was approved for use in alleged pediatric mania in August 2007, based upon only one study. These sorts of approvals are a bad trend at the FDA, one that I hope its incoming commissioner and deputy commissioner work to rectify.
Absent some logical answers from the FDA and Forest on all of this, I'd say the Lexapro for teens approval is suspect. Parents, teens and clinicians should proceed with caution.
I wasn't planning on this being Lexapro theme day, but over the weekend I got the following comment in response to a post of mine on Lexapro's FDA approval for teens. The commenter authors the It's Me With OCD blog.
"I am curious to know the reason for the author's hostility towards giving Lexapro to adolescents? I apologize, I am new to your blog, so maybe the answer is here and I just haven't read enough yet."
Here are my primary reasons for being against--"hostility" is sort of overstating the case--Lexapro use in teens and kids (and, yes, even adults).
Suicide/suicidality: As established by the FDA's black box warning and a recent WHO study, both of which found quite a bit of suicide and suicidality connected with anti-depressants, especially in kids and teens. The evidence in adults is more mixed.
Withdrawal problems: while Lexapro isn't as rough in this regard as Paxil and Effexor, the reality is that it's not an easy drug to get off of and I don't particularly fancy giving brain zaps to teens. I went through them myself. Not fun.
Efficacy issues: Forest Labs hasn't published the efficacy data of Lexapro for major depression in teens, so it's impossible to know how well the drug allegedly works. Generally, when pharma companies aren't publishing efficacy data, they are hiding something.
Suspect FDA approval: see my post from earlier today.
Because anti-depressants represent America's quick fix culture: compare our approach with the UK's, where anti-depressants are mostly banned for anyone under 18 and where its own health care agencies (ie, NICE) recommend approaching depression treatment by going through watchful waiting, making sure patients are eating properly and exercising, psychotherapy and, then and only then, moving to anti-depressants. Since making that shift a few years ago in the nation's depression treatment policies, I've heard no reports of British teens going through a suicide epidemic. In fact, the suicide rate went down over there when most anti-depressants (except Prozac) were banned for under-18s.
We should be taking a similar approach in this country with depression.
Thanks for asking.
In a sign of just how bizarre things have gotten in DC, the FDA today approved Symbyax for treatment resistant depression, meaning depression that hasn't responded to two anti-depressants. Since anti-depressants don't work too well, that ought to be an easy market for Eli Lilly to market to. Symbyax is Lilly's longstanding Zyprexa/Prozac combo drug. So the FDA just approved a drug that's known to cause diabetes, epic weight gain and suicidality to treat depression. This makes so much sense!
Symbyax has never sold well, so it'll be interesting to see how this plays out.
Separately, the agency also approved Lilly's request to approve Zyprexa and Prozac in separate pills to treat bipolar depression and treatment resistant depression. Seriously.
At this point, I'm certain that you could get literally anything approved for depression.
Let the TV ads begin.
I feel the need for a deep sigh before writing this: on Friday JAMA published online an editorial laying out the journal's version of events surrounding a recent unreported conflict of interest connected to a JAMA-published paper on Lexapro, a correction published in the journal and coverage of the matter by the Wall Street Journal's Health blog. The editorial was written by Catherine DeAngelis and Phil Fontanarosa, the editor in chief and executive deputy editor of the journal and it marks a rather ill-considered attempt to cover their respective butts and kick Leo around for allegedly violating confidentiality of the journal's review process.
In it, the pair lash into Jonathan Leo, a neuroanatomy professor at Lincoln Memorial University in Tennessee, who brought the unreported conflict of interest to the journal's attention last fall and, then, wrote about it earlier this month on the BMJ's website. You read about the background here. Soon after the WSJ's David Armstrong wrote a piece on the paper's website, detailing the original study and unreported conflict and quoted DeAngelis as calling Leo "a nothing and a nobody." This all caused quit a stir in medical publishing circles--enough that several dozen people from the AMA read my writing on the matter.
Here's what the editorial authors say about the WSJ:
"One of us (C.D.) was erroneously reported to have referred to Leo as 'a nothing and a nobody.' As a faculty member (assistant dean of students) of a school preparing physicians who will care for patients, Leo certainly is 'somebody doing something' very important. To characterize Leo any other way would be erroneous and disrespectful, and this was never done by the editor in chief of JAMA."
So DeAngelis is accusing the WSJ's reporter of making up quotes, which is tantamount to accusing him of lying. That's a huge accusation and one hopes DeAngelis has some kind of proof to back it up (or is she just relying upon her sterling reputation as a mighty medical doctor?), since us journalist sorts take quoting people accurately very seriously, especially on sensitive matters, and it's an attack on our reputation/s to suggest otherwise absent proof--particularly since reporters almost always take contemporaneous notes of interviews and/or make audio recordings of interviews. It'll be interesting to see what kind of response the paper offers.
Beyond that issue, instead of sharply criticizing the Lexapro study author who had received monies from the drug's maker (Forest Labs) but didn't report them in his NIMH-supported study, the JAMA editorial alleges that Leo committed an ethical breach for going to the BMJ in early March. Since the initial article wasn't Leo's what possible ethical contract could he have with the journal? Since the journal didn't ask him to keep his yap shut while it was investigating the allegation, what breach exists? None. The journal is also critical of Leo for informing the press (namely, the New York Times, the WSJ and me) about all of this, claiming that one and all need to stand-off and let the journal do its own "rigorous" investigation. Leo informed the journal of the conflict in mid-October 2008. It wasn't until the end of January 2009 that the journal had in hand a letter to the editor from the study author, 'fessing up to the unreported conflict. Instead of letting Leo know that the investigation was over and that he could wait for further news in the near future, the journal didn't contact him and instead let him operate under the impression that JAMA wasn't rooting out the conflict. It's the journal's fault that it didn't keep Leo in the loop, which it easily could've done and avoided this entire dust-up. But then I am a journalist and love me some dust-ups.
BTW, why is it that when doctors investigate something it's always cast as deeply time-consuming and "rigorous" even if the matter at issue takes about five minutes to figure out through a Google search? I know doctors feel a huge need to preserve the public's view of them as being god-like in all things and at all times, but the journal's claim that it takes so long to do what you and I can figure out in mere minutes is laughable.
What isn't laughable is that from here on out JAMA claims:
"The person bringing the allegation will be specifically informed that he/she should not reveal this information to third parties or the media while the investigation is under way...."
First, I doubt that the AMA can make that stick legally, although I'm sure DeAngelis can try and intimidate doctors into complying. But what if an issue is brought to its attention by a member of the general public or the media? There's no way JAMA and the AMA could impose a gag order on them. Second, the journal is now setting a policy that gives researchers who publish in its pages greater protections than cops being investigated for excessive use of force. Why is it that the medical profession--and the AMA in particular--is always so protective of its members even where they've committed substantial breaches of trust with other doctors and member of the public who rely upon them for accurate and unbiased science?
You've got to wonder.
This is all very sad to pass along, but news is out that Nicolas Hughes, the son of poets Sylvia Plath and Ted Hughes, killed himself in Alaska, according to the Times of London. He was 47 years old and was a professor at the University of Alaska at Fairbanks. Hughes hanged himself on March 16, 46 years after his mother, Plath, gassed herself to death. Hughes' father died in 1998.
Sad.
News is out that the FDA today approved Lexapro, made by Forest labs, for the treatment of major depression in adolescents aged 12 to 17 years old. The drug will of course carry the suicidality black box warning.
Forest Labs has been in the news lately over accusations that it off-label marketed Lexapro for use in kids and paid kickbacks to doctors, a scandal that also includes a Harvard child psychiatrist who got $750,000 to help the company in its efforts.
I simply cannot wait to see what studies the FDA thought were of sufficient quality to approve the drug for kids.
In a deposition in a lawsuit against J&J/Janssen, controversial Harvard child psychiatrist Joseph Biederman testified under oath and was asked what rank of professor he is at Harvard. His answer is revealing about more than Biederman. (Via the In Vivo blog.)
Lawyer: "What rank are you?"Biederman: "Full professor."
Lawyer: "What's after that?"
Biederman: "God"
Lawyer: "Did you say God?"
Biederman: "Yeah."
Is this how Harvard profs see themselves? If it is, it sure explains a lot about the financial crisis this country faces because Wall Street is basically the post-grad rumpus room for elites who went to Harvard and other Ivy League schools, or who taught at them. Larry Summers? Harvard. President Barack Obama? Harvard (and Columbia). President George W. Bush? Harvard (and Yale). Timothy Geithner? Dartmouth.
The list is endless and I think Biederman is basically expressing the world view of how many Harvardites and Ivy Leaguers see themselves--infallible, God-like, better than you, step aside and hand me my entitlement. Exactly the kinds of Ivy League snots I had to deal with in grad school at UC Berkeley. I so enjoyed crushing them on a regular basis.
The reality is that a fair number of these folks aren't so smart and are first-class screw-ups surviving on arrogance and attitude. Let's just hope President Obama is better than the rest of them.
Biederman is under investigation for loads of conflicts of interest between himself and various pharma companies and there's a whole load of background on him here.
As noted elsewhere today, I've obtained a copy of Seroquel Study 15 which was conducted in the mid-1990s and which AstraZeneca suppressed and did not submit anywhere for publication, as the Washington Post and others have reported. The study was before Seroquel was approved by the FDA, was completed in 1996, and sought to measure Seroquel's efficacy at treating psychosis versus Haldol.
After reading a portion of the very lengthy study, it's obvious why AZ didn't want this study published. It established that Seroquel wasn't a very efficacious antipsychotic at all with anywhere from 53 percent to 65 percent of patients in different Seroquel study groups withdrawing from the clinical trial due to psychotic relapse. That compares with 30 percent of Haldol patients who relapsed during the trial. Study 15 was submitted to the FDA as part of the company's application for the drug, which was approved by the FDA in 1997.
I've made the relevant withdrawals portion of the study available here, including Study 15's cover pages. It's three pages, but a slice of Study 15's 3,459 pages.
Drugs are approved if a company can provide two positive clinical trials of a new drug demonstrating its efficacy and safety over placebo and/or another drug of known efficacy. The FDA obviously had possession of Study 15 and with its feeble results, you have to wonder how the hell this drug ever got approved. Obviously, AZ had some positive studies for the drug, but you have to wonder how it could be so lousy with the Study 15 group and turn out to be positive-enough-for-approval later.
Later independent studies such as CATIE showed that the drug didn't work for 84 percent of patients.
I've obtained a copy of Seroquel Study 15, which AstraZeneca never published. It's a study of Seroquel's use in treating psychosis versus Haldol, finished in 1996 and submitted to the FDA as part of Seroquel's initial approval for use in treating schizophrenia. The results for Seroquel were not impressive. The drug was FDA approved in 1997.
I am now making it available to the public with one caveat: it is 43 MBs and amounts to 3,459 pages, many of them deeply technical. I'm already well over my site's bandwidth limit for the month and am being hit with overage charges due to other Seroquel documents I've made available to the public. I simply cannot handle tons of people downloading this study until the first of the month. I'll see if I can put together an abridged version of the study without all the technical details at some point in the near future.
So here's the deal for now: if you are a mental health researcher or clinician of any kind and you want to see the study, send me an email and I'll provide you with a link so you can download the study and do as you wish with it. If you are a journalist, send me an email and we'll work something out.
The New York Times is reporting that controversial Harvard child psychiatrist Joseph Biederman was selling J&J/Janssen on results of clinical trials in children of its antipsychotic Risperdal and its stimulant Concerta in advance of conducting the actual studies. Biederman is of course the godfather of the alleged bipolar child diagnosis and took oodles of money from J&J and other pharma companies, and is under investigation by Sen. Charles Grassley for possible violations of federal research rules regarding conflicts of interest and by Massachusetts General Hospital. You can read my Biederman collection here.
This stuff is amazing.
"The psychiatrist, Dr. Joseph Biederman, outlined plans to test Johnson & Johnson’s drugs in presentations to company executives. One slide referred to a proposed trial in preschool children of risperidone, an antipsychotic drug made by the drug company. The trial, the slide stated, 'will support the safety and effectiveness of risperidone in this age group.'"Dr. Biederman was the lead author of a trial published last year concluding that treatment with risperidone improved symptoms of attention deficit and hyperactivity disorder in bipolar children."
In essence, Biederman was telling the company that he'd turn out a study that was positive for the drug in advance of conducting the actual study. That's quite the scientific method he's got there and it ought to make the FDA and everyone else deeply skeptical of any Biederman study submitted to the agency for the drug's pediatric bipolar disorder approval.
Biederman also sought to help out J&J's Concerta, an ADHD drug:
"One set of slides in the documents referred to “Key Projects for 2004” and listed a planned trial to compare Risperdal, also known as risperidone, with competitors in managing pediatric bipolar disorder. The trial 'will clarify the competitive advantages of risperidone vs. other neuroleptics,' the slide stated. All of the slides were prepared by Dr. Biederman, according to his sworn statement."In 2005, Dr. Biederman was the lead author of a study comparing Risperdal and Zyprexa, made by Eli Lilly. The study concluded that Risperdal improved subjects’ depressive symptoms but that Zyprexa did not.
"A slide listing 'Key Projects for 2005' mentioned a planned study in adolescents of Concerta, a stimulant manufactured by Johnson & Johnson. The study will 'extend to adolescents positive findings with Concerta in A.D.H.D. N.O.S. in adults,' the slide said, referring to unusual cases of attention deficit hyperactivity disorder.
"In 2006, Dr. Biederman was co-author of a study showing that children given Concerta for a prolonged period did not have reduced growth, allaying a significant concern about the medicine."
The paper quotes an ethicist as saying this evidence casts another "shadow" on Biederman's work. I'd say it slams the door shut.
The St. Paul Pioneer Press has a fine article out today detailing how one University of Minnesota psychiatry professor, Charles Schulz, claimed that Seroquel's performance was superior to older drugs like Haldol when in fact the research data he was working with showed Haldol to be more efficacious. Schulz made this claim in 2000. From 2002 to 2007, he receieved $112,000 in fees from AstraZeneca, the drug's maker, plus about $450,000 from Eli Lilly, the paper reports.
The details of this are stunning, so read the article and remember that the anonymous blog referred to in the paper's account of Schulz, who defends his work, is none other than Clinical Psychology and Psychiatry: A Closer Look, authored by none other than CL Psych, which broke the news around Schulz on March 2. And that news came out of the Seroquel documents, which CL Psych got from this website.
Check out how the paper attributed to Cl Psych:
"An Internet psychiatry blog first raised questions March 2 about the research Schulz presented at the APA conference and why it lacked any of the company's findings."'It raises troubling questions when an independent academic author presents results that are in direct opposition to the underlying data,' wrote the blogger, an anonymous academic."
I've never before seen a paper attribute to an anonymous blog, except for some of those satirical blogs such as the one allegedly detailing Steve Jobs' life.
Meanwhile, AZ spokesman Tony Jewell issued this statement, which says in part:
"AstraZeneca believes the totality of the science around Seroquel – including company-sponsored studies, research sponsored by the federal government, and physician experience – confirms it is an effective and appropriate treatment choice for patients with serious mental illness."
Would AZ like to include unpublished studies and buried studies in the "totality of the science around Seroquel?" Or is the company planning to make Study 15 available to the public?
Joel Kauffman is an emeritus chemistry professor at the University of the Sciences in Philadelphia and in an article in the current Journal of American Physicians and Surgeons he does everything but call SSRIs--Prozac, Paxil, Zoloft, Luvox, Celexa, Lexapro--unsafe at any speed. You can get a pdf of the article here.
From Kauffman's conclusion:
"Antidepressants are extraordinarily difficult to assess for risks or benefits in trials."At most, 11%–30% of patients with depression or related conditions who take SSRIs actually benefited beyond the placebo effect on normal doses. Of the perceived benefit, 32%–67% can be attributed to the placebo effect.
"Adverse effects, mostly dose-dependent, will appear in up to 75% of patients on normal doses. Of these, studies suggest that suicidality will be observed in an additional 2%–13% (1 in 50 to 1 in 8) of patients on normal doses, beyond what is seen on placebo or many non-SSRI antidepressant drugs. This is sufficiently frequent that a typical prescribing physician should observe examples in routine practice.
"The actual suicide rate could be about 123/100,000 (1 in 813) higher in patients on SSRIs than in those on tricyclics or placebo. Studies show that many more suicides are on normal doses of SSRIs beyond what is seen on placebo or many non-SSRI antidepressant drugs."
If the placebo effect is as large as Kauffman asserts, then the actual effect size of SSRIs runs from about 10 percent to 20 percent--pretty darn small. The adverse events and suicidality data speak for themselves.
I know I'm far from the only reader of this article who appreciates the fact that some doctors are finally pressing for caution in the use of SSRIs and anti-depressants. It's refreshing and long overdue.
There was an odd article in yesterday's Washington Post concerning suppressed Seroquel studies. It appeared on A-1 and was authored by Shankar Vedantam, who usually does good work. But this time out, not so much.
First, the story is old news and contains little that hasn't been previously reported by myself, Bloomberg, the St. Petersburg Times and some other media outlets and blogs. Short story: Study 15 shows patients getting super fat on Seroquel; company knows it has problems with the drug; FDA approves the drug for schizophrenia in 1997; AstraZeneca never has study 15 published, but pushes into the public realm studies showing that the drug doesn't cause weight gain; later evidence shows that patients gain tons of weight and develop diabetes on the drug. That's it. Nothing new there, except that it's on A-1 of the Post.
Second, the paper gave the article the headline "A Silenced Drug Study Creates An Uproar." Nowhere in the article is there anyone quoted calling AZ's tactics outrageous or hinting at any uproar of any kind. In fact, aside from a teensy quote from Columbia University's Jeff Lieberman and quotes from AZ's Tony Jewell, no one is quoted in the article, which is just odd as hell for a longish front page story in a daily newspaper, especially one asserting an "uproar."
It makes you wonder if the author wasn't talking to some sources who claimed an uproar, but an editor hacked their quotes from the article, which would also be damn odd.
I don't often comment on this site about famous people who've died, but as most of you know the wonderful actress Natasha Richardson died yesterday, following a skiing accident on Monday. She was 45 and had won a Tony award, appeared in many films and was married to Liam Neeson. Her mother was Vanessa Redgrave and, of course, her aunt was Lynn Redgrave.
Much of the press coverage of Richardson's death notes that she was a very real person who didn't take herself too seriously, despite coming from the royal family of theatre (her grandfather was Sir Michael Redgrave, as great a stage actor as Olivier). I didn't know Richardson, but I did know her aunt. Lynn Redgrave was in a production of Chekov's "The Cherry Orchard" at La Jolla Playhouse in 1990 (here's a production picture), where I worked as an accounting clerk at the time, about as low on the rung as anyone in the place, but since I wrote the actors' paychecks I got to know several of them (some famous, some not; some cool, some not).
I'll never forget how at the cast party for the play, I was sitting alone on a couch at the director's house, stoned on Prozac (I'd begun taking it a few months before) and feeling very lost. Suddenly, Lynn Redgrave (Georgie Girl for God's sake) sat down next to me and began chatting me up for oh, like, a half hour (we also talked several other times during the production's six-week run). I can assure you that she is one of the most charming, real people on the planet and if Richardson was anything like her, then the world is poorer. I'm simply shattered for her family. Last evening, I sat at home with the strangest feeling of ennui. It's all just so sad.
The other thing I find so disturbing is that Richardson's fall was apparently quite minor and it's not even clear to me that she struck her head on the snow. I've been skiing hundreds of times and have fallen hundreds of times, sometimes at very high speeds. I've never worn a helmet skiing. Aside from one concussion after crashing from a risky jump, nothing ever happened to me. Richardson falls once and she's dead. That rattles me in ways I cannot explain.
Sometimes, life is even more fragile than we think.
My back is acting tricky again, so I need to lay off the computer for a bit to keep from winding up in a bad place (a la early January). More from me later today, or so I hope.
If you are in the DC area, Alison Bass (author of "Side Effects") will be doing a talk at GWU later this afternoon. Details are here.
The FDA psychopharmacology advisory committee is holding hearings on AstraZeneca's applications to have its antipsychotic Seroquel approved by the FDA for one of three depression indications (including long-term maintenance) and anxiety. If you want to make your voice heard on this, there's information below on how you can do so. It is significant that the FDA is having the committee review the applications and offer its opinion instead of just approving the drug itself.
Keep in mind that the committee is comprised mostly of psychiatrists and other researchers and that the committee is only making a recommendation to the full FDA. The committee does not approve a drug. Only the FDA proper can do that.
You can either testify in person or in writing. It's 2009, but the FDA still makes no provision for testimony by phone or webcam, which strikes me as being very 1965 on the agency's part, but whatever. To testify in person, you must contact Yvette Waples, at (301) 827-6790 or by email at Yvette.Waples@fda.hhs.gov by the close of business on March 18. That's tomorrow. The hearings are set for April 7 and April 8 in Silver Spring, MD.
I'll be testifying in writing later this week.
There are three ways you can submit written testimony to the committee. One is by submitting an email to Yvette.Waples@fda.hhs.gov. Or you can fax your testimony to (301) 827-6778. Or you can mail your testimony to:
Yvette Waples, Center for Drug Evaluation and Research (HFD–21), Food and Drug Administration, 5600 Fishers Lane (for express delivery, 5630 Fishers Lane, rm. 1093), Rockville, MD 20857.
The deadline to submit written testimony is March 27.
So I woke up this morning in hopes of finding a copy of the final edition of the Seattle Post-Intelligencer, but, alas, no copies were to be found. If you are in Seattle and have an extra copy, shoot me an email please. I want a copy of that edition in the best way possible.
In other news, a couple of former P-I reporters have started their own blogs. Here's Robert McClure's Dateline Earth and Rebecca Denn's Eat All About It.
As many of you know the FDA's psychopharmacology advisory committee is holding hearings on AstraZeneca's request to have the agency approve Seroquel for three depression indications and generalized anxiety disorder. The committee wants to hear from the public and here's some written testimony submitted to the committee that was passed along to me.
"I was prescribed 300 mg.seroquel in 2000 for sleep problems. I gained 75 pounds in 6 months. I developed diabetes. I went through profound withdrawals when I inadvertently missed a dose and had to be hospitalized. The withdrawal caused psychosis which was attributed to a new diagnosis rather than to the drug. I lost all my teeth due to dry mouth. I developed cataracts. I had constant intrusive suicidal ideation. I had akathisia, difficulty swallowing and severe muscle cramps. I lost my critical thinking ability, the ability to make decisions and generally access my 'executive functioning.' Because the medical establishment refused to accept that their "therapy" could be poisonous they continued me on this drug for 8 years and added new drugs to cover up the symptoms of massive endocrine dysregulation."The use of these classes of drugs must be sharply curtailed. These drugs must not expand the wealth of shareholders as they destroy the bodies and brains of the most vulnerable classes of people in our society. Psychoactive chemicals 'work' by disabling nerves, not by restoring their normal function. Emotions cause chemical changes in the brain not the other way around. No-one knows how the staggeringly complex interactions of neurons actually work. The neurotransmitter theory is based on observing the brain damage caused by psychoactive chemicals, not on any understanding of how a normal brain operates. Time and human support are the safest and most effective means for getting through difficult emotional challenges."
I'll have more later today on how you can submit testimony or testify in person.
Everyone knew this was coming: Tuesday's edition of the wonderful Seattle Post-Intelligencer will be its last as a newspaper, ending a 140-year plus run. Seattle now becomes a one-newspaper town, although the financial status of the Seattle Times is pretty shaky.
The P-I will continue as an online-only product, but with only 20 reporters (likely younger ones who can handle the pay cut) and editors, meaning that about 130 people are being laid off by the paper's publisher, Hearst. I know some of these people, just talked to one of them in fact.
I'm so crushed, not just for the paper, but for the impending end of print journalism in the US. My career is over, so are those of many thousands of others and the Internet really isn't a replacement. Meanwhile, the federal government is letting AIG pay millions in bonuses to Wall Street crooks.
It all makes sense!
Late last week, Jim Edwards at BNET.com had a fine piece detailing some of the sex-for-Seroquel-studies emails which I first reported on last month. It appears, as I reported back then, that Wayne Macfadden, AstraZeneca's former US Seroquel medical director, used sex (and bondage even) to get competitive intell on Abilify and, yes indeed, even suggested prescribing Vicodin, a narcotic pain killer, to a ghostwriter with Parexel MMS. I simply love how Big Pharma does business and I love the fact that the FDA continues to blow off my questions as to whether it has any qualms about its approval of Seroquel for bipolar depression (in 2006) since Macfadden was in charge of the studies, authored some of them, and clearly was putting out questionable research. You'd think the FDA would want to give it all a little look-see, but no. The FDA doesn't care.
The details of the emails speak for themselves. Apologies for the formatting, which I cannot get fixed. The "Q" is a plaintiff's attorney and the "A" is Macfadden:
Q: Do you believe, in your roles as the senior director of clinical research, you acted with honor, integrity and ethics? A: In my professional responsibilities, yes. Q: Why are you qualifying that answer, sir? A: There are things in my personal life that I have regrets about.
Here comes the affair with a psychiatric researcher at the Institute of Psychiatry, King's College, which has also refused to answer questions.
Q: Sir, the truth of the matter is, you were having an illicit sexual affair with REDACTED weren’t you? A: I was having a personal affair with REDACTED yes. Q: You were having an intimate affair with REDACTED and you were doing it on company time, and you were doing it when you were a researcher for AstraZeneca, correct? A: I would see REDACTED Usually, to the best of my recollection, it was off hours, but I can’t state for sure if that’s all true. Q: It wasn’t all true was it? Y’all arranged to meet at conferences on the company dollar, right? A: We would meet occasionally at conferences, yes. Q: And in hotel rooms that the company paid for, AstraZeneca paying for both hotel rooms, right? A: My travel was generally reimbursed by AstraZeneca, yes.
Now for Abilify and attempted corporate espionage:
[Lawyer reads from an email]Q: Let’s read it. Hey, “Babe, just as a friendly reminder, as requested, to obtain info from BMS re bipolar depression, specifically, when they plan to complete their trials & when they plan to file in the U.S….”… That’s insider competitive information from Bristol-Myers Squibb on the product Abilify’s filing for bipolar depression, correct?A: To the best of my knowledge I never received information from REDACTED or anyone else about this.
Now for Ms. Parexel:
Q: By the way, you were having an illicit sexual affair with REDACTED too, weren’t you? A: Yes. Q: She’s another person who was involved in studies, this time at Parexel, right? A: She was an employee at Parexel, which is a company was involved with the publication process, yes.Q:… because of the relationship that you had with this researcher REDACTED the executive over at Parexel, that’s what got you in the position where you were given an opportunity to resign, right?
A: AstraZeneca confronted me with personal emails. To my recollection they were between REDACTED and I, and they eventually offered me the opportunity to resign. That’s it.
And, now some of an email from the IOP researcher to Macfadden:
Jan. 13, 2006, from REDACTED to MacFadden: "Just a quickie as I’m writing frantically at my desk trying to finish my quetiapine paper; hope your day is going well. Was wondering if you have access to a paper (you won’t like it much because it says that quetiapine isn’t as effective as olanzapine or risperidone!!!)…In fact I will probably need to be punished for even looking at it.”MacFadden’s Reply:
"Hi, doll, logged off early to hang with the kids … hope this is not getting to you too late!!! And yes, you will be punished (in the usual fashion!) when I see you … but perhaps more harshly this time!!!"
In the deposition, MacFadden said this:
A: I believe this is a reference to sexual play.
Q: Bondage?
A: Perhaps.
What a sexy guy Macfadden is. This is how research is getting done people. Isn't it amazing? Isn't it amazing that the FDA, the IOP, Parexel and the journals where Macfadden published on Seroquel all don't care and none of them will answer questions?
I'm sorry to keep harping on this sort of thing, but pharmaceutical research and its intersection with academia is so corrupt that...that I really don't know what to say anymore.
Macfadden resigned from AZ in 2006. The rumor mill tells me that he now works for J&J/Janssen in some capacity, perhaps as the chief bondage officer in charge of Invega studies.
There's a new interview out with Elizabeth Wurtzel, whose writing I despise, who even though she writes very little these days and is now practicing civil law--meaning she didn't pass her bar exam, awwwwwww--she still gets interviewed all the time because she's famous and the New York press likes nothing more than it likes a vapid child of privilege who was famous once and whose crap still gets published from time to time (kind of like Brett Easton Ellis). Wurtzel fits the media's needs to a T.
She says a few things about mental disorders amidst all her other loopy talk:
"When I was your age, or a little younger, you could tell doctors that you feel chemicals bouncing around in your head, and they’d say ‘no, you just need twenty years of therapy.’ They really didn’t give out medication until you were already in the hospital. But now you have the opposite problem, that you need therapy, and people just hand you medication. Both things are kind of a way of not taking the problem seriously. Like suddenly all these people are bipolar. That’s a really rare problem, to be bipolar. But whatever medication they have that works for something, they attach a disease to, because these diseases are all so similar, frankly."At the same time there are people who need medication who are now getting it, so I think it’s a net gain. And then there are even people who just want medication, and who can say that it isn’t fine? If it’s not hurting them and they feel better, is there just a moral qualm about that?"
Oh, Liz, you are a sage.
Yes, you read that right: AstraZeneca, maker of Seroquel, is tossing everything it has at legal cases claiming the company's drug gave people who took it diabetes. Back when Eli Lilly was initially defending itself against similar claims involving Zyprexa, Lilly claimed that mental illness caused diabetes, but that bogus claim only landed the company with billions in settlements. Now, AZ's lawyers are claiming that one patient's ethnicity caused her diabetes, not Seroquel:
"In the case of [Nina] Scaife, for instance, lawyers argued that factors including her obesity and African-American ethnicity had already elevated her risk of diabetes before she took Seroquel."'I can't see how the plaintiffs can win,' said Michael Kelly, a Wilmington-based partner in the law firm McCarter & English, who's slated to try the Scaife case for AstraZeneca."
Wow, I'd love to see jurors' faces when AZ tries that argument out in court, possibly sometime in June when it's scheduled to go to trial. I'd heard through the grapevine that AZ's British overlords want these cases fought tooth and nail, and it appears that that's what's going on--the company has already racked up $500 million in legal bills, and is making wild arguments like the one above in order to defend its $4.4 billion a year drug, which it now wants the FDA to approve for depression and anxiety.
Yesterday, I reported on a dustup between Jonathan Leo, a neuroanatomy professor at Lincoln Memorial University in Tennessee, and Catherine DeAngelis, editor in chief of JAMA and an alleged foe of conflict of interest in academic publishing. Leo and his colleague Jeffrey Lacasee, an assistant professor of social work at Arizona State University, had raised a ruckus with the journal for an unreported conflict in a study of the use of Lexapro and psychotherapy in post-stroke patients published in JAMA last year. The lead author had gotten money from Lexapro's maker in the past, but didn't report it to the journal.
The Wall Street Journal's health blog is now reporting some details of Leo and JAMA's exchange and it sure makes the journal look stupid, especially considering that Leo and Lacasse were helping to journal hew to its mission on rooting out conflicts of interest:
"Leo says he received an angry call from JAMA executive deputy editor Phil Fontanarosa last week, shortly after Leo’s article was published on the BMJ Web site. 'He said, "Who do you think you are,"' says Leo. “He then said, ‘You are banned from JAMA for life. You will be sorry. Your school will be sorry. Your students will be sorry.” Fontanarosa referred a call for comment to a JAMA spokeswoman, who said Leo’s retelling of the conversation was 'inaccurate.'"'He did talk to the guy, but he said he didn’t threaten him,' the spokeswoman said. 'It was something along the lines of not setting a good example for students. He didn’t say he would be banned. He didn’t think Leo was taking a very good approach by taking this confidential process within JAMA out to media and another medical journal. It’s just not the way things are handled here.'
"The call from Fontanarosa was followed up by ones from JAMA editor-in-chief Catherine DeAngelis to Leo’s superiors, Leo says. He said she asked his superiors to get him to retract his article in the BMJ. Leo says he decided to call DeAngelis directly to find out what, in particular, she might be objecting to. He said she was 'very upset' but didn’t make specific complaints about the article.
"In a conversation with us, DeAngelis was none too happy to be questioned about the dust-up with Leo.
"'This guy is a nobody and a nothing' she said of Leo. 'He is trying to make a name for himself. Please call me about something important.' She added that Leo 'should be spending time with his students instead of doing this.'
"When asked if she called his superiors and what she said to them, DeAngelis said 'it is none of your business.' She added that she did not threaten Leo or anyone at the school."
You begin to wonder who the hell the folks running JAMA think they are and you have to wonder if they were actually going to force the study author to reveal his conflict, as he did in JAMA earlier this week, or if JAMA was pressed to do so by what Leo and Lacasse published on the British Medical Journal website last week.
Either way, I hope JAMA's board looks into this affair, which seems to be way out of order.
I was utterly pooped last evening, likely due to a combination of the time change and hard work the last few weeks, so I'll be late today with posts. I'm too tired to write anyway and it wouldn't be pretty to read (not that it ever is!).
Have a nice Friday the 13th till I catch up with you all.
An ironic and odd tale has come to my attention, one involving the editor-in-chief of JAMA, Catherine DeAngelis, researchers who failed to report conflicts of interest to the journal on a Lexapro study, and DeAngelis calling one other researcher, who brought the unreported conflict to the journal's attention, by phone to chew him out. What's ironic is that DeAngelis has made much hay out of her efforts to eliminate conflicts of interest from medical studies and yet there she was picking up the phone to call Jonathan Leo, an associate professor of neuroanatomy at Lincoln Memorial University in Tennessee, and give him hell when she should have been thanking him for identifying an unreported conflict of interest that got past reviewers and editors at JAMA. That's as odd as odd gets. I'll come back to DeAngelis in a bit, because the science piece of this story is almost as odd.
I contacted JAMA to interview DeAngelis, but did not get a reply from her.
The story begins last May when JAMA published a study by Robert Robinson, a psychiatry professor at the University of Iowa, and others. Their work was funded by NIMH. In the study, the researchers examined the effects of Lexapro, Problem Solving Therapy and placebo on depression in post-stroke patients without depression for one year. The results were 8.5 percent of Lexapro patients developed depression, 11.9 percent of the PST patients developed depression and 22.4 percent of placebo patients developed depression. Oddly, the authors didn't address the statistical significance of the small difference between Lexapro and psychotherapy on post-stroke depression, even though they did examine the significance between medication and placebo. Remember that point.
Soon after the study appeared, the benefits of post-stroke treatment with Lexapro were being touted in the press. "Study: Antidepressants help stroke victims," declared USA Today. Robinson told the paper, "I think every stroke patient who can tolerate an antidepressant should be given one to prevent depression." Tom Insel, NIMH director, pretty much pooh-poohed the psychotherapy results, telling the paper, "We find most people would rather just take a pill."
Robinson told the AP this: "I hope I don't have a stroke, but if I do, I would certainly want to be placed on an antidepressant."
Robinson's claims are significant because he is claiming that all stroke patients should be placed on an anti-depressant--regardless of whether or not they have depression--as a preventative measure, but he made no mention whatsoever of PST as being a similarly effective. Approximately 780,000 Americans have a stroke each year. So that kind of omission represents something of marketing pimpery for Lexapro's maker, Forest Labs, especially since PST had been shown to be as effective as Lexapro and that the difference between the two modalities didn't seem to be statistically or clinically significant.
Last October, JAMA published a letter by Leo and Jeffrey Lacasse, an assistant professor of social work at Arizona State University, challenging the omission:
"The reported incidence data showed that the rate of depression was approximately the same in both escitalopram (8.5%) and problem-solving therapy (11.9%) groups. This difference does not appear to be either clinically or statistically significant. The authors could enhance the value of their research by providing this additional piece of analysis."
Robinson and his colleagues replied in the same issue of JAMA. I don't have access to the full text of their response, so here's how Leo and Lacasse characterize their response:
"[A]cknowledgement from the original authors that indeed the difference between therapy and medication was not statistically significant."
So, in essence, PST and Lexapro had the same effect in post-stroke depression treatment, even though there are vast differences in the side effect profiles of psychotherapy and SSRIs and in the corporate interests regarding Lexapro and psychotherapy. But that wasn't the story the media and Robinson told the public. Given how well known are problems such as withdrawal from anti-depressants, suicidality induction and, as recently revealed by the Nurse's Health Study, sudden cardiac death in women connected to anti-depressant use, you'd think the media and Robinson might want to give psychotherapy a wee bit of credit, but no.
In the May 2008 study, Robinson reported receiving monies from Hamilton Pharmaceutical Company (now a subsidiary of Neuren Pharmaceuticals), Avanir, Lubeck and Pfizer.
Not long after the October 2008 letter exchange, Leo and Lacasse began examining Robinson's recent publications and found that in other publications Robinson had reported receiving monies from Forest Labs--which of course makes Lexapro. Leo told me in an interview yesterday that he then made JAMA aware of the incomplete disclosure by Robinson in November 2008.
On March 5, Leo and Lacasse published a piece on the website of the British Medical Journal, detailing this odd affair. Leo told me that the same evening he was contacted by phone by an editor at JAMA (he doesn't recall their identity) and was told that JAMA wasn't happy that he and Lacasse had written about Robinson's failure to report a major conflict. Leo says that the editor didn't tell him why they were upset with the BMJ piece and didn't dispute any of the facts in the piece.
That's when things got even more interesting.
The next day, March 6, Leo got a phone call from Catherine DeAngelis, the editor-in-chief of JAMA. Leo told me that he had never heard from DeAngelis before. He didn't want to discuss the details of what she said, since DeAngelis is quite important in medical circles--or so say my sources--and she wouldn't be a good person to have angry at you. Leo told me that DeAngelis was "upset" and that her conversation with him left him "quaking in my boots." Leo told me that DeAngelis didn't dispute the facts of the BMJ piece.
Feel free to read into DeAngelis' call whatever you want. My own view is that she was likely angry and was calling Leo to intimidate him. She didn't call Lacasse. DeAngelis didn't return a request for comment. A spokesman for JAMA told me in an email that "It is unlikely that she will respond as she would consider her conversation with Jonathan Leo confidential information."
He didn't answer my further question of how regularly DeAngelis picks up the phone to express her upset to researchers. JAMA also didn't answer questions about whether Forest purchased article reprints of the May 2008 study from JAMA. That's an important point because when a pharma company has its product appear favorably in a medical journal, they invariably purchase glossy reprints from the publishing journal in order to distribute them to doctors. And what pharma company wouldn't want to waive a positive study of its soon-to-be-off-patent drug in the face of every cardiologist and internist in the country? It's well-known that Forest is a very aggressive company when it comes to marketing as established by last month's revelation that the feds had filed a complaint against Forest for allegedly illegally marketing Lexapro and Celexa (which it also makes) for use in children even though the drugs are not approved for use in children.
Making matters more interesting is that yesterday, JAMA published a letter (pdf) from Robinson and one of his study colleagues, fessing up to Robinson getting money from Forest Labs in the past and to Stephan Arndt, a co-author, failing to disclose that he had owned Pfizer stock in 2005 and 2006. It reads, in part:
"We would like to apologize to the editors and readers of JAMA for our failure to report these financial disclosures in our article. Although Forest Laboratories provided honoraria and expenses through their speakers’ bureau for Dr Robinson, neither the design, analysis, or any of the expenses (including the cost of medications) of our study were supported by monies, materials, or any intellectual input from Forest Laboratories. We sincerely regret this lack of transparency in our initial disclosures that resulted from these errors of memory." (Emphasis mine.)
Errors of memory is an interesting explanation. JAMA didn't respond to my question as to whether Robinson and Arndt contacted the journal recently after they remembered their incomplete disclosures or if JAMA contacted them after Leo and Lacasse brought Robinson's conflict to JAMA's attention.
I find it difficult to understand why DeAngelis would be upset with Leo since he had aided the journal is setting the record straight on whatever conflicts the Lexapro study authors had and on establishing that the authors found psychotherapy as effective as Lexapro. I find it tough to fathom in light of various hosannas that are regularly sung to DeAngelis, such as this one last year from the American Academy of Child and Adolescent Psychiatry:
"Catherine D. DeAngelis, M.D., M.P.H, is the recipient of the American Academy of Child and Adolescent Psychiatry (AACAP) Catcher in the Rye Humanitarian of the Year Award. Dr. DeAngelis is Editor of the Journal of the American Medical Association (JAMA) and is credited with enforcing one of the most rigorous disclosure policies of any academic publication."Dr. DeAngelis was chosen as AACAP’s 2009 Catcher in the Rye Humanitarian of the Year because of her leadership on discussions of conflicts of interest in medicine."
That's quite some leadership she's showing, but when the judges are the AACAP, which represents a branch of psychiatry so riven by conflicts of interest (Harvard's Joseph Biederman anyone?) that it's hard to sort out where the science begins and the pharmaceutical propagandizing stops, then that's saying something. It's of course ironic that DeAngelis would get the Catcher in the Rye award. Holden Caulfield, the book's hero, often refers sarcastically to people he doesn't care for as being a "prince." Which I suppose makes DeAngelis a princess, at least in Holden's eyes.
Last week I wrote about the case of Scott Reuben, a well-regarded Massachusetts anesthesiologist, who was outed by Anesthesiology News over publishing at least 21 studies where he faked data and committed publication forgery. The various journals where his work was published are in the process of retracting the studies.
It will be interesting to learn if a 2004 study Reuben published in the Journal of Pain and Symptom Management will be among the retracted studies. In it, Reuben claimed that Effexor was effective at reducing post-operative pain in breast cancer patients--Reuben's research mostly focused on management of post-op pain--and that patients should be given it the night before surgery and for a period of time thereafter. An abstract of the article is here and I can find no notice on the journal's website that the study is in question, but I'd think it would have to be as it is making some very lofty claims for Effexor's pain management efficacy.
Rueben's faked studies centered on the use of non-opiods in pain management and included drugs like Celebrex, Bextra and Lyrica. He also wrote positively of Vioxx, a drug that like Bextra has since been pulled from the market due to increased stroke and heart attack risks.
Reuben's studies reportedly were quite influential in anesthesiology.
Rueben's attorney told the AP:
"'Dr. Reuben deeply regrets that this happened,' his attorney, Ingrid Martin, said. 'Dr. Reuben cooperated fully with the peer review committee [at his hospital]. There were extenuating circumstances that the committee fairly and justly considered.'"
I wonder what the extenuating circumstances for faking data might be.
I've not written much about Chantix since last year, simply because the noise around Pfizer's stop-smoking pill had seemed to die down after oodles of reports of suicide, suicidality and odd behavior connected to the drug. Now, JAMA has a news article out on the drug and its problems, and the fact that it appeared in JAMA is significant. It's one of two medical journals that almost every doctor in America reads (at some point) and it's not usually too harsh on meds (in my experience at any rate). The other is the New England Journal of Medicine.
"Emerging evidence suggests the smoking-cessation drug varenicline (Chantix/Champix) is among a growing list of medications that might cause serious psychiatric adverse events...."The latest findings emphasize the importance of physicians monitoring pa-
tients taking varenicline for such adverse events. They also raise questions about how well new drugs are being screened for unwanted psychiatric effects. Continued reports of crashes and other serious adverse events among patients taking this drug also have raised concerns about other possible risks."
That kind of language in JAMA will hopefully mean something to physicians who prescribe the drug and encourage a high degree of caution. It's especially nice to see this in the journal since I have been waving red flags about this drug since September 2007, when reports began surfacing of troubling reactions to the drug.
I've speculated on a few occasions that bad reactions to the drug seemed to mostly crop up in people who had some kind of psychiatric diagnosis history (especially depression) or who had had awful reactions to anti-depressants. I was about half right.
"Half of the patients reporting either suicide ideation or suicidal behavior had a history of psychiatric problems, 26 percent had no such history, and 24 percent had an unknown psychiatric history."
I'm surprised that so many people taking this drug had no psych history and yet ran into big problems. That ought to tell you--and doctors--just how tricky a drug this is. The article also notes that bupropion (Wellbutrin, Zyban) also has plenty of problems as well.
If you think I am exaggerating, go skim through the FDA's adverse events database on Chantix through the FDAble.com site. There are 8,290 adverse events reports through September 2008. That's a ton for a drug that first hit the market in 2006.
You can also read the FDA's drug safety newsletter on the two drugs here (pdf).
A new round of the so-called Nurse's Health Study of women--a long-term, multiple measures of women's health that included tens of thousands of women--hit the news yesterday. The principle takeaway is that researchers found a link to depression and sudden cardiac death (aka, heart attack) in women. Researchers also found an association between sudden cardiac death and anti-depressant use in women. The study was published in the Journal of the American College of Cardiology and while I don't have access to the full study, here's how researchers put their conclusion in the abstract:
"In this cohort of women without baseline CHD, depressive symptoms were associated with fatal CHD [coronary heart disease], and a measure of clinical depression including antidepressant use was specifically associated with SCD [sudden cardiac death]. Although antidepressant use might be a marker of worse depression, its specific association with SCD merits further study."
This was found to be true among a group of over 63,000 women, so this wasn't a small scale study. While I'm not surprised by the link between depression and sudden cardiac death, I must admit to being somewhat bowled over by the anti-depressant link. The study authors and others in the media were quick to try and defend anti-depressnt use.
From Medscape (via Beyond Meds):
"But the authors and accompanying editorialists conclude that, at the present time, the benefits of appropriately prescribed antidepressant use likely outweigh the risk of SCD."
From MSNBC.com:
"Studies of the newer antidepressants most often used today so far haven't signaled a risk of irregular heartbeat, and some even have suggested protection, noted Dr. Redford Williams of Duke University, a specialist in how psychosocial factors affect health."The drug question aside, Williams said the work adds to growing evidence that depression is an independent risk factor for heart disease — on top of the classic risks of high blood pressure, diabetes, high cholesterol and smoking."
Protection? What study would that be? MSNBC doesn't say.
Meanwhile, NBC's "Nightly News" gave the depression and cardiac death link huge play on its program last evening, but Brian Williams, the show's anchor, completely failed to mention the anti-depressant link. I'm not sure who is writing Williams' copy, but either they or he are utterly blind to not mention that point. Or is the TV media too scared of being dinged for allegedly scaring people off their meds?
All that aside, most studies of anti-depressants and sudden cardiac death have found the problem to exist mostly with older tricyclics, with some amount of risk found in SSRIs, as in this 2004 study. While there would be obvious questions in the new study about what anti-depressants the women were taking and for how long, there is certainly evidence that newish anti-depressants like Effexor and Effexor XR can raise patients' blood pressure, potentially a clue to researchers looking to do further study. In fact the Effexor XR website notes:
"EFFEXOR XR may raise blood pressure in some patients. Your blood pressure should be controlled before starting treatment and should be monitored regularly."
It'll be interesting to see what developments come out of the new paper and what further evidence pops up.
And for anyone in medicine who thinks that maybe they ought to just shift their female patients to atypical antipsychotics and use them to treat depression, they may want to read this study from the New England Journal of Medicine showing a 200 percent increase in sudden cardiac death in patients who take atypicals. And then there's the weight gain, the diabetes, the boosted cholesterol, the increased lipids, the altered Q-T rhythms, the...well, you know.
Two final points: over the last few years supposedly safe and beneficial anti-depressants have been taking huge hits over suicide, suicidality, mania induction in some people, birth defects, making people act oddly and for their makers overstating their efficacy, so why do doctors keep acting like they are so safe and that "more study" is needed to establish their risks? Please. We already know they are risky drugs.
Two, where is the long-term study of men's health and anti-depressant use?
Most of you are aware that AstraZeneca applied last year with the FDA to have Seroquel, it's $4.4 billion a year antipsychotic, approved as a treatment for three different depression indications as well as for generalized anxiety disorder. It's a sign that something unusual is afoot since the FDA has decided to have its psychopharmacology advisory committee hear public testimony on the matter when it meets April 7 and April 8.
While I'm still trying to confirm details with the FDA, what I know so far comes from a reader of this site via the impossible-to-understand Federal Register:
"Written testimony has to be in by 3/27 to Yvette Waples. Her email is yvette.waples@fda.hhs.gov. Her fax is 301-827-6778. Phone is 301-827-7001. You have to contact her if you want to speak at the meeting, which is to be held on April 7 and 8 at the Hilton Wash. DC/Silver Spring Hotel, the Ballrooms, 8727 Colesville Rd. Silver Spring MD . When asking to speak (1-2 each day) tell name or names of presenters, brief statement of topic, and time needed.....time needed is a joke because they usually give five min. If speaking, good idea to give written copy of speech and attachments, if any, to the psychopharmacological committee. I'd say make about 20 or 30. Sometimes press take copies so put your name and phone/email on the material."
As much as I'd like to speak to the committee in person, I simply don't have the money to fly to DC, etc. I will submit written testimony, as things stand now. I'm trying to find out if the FDA will permit testimony via phone--hell, it's 2009 and federal courts allow it and video testimony to a degree. I am not sure if the written testimony can be submitted by email. I'm trying to find out from the FDA.
But those are the basics as I know them now. I'll update when I know more.
I know there are many former Seroquel users who read this site and I would strongly suggest that you all offer written testimony. The committee needs to hear from people who've taken this drug as it weighs its recommendation to the FDA.
I've been following this tragic tale for some time and now it appears to have come to an end.
" Christian Hageseth, 68, who had practiced in Colorado, pleaded no contest Feb. 24 to a felony count of practicing medicine illegally in the case of John McKay, a 19-year-old Stanford University student who killed himself in August 2005 by inhaling car exhaust fumes at his mother's home in Menlo Park, the San Francisco Chronicle reported Monday. Hageseth faces up to one year in jail when he is sentenced April 17 in San Mateo County.The newspaper called the case precedent-setting since county prosecutors in California were allowed to prosecute a doctor in another state for engaging in "telemedicine" without examining or even seeing a patient.
McKay had ordered 90 capsules of fluoxetine, the generic version of the antidepressant Prozac, from usanetrx.com, a Web site in India that in turn forwarded his order to a Texas company, JRB Health Solutions, which then sent it to Hageseth, its physician contact in Fort Collins, Colo.
"Hageseth filled the prescription without contacting McKay and sent it back to JRB, which then had a Mississippi pharmacy ship the capsules to McKay.
Traces of the drug and alcohol were found in McKay's system but not at lethal levels."
While I suppose there are conditions and medications where telemedicine might be workable, depression isn't one of them and neither are anti-depressants. The doctor has surrendered his medical license.
I'm ending the spring fundraiser, which has met its goal of $4,000. Eighty-six people contributed this time out, an increase over the winter fundraiser in early December. Thanks so very much to all of you, especially given how rotten the economy is right now (and hopefully won't be much longer). I'm humbled by your generosity.
BTW, there are a few people who sent me checks whom I don't have emails for so I can thank them. So if you are one of them, know that I appreciate your contributions.
I just got a nice check in the mail. There is $45 left to go in the fundraiser (I've already included the Bremner challenge numbers in the total raised), so if a few of you want to help wipe out that $45 remainder today, the PayPal button is on the right.
Thanks.
I've noted many times in the past that current PTSD treatments seem to not be working very well, especially among combat veterans, and that we need to find another solution/s. Now comes a new study in the Journal of Psychopharmacology asserting that MDMA (Ecstasy) may be an effective treatment for some people with PTSD. A press release on the study is here. I don't have access to the full paper, but pass this along because there have been other recent reports of positive effects of MDMA in treating PTSD. Certainly, the results are robust enough to merit further research, regardless of MDMA's legal status and street drug reputation.
"Psychiatrists that have administered MDMA to anxiety patients have noted that it promotes emotional engagement; strengthens the bond between the patient and doctor, known as the therapeutic alliance; decreases emotional avoidance; and improves tolerance for recall and processing of painful memories."According to Johansen and Krebs, 'MDMA [ecstasy] has a combination of pharmacological effects that…could provide a balance of activating emotions while feeling safe and in control.' They suggest three possible biological reasons why ecstasy could help individuals with PSTD. First, ecstasy is known to increase the release of the hormone oxytocin, which is involved in trust, empathy, and social closeness.
"Because people with PTSD often report feeling emotionally disconnected and unable to benefit from the supportive presence of family and friends or therapists - a situation that is likely to contribute to the development and maintenance of the disorder - use of ecstasy might also help ameliorate these symptoms, suggest the authors.
"'By increasing oxytocin levels, MDMA may strengthen engagement in the therapeutic alliance and facilitate beneficial exposure to interpersonal closeness and mutual trust,' they write.
"The second biological explanation for ecstasy's useful effect is that it acts in two brain regions to inhibit the automatic fear response (mediated by the amygadala) and increase emotional control (mediated by the ventromedial prefrontal cortex) and therefore permits bearable revisiting of traumatic memories.
"Thirdly, ecstasy increases the release of two other hormones, noradrenaline and cortisol, which are known to be essential to trigger emotional learning, including the process that leads to fear extinction, on which therapy for PTSD relies."
All quite fascinating.
OK, a nice contribution came in late last night and that means the fundraiser is now $95 away from hitting its goal. If anyone wants to contribute before day's end, the PayPal button is on the right.
Thanks to all of you for your support.
$110 came in on Saturday and Sunday, which cuts the remainder to $115 left. I know of a couple of checks headed my way this week, so I'm just going to leave the fundraiser open for today. If anyone wants to help reduce that remainder today, the PayPal button is on the right.
Thanks to everyone who has contributed so far.
Among the many lawsuits floating around against makers of atypical antipsychotics is one brought against J&J/Janssen by former company sales reps, alleging that they were retaliated against for complaining about allegedly being pressed by the company to market Risperdal off-label for a host of conditions other than its then-approved use in schizophrenia. among other conditions, they allege that the company off-label marketed the drug for bipolar disorder well in advance of its approval for acute mania in 2003, for example.
From Bloomberg:
"J&J tried to promote Risperdal for conditions beyond schizophrenia, its approved use until December 2003, according to sworn statements among almost 1,000 pages of documents in the case in Trenton, New Jersey. To boost sales of the medicine, J&J urged doctors to prescribe Risperdal for conditions such as bipolar disorder and depression, the declarations say."'We (sales representatives) were directed to grow share in these off-label populations,' ex-saleswoman Kristel Kellner said in a statement as part of the lawsuit filed by Lynn Powell, one of the former salespeople. Powell claims J&J fired her in 2004 for complaining about such practices, violating a law shielding workers from retaliation."
This news pisses me off for two reasons. One, I was given Risperdal in December 2000, when a psychiatrist in Portland gave it to me for agitation (likely a result of the Wellbutrin/Depakote combo I was on) and depression. I was an unquestioning patient in those days and I never thought to be bothered by the rapid weight gain and frozen facial features I experienced until two years later. I just figured patients were supposed to put up with side effects.
Two, Bloomberg quotes Columbia University's Jeffrey Lieberman as defending this sort of off-label use.
"While drugmakers aren’t allowed to urge off-label uses, doctors can prescribe medicines for conditions not approved by the FDA. Dr. Jeffrey Lieberman of Columbia University Medical Center said off-label prescribing “is done all the time in the practice of medicine in a very rational and useful way."'Researchers are pushing the boundaries of trying to determine how a therapeutic agent can be effectively applied,' said Lieberman, the psychiatry department chairman. 'The process of getting FDA approval is a lengthy, complicated and expensive one.'"
It's lengthy and complicated for a reason, Lieberman, minimal proofs of patient safety and efficacy being part of the picture. I'm not convinced that the off-label marketing we've seen with the atypicals, often shepherded by allegedly independent academics, was safe or efficacious or that psychiatrists prescribed these drugs appropriately.
Interestingly, Lieberman was on of the authors of the recent AJP editorial on how the journal's editors have suddenly declared conflict of interest important. I wonder how much conflict of interest there was among academics pushing Risperdal for off-label uses. I wonder if Lieberman was one of the conflicted ones.
It's even stranger that Lieberman would be defending this kind of horse shit in 2009, when in 2005 he was the lead author of the CATIE studying, establishing that the atypicals didn't work well in treating schizophrenia and were downright dangerous in terms of the metabolic syndrome they created in patients. And in a 2007 interview, Lieberman damn near declared the death of the atypicals. So his views in the context of the off-label marketing of Risperdal make little sense and infuriates the hell out of me.
As I've interviewed researchers over the last couple of years, some of my sources have told me that not only was psychiatry a mess with huge conflicts between Big Pharma and researchers, but that other branches of medicine were just as screwed up. Now, via Anesthesiology News comes a total scandal--a well-known doctor who allegedly committed acts of data falsification and publication forgery. Now, almost two dozen of his published papers are being retracted by several anesthesiology journals. (The details are over at Pharmala.com, as the original website requires a log-in for read the article.)
"Scott S. Reuben, MD, of Baystate Medical Center in Springfield, Mass., a pioneer in the area of multimodal analgesia, is said to have fabricated his results in at least 21, and perhaps many more, articles dating back to 1996. The confirmed articles were published in Anesthesiology, Anesthesia and Analgesia, the Journal of Clinical Anesthesia and other titles, which have retracted the papers or will soon do so, according to people familiar with the scandal (see list). The journals stressed that Dr. Reuben’s co-authors on those papers have not been accused of wrongdoing."
When you read details like these, you know the big hand of Big Pharma cannot be far away:
"A cornerstone of Dr. Reuben’s approach has been the use of the selective cyclooxygenase-2 inhibitor celecoxib (Celebrex) and the neuropathic pain agent pregabalin (Lyrica), both manufactured by Pfizer. Dr. Reuben has received research grants from the company and is a member of its speakers’ bureau. However, a source told Anesthesiology News that Pfizer recently alerted its speakers to remove any reference to Dr. Reuben’s data from their presentations. Pfizer was unable to comment by the time this article went to press. The company has not been accused of wrongdoing in the matter."Jacques Chelly, MD, PhD, MBA, director of the Division of Regional Anesthesia and Acute Interventional Perioperative Pain at the University of Pittsburgh Medical Center (UPMC), said that the Reuben episode has left multimodal analgesia 'in shambles concerning many of the drugs we use'—particularly celecoxib and pregabalin. 'The big chunk of what people have based their protocol on is gone.'"
This is a huge scandal, one that I hope gets broader press attention. It also makes me wonder if there is any branch of medicine with clean hands. Feel free to speculate in comments.
Another $25 came in today from two contributors, meaning that this fundraiser is now $225 away from hitting its goal of $4,000. I am going to keep it open at least through Monday, simply because I'd hat to end the fundraiser so close to its goal but not make it to the finish line.
So for those readers who've not contributed so far, any contribution that helps chip away at that $225 over the next couple of day would be greatly appreciated.
As usual, the PayPal button is on the right, or send me an email and I'll send you my mailing address.
Thanks to all of you for your support.
A quick note to let you all know that four people have contributed today and brought the total remaining in the fundraiser to $250 left. Today is the last day of the fundraiser, officially, and it'd be great if that $250 remainder disappeared by midnight PST. Or I might leave things open for a few days. But not a single fundraiser in the two years that I've been doing these has failed to meet or exceed goal by the deadline. So it'd be cool if that streak stays alive. That'll only happen though if $250 comes in via PayPal by midnight.
As usual, the PayPal button is on the right.
Thanks to all of you for your support.
There's no more controversial case in the mental health world than that of the 2006 death of 4-year-old Rebecca Riley, a Massachusetts girl who was diagnosed with alleged child bipolar disorder at the age of 2 and was put on a host of medications including clonidine, Seroquel and Depakote. Her parents stand charged with first-degreee murder, allegedly for purposely over-medicating her to death, while the girl's psychiatrist faces a civil lawsuit and a malpractice tribunal. This week, the tribunal heard arguments in the case:
"In an initial hearing as part of a civil suit brought by Rebecca's estate against Dr. Kayoko Kifuji, the plaintiffs presented a letter yesterday from a child psychiatrist in Florida they hired to review Kifuji's care of the girl."Dr. Howard A. Goldman stated in the letter that Kifuji endangered Rebecca by overprescribing several heavy-duty medications and failing to monitor her condition well enough. He offers a 'list of deviations from the standard of care, all of which he connects to her death,' the plaintiffs' lawyer, Krysia Syska told the tribunal.
"A lawyer for Kifuji defended her by noting that Rebecca's parents stand accused of overdosing her on purpose. 'It is hard to find how a physician can be criticized if there was an intentional overdose of the medication provided,' said William J. Dailey Jr.
"Goldman's letter, however, says Kifuji diagnosed Rebecca with bipolar disorder too quickly; ordered too many drugs; failed to monitor their potentially deadly side effects; and did not heed warnings from Rebecca's school nurse that the girl had become like a 'floppy doll.'"
There will be much more on this case this year. Background here.
Another $170 came in yesterday from three contributors, which means there is but $630 to go to reach the overall goal of $4,000. Today is supposed to be the final day of the fundraiser, so we'll have to see how today goes in terms of whether I'll extend it a few days more or not.
If you'd like me to not write another fundraising post for three months or so, then help knock that $650 remainder down today.
As usual, the PayPal button is on the right. If you prefer snail mail, send me an email and I'll end you my mailing address.
Thanks to all of you for your support.
I had hoped to have a couple more posts up by now, but I was doing some very annoying outside work (nothing journalistic or interesting) yesterday that seems to have swallowed my brains and energy. Hopefully, I'll have more of both later today.
Although he'd not been formally nominated, word had been flying about since early January that CNN's chief medical correspondent and neurosurgeon Sanjay Gupta was President Barack Obama's likely nominee to become US Surgeon General. Gupta's name generated much criticism, including from me over his being a journalistic lightweight and for getting his facts wrong about anti-depressants and suicides among youngsters. He's also reflexively pro-pharma. I'm sure he's a fine surgeon, however.
Last night, Gupta took himself out of the running for the S-G slot.
NBC News did report that Gupta would take a significant pay cut were he to leave his TV and surgery slots, but no official reason was given for Gupta's backing out.
"Dr. Gupta’s wife, Rebecca Olson Gupta, is expecting a child, and Dr. Gupta wants to spend more time with his family and continue practicing medicine and serving as a CNN correspondent, the CNN anchor Wolf Blitzer said on Thursday."Dr. Gupta presides over a small media empire that includes appearances on the “CBS Evening News” and columns in Time magazine. He published a book about the search for immortality in 2007. He is paid for speaking engagements, a controversial practice for a journalist."
I'm glad he's gone. Let's see who the President ends up nominating.
Another $60 came in yesterday from three contributors, bringing the total raised to 3083.95 from 69 contributors. That officially leaves $916.05 to go to reach the fundraiser's goal of $4,000 on or about the end of tomorrow. In reality, that total is likely closer to $800 remaining owing to the Bremner challenge to psychiatrists and other mental health providers as well as to the fact that I know a couple of checks are headed my way in the mail, which I won't see until the weekend.
Thanks to all of you who've contributed so far.
So, yes, there's about $800 left to raise and it'd be great if that could happen by the end of tomorrow. It should be a pretty simple matter for 20 or 30 contributors to erase that remainder in short order.
As usual, the PayPal button is on the right. Or if you prefer snail mail, send me an email and I'll send you my mailing address.
A new study examining the safety of placebo arms in clinical trials of anti-depressants in teens is out in the American Journal of Psychiatry and, while it doesn't directly examine the placebo effect per se, it certainly shows that there is a sizable placebo effect in these trials, that the effect size of anti-depressants is modest and that the suicide attempts that cropped up among placebo arm patients happened after the teens were on an active treatment later in the trial.
The paper is an analysis of data from the TADS Study (Treatment for Adolescents With Depression Study). It was a fairly long term study and involved 439 patients, aged 12 to 17 years, who were either given Prozac, CBT-alone, CBT and Prozac or placebo. After the first 12 weeks of the study, placebo patients either went into active treatment or left the study.
The safety of placebo arms in depression trials among teens and kids has been questioned over possible harms caused by denying kids the wonders of active anti-depressant treatment and over what negative effects being in a placebo arm initially might present for later anti-depressant treatment. This new study sorts out most of these issues and there are several take-aways.
1. Placebo treatment didn't hurt teens, researchers found, so the ethical question of "denying" treatment is addressed.
2. The teens who were in the initial 12-week placebo arm did fairly well. Of kids on placebo-only for 12 weeks, 35 percent responded to their "treatment" while 58 percent of the other groups did (a very common 23 percent effect size for active treatments including CBT).
3. At week 36, the response rate was 82 percent in the initial placebo group and 83 percent in the active treatment groups, which certainly argues for some level of sustained placebo effect ("Patients who responded to placebo generally retained their response," the study authors note.) The remission rate was 48 percent in the initial placebo patients and 59 percent in the active treatment groups, so certainly not much of an argument can be made that offering kids a placebo limits their ability to respond to other treatments. (It also make me wonder, skeptically of course, about the various prevention paradigm claims made for anti-depressants.)
4. Although the authors don't address this point, I think you can reasonably make the case that the placebo effect exists in both kids and adults undergoing various depression treatments (or taking a placebo) and it ought to become a legitimate object of research. Certainly, a study by Arif Khan last year showed an enormous and long-last placebo effect among adults and a recent meta-study in the AJP showed a large placebo effect in a slew of depression trials in kids and teens.
I'm not sure how much money NIMH is getting of the $1.1 billion in stimulus money designed to sort out which medical treatments work best (I'm dubious of how much of this money will actually create jobs but that's a separate issue), and it would make sense for NIMH to allocate some money to funding real world research on the placebo effect in depression treatment. There's too large of a consistent effect out there to not want to understand how large it is and, if possible, what's driving it (beyond psychological suggestion).
5. There were suicide attempts among initial placebo patients, mostly occurring when the patients either moved to active medication or psychotherapy or a combination. The authors note:
"It is important to note that the large majority of suicide attempts among placebo/open patients (80 percent; 12/15) occurred after the period during which they were on the placebo. Thus, depressed adolescents assigned to placebo condition are for the most part able to tolerate the waiting period without significant clinical distress."
6. Anti-depressant true believers among doctors and advocates are simply running out of road when it comes to making the "anti-depressants for kids are awesome!" argument. Given that a WHO study recently lined up with the FDA black box warning on anti-depressants (at least through the age of 18) as well as with the British ban on their use in under-18s in finding an increased risk of suicide among kids and teens using anti-depressants, it's time for the true believers to reassess their arguments and perhaps argue for extreme caution in the use of anti-depressants in kids and teens, at a minimum. (I'm making no argument here about young adults and adults.)
What's more, the obvious placebo effect apparent in these trials hardly argues in favor of casual anti-depressant use either. Perhaps, it's all really an argument for sugar pills painted to look like Prozac.
I was watching NBC's "Nightly News" last evening and just about fell out of my chair when the program touted the giant Kaiser-Permanente as the future of health care we could be living with under the Obama health care reforms, whatever those are supposed to be. While Kaiser does pay doctors salaries and keep costs down compared to some medical systems, NBS acted as if Kaiser's quality of care is the best thing ever.
That's a bizarre claim, as many Californians could tell you, myself included. Kaiser docs didn't listen to me when I told them Prozac and Paxil were causing me problems in the 1990s and when I was a broken nose in 1992, a Kaiser doctor didn't fix it properly and I had to have surgery to repair their screw-up in 2001. If Kaiser is the future of health care, then I'm moving somewhere else. Some Kaiser docs were just fine (especially the pediatricians in the Bay Area of my youth), but I encountered more than a few docs when I was an adult in San Diego who weren't exactly hitting the quality ball out of the ballpark.
It's odd that NBS focused on a Kaiser clinic in Maryland. Maybe it's time for NBC to get off the East Coast and maybe talk with some patients who've been in the Kaiser system the longest--people in California. Stories are legion in the Golden State of people who've had awful experiences with teh uber HMO. Here's one Kaiser-hating website.
Here's NBC's report:
Visit msnbc.com for Breaking News, World News, and News about the Economy
Since the fundraiser is close to its end on March 6, I wanted to let you know that with what's come in today the fundraiser is $931.05 short of its $4,000 goal. But adding in the Bremner challenge for psychiatrists, psychologists and nurses, the amount left is about $885 from goal. I know a couple of checks are coming from Back East, but I won't see them for a few days still, so the total remaining could be closer to $800 left.
There are two days left plus what's left of today, and I'd love that remainder to get down closer to goal today. That amount remaining is not large and would be pretty easy for 10 or so contributors to help take a substantial bite out of it by the end of today.
If you'd like to contribute, the PayPal button is on the right. Or send me an email and I'll send you my mailing address.
Thanks for your support.
News is just out that US Supreme Court has ruled against Wyeth in a landmark case wherein the drug and device maker had sought to have federal preemption rules override state laws on injuries caused by drugs and devices. Preemption basically holds that if the FDA has approved a drug or device as safe, then a pharma company couldn't be held liable for an unsafe product under state laws. The USSC didn't buy it, however, and shot down Wyeth's case 6 to 3.
Preemption has been Big Pharma's wet dream for ages. Looks like Big Pharma needs a new dream.
$136.95 came in yesterday from three contributors, bringing the total raised so far to $3,023.95 from 65 contributors. That leaves $976.05 from 35 contributors to go to reach the overall goal of $4,000 from 100 contributors by the end of Friday. That means the end is near and it'd be great if some more contributions came in today to get that remainder even lower.
Thanks to all of you who've contributed so far.
As usual the PayPal button is on the right, or if you prefer snail mail send me an email and I'll pass along my mailing address.
One reason I'm glad I made the Seroquel documents publicly available the other day is because I knew people like Jim Edwards at BNET.com would go dig through them and post their findings, saving me from writing too much about a drug that injured me personally.
Edwards wrote an excellent post yesterday detailing what AstraZeneca knew about weight gain problems with Seroquel and it appears the company knew about it as far back as 1997, the year the drug was first approved.
"Feb 12, 1997, memo from Richard Lawrence: I am not 100% comfortable with this data being made publically available at the present time … however I understand we have little choice … Lisa has done a great ’smoke-and-mirrors’ job!"Aug. 13, 1997, memo from Lisa Arvanitis to her colleagues:
1. Is there a competitive advantage for SEROQUEL re-weight gain which we can articulate in posters/talks/vis aids? We know we have weight gain but is it limited to the short term …? … I was really struck by how consistent the data was."Feb 24, 1999, memo from Nick Hough, regarding a single study that appeared to find weight loss among users:
We must not get too carried away with ‘weight loss’ when we know the rest of our data appears to point in the other direction…"Dec. 6, 1999, email from John Tumas:
The larger issue is how do we face the outside world when they begin criticizing us for suppressing data."1998 draft paper intended for 11th ECNP conference in Paris:
Clinically significant weight gain , that is more than 7 percent increase in body weight, was seen more with quetiapine [Seroquel] than placebo - 24 percent compared with four percent …"
It goes from there, basically with AZ admitting internally that it knew it had issues with weight gain and some reports of diabetes and deaths, but with the company seeking to minimize those problems and clearly directing its sales force to not tell the whole truth about the matter.
Then, this:
"Dec. 18, 2008, memo from FDA: The weight gain signal is significant for both adult and pediatric populations and should be elevated to the Warnings and Precautions section [of the drug's label]."
Gee, nice of the FDA to catch on to this problem so quickly.
As I've mentioned before, it'll be a while before I can write about these documents more formally. Right now, when I look at them, it's like watching a drugmaker dance around issues which have directly affected my personal life.
There's a commentary in the March issue of the American Journal of Psychiatry, gingerly addressing the conflict of interest scandals roiling psychiatry--and bringing it to its knees, in the words of Tufts' University's Danny Carlat--and one of the very psychiatric researchers who's been caught in one of the scandals signed on as an author of the piece. That would be A. John Rush, formerly of the University of Texas and now at Duke University's medical school in Singapore. He was outed by Sen. Charles Grassley (R-Iowa) last year for underreporting payouts from pharma companies. Rush was also director of the controversial Texas Medication Algorithm Project, itself a veritable conflict of interest petri dish, pharma influence and a lawsuit brought by the State of Texas against J&J/Janssen.
What's more, the journal's editor Robert Freedman is an author. It's kind of interesting that he would express an interest in conflicts of interest in psych research, since last month I wrote to him to ask him what the journal would do to address undeclared conflicts of interest in a 2005 AJP article and got no answer. Maybe, the fact that the conflicts involved sex between an AstraZeneca researcher and a medical ghostwriter made it too hot to touch, but conflict is conflict.
Even more fun is that the American Psychiatric Association, which publishes the AJP, is itself the subject of Sen. Grassley's ongoing investigation of collusion between pharma and academia, find that in 2006 the APA raked in about $20 million from pharma companies, roughly half of that in the form of advertising in the APA's journals.
Here's the full author list, essentially the editors and editorial board of the journal:
"Robert Freedman (Editor-in-Chief), David A. Lewis (Deputy Editor), Robert Michels (Deputy Editor), Daniel S. Pine (Deputy Editor), Susan K. Schultz (Deputy Editor), Carol A. Tamminga (Deputy Editor), Nancy C. Andreasen, Kathleen T. Brady, David A. Brent, Linda Brzustowicz, Cameron S. Carter, Leon Eisenberg, Howard Goldman, Daniel C. Javitt, Ellen Leibenluft, Jeffrey A. Lieberman, Barbara Milrod, Maria A. Oquendo, Jerrold F. Rosenbaum, A. John Rush, Larry J. Siever, Patricia Suppes, Myrna M. Weissman, Michael D. Roy (Editorial Director, American Journal of Psychiatry), James H. Scully Jr. (Medical Director and CEO, American Psychiatric Association), and Joel Yager (Vice-Chairperson, APA Steering Committee on Practice Guidelines)"
Look, all these conflict of interest scandals represent a tipping point for the psychiatric profession and particularly for psychopharmacology as it's currently researched and practiced. I don't think I even need to explain why that is so. It sounds like the AJP commentators agree with me, at least in part.
"The impact of investigations of conflicts of interest extends beyond their targets and potentially affects the credibility of all psychiatrists. Psychiatry is reexamining its standards and ethical boundaries for interactions with the pharmaceutical industry. Our standards should address not only the conduct of high-profile opinion leaders, but also our responsibility as individual physicians to deliver to our patients the highest-quality evidence-based medicine...."
Basically the piece wanders around the issue, refuses to refer to specific cases, doesn't offer any real solutions, but acknowledges how important the matter has become.
"As individual practitioners, we may feel that we are not affected by public concern over these issues, which often focuses on the acts of a few of our colleagues. Congressional hearings and articles in the New York Times or Boston Globe are far removed from our own practices. But our profession suffers from these episodes and, more important, our patients do as well, because the public and private resources available for the care of our patients depend upon the public perception of the integrity of our profession as a whole. Therefore, each of us has a personal stake and a professional role in the conflict of interest issue. Most of us may never receive a check from a pharmaceutical company. However, by allowing companies to pay for and thus dictate our CME, we support the marketing context in which these acts occur. Our ethical principles as physicians are designed to protect our patients in many ways— primum non nocere, confidentiality, prohibitions of boundary violations. We now need to protect our patients from conflicts of interest in the selection of their treatment. The FDA has already taken leadership in limiting gifts and other inducements that historically were part of drug marketing. Guidelines for the type of pharmaceutical industry support that we each accept for our professional activities, including CME, and how our receipt of this support is shared with our patients when we prescribe drugs need to be more precisely defined by APA and our other professional organizations....""More acceptable alternatives—-industry support of education through unrestricted gifts to APA, universities, or other public institutions and journal advertising that resembles sponsorships on public television rather than network prime time commercials—-will likely result in less financial support than we currently receive for our professional activities, because this financial support would no longer be assumed by the companies as part of their marketing strategy. The subsidy that each of us has been receiving is part of what has fueled the excesses that are currently under investigation. Accordingly, in the future it may cost more to attend meetings, to earn CME credits, and to receive journals. Pharmaceutical companies may continue to hire their own speakers and to offer subsidized CME and publications to clinicians through their marketing divisions and private medical education companies. Each of us must acknowledge—-in the choices that we make—-our own responsibility to limit conflicts of interest in order to preserve the integrity of the field that is so important to us all."
I guess this is better than nothing, and it's likely an opening shot in upcoming APA board meetings and whatnot on CME and pharma funding rules and broader questions about conflict of interest. But I find it incredibly childish that the authors should whine about possible decreases in funding and "subsidy" from Big Pharma and possible increased costs of CMEs. The average US psychiatrist makes $180,000 a year and can afford to pay for their own CMEs--and should want to.
As I mentioned last week, the FDA's psychopharmacology advisory panel is going to review the possible approval of Seroquel for three depression indications and anxiety in early April. My hunch was that the clinical trials must be producing loads of fat, high-blood sugar patients, especially since one of the depression indications for which approval is being sough is for "maintenance," meaning long-term use.
Reuters is out today with a brief note on the April 8 hearing:
"The issues for discussion at the April 8 meeting include "concerns regarding exposing a greatly expanded population to a drug with known metabolic side effects and a possible risk of tardive dyskinesia," an FDA meeting notice said."Tardive dyskinesia causes involuntary, repetitive movement of the limbs and lip smacking, grimacing and other symptoms."
I'm glad the FDA is paying attention to these issues, but I don't have much confidence in the psychopharm panel as it's stacked with psychiatrists and the lone consumer rep--Gail Griffith--is a big time NAMI-ite.
But who knows? Perhaps, I'll wind up surprised.
Another $510 came in yesterday from six contributors bringing the total raised to $2,887 from 63 contributors. That leaves $1,113 from 37 contributors to go before the overall goal of $4,000 from 100 contributors is met on or about March 6. That's this Friday.
Thanks to all of you who've contributed so far.
If you'd like to support this site--which, among other things, made the Seroquel documents available yesterday when the major media isn't posting document one--then the PayPal button is on the right. If you prefer snail mail, then drop me an email and I'll shoot you my mailing address.
Thanks for your support.
Bloomberg reported yesterday that after being ordered to warn doctors in Japan about Seroquel in 2002, AstraZeneca continued to insist in the US market that there was no link to diabetes.
"The London-based drugmaker issued a letter to Japanese physicians in November 2002 that said AstraZeneca had received 12 reports that Seroquel users were diagnosed with high blood-sugar levels over a 21-month period, according to company documents unsealed last week in connection with litigation over the drug."'Since February 2001 when Seroquel started to be marketed [in Japan, US marketing began in 1997], 12 serious cases (including 1 death) of hyperglycaemia, diabetic ketoacidosis and diabetic coma where causality with the drug could not be ruled out have been reported,' AstraZeneca officials said in the letter."
And yet in 2005 company marketing officials continued to inform sales reps by company voice mail that weight gain on the drug was low and that there was no link to diabetes.
You can read the letter to doctors in Japan here. The voice mail in question can be read here.
This situation is similar to what I reported two years ago regarding Lilly and Zyprexa. In April 2002, Japanese regulators required Lilly to advise doctors in that country of diabetes, hyperglycemia and other issues connected to Zyprexa and yet, two months later, in June 2002, Lilly rolled out a Zyprexa marketing campaign aimed at PCPs. As Lilly noted in relation to the Japanese label change, "This does not change the status of Zyprexa as a safe, effective and cost effective agent in the US market."
In the Seroquel instance, AZ spokesman Tony Jewell told Bloomberg:
"'Every country has a different regulatory administration with different regulatory standards and requirements,' Tony Jewell, an AstraZeneca spokesman, said in an e-mailed statement. 'AstraZeneca marketing companies are required to comply with the rules and regulations of the regulatory authorities in the country in which they operate....'"Jewell noted that under U.S. law, drug company salespeople are required to use information from 'the label approved by the FDA.' AstraZeneca officials contend that Seroquel’s warning label provided 'adequate and appropriate information' about possible diabetes-related side effects."
While I don't doubt Jewell on what the FDA requires, it's completely bizarre for a situation to exist where AZ (and Lilly) can act as if health effects experienced in other countries wouldn't have some applicability in the US. Human beings aren't that different.
Either way, this sort of arrangement deprives doctors and patients of appropriate information about the risks of taking a drug.
Maybe what ought to be required here is that the FDA change its regulations so that any company that is ordered to deliver a warning about a drug in country X would have to inform doctors and the public that they've had to issue a warning overseas. Hell, maybe the FDA could do something smart and realize that if there's a safety signal popping up in another country, then maybe it might apply in the US and the agency ought to look into the matter.
Crazy idea, I know.
As I noted yesterday, I'm still a couple of days out from writing much about the Seroquel documents because I took the drug, experienced problems on it, and would like to have some distance between my personal aggravations and the documents before holding forth more formally.
This just hit the press yesterday: last week, a judge in West Virginia sided with the state's Attorney General over allegations that J&J/Janssen had sent misleading mailings to doctors in the state, ones that made misleading claims about Risperdal and, separately, J&J's pain patch Duragesic.
The court assessed a fine totaling $4.475 million. The Attorney General had sued J&J/Janssen in 2004. I don't know if any other states are suing the company over the same mailings.
The court found:
"'The wording of [the defendants’] November 2003 Risperdal letter was intentionally constructed to modify the FDA’s warning language and mislead healthcare professionals, who rely on this information when prescribing medication for their patients.'"
I've not been able to find a copy of the letter, but it's described thus by one legal website:
"Johnson & Johnson, also known as Janssen Pharmaceutica, has touted Risperdal as having a reduced risk of side effects or adverse health reactions in comparison to other atypical antipsychotics. Although the FDA had approved Janssen’s revision to its warning labels regarding the increased risk of hyperglycemia and diabetes mellitus, it concluded that Janssen’s warning letter dated November 10, 2003 contradicted these revised warnings on the product labeling; the warning letter actually claims that Risperdal is associated with a lower risk of diabetes than other atypical antipsychotics. In fact, the FDA summoned Janssen to provide such evidence to support this claim of decreased incidence of hyperglycemia and diabetes."
Can't any of these atypical makers do anything right?
I received the following statement from Tony Jewell, an AZ spokesman:
"AstraZeneca has studied Seroquel extensively and shared all relevant and required data with the FDA -- both before and after the agency approved it as safe and effective. The company has worked diligently with the FDA to ensure that the safety profile of Seroquel is reflected appropriately in the prescribing information that health care professionals use when making treatment decisions."Seroquel has helped millions of people suffering from schizophrenia and bipolar disorder, which can be serious, debilitating mental illnesses.
"AstraZeneca stands behind Seroquel and its clinical research. AstraZeneca has an internal quality assurance program to ensure that our clinical research complies with good clinical practices and meets the highest ethical standards.
"This litigation is about whether Seroquel caused diabetes in individual plaintiffs. The court in the first two cases in the federal multi-district litigation in Florida granted summary judgment because the judge concluded that plaintiffs did not have sufficient evidence to establish Seroquel was responsible for their alleged injuries.
"At this point, there is no trial scheduled in the multi-district litigation because no plaintiff yet has come up with a demonstrated triable claim. AstraZeneca intends to litigate these cases on their individual merits and will defend ourselves vigorously."
Two thoughts: my understanding of why the two cases were dismissed related to Florida state law being applied in the federal court case since the two people are from Florida and there's some kind of local rule down there that gives a different standard from federal law. Two, I don't think the federal court judge has determined that there are no triable claims in the other cases. The plaintiffs' side and the defense team are still wrestling over evidence.
Another $125 came in yesterday from three contributors, which brings things to $2,377 raised so far from 57 contributors and leaves $1,623 from 43 contributors to go to reach the overall goal of $4,000 from 100 contributors on or about March 6. March 6 is this coming Friday and it would be great if the fundraiser met its goal on time.
I truly appreciate the contributions that came in on Friday and over the weekend because, as you can tell from another post today, I spent much of the weekend poking through the Seroquel documents. I've also gone and made the entire set publicly available. As far as I know, this is the only site making them available to the public right now and I know a few other small sites will post them within days. Meanwhile, the mainstream media isn't making the documents publicly available. Why they leave it to guys like me is beyond my burned cinder of a brain.
If you'd like to support a site that's offering a public service now, as it has for over two years with the Zyprexa documents, then the PayPal button is on the right. Or if you prefer snail mail, drop me an email and I'll send you my mailing address.
Thanks to all of you for your support.
As I mentioned elsewhere today, the major media has done a decent job of covering the Seroquel documents released by a federal judge last week. Bloomberg and the Wall Street Journal were first out of the chute on Friday, soon followed by the New York Times and the St. Petersburg Times. Most everyone has gotten the basic story out there now that the evidence from the documents is that AstraZeneca, Seroquel's maker, openly discussed "buried" studies of Seroquel (ie, less than positive studies of its drug), told sales reps to ignore evidence of diabetes and weight gain issues with the drug and tell the docs all was well, and was slow to warn the public about diabetes and weight gain concerns about the drug.
They also quoted AZ stating that it did all that it was required to do by the FDA.
But the St. Pete paper had the best article of all, since it got into a Chicago psychiatrist who wrote a paper asserting that Seroquel didn't cause patients to gain weight. AZ then made use of his claim--which the researcher's evidence may have supported, but which sure runs counter to what AZ knew otherwise, according to the Seroquel documents, and which sure runs counter to what many doctors and patients have observed in the real world--to create a marketing brochure of sorts.
"Among the documents was harsh criticism from an AstraZeneca executive of Dr. Michael J. Reinstein, a Chicago psychiatrist who was one of the company's paid consultants for Seroquel. In a note in October 2001, Georgia Tugend, U.S. brand manager for Seroquel, slammed the quality of research performed by the doctor's group."'Our clinical colleagues have significant and numerous issues in the past with the quality of research that this group has produced,' she said in the internal memo. 'There is little confidence that Good Clinical Practices can be adhered to.'"
"This is surprising because the documents also included a Seroquel marketing piece featuring Reinstein's research showing that the drug had led to weight loss in a patient.
"Reinstein said Friday that AstraZeneca paid him about $40,000 a year for 10 years to promote Seroquel among doctors. Reinstein, who said AstraZeneca ended his contract at the end of 2007, described the company's negative comments as 'sour grapes.'
"'We sent them criticism, saying they were not doing proper research, so of course they're not going to say we're wonderful,' he said. 'It's character assassination.'
"Though no longer on AstraZeneca's payroll, Reinstein said he still prescribes Seroquel.
"'Some patients gain weight, some stay the same, some lose weight,' he said. 'The results over time in terms of not gaining weight and not getting diabetes are better with Seroquel than with Zyprexa.'"
That's an interesting way of putting it, to be gentle about it. You may wonder about the $40,000 a year and ask yourself, "Why would AZ give $40,000 a year to a researcher it held in low esteem?" According to this document, Reinstein's group ran community mental health clinics where 1,000 patients a year were being prescribed Seroquel each year in the 1990s. While I don't know how much Seroquel sold for then, drugstore.com lists the 300 mg. size at $663.44 for 60 tablets, a month's supply in some cases. That would work out to $7.96 million a year from Reinstein's clinic alone and he's described, in the above document, as one of the five biggest Seroquel prescribers in the US at the time. I have no idea if there's any possible connection to the $40,000 a year
And, in the above document, you can see evidence that Reinstein and his colleagues were upset with AZ because it wouldn't fund a study of Seroquel at, drum roll, 1,600 mgs. a day for people diagnosed with schizophrenia. Seriously. That's roughly twice of the high end that you ever see anyone on with this drug, and you hope no one is ever on 800 mgs. for long.
Unless, of course, they lose weight at that dose. (Only joking.)
As many of you know, a bunch of documents in the federal lawsuit against AstraZeneca over allegations surrounding its drug Seroquel were released in open court Feb. 26. The next day, I obtained the entire set of pdfs and after reading all of them over the weekend, I am now making them publicly available. The set of documents in .zip format runs to 44 MB. They will also become available on other sites soon.
It's going to be a day or so more before I write about them myself, beyond what I offered on the initial press accounts of these documents last week. There's enough evidence of downplaying of side effects and risks in these documents that I need to divorce my personal frustrations from the evidence. For those who don't know, I took the drug for 14 months in 2004 and 2005 and it caused me serious problems, including ones that linger to this day.
When I write about the documents more formally, I'll make individual documents available as I go along. So will others on the Net.
So far, I'd say the press has done an admirable job of getting the set of facts in these documents out into the public realm. I'll cover that in a separate post today. This set of documents is nothing like the Zyprexa documents in sheer volume (those documents are about 260 MBs zipped and there are hundreds of individual files) and, after my initial review of them, I don't see any major smoking guns that the media has missed so far.
One note: one of the documents was, as I got it on the 27th, scanned into a huge file (22 MBs) for four pages. So I printed it out and rescanned it and put it into the .zip file above as "Omnibus MSJ Exhibit 47fs.pdf," the "fs" denoting my rescan, which came in at a slim 1.5 MB, saving me about 20 MBs every time someone downloads the entire .zip. I assure you it's a true copy of what I got last week.
Meantime, if you want 'em, download 'em.
