- In terms of efficacy, antidepressants + mood stabilizer = placebo + mood stabilizer in bipolar disorder according to a new study. I've not yet read it, so I'll refer you to Furious Seasons for an analysis (1, 2).
- Oh, the University of Medicine and Dentistry of New Jersey (UMDNJ). It seems like nary a week goes by without some sort of serious ethical/corruption issues rear their ugly heads. For more on the situation, check out Health Care Renewal. Maybe that's why Lilly partnered with them to create a Center of Excellence for Psychiatry?
- Antipsychotics linked to death in the elderly, again. Thanks for PharmaGossip for pointing this out.
- Pharmalot wonders why the FDA is patting itself on the back for protecting public health at the same time that it is performing less enforcement.
- John Mack basically says this blog is close to useless according to his rating scale. That hurts, Mr. Mack.
- Seroxat/Paxil is an easy target, but that doesn't mean we should stop kicking it while it's down. Fiddaman scores points with a good post on how GSK covered up its data on the drug, while Seroxat Secrets has been ablaze with posts pointing out the patently false statements made by GSK employees about Seroxat/Paxil.
Friday, March 30, 2007
Zyprexa Weighs In (Pun Intended): I posted recently about the "science" of treating "bipolar disorder" in kids. Here's an example of what passes for evidence in the child bipolar treatment world.
An open label (i.e., not placebo-controlled) study indicated that olanzapine (Zyprexa) was “efficacious and well tolerated in the treatment of acute mania in youths with bipolar disorder.” By definition, it’s pretty tough to show that your treatment works in the absence of a control group (see research methods 101), so how can it be said that the treatment was efficacious? And as for being “well-tolerated,” keep in mind that the average participant gained five kilograms in eight weeks. That’s not so healthy. If this is what passes for solid evidence, then I suppose bipolar in kids as young as two years old is widely underdiagnosed, and that Zyprexa is a godsend for these poor undertreated children.
There is a lot of uninformed discussion out there on early-onset bipolar, but none of it is coming from the Papoloses [the folks behind the book The Bipolar Child]. All their work is concerned with rigorous examination in both the lab and the real world, and on enlightening and educating clinicians, researchers, educators, parents, and the general public. The misguided fear-mongers who criticize them invariably have proved to be too lazy to talk to parents of bipolar kids, much less read their book.
Well, well, well. Allow me to respond. **Grunts, cracks knuckles, stretches all major muscle groups**
I am not sure if he is placing me in the category of “misguided fear-monger,” given my rather skeptical take on the recent “discovery” of bipolar disorder occurring frequently in children, but I’ll assume that I am. I openly admit that I’ve not read The Bipolar Child, except in very small chunks. The only thing I remember thinking was, “Where’s the evidence?” More on that in a minute.
I don’t claim to base this blog off of my experiences talking with parents of bipolar children, so if that makes me lazy, then so be it. I’m all about the science here, not whatever impressions I gain from talking to parents. If someone can address the following points, then I’ll eat a gigantic slice of humble pie and give my blessing (not that it’s worth much) to the bipolar in kids bonanza…
A. Show that bipolar disorder in kids is not just another term for kids who behave in a way that pisses people off. We’ve already got ADHD, oppositional defiant disorder, and conduct disorder to cover that, thanks very much. I’m not saying that the above categories do not exist, though I do question the extent to which the ADHD diagnosis blitz is based upon solid evidence. Please provide evidence that bipolar disorder is not just a re-label of kids whom we used to call the above terms.
B. Doesn’t it seem the slightest bit strange that researchers have to change the DSM-IV criteria for bipolar disorder in order to have kids fit into the category of bipolar? Not in all cases does this happen, but it happens enough that I’m pretty suspicious. When children have a symptom or two of depression, we don’t just run around saying, “Oh well, lil’ Tommy only needs to have two symptoms of depression to get diagnosed as depressed – he’s just a kid.” What’s up with that? Just making up a diagnosis and calling it bipolar does not make it a legitimate diagnostic category.
C. How does labeling youth as bipolar lead to beneficial outcomes? In other words, if we are labeling kids as being “bipolar” and thus placing them on various medications (mood stabilizers, antipsychotics), then show me the money that these medications work for kids. Showing data over the long-term would be nice, by the way.
Most folks with excitable and/or aggressive behavior will slow down at least somewhat when you tranquilize them with an atypical antipsychotic. Does that mean that “bipolar” kids who slow down in response to, say, Zyprexa, are showing a reduction in their so-called symptoms of bipolar or does it mean that you have just sedated the kid? Or are sedation and a decrease in mania one and the same.
Where's the treatment data? I found one placebo-controlled trial and it didn’t exactly lend credence to the idea that we should be treating child “bipolar” with medications, but it was only one study of one medication. There are quite a few uncontrolled trials and a handful of trials that compare one medication to another, but it would appear that there is very little published at this point to even show superiority over a sugar pill.
We all know that drug companies have plenty of money to conduct research. So why such meager and poor quality research on kids labeled as bipolar? Seriously. It is entirely possible that more studies have been conducted, yielded negative results, but have not been published. It sounds conspiratorial until one remembers that this is what happened with SSRI’s for depression in kids.
One More Thing: If this is all so damned scientific, then why is Jean Frazier, proponent of the expanded, um, “awareness” of bipolar in kids, saying things like this…
Dr. Jean Frazier, director of child psychopharmacology at Cambridge Health Alliance and an associate professor at Harvard, said that up to three-quarters of children who exhibit bipolar symptoms become suicidal, and that it is important to treat the problem as early as possible.
"We’re talking about a serious illness with high morbidity, and mortality," Dr. Frazier said, "and for some of these children the medications can be life-giving."
No data, to my knowledge, support the above statements on suicidality, the importance of early treatment, or that medications for these kids “can be life-giving.” Perhaps Dr. Frazier’s statements were from “rigorous examination…in the real world”. Who knows? Seems to me that her statements, though, would fall into what Mr. McManamy might consider “fear-mongering,” and we know that he doesn’t like fearmongers.
Thursday, March 29, 2007
For the fourth quarter of 2006, Corcept reported a net loss of $3.9 million, or $0.16 per share, compared to a net loss of $5.2 million, or $0.23 per share, for the fourth quarter of 2005. For the full year 2006, the company reported a net loss of $24.9 million, or $1.09 per share. This compares to a net loss of $20.1 million, or $0.89 per share, for the full year 2005.As of December 31, 2006, Corcept had cash, cash equivalents and marketable securities of $9.5 million. The total cash used in the company's operating activities for the full year 2006 was $23.2 million. Commenting on Corcept's financial guidance for 2007, Fred Kurland, Corcept's Chief Financial Officer, stated, "Based on the currently planned timeline of our clinical development program and assuming that we are able to raise funds for intended operations, we expect that net cash used in 2007 will be between $10 million and $15 million. If we are not able to raise additional funds, we will not be able to continue operations beyond the second quarter of 2007."Sounds like a plea of desperation to me. Anyone willing to sign up? I'll just get my checkbook out now. Corcept stock (incredibly) was once valued at over $10 per share, and now sits at 71 cents. I guess you could call this an extreme form of value investing (except for the company's lack of earnings). It appears that just issuing press releases and/or writing journal articles that spin their negative findings as positive is not working so well.
Wednesday, March 28, 2007
Can would-be patients or families dupe doctors like this all the time? How many more of the millions of kids diagnosed with ADHD and bipolar disorder carry their diagnoses as a result of parental reporting alone, with whatever biases might be present? Is there a way for child psychiatrists to filter out parental bias?Remember that when kids are quite young (like four years old), they don't have the cognitive skills to report on their own symptoms all that accurately. Yes, the kid should be interviewed, but don't expect much. So, that naturally causes mental health professionals to rely on parent reports. Should doctors try to obtain collateral information? Yep. Teachers, friends' parents, babysitters. It is interesting that parent, teacher, and child reports of children's behavior often differ quite a bit (1, 2, 3). Why?
Environment: Well, the environment impacts behavior. If the parents have a chaotic home environment where discipline is inconsistent, expectations are unclear, and negative emotions run high, then the kid has a better chance of showing a variety of behaviors and emotions that could come across (rightly or wrongly) as some sort of mental disorder. If these same symptoms are not expressed at school, then maybe the controlled environment, positive peer interactions, relationship with the teacher, teacher's strong classroom management skills or whataver are helping Junior keep a lid on the problem behaviors at school. So if the kid can keep it together at school but not at home, is this the kid's problem or the parent's problem?
But teachers are not always tuned in all that well to all students' behavior and certainly not to all of their kids' emotional state, as their job is not to play psychiatrist to kids, but to teach. So their ratings will not be completely accurate either. My personal belief is that getting opinions of teachers (note the plural), parents, the child, and whomever else spends significant time with the kid is much better than relying on the point of view of just one source.
Making Up Symptoms? There will always be bad apples who fabricate symptoms in their kids. I've seen little evidence that such behaviors are common. It is more common that parents don't set up a solid discipline system (discipline, by the way also involves positive reinforcement, not just punishment) and develop strong relationships with their kids. One can also not discount peer influences, especially as kids get a bit older. Bad peers can lead a reasonably good kid down a pretty bad path. I'm also pretty sure that a steady diet of McDonald's, Grand Theft Auto, and other brain-numbing delights is probably not good for development in general and that our lazy-ass American lifestyle could have something to do with some of these cases.
Tuesday, March 27, 2007
Well, Brandweek NRX is now reporting that Decision Resources is claiming that the yet-to-be-FDA-approved Acomplia is set to become the new (you guessed it) “gold standard” in treating obesity. Never mind the side effects of depression and anxiety. Text of the press release can be seen here.
It would appear that Decision Resources likes to bandy about the term “gold standard” quite a bit in their reports. In fact, look what happens when you combine “gold standard” with “Decision Resources” – click here.
I’m not really sure what this company actually does and I’m not going to take much time to figure it out. I just find it odd when a company keeps churning out reports labeling various treatments as being the “gold standard” in the absence of any good clinical trial evidence.
Friday, March 23, 2007
- Health Care Renewal's post on the study in the Journal of the American Medical Association that found many MD's get a lot of cash from drug companies. In addition, companies are also covering up many of these payments as "trade secrets." For more on this, you must head to HCR's nice post on the topic, which provides many interesting details. Oh, and psychiatry appears to be the biggest recipient of cash. Congrats!
- Another instance of astroturfing was uncovered this week -- the head of an organization (Elzora Brown of the Breast Cancer Resource Committee), who serves as the head of a patient advocacy group has apparently been making some serious cash, courtesy of a huge influx of drug industry money. Health Care Renewal was all over it. AHRP has also weighed in on the topic.
- PharmaGiles notes how Big Pharma gets its way through effective lobbying.
- John Mack at the Pharma Marketing Blog noted that the FDA's chief ain't too keen on whistleblowers. Looks like David Graham had best watch his back? Among other good recent posts, Mack had one about the loophole in the FDA's now allegedly tough guidelines on conflicts of interest among its advisors.
- Seroxat Secrets is becoming one of my favorite blogs. The site points out how GlaxoSmithKline repeatedly settles lawsuits without ever, of course, admitting any wrongdoing, and with the condition that everyone keep hush-hush about the details surrounding the case. The post is aptly titled Buying Our Silence and I liked it quite a bit.
- Last but certainly not least, Furious Seasons quite aptly notes, at length, how the "in-betweeners" are increasingly being diagnosed as having a variety of mental illnesses. He's referring to the kids who are in-between the goody-goody, straight A, never get in trouble crowd and those who are lighting the school on fire and having hallucinations. If you occasionally get in trouble and are obnoxious, does that make you ADHD and/or bipolar, and, more importantly, does this mean you would allegedly benefit from treatment. The market keeps expanding...
You conduct enough studies using a drug that is mildly better than a placebo, making sure to usually enroll a large sample of people. At least two of the studies will turn out to be "statistically significant" and who cares what happens in the other studies -- just don't publicize them or include them in your FDA application! If there are seven or eight studies examining Seroquel in depression currently, then we shouldn't be surprised if two of them yield somewhat better results for Seroquel. Considering that some depression rating scales rate an improved appetite as an improvement in depression, then Seroquel-induced weight gain actually counts in its favor.
Hat Tip: Furious Seasons
Quotes from the relevant New York Times article (by Stephanie Saul) will be dispersed throughout, such as this…
Many states, looking to rein in the cost of expensive antipsychotic drugs like Zyprexa, have turned to an unusual ally for help — the very company that sells the drug. At more than $300 for a monthly prescription, Zyprexa, which is used to treat schizophrenia and bipolar disorder, is the single biggest drug cost for state Medicaid budgets. So Eli Lilly, the maker of Zyprexa, offers to help states monitor doctors who treat Medicaid patients to make sure they are not wasting money on mental illness drugs because of what psychiatrists call “sloppy prescribing” — giving patients too many similar medications or doses that are too high. Twenty states use Lilly’s free service. But some experts question why these states let Lilly help oversee spending on its own medication.
“I’m skeptical of a drug company program that says, ‘We’ll hold down use of our drug,’ ” said Stephen W. Schondelmeyer, a professor of health care economics at the
. He described such programs as thinly disguised marketing. Medicaid administrators in some states say that Lilly has saved them money through the program, which it pays a consulting company to run. Universityof Minnesota
But Lilly’s help also can come with strings attached, according to current and former Medicaid officials. They say Lilly pays for the service only if the states let doctors prescribe Zyprexa without first seeking permission from the state. Medicaid officials in
found that out last year, after trying to reduce the state’s $22 million annual spending on Zyprexa by requiring doctors to seek permission before prescribing it. Lilly responded by ending the program. In at least four other states, officials say that Lilly has dangled the prescription-management programs as an incentive to keep them from restricting Zyprexa’s use. Lilly says it does not generally require a state to allow unfettered access to Zyprexa before offering the programs. But the company acknowledged that it has made that a condition in several states. Wisconsin
Lilly pays a company named Comprehensive NeuroScience to run the program and the program is reported to have run in 24 states. How are “bad prescriptions” managed? Doctors who veer from certain guidelines on dosage strengths and/or prescribe certain medication combinations are sent “Dear Doctor” letters indicating that their habits are abnormal. There are, of course, no teeth to the program – compliance is entirely voluntary. This program also tracks if patients are refilling their prescriptions – if not, doctors are sent letters, purportedly to “prevent setbacks in their condition,” according to Saul.
Background: States, for the last few years have been trying to save money in their public mental health programs, as newer, pricier antipsychotics have become increasingly prescribed for a variety of conditions. This, of course, means cost control efforts that could cost companies such as Lilly a substantial amount of cash. Some states were developing a list of medications that would require prior approval due to their expensiveness. Many mental health advocacy groups rallied against such moves. Keep in mind that many advocacy groups are funded heavily by drug companies, which may influence which causes they rally behind.
Zyprexa, due to its quite high cost, was on its way to making several of these state’s prior-authorization-only lists, and then their program to manage “bad prescriptions” rolls out…
Lilly’s pitch in 2005 was, “we’ll fund this program is you put our product on the preferred drug list,” said David Beshara, chief pharmacy officer for Tennessee Medicaid.
, concerned about Zyprexa’s side effects and the $69 million it spent on the drug in 2004, declined to adopt the program. Tennessee
Some states, notably
and Michigan , have publicized results showing that the Lilly program helped save money. And they generally praise the program. “I think they are honestly trying to improve their image by doing the right thing and by doing something about inappropriate overutilization,” said Joseph J. Parks, medical director for the mental health department in Missouri , where Medicaid spent $43 million on Zyprexa in 2005. Dr. Parks has served as a paid consultant to Comprehensive Neuroscience. Missouri
There is some evidence that such a program yielded better outcomes for patients, though I admit to being quite suspicious about it. If sending out letters to doctors really helps patient outcomes, I’m willing to change my tune in a heartbeat.
A mental health advocate in
Now let me be absolutely clear. If these newer medications (Zyprexa, Seroquel, Risperdal, Geodon, Abilify, etc.) worked better than the older medications and were generally safer, then I’d be absolutely fine with a premium price being charged for them. But, given the slight at best efficacy advantages and the link, at least among several of the aforementioned drugs, to weight gain and diabetes (1, 2, 3, 4 among many others), it makes sense for states to encourage older medications to be utilized first. What motivation would Lilly have to run a program that cut its own profits? Am I entirely missing something here? Read the whole story over at the New York Times. Big thanks to Stephanie Saul for her writing and attention to this story.
Thursday, March 22, 2007
When a company funds a study that finds unfavorable results, they can always deep-six it. But what if someone else conducts the study -- someone you did not fund? Well, a Lilly employee had some interesting thoughts on the matter.
A study was conducted, then presented at a conference. A Lilly employee found out about it, noted that it pointed toward negative safety implications for olanzapine (Zyprexa) and then had some ideas [bold in original, color highlights added]...
If we work on the assumption that this poster WILL be published as a full manuscript soon, our attention needs to turn to how we can minimise its impact on both the global and local level... Where will this paper be published?... Can we stop/delay it? I think it would be very difficult to delay except if one of our scientists could show them that their methodology was flawed...To review, one idea was to find out where the paper might get submitted for publication, then try to influence the editor, as well as sending out a "communications initiative" in an attempt to bias individuals who might review the article to determine its suitability for publication. Or, "influence" the author -- with what? Cash, a baseball bat, hookers and cocaine, what? How does a drug company that did not even sponsor study X call on study X's lead investigator and tell him, "Hey you really shouldn't publish that!" Unbelievable.
Do we know the author? Can we exert any influence? this would be very dangerous as it would be seen as lilly behaving unethically and applies to the below points.
Who sits on the editorial board of the targeted journal? Can we influence them in any way, with respect to the limitations of this methodology? Should we conduct a communications initiative aimed at all influential referees, addressing the above point?
Happy Ending: The author in question has published multiple studies in the area, so either Lilly thought better of their idea to suppress the evidence or their efforts failed miserably. It would seem as if Lilly may wish to hire a Dr. Purple-type character for future efforts (1, 2, 3)??
Source (one of the infamous Zyprexa Documents).
Here's the deal. If 120,000 employees each get a blog from their employer, that employer will know exactly what those 120,000 employees are saying. Does anyone think for a second that they will say aaaaaaaaaaanything critical? Of course not. Instead you'll have the Internet flooded with happy little messages about the company they work for.Yep, couldn't agree more. Next up: Lilly opens up the Zyprexa Off-Label Blog and AstraZeneca starts the Seroquel Lawsuit Chatline. This will occur shortly after George Bush and Dick Cheney start the Weapons of Mass Destruction -- Lies R Us site.
I'm open to more ideas...
Wednesday, March 21, 2007
There is apparently some talk at J & J about giving every employee their own blog and letting them talk about whatever they want. I can see it now -- this one from a hypothetical employee in the Janssen division...
Time to come clean. We've marketed Risperdal off-label for dementia, bipolar disorder (thank God we eventually got FDA-approved for bipolar!), depression, and pretty much whatever else we could for years. We were involved in getting Texas to adopt those funky TMAP guidelines that essentially mandated that state-funded mental health patients receive pricey drugs like Risperdal, even though the evidence favoring this idea is pretty flimsy. Oh, and Invega -- who's falling for THAT?? Seriously? It's the freaking metabolite of Risperdal. So when Risperdal goes generic, this is how we plan to keep the gravy train rolling. Hey, it worked for Lexapro (son of Celexa). But before you get all upset about it -- everyone else is doing it (1, 2)!Again, this is just what a hypothetical employee might say. Maybe I'm just too cynical. If J & J is cool with employees draping the dirty laundry on blogs, then they've just become my favorite member of the Big Pharma team and I'll sing their praises until the cows come home. I would bet that their PhRMA membership would be immediately revoked should the open blog concept become a reality.
Tuesday, March 20, 2007
The interesting thing about Corlux (mifepristone/RU-486) is that no matter how it fares in clinical trials, it is always a winner. In the latest trial, Corlux was again not effective on the primary outcome measure, which assessed the psychotic symptoms of psychotic depression. This is not surprising, since it has generally shown mediocre results, which are then spun by the company executives/academics as evidence of treatment effectiveness. Oh, and despite this being pushed as a treatment for psychotic depression, the treatment has never yielded anything resembling efficacy for depression, which strikes me as pretty odd.
Dr. Joseph Belanoff, Corcept CEO, had the following to say about the latest trial results:
In other words, there was no difference between any of the three groups taking Corlux and placebo. None. So it appears that they started data dredging (e.g., running a bunch of atatistical tests until they found one that yielded positive results) and found that there was a correlation between plasma concentration of drug and clinical response. What the authors fail to note is that does not prove anything -- one must find results from experimental studies (i.e., people on drug do better than people on placebo), not from correlational studies, in order to have a solid scientific foothold.
While we are disappointed that the trial did not meet the primary endpoint, we are particularly encouraged to have met the important predefined threshold concentration endpoint with statistical significance," said Joseph K. Belanoff, M.D., Corcept's Chief Executive Officer. "This study confirms our previous observation that at higher plasma levels the drug candidate is able to demonstrate desired clinical effects. In particular, those patients in Study 06 who achieved a predetermined level of 1661 nanograms of CORLUX per milliliter of plasma separated from the placebo group with statistical significance.
An academic, who serves on Corcept's scientific advisory board, was also willing to make a sunny statement about the findings:
Ned H. Kalin, M.D., Hedberg Professor and Chair of the Department of Psychiatry at the University of Wisconsin, said, "The correlation between plasma levels of drug and response rates found in this trial is very exciting. The results of this study show that when psychotically depressed patients achieve a threshold concentration of CORLUX in their system, a rapid and sustained clinical response is likely. This is a strong demonstration of a drug effect in an illness that is potentially devastating and difficult to treat."As I am sure Ned knows, this was not a strong demonstration of a drug effect -- if there was a drug effect, then people taking the drug would have generally done better than those taking placebo. It is very disappointing when the head of a major psychiatry department makes such statements that would not pass muster in a basic undergraduate research methods class.
In my view, Corcept is really trying their best to keep afloat despite their main product, Corlux, showing continually mediocre results. Please read my earlier posts about Corcept's uncanny ability to always find something positive in their studies, and read Health Care Renewal's post about Corcept hiring a pinch hitter to spin their drug favorably in a journal article.
Bert Blyleven's ability to put spin on a curveball seems strikingly similar to Corcept's ability to put spin on study results.
Monday, March 19, 2007
I have been tagged for a Thinking Blogger Award by two sites in the recent past. Thanks to both Junkfood Science and ShrinkRap for the kind nominations.
When one is nominated, it is apparently one’s duty to pass along five sites that make one think. Um, ONLY five? That’s tough, since I draw inspiration from many sources, which is a credit to the many excellent mental health and scientific misconduct-related blogs. So, in alphabetical order, I offer the following, with no insult intended for the many other great sites I visit regularly that did not make the list… [Update: Links to sites below now functional]
Again, I feel bad limiting the list to only five, but rules are rules! If you have been nominated and want to play the game, then you must do the following:
1. If, and only if, you get tagged, write a post with links to five (no more, no less!) blogs that make you think,
2. Link to this post so that people can easily find the exact origin of this blog-love thread,
3. Optional: Proudly display the 'Thinking Blogger Award' with a link to the post that you wrote (here is an alternative silver version if gold doesn't fit your blog).
Friday, March 16, 2007
- The Daubert challenge is dissected at the AHRP blog. Any time a legal challenge is based on "expert consensus" in a field, one should be afraid, since we all know that expert consensus tends to dovetail oh-so-nicely with the Big Pharma party line.
- AHRP also slams what appears to be the overprescription of psych meds for children in foster care.
- Philip Dawdy has taken the lead on pointing out that the great state of Montana is accusing Lilly of doing some pretty bad things in its promotion of Zyprexa.
- Brandweek NRX notes that a Lilly spokesperson named Marni Lemons is attempting to make "lemonade" out of the Zyprexa situation (an apt analogy), and that she has proven her acting mettle in a venue outside of her professional role.
- Health Care Renewal takes a couple of shots at the University of California system for poor use of resources as well as corruption.
- The Great Beaver Controversy continues -- starting with John Mack, then moving to PharmaGiles and PharmaGossip (here and here).
- Pharmalot indicates that the Supreme Court may review the practice of Big Pharma paying off generic manufacturers to not introduce generic competitors to the market. Back story here and here.
- Seroxat Secrets raises some questions about Alastair Benbow and the Big Lies about Paxil/Seroxat.
One researcher has described the link as follows:
We found that paternal age explained over a quarter of the risk for schizophrenia in the population. At the time, people were skeptical. But the findings have been replicated many times now, and not a single study has failed to find this strong relationship between father's age and the risk for schizophrenia. And at this point, other explanations for the relationship have been ruled out, including social factors in the family, prenatal care, and parental psychiatric ailments. There simply seems to be a relationship between paternal age and schizophrenia risk.
Wow – one quarter of the risk for schizophrenia explained by paternal age? I’ll admit that these types of studies are not my area of expertise, but from my review of some of these studies, I’m willing to buy that paternal age is a significant risk. These findings have indeed been replicated on numerous occasions.
One of the main researchers in the area, Dolores Malaspina (quoted above), has said that findings such as this should not discourage parents from having children at whatever age they choose. I am not in agreement – older parents should be made aware of the risk and make an informed decision.
Why the effect? Here’s what seems to be a decent explanation…
"Every cell division makes a copy of DNA," [researcher] Gavrilova says. "And the same thing happens with the next division and this final copy is of less quality. This can introduce a slight risk of error in the genetic material of the new sperm. You can call it a kind of copy error.
The longer a man ages, the greater the chance of sperm mutations that could lead to schizophrenia or other problems in offspring.
There is also research linking autism to older fathers. It appears that such information is not widely known. I was certainly not familiar with it until recently. Consider the trends in Western societies – fathers having children at older ages is likely leading to a decent sized increase in rates of schizophrenia, autism, and perhaps other problems as well. While this is excellent news if one is in the antipsychotic business, is this really good news for everyone else?
Shouldn't this information be more widely discussed?
Hat Tip: Just Noticeable Differences.
Thursday, March 15, 2007
The Procter & Gamble –Aubrey Blumsohnn saga has officially turned into tragicomedy to the 7th power. As you may know, Blumsohn was performing research for P & G regarding its osteoporosis drug Actonel. To make a long story short, Blumsohn discovered that P & G’s data analysis strongly appeared to differ from reality. When Blumsohn attempted to make such knowledge public, he nearly lost his job. But worry not, the poorly done data analyses resulted in several scientific presentations and a publication in the Journal of Bone and Mineral Research that has yet to be retracted. So the official scientific record still seems to paint an unrealistically favorable picture of P & G’s Actonel.
Latest Installment: Dr. Blumsohn has decided to present the results of some of the real data analyses, (i.e., data not, um, creatively analyzed, by Procter & Gamble) so that the scientific and medical communities may become familiar with what appears to be the real story of Actonel rather than the PR currently posing as the official scientific record.
Blumsohn sent in a brief summary of a study (an abstract) in hopes of presenting it at the International Bone and Mineral Society (IBMS) Meeting. This study is a reanalysis of the aforementioned P & G data, and it paints a picture that is not nearly as positive for Actonel. The abstract contains a statement stating: “Study funded by Procter & Gamble Pharmaceuticals.” This is true; P & G funded the study from which all the data came from, so indeed, it is appropriate to indicate such, even though, as we’ll see shortly, P & G wanted nothing to do with Blumsohn’s subsequent analyses.
Enter Dr. Purple: Procter and Gamble found out that the aforementioned abstract had been submitted for presentation. A man named Dr. Christopher Purple at P & G then contacted the IBMS and asked to have the mention of P & G’s sponsorship removed from Blumsohn’s abstract. Mind you, Dr. Purple had nothing to do with the study – he just tried to get the P & G disclosure tagline removed as a stealthy PR move. The IBMS people then replied to Dr. Purple that the P & G line would indeed be removed.
Unfortunately for Dr. Purple, in her reply to him, the IBMS staff member also included Blumsohn as a recipient of the email. Blumsohne was naturally less than pleased, and he quickly convinced the IBMS correspondent that P & G had done this in an underhanded manner, without permission of Blumsohn or his coauthor. The P & G disclosure tagline was then re-added to the abstract.
Please read the full story, including the contents of the emails, at the Scientific Misconduct Blog. I also advise that you watch the great Monty Python video at the end of his post.
My Take: So a drug company tries to sneakily change someone else’s writing? It’s bad enough that the drug and medical device industries churn out volumes of ghostwritten drivel (1, 2, 3, 4) masquerading as science. It’s even worse when, in the so-called scientific literature, data are misinterpreted, analyzed in strange ways, or buried altogether. Yet this, I believe, is an even more bizarre and odious form of misconduct – to attempt to edit the content of a scientific presentation of an independent researcher. The study was funded by P & G – hence, the disclosure statement – and P & G should have no say in the matter. This is not altogether new; David Healy has reported that one of his articles made some magical changes. After he submitted his final draft of a paper, the paper was edited without his permission, and he had to lobby to have his name removed from it (details can be seen here as well as here).
Perhaps I’ll email the good Dr. Purple and see if he has an opinion he’d like to share on the matter.
Tuesday, March 13, 2007
BP-NOS: In the February 2007 issue of the Journal of the American Academy of Child and Adolescent Psychiatry is a study where the demon of bipolar disorder not otherwise specified (bipolar NOS) rears its ugly head. Check this out.
Children, aged 7 to 17 years, in this study could be diagnosed with bipolar NOS if they had a
distinct period of abnormally elevated, expansive, or irritable mood*plus two of the following symptoms (three if irritated mood only) that were "clearly associated with the onset of abnormal mood"
(1) inflated self-esteem or grandiosity
(2) decreased need for sleep (e.g., feels rested after only 3 hours of sleep)
(3) more talkative than usual or pressure to keep talking
(4) flight of ideas or subjective experience that thoughts are racing
(5) distractibility (i.e., attention too easily drawn to unimportant or irrelevant external stimuli
(6) increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation
(7) excessive involvement in pleasurable activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments)
*The above symptoms must have been associated with "clear change in functioning"
*Mood and symptom duration of a minimum of 4 hours within a 24-hour period for a day to count toward bipolar disorder diagnosis
*"A minimum of 4 days (not necessarily consecutive) meeting the mood, symptom, duration and functional change criteria over the subject's lifetime, which could be two 2-day episodes, four 1-day episodes, and so forth."
What This Means: Suppose little Johnny (age 9) is throwing tantrums, beating on his little sister, and generally being a behavior problem. In addition, he thinks he is really important (inflated self-esteem), not sleeping much, talks pretty fast, has a hard time keeping on one subject when speaking, is distractible, engages in an "excessive" amount of physical play, and engages in some higher risk play activities. During these times, Johnny annoys his parents, other kids, and his teachers.
Some combination of the behaviors listed above generally occur for four to six hours at a time, except that his sleep is poor at times for a couple days at a time. Suppose he's had a total of 6 days in his life when this type of behavior has occurred. Well, according to some researchers, it is clear that lil' Johnny has bipolar disorder NOS, though it seems to me like he's just a nine year old whose behavior could at times be better, as is the case with most boys his age.
If Kids Have Bipolar Disorder: Of course, the upshot to a bipolar diagnosis is that it requires treatment, so should we really be breaking out Zyprexa, Depakote, or Risperdal for Johnny? As the diagnostic criteria become increasingly liberal, medication will be dispensed more frequently to those who need it less or not at all. Yet this passes for scientific progress in some circles. Kids who are now "bipolar" were labeled as having conduct disorder and/or ADHD (or were not given a label -- God forbid!) a few years ago, but the bipolar child/adolescent paradigm is now sweeping across parts of the nation despite the rather meager data that this disorder exists to any meaningful degree or that treatment yields much benefit, especially in the longer-term.
Do Kids Have Bipolar Disorder? In some cases, I think they do, especially in adolescence. But we are absolutely kidding ourselves by labeling every moody kid with an occasional behavior problem as "bipolar". It is this kind of diagnosis-extension program that leads many people to claim that psychiatry cares more about expanding market share than anything else.
For a great read on this topic, please read Intueri's earlier post. Also feel free to read my earlier post about incredulous statements made regarding bipolar children.
Friday, March 09, 2007
Health Care Renewal has a great post about how teaching is the bottom priority at many academic medical centers where physicians are trained. Teaching physicians are paid less than public school teachers for their teaching duties in many instances, and nearly always get paid much less per hour for teaching than for research or patient care.
I've known psychologists and psychiatrists at medical centers and they often seemed nervous to me. Why? Because their salary was based on algorithms that most closely resembled a Choose Your Own Adventure book.
The base salary was close to nil, and they then had to make their salary through seeing patients and/or working on funded research. If you wanted to work on research on something unsexy (read: not funded by the government or a drug company), you were pretty much doing it for free. Hence the lack of academics working at medical centers who can conduct research that challenges the dominant paradigms of today. Teaching? Hey, just because they were teaching future psychologists and physicians doesn't mean they actually got paid for it.
Maybe that's also why academics at medical centers also tend to avoid speaking out in most cases -- they wouldn't want to get labeled as a "bad apple" who no drug company wishes to fund. Maybe that person could find some government grant money but getting blacklisted by Big Pharma does not exactly make you a top dog for getting government money.
If you follow the "correct" choices, you can make a bunch of money and become a "key opinion leader." If you choose incorrectly, well, you can become David Kern, Betty Dong, David Healy, Nancy Olivieri, Gretchen LeFever, or the like.
Read Health Care Renewal's excellent take on the situation.
I appreciate that the FDA is getting off its duff, but Stephany at the Soulful Sepulcher has an even better idea -- how about the FDA investigating the safety of psychiatric medications in kids? Something tells me that Zyprexa, Seroquel, and Depakote might, just maybe, have more safety issues in kids than Dimetapp or Robitussin. Hey, maybe there is a problem with the cold meds, but can we at least consider that heavy duty psych meds might also impact the health of youth? After all, meds such as the atypical antipsychotics are experiencing quite the boom in prescriptions for kids -- wouldn't we want to be sure that this boom was not leading to a corresponding increase in health problems?
Transcripts of the meeting (part 1 and part 2) are also available. Kudos to the FDA for their willingness to post all this material online.
Hat Tip: ShrinkRap.
- My vote for informed rant of the week easily goes to Philip Dawdy, who covers many topics in his post about a man with schizophrenia who is running into problems with, to use Dawdy's words, the "Nanny State."
- Regarding Deborah Powell, Dean of the University of Minnesota Medical School, taking a seat on the board of PepsiAmericas, please check out Health Care Renewal and the Periodic Table. In fact, Health Care Renewal has been bubbling with a slew of good stuff this week.
- Pharma Giles is now, at least in my world, the undisputed king of acronyms! Check out the TAMPONED initiative and what kind of TARTS make such a program possible. Under the TARTS link, make sure to read the section about SSRIs.
- Bipolar Blast has a good post regarding problems related to withdrawing from benzodiazepines.
- Speaking of drug withdrawal, Fiddaman has an excellent picture that summarizes the problem (well, one of many problems) with Paxil/Seroxat quite nicely.
- On the same topic, Seroxat Secrets has also been going to town about Seroxat's problems.
- In addition, Depression Introspection wonders if there's something fishy about the Mood Disorders Questionnaire.
- And as always, check out PharmaGossip and Pharmalot to catch the latest breaking news on almost everything of note in the Pharma world.
Thursday, March 08, 2007
Much has been made of the Texas Medication Algorithm Project. I have written about it earlier (1, 2), as have others (3). A lawsuit has been filed alleging that TMAP was a sneaky way to convince state mental health programs to switch their patients to newer, much more expensive medications. TMAP defenders, on the other hand, say that TMAP was simply allowing patients access to the state of the art, most effective medications.
What is TMAP? Essentially, TMAP is a program that used “expert consensus” to develop treatment guidelines for patients (depression, bipolar, and schizophrenia) in the public mental health system. On one hand, I can see why care should be improved – not many people seriously argue that patient care is very good in most public mental health systems.
According to the TMAP model, medication treatment is provided in stages according to these guidelines. If you are not responding to treatment #1, then you move to treatment #2, and if that does not work, then to treatment #3, and so on. Naturally, the “objective experts” who developed said guidelines stuck the newer, more expensive medications on the top of the list for treatments, especially as the guidelines have been revised during the past couple of years.
TMAP was unfurled in the mid 1990’s and similar programs have since been sweeping across many states.
Was this a way to backdoor newer medications onto patients? Well, I think that is probably the case, but the issue I am going to address here is one that I think is even more important…
Does TMAP Work? Do TMAP patients show more improvement than patients who were not on the TMAP treatment regimen? The TMAP team has produced some evidence in which they claim that TMAP treatment works better than “treatment as usual,” which was standard state mental health care. In this case, we’ll discuss TMAP for bipolar patients.
The Study: Some patients received TMAP, which included both a standardized medication algorithm as follows:Manic:
Stage 1 – Depakote or Lithium or Tegretol
Stage 2 – Depakote + Lithium OR Tegretol + Lithium
Stage 3 – Depakote + Lithium OR Tegretol + Lithium
Stage 4 – Depakote + Tegretol
Stage 5 – Add atypical antipsychotic to mood stabilizer
Stage 6 – ECT
Stage 7 – Other (e.g., Lamictal, Neurontin)
Stage 1 – Wellbutrin or SSRI + mood stabilizer
Stage 2 – Wellbutrin or SSRI or Effexor or Serzone + mood stabilizer
Stage 3 – Mood Stabilizer + two antidpressants
Stage 4 – Mood Stabilizer and MAOI antidepressant
Stage 5 – ECT
Stage 6 – Other (e.g., Lamictal)
Note that in the 2005 revision of this standard, atypical antipsychotics are featured much more prominently. But when the study on bipolar patients was conducted, this was not the case.
Those who received “treatment as usual” (TAU) received whatever care they would normally receive.
The Results: On some measures, TMAP patients did modestly better than TAU patients. This could be interpreted as evidence that these strict treatment algorithms that involve a high frequency of prescribing Depakote and Tegretol, and to a lesser extent, newer antipsychotics, are a good idea for patients. However, one would be fooling oneself to buy this conclusion. Why?
The (Huge) Caveat: The TMAP patients all received: Group education, consumer to consumer discussion groups, individual patient education from the physician, referrals to therapy groups and more. These interventions were rolled out exclusively for the TMAP group. Why does this matter? Well, patients in the TMAP group were likely getting more time with their physician, which is likely going to boost their relationship with the physician, which will likely lead to better outcomes regardless of the medication taken. In addition, the patient education groups provide additional support for patients, which has been shown to improve outcomes.
Even the study authors, to their credit, admit this is a gigantic potential issue:
At this time, the relative contributions of different elements [i.e., medication versus the extra patient care] of the “disease management package” to the obtained results has not been evaluated.
A Better Idea for TMAP: If you wanted a study that would have compared the effects of a) extra patient education and support, b) use of medication algorithms that favored use of newer medications and c) “treatment as usual” – regular care in the state mental health system, then why not have a study that looks like this:
A) Treatment as usual (No extra patient support)
B) Extra Patient Support + TMAP Algorithms
C) TMAP Algorithms (No extra patient support)
D) Extra Patient Support + Treatment as usual
If C’s outcomes are better than A’s outcomes, then you can shout about the evidence base of your algorithms. If B is greater than D, then you can also do your evidence-based practice speech. However, the TMAP bipolar study as was actually conducted was A versus B, – that is a pretty lame comparison. Was it the patient support (which is my guess) or was it the algorithms?
Why Was TMAP Investigated This Way? This is where it gets interesting but murky. Could such a study have been designed because it was biased to find favorable results for the TMAP intervention (due to TMAP patients receiving extra support not received by treatment as usual)? Then, finding positive results, it becomes a lot easier to sell the program to other states because TMAP is now “evidence based”. Maybe I’m off in Conspiracyville, but one has to admit this is pretty weird stuff.
Wednesday, March 07, 2007
It is amazing what passes for evidence these days in psychiatry. A December article in the journal Current Psychiatry is titled “Antipsychotics for patients without psychosis? What clinical trials support”. It’s a doozy. As you can see from the table above, the authors are in favor of antipsychotics for many conditions. More on the table later.
The authors point out a positive feature of second generation antipsychotics (SGAs; Risperdal, Zyprexa, Seroquel, Abilify, Geodon). The sentence reads:
In schizophrenia patients, antipsychotics have been shown to improve psychotic and nonpsychotic symptoms [long list]…, insomnia, poor appetite, …
Sure, it might lead to diabetes, but enjoy your increased appetite in the meantime! Sure, you might feel entirely zonked out for much of the day, but that’s part of improving your insomnia. How’s that for spin?
SGAs do offer clinicians unique tools; no other class of psychotropics can claim efficacy in psychotic disorders, bipolar disorder, depression, and other disorders we describe in this review.
This is quite reminiscent of the attempts of Janssen to label Risperdal as a “broad spectrum psychotropic agent” and of Lilly to label Zyprexa as “the safe, proven solution in mood, thought, and behavior disorders.” The evidence for these medications as treatments for depression is quite weak, especially in the context of their heavy side effect burden.
The article goes on to discuss the “evidence,” nearly all of it quite meager, that allegedly supports the use of SGAs in obsessive-compulsive disorder, PTSD, social anxiety disorder, developmental disorders, and personality disorders. In no case is it ever mentioned how large of an effect these medications have versus a placebo. The authors almost entirely discuss positive findings, no matter how small the positive effects were in the clinical trials they cite. Non-positive findings are rarely mentioned, as is par for the course in most review articles in psychiatry.
So, let’s have a brief review of what the clinical trial data actually say about the use of SGAs for these various nonpsychotic conditions.
OCD: For people with OCD who have not shown much improvement after receiving an SSRI (Zoloft, Paxil, etc.), adding an SGA may bring, on average, a small benefit. On the other hand, the side effect profile, as mentioned earlier, is likely to not be friendly. Assuming that an individual stops taking the antipsychotic at some point, it is quite likely that whatever benefit was gained from the medication will be lost. Nowhere mentioned in the article is the prospect of behavioral psychotherapy, which has a pretty good (though not great) track record in treating OCD without the, um, “improvements” in sleep and appetite brought on by SGAs.
PTSD: Evidence for SGAs so weak it barely merits comment. Please let me know if I’m missing something here.
Social Phobia: No kidding. If you give people a major tranquilizer like Zyprexa, they will probably feel somewhat less anxious. Again, check out the side effect profile and determine if a lifetime of Zyprexa makes sense in treating social anxiety. Again, there are nondrug treatments that often work pretty well, so why would someone prescribe an SGA for social anxiety? Oh, and there is very little data to actually support that SGAs actually work for social anxiety.
Borderline Personality Disorder: Again, throwing a big tranquilizer at people who are impulsive may calm them down a bit. But has anyone ever heard of a personality disorder being changed significantly by the administration of an antipsychotic? The evidence is pretty clear that SGAs yield only modest effects for borderline personality.
Alzheimer’s/Dementia: Here’s a quote you cannot miss, because it is featured in white text against a black background on the fourth page of the article:
SGAs remain the first therapeutic option for psychosis and agitation in Alzheimer’s patients.Yeah, so what if they are linked to a higher rate of death among patients in this group? The authors acknowledge this point, and also acknowledge the findings of a recent study (CATIE-AD) which found poor efficacy for SGAs in Alzheimer’s patients. Yet they make the statement about SGAs being the “first therapeutic option” – oh, to be a “thought leader” and to make such statements…
Back to The Table: Let's come back to the table (top of page) one more time. The authors' definition of SGA uses being "supported" means that on at least one measure (out of several), the SGA was "significantly" better than a placebo.
What if the difference versus a placebo was small? What if patients still had moderate to severe symptoms after taking the SGA? What if the side effect profile was poor? What about unpublished studies that did not yield any positive results? These questions were, of course, not taken into consideration. It's all about cherry picking the most positive findings.
I could write more about this so-called article, but it is making me cranky and causing my head to spin. Fortunately, I’m sure that SGAs are also effective for dizziness and crankiness – perhaps I should go grab a “safe, gentle psychotropic” and take a nap.
Monday, March 05, 2007
California House Representative Henry Waxman, in his role as chair of the Committee on Oversight and Government Reform, has requested information from Lilly and AstraZeneca regarding their marketing of antipsychotics Zyprexa and Seroquel, respectively. AZ was further asked to provide information regarding its marketing of Actiq, a narcotic lollipop (!) and Fentora, a narcotic lozenge.
Information regarding the safety and purported off-label use of drug coated stents from Boston Scientific and Johnson & Johnson was also requested.
I’d like to point out that bloggers, including Philip Dawdy, myself, and Roy Poses, have written about the shenanigans associated with Zyprexa’s marketing while the major news outlets (except the New York Times) have remained stunningly silent. Perhaps Waxman’s latest move will revive the brain dead media from the fascination with Anna Nicole Smith, Britney Spears, and other stories that are completely unworthy of journalistic attention.
What, is that a blond celebrity with her breasts becoming unhinged from her top? Zy-what? Sero-who? Ugh.
Hat Tip: Furious Seasons.