“Youthful Tendency Disorder (YTD), a poorly understood neurological condition that afflicts an estimated 20 million U.S. children, is characterized by a variety of senseless, unproductive physical and mental exercises, often lasting hours at a time. In the thrall of YTD, sufferers run, jump, climb, twirl, shout, dance, do cartwheels, and enter unreal, unexplainable states of "make-believe."OK, OK. So this was really from the Onion. But I bet some of you thought it was a real story and you at least have to admit that it was a darn fine bit of satire! In the real world, of course, we have Risperdal and Zyprexa, among others to tame our kids (and make them plump), but I think Juvenol could have been a contender!
"The Youthful child has a kind of love/hate relationship with reality," said Johns Hopkins University YTD expert Dr. Avi Gwertzman. "Unfit to join the adult world, they struggle to learn its mores and rules in a process that can take the entirety of their childhood. In the meantime, their emotional and perceptive problems cause them to act out in unpredictable and extremely juvenile ways. It's as though they can only take so much reality; they have to 'check out,' to go Youthful for a while."
On a beautiful autumn day in Asheville, NC, six-year-old Cameron Boudreaux is swinging on a park swingset–a monotonous, back-and-forth action that apparently gives him solace. Spotting his mother on a nearby bench, Cameron rushes eagerly to her and asks, "Guess what?" His mother responds with a friendly, "What?"
With unbridled glee, Cameron shouts, "Chicken butt!"--cryptic words understood only by him--before laughing and dashing off again, leaving his mother distraught over yet another baffling non-conversation.
"Jesse knows when it's his turn to take out the trash. We've gone over the house rules a dozen times," said Richard Torres, a Davenport, IA, father of three whose nine-year-old son Jesse was recently diagnosed with YTD. "And still he neglects the job time and again."
Slowly, methodically, through an elaborate system of rewards and punishments, Jesse has shown improvement. But the road ahead is long.
"We get a lot of platitudes from the so-called experts," Torres said. "We hear a lot of, 'Oh, he'll grow out of it, just give it time.' That's easy for them to say–their kid's not running around the neighborhood claiming to be Superman."
Help for families struggling with YTD may soon be on the way. At last month's annual AMA Convention, Smithkline-Beecham unveiled Juvenol, a promising YTD drug which, pending FDA approval, could reach the U.S. market as early as next spring. Already available in France and Sweden, Juvenol, the Swedish newspaper Aftonbladet reported, resulted in a 60 percent decrease in running and jumping among users.
But until such help arrives, the parents of YTD sufferers can do little more than try to get through each day.
"I love my child with all my heart," said Alexandra Torres, Jesse's mother. "But when he's in the throes of one of his skipping fits, it's hard not to feel a little envious of parents with normal, healthy children."
Saturday, December 30, 2006
“The primary effectiveness endpoint for the randomized, sham-controlled study was an analysis of the percent responders (greater or equal to 50% decrease in HAM-D score from baseline to exit) between the 2 groups. In an evaluable patient population, 15.3% (17/111) of the active stimulation group were considered responders as compared to 10.0% of the sham group (11/110). The difference was not statistically significant (p=.238). [emphasis in original].” There were five other measures of depression and VNS was superior only one of them. VNS batted one for six in its pivotal outcome study.
To put it in layman’s terms, VNS was no better than sham (fake) VNS therapy. Yet this was the main study upon which the evidence for its efficacy rests. Uncontrolled studies seem to yield results of about 20% relapse at 2-year follow-up. Since these studies are uncontrolled, there is simply no way of knowing about how much of the 20% is due to VNS or the passage of time or other factors. Given that the sham therapy produced pretty much equivalent results to VNS, I believe that something outside of VNS is likely producing much of the 20% remission rate.
I understand the desperation of patients who have not found success through a variety of treatments. Perhaps VNS should be made available for some patients, but should insurers and/or the government pick up the tab for an expensive procedure that has such weak evidence of efficacy? Should controlled research emerge indicating VNS works better than psychotherapy, medication, and other alternatives in the long run, then I’ll gladly eat my words. Until that point, I see no reason to get on the bandwagon.
If readers can add something new to the debate, I'll likely jump in. If readers wish to rehash old, already posted arguments, I won't be participating.
Friday, December 29, 2006
Wednesday, December 20, 2006
I have several other pressing matters to which I must attend for the next little while. I will likely not be posting until the end of December or perhaps early January. However, I will likely be doing some writing on at least some of the following topics in the interim so that I am ready to hit the ground running upon my return.
Medication Algorithm Project Texas
- SSRIs and Suicide
- Troubles associated with having children when older
- Reply to Herb on VNS
- Corcept and mifepristone
Look at the above table. On the left are data from the FDA showing an increased risk of suicide on active treatment. On the right are the current data that the FDA, upon which the recent FDA panel made its recommendations about the risks of SSRI treatment.
David Healy presented the above slide in his testimony to the FDA about a week ago. Below, I present some excerpts from his speech made that same day:
“This study presented by FDA over 3 years ago shows a clearly increased rate of suicides on active treatment. There were more patients, suicides and trials in this study than in the material FDA have presented to this meeting, and this study included withdrawal suicides.
FDA got their 2003 problem to vanish by controlling for age, sex, and the location of the trial giving the results you see on the right.
But if age and sex were substantially imbalanced in these trials, then the studies must have been invalid.
Regarding study location, this year FDA cited lower rates of suicide in
At the 2004 PDAC meeting, FDA did not have all the pediatric trials. I bet they don’t have all the adult studies I’ve seen. We know for certain that all of the 2003 material is not included today. Do you know why not? I know FDA do have the placebo suicide who was taking an antipsychotic, antidepressant and 2 benzodiazepines, but don’t know what they’ve done with him. Do you?”
Healy apparently concluded his remarks with this: “So Truth of Fiction? Well the FDA document and presentation are exceedingly strange and this might following Mark Twain suggest truth. But there is too much blatant manipulation of the data for that. We are left with fiction; perhaps the strangeness derives from the fact that we are missing a key element of a good fiction, namely the final line as to who is doing what to whom.”
For more on the magically changing FDA data on SSRIs and suicide, see my earlier post. Always keep in mind that sponsors were responsible for providing the data, and the sponsors have a history of manipulating the placebo suicide data to make placebo appear more risky. Not that one can entirely blame the sponsors, as FDA has been fully compliant with this manipulation of data. To see how rose-colored glasses have been worn when interpreting the SSRI-suicide data, see another earlier post, which also discusses some of Healy’s work.
There's more to be said about the FDA's handling of this data. Thanks to an anonymous reader for providing me with the chart and speech excerpts.
I’ll be quoting a few pieces from the actual legal document stating claims against Johnson & Johnson in the TMAP case. The lawsuit alleges that J & J (I’ll just generically refer to the defendants as J & J aka Johnson & Johnson throughout this post):
“unduly influenced at least one mental health program decision maker to become a chief proponent of Risperdal’s inclusion in the TMAP protocol and to help secure TMAP’s adoption and implementation.”
Additionally, “After TMAP’s initial adoption by
One more… “Defendants bypassed governmental safeguards and scientific review by promoting TMAP and the related child and adolescent algorithms, TCMAP as “treatment models” developed by panels of “experts.” Defendants relied upon paid consultants on their expert consensus panels, peer-to-peer, or ‘viral’, marketing strategies, and administrative decisions made by a select few public officials to facilitate the adoption of TMAP-like programs in other states. To date, at least seventeen states, including
Here’s the lowdown: TMAP is allegedly based on “expert consensus.” But, the lawsuit is essentially saying that these “experts” were, in some cases, acting as paid J & J shills. These folks were wined, dined, and received payments from J & J while putting the TMAP-related materials together. How many of the “experts” and government officials were in on this? That will hopefully come out during the legal proceedings. As Lilly learned earlier this week, release of company documents often makes for some pretty bad PR. I am by no means stating that more than a few of these “experts” or governmental officials were on the take. If the correct wheels are greased, one needs not bother to bribe everyone.
You can bet there will be more on this...
“Jones' lawsuit alleges that the companies launched a drug named Risperdal in 1994 to treat schizophrenia. About the same time, the state was developing a protocol, or treatment guidelines, for which drugs should be used in public mental health programs. [This is the Texas Medication Algorithm Project.] The defendants "provided substantial financial contributions to and improperly influenced the development" of the protocols, the lawsuit said, and Risperdal took precedence in the protocols over cheaper, equally effective medicines.
The drug later received recommendations as the medicine of choice in the state's mental health protocol for treating children and adolescents, even though it lacked a Food and Drug Administration indication for those age groups, the lawsuit says. It says side effects and health risks include increased chance of stroke, renal failure and hyperglycemia.
The companies pushed Risperdal in other states through paid consultants on expert panels, peer-to-peer marketing strategies and "administrative decisions made by a select few public officials," the lawsuit says. The companies sent an unnamed
The lawsuit says at least 17 states, including
“A commission spokesman did say
That hopefully piqued your interest. Essentially,
The plot thickens. In Pennsylvania, a state official (Steven Fiorello) who was on a committee that helped decide which meds would get used for mental health treatment in state hospitals was charged criminally. Why? Because he had received honoraria and other income from drug companies and failed to disclose these conflicts of interest. My earlier post (Bribery Pays) tells a little more about his story. Why is this relevant? Because the program in
So what about TMAP and money? Oh, right, the lawsuit. That’s coming in my next post…
Tuesday, December 19, 2006
I'm reposting his comment followed by mine. Note that any highlighting is added by myself...
I happened upon your blog and I’d like to take a moment to share my perspective as it relates to several of your postings relating to the VNS Therapy for TRD. Unlike you I do not hold any academic degrees in Psychology or Psychiatry but I do have hands on experiences, research and knowledge of 43 years as a support person to my spouse and as a mental health advocate and activist. Amongst the many hats I’ve worn through the years I’m a retired business executive and entrepreneur as well as a former DBSA (Depression Bipolar Support Alliance) facilitator, President and Board Member of a local chapter and a state appointment as a Guardian Advocate.
While you may be “an academic with a respectable amount of clinical experience and no drug industry funding” you don’t indicate if you’re an M.D. or PhD. nor do you elaborate on what a “respectable amount of clinical experience” represents or the fact that you receive no drug funding. Is the fact you receive no drug funding a shortcoming and/or reflection upon your lack of expertise or abilities? There’s something to making innuendos when reading from a couple of lines of text without really researching and digging deep as I’ve found from some of your commentary. The fact that researchers and other medical professionals receive funding from sponsors is not an indictment of their research, ethics, integrity or honesty or in the case of Dr. Nemeroff an admission of guilt that his research is incorrect or that his peers think any the less of the man’s work. It certainly is an impropriety and rightfully cited but is not necessarily a cause for indictment as to the information. Nor do you explain to your readership the nature of funding for research and without sponsor funding most research would be non-existent.
I shall also add to the other hats that I’ve worn I am also intimately involved in researching the VNS Therapy for TRD simply because my spouse was one of the earliest research study subjects for this treatment option. Unlike you reading the Public Citizen and the comments of Drs. Lurie and Wolfe, both of whom are not trained in the field of Psychology or Psychiatry and both questioning the safety and efficacy when in fact the therapy has safely been used for over 10 years and longer-term study results (2 years) are establishing long-term remissions and efficacy for TRD when compared to the failures of other treatment options for this extremely difficult to treat and disenfranchised group of patients. I also wrote to Dr. Lurie regarding his assertions of a “placebo effect.” I asked him to please cite for me any medical literature relating to a “placebo effect” lasting 3 or more years which many of these patients are experiencing contrary to Public Citizen’s letter(s). I still have not received a response from him. Maybe you’d care to respond as you seem impressed with their writings?
Obviously you’ve not read nor have you commented upon the 300 or more medical professionals and leading researchers, who also take exception to many of your comments, some of whom have correctly divulged their relationships to the sponsor. Then too, so has the membership (about 36,000) of the APA having no relationship to the sponsor responded contradicting your position which you’ve omitted from your commentaries to your readership.
The facts are the D-02 (double-blind study) was an acknowledged blunder from the standpoint of the protocol being based upon the protocols of drug studies but then again I’m sure you had an understanding of that fact. This is a medical device and not a drug and the requirements are different. You also omitted in your commentaries that the independent device panel of experts favorably approved the therapy too. While you seem to arrive at the conclusion that the study was a failure it appears many of your colleagues do not see it as such but as I’ve previously stated you haven’t read their commentaries as it is not apart of the news media’s sensationalistic forms of reporting that you appear to be reading without getting to the nitty-gritty of the story.
I happen to have a website which I utilize as a repository of information that I’ve garnered through the years and a means to share my unbiased thoughts and information relating to the therapy. It is called VNSdepression.com.
The link to the site is:
More importantly from a real-life and real-time standpoint after 37 years of failed psychotherapy, medications, holistic approaches and other alternative as well as adjunctive therapies my spouse has achieved almost 6 years of continuous remission with little or no medications. Then too so are many others who have had similar experiences to my spouse.
While the therapy is not a panacea it does afford a new an innovative approach to a percentage of the most difficult patients to treat with varying degrees of efficacy not obtainable elsewhere and therefore the need for this therapy and the continued research into other new an innovative approaches to treat this unique population of patients.
I’ll add that my spouse’s psychiatrist maintained an attitude similar to yours as it pertained to the initial data but he was willing to listen and be educated. Of his clinical patient load he now has about 14 patients who were some of the worst of the worst now experiencing varying degrees of wellness not achievable through other means. His opinions have changed and this therapy affords him an additional tool to help his patients. This same clinical fact is also being observed and shared by other physicians.
Maybe to help you along in your academics and research on this subject matter is a compilation I’ve made of the comments from other professionals which you can find at the below listed link:
So while I maintain there are doctors, good doctors and better doctors so too do I maintain that when a physician hangs out their shingle to practice it doesn’t indicate if they graduated first or last in the class or if they read headline news articles or seriously delve into the subject matter.
I thank you for this opportunity to share with you and your readership what is in this instance an opposing viewpoint. I am a very vocal advocate for all treatment options that may help this unique and seriously ill population of patients including the oft maligned therapy of ECT. I have known as a support person the desperation of having little or no choice and the pain and anguish of my spouse to end her suffering on eight separate occasions. Today she is depression free, has a reasonable quality of life and looks at life from a much happier perspective regardless of situational stresses and/or trauma.
I’ll respond to your points here – please let me know if I miss anything.
*First, I have a Ph.D., not an M.D. However, the letters after one’s name are not the most relevant marker of one’s expertise, as someone with a lesser education than I, with proper training and education, could certainly know as much or more than myself.
*I have seen many clients suffering from a variety of conditions. There are many, many practitioners with much more clinical experience than myself. You’ll note that in my posts, I typically allude to research, not relying on my clinical experience. One’s clinical experience can prove virtually any point, which is one major reason why research is conducted.
*I find it ironic that you end your post with “warmly” while asking me “Is the fact you receive no drug funding a shortcoming and/or reflection upon your lack of expertise or abilities?” Herb, that ain’t so warm. In any case, I’ll leave it up to my readers to register their opinions regarding my expertise or abilities. I can tell you that I have published several articles in peer-reviewed journals and continue to perform research; personally, I think I’m a pretty good researcher. I am just stating that I have no conflicting financial interests that could potentially impact my work.
*Receiving industry funding is not, in itself, a sign of poor integrity or ethics. Failing to report conflicts of interest, however, is an issue.
*Without industry funding, most drug research would not be conducted. There, I said it. I’ve argued on numerous occasions that “research” is often meaningless – see my posts on the ARISE-RD Risperdal (here) study or another on mifepristone (here) for an example. Due to biased measurement, unrealistic dosages, failure to fully disclose data (suppressing negative findings), biased interpretation of the results (putting a very positive spin on dubious findings), etc. – a lot of so-called research makes for great marketing copy yet often shows few if any advantages for a product over existing (and cheaper) products, or, in many cases, little or no superiority over a placebo.
*Lurie and Wolfe may not be trained in psychology or psychiatry. That is not very relevant. If they can interpret research findings (as it appears they can), their lack of clinical expertise in these areas is not relevant. Similarly, I can look at data on Vioxx and say “Wow, that drug sure killed a lot of people” without being a cardiologist because I can interpret the research.
*As for VNS 2-year outcomes, I tracked down the linked abstract from the Journal of Clinical Psychiatry. Among individuals who showed an initial response to VNS therapy, 22% had a remission of depressive symptoms at 2-year follow-up. I am not impressed.
*What would impress me are solid data from trials in which VNS therapy showed clear superiority to fake-VNS therapy (aka sham VNS therapy). If you have such data to share, please share your reference.
*You cite letters from doctors and (I think) an endorsement from the American Psychiatric Association. I’m not sure about how APA’s 36,000 members tie into this. I don’t believe APA officially endorsed the treatment. You indeed have posts from various physicians on your site. These are a selected sample of individuals who testify to positive experiences. When faced with choosing between clinical opinion and research data, I fall on the side of research
*I am happy to hear that your wife has shown significant improvement in her depression. That is always good news!
*Please feel free to respond if you would like. I am glad that you have taken the time to become involved in this issue.
Sounds nice, but methinks a bit naive. My prediction is that nothing worse than a slap on the wrist awaits Lilly. However, sales of Zyprexa are nearly certain to suffer. Somewhere, AstraZeneca execs are licking their chops as this can only help sales of Seroquel, which may be marketed for anxiety, depression, and alcoholism, along with bipolar and schizophrenia before long.
In addition, it is quite possible that FDA saw the marketing materials and did nothing. Nobody has seriously accused FDA of enforcing its regulations on advertising with anything approaching the barest amount of rigor.
Monday, December 18, 2006
From the article: "In the campaign, called Viva Zyprexa, Lilly told its sales representatives to suggest that doctors prescribe Zyprexa to older patients with symptoms of dementia.
A Lilly executive said that she could not comment on specific documents but that the company had never promoted Zyprexa for off-label uses and that it always showed the marketing materials used by its sales representatives to the Food and Drug Administration, as required by law."
Oh, really? Lilly sales reps were given made-up case scenarios to use in conversations with physicians. One of the cases is described as: " 'Martha,' a widow with adult children “who lives independently and has been your patient for some time.” Martha was described as being agitated and having disturbed sleep, but without the symptoms of paranoia or mania that typically marked a person with schizophrenia or bipolar disorder." Gee, sound like dementia to anyone?
In 2002, the marketing campaign's title was changed to "Zyprexa Limitless." It is unclear if the company was referring to limitless weight gain, limitless new cases of olanzapine-induced diabetes, or trying to pimp olanzapine for a limitless number of conditions.
Part of this campaign featured the use of a patient profile named "Donna" who appeared to possibly have symptoms of bipolar disorder, though it appears the symptoms are mild in severity. What a great way to expand the market -- if someone is irritable and not sleeping regularly, pop a Zyprexa -- the possibilities are "Limitless."
There's much more over at the New York Times. Also see my prior post about the first NYT article on the Zyprexa coverup.
"In this case, you can buy a $10 drug development stock for under a buck, which makes a nice present for someone going to college or needing more money...
Why all the interest in a stage three clinical trial drug development company that this summer reported a setback in trial outcomes?
Corcept is developing state of the art neuropsychiatric medications to treat Psychotic Major Depression, PMD, the number one psychiatric illness that paralyzes some 3 million people a year.
In addition to PMD, Corcept is working with Eli Lilly and other partners to develop a patent portfolio of state of the art psychopharmaceuticals to treat Alzheimers, Catatonia, Cognitive impairment, Cocaine Addiction, Dementia, Delusion, Migraines, Postpartum depression, premature infants, stress, weight gain and a host of widespread concerns using the cortisol mechanism, with fewer side effects than previous medications.
The market for these medications is blockbuster size. CORT is remindful of some other drug companies owned like Alza, Smithkline and Syntex that hit home runs."
So what are you waiting for? Oh, you’re waiting for research that actually backs mifepristone's efficacy given its meager performance to date. Or maybe you’re waiting to see if anyone beside company employees and consultants (here and here) has anything nice to say about the drug. Well, it could be your loss! Personally, I’ll sit this one out.
In a study published in European Psychiatry, Croissant et al. investigated the effects of quetiapine (Seroquel) in preventing relapse for people dependent on alcohol. Their case series of nine patients had a very positive response. In fact, a placebo-controlled trial is currently getting underway, as you can see here. The rub is that Seroquel will be used only to treat individuals with alcohol dependence with comorbid anxiety since, after all, Seroquel is the next great anti-anxiety medication.Oh, if you're new to the site, you may have missed the sarcasm in the last paragraph. You'll catch on with time.
Sunday, December 17, 2006
“To reassure doctors, Lilly also publicly said that when it followed up with patients who had taken Zyprexa in a clinical trial for three years, it found that weight gain appeared to plateau after about nine months. But the company did not discuss a far less reassuring finding in early 1999, disclosed in the documents, that blood sugar levels in the patients increased steadily for three years.
In 2000 and 2001, more warning signs emerged, the documents show. In four surveys conducted by Lilly’s marketing department, the company found that 70 percent of psychiatrists polled had seen at least one of their patients develop high blood sugar or diabetes while taking Zyprexa, compared with about 20 percent for Risperdal or Seroquel. Lilly never disclosed those findings.”
Lilly also instructed its sales reps to downplay the medication’s risks. Lilly’s written response to these documents? “In summary, there is no scientific evidence establishing that Zyprexa causes diabetes.” It also said that the release of the documents was “illegal.” Nice defense – deny it and then say that the documents are not valid because they were obtained illegally. This ought to make for quite a legal spectacle.
Another apt quote from the NYT: “In some ways, the Zyprexa documents are reminiscent of those produced in litigation over Vioxx, which Merck stopped selling in 2004 after a clinical trial proved it caused heart problems. They treat very different conditions, but Zyprexa and Vioxx are not entirely dissimilar. Both were thought to be safer than older and cheaper drugs, becoming bestsellers as a result, but turned out to have serious side effects.”
You really should read the full article, since I have only covered some of the evidence here. The only surprise is that the company documents were made public (Thank You James Gottstein!), as the evidence has been mounting for some time that olanzapine was a risky drug whose small at best efficacy advantages were offset by its nasty tendency to produce diabetes.
Hat Tip: Furious Seasons.
Friday, December 15, 2006
The data: I found one study from which I could estimate the treatment estimate based on the abstract (Kennedy and Emsley, 2006). Here’s what the abstract said, in part: “The efficacy and safety of flexible dosing with the antidepressant agomelatine (25-50 mg/day) was evaluated in a 6-week, double-blind, randomized, placebo-controlled study involving 212 patients who met Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV) criteria for major depressive disorder-current major depressive episode. Patients receiving agomelatine (25 mg and 50 mg/day) had a significantly lower mean Hamilton Rating Scale for Depression (HAM-D) score at endpoint compared with those who received placebo (14.1 +/- 7.7 vs. 16.5 +/- 7.4, p = 0.026)” Based on these means and standard deviations, I come up with an effect size of .31, which is considered small. A small effect does not make for “the ideal antidepressant.”
Duplicate Publication Watch: Read the abstracts from these two articles (Montgomery, 2006 and Kennedy and Emsley, 2006). I reproduced a segment from the Kennedy/Emsley abstract above and here’s a piece from
“In a recent placebo-controlled study, 212 MDD patients were randomly assigned double-blind to receive placebo or agomelatine 25 and 50 mg/day. There was a significant advantage for agomelatine after 6 weeks according to scores on the Hamilton Depression Rating Scale (HAM-D) (P = 0.026) and the Clinical Global Impression Severity (P = 0.017), with an improved response rate (P = 0.03).”
I have not seen the tolerability-related data, but I see not one shred of data to support “additional clinical benefits," unless he's referring to potential improvement in sleep. But if we're thinking of clinical benefits in the manner of better reduction of patient symptoms, there is simply no data to support that assertion. The "gap in the current therapeutic armamentarium" is that current treatments are not much more effective than placebo (as demonstrated by agomelatine), and they have notable side effects. When SSRIs and atypical antipsychotics emerged, they were considered to be much safer and better tolerated treatments than their predecessors and we now know that is not the case. Does this new “ideal” drug have a better safety profile? We had better wait and see before jumping on yet another bandwagon for a treatment that is overly hyped.
By the way, I tried to find more clinical trial data on this drug from the Novartis website, but their clinical trial register was not functional at the time.
Remember folks, if a trial has a huge number of participants, a trivial difference between the drug and placebo will be labeled as statistically significant, but don't be fooled. We must also know the magnitude of the effect, and, as I've noted on many occasions (such as here, here and here), the size of the treatment effect is often fairly unimpressive.
I must include one quote from Carroll's letter: "The study has all the hallmarks of an “experimercial,” a cost-is-no-object exercise driven by a corporate sponsor to create positive publicity for its product in a market niche." This is reminiscent of the ARISE-RD (Risperdal as an add-on treatment for depression) study that I have written much about recently (here, here, and here), in which relatively minimal treatment effects were seen, yet the accompanying press release and, indeed, much of the discussion in the article itself, is overly optimistic regarding the treatment.
Thursday, December 14, 2006
I mentioned yesterday that Dr. Bruce Pollock received a waiver to sit on the Advisory Committee although he was not given a vote. Even without a vote, he was obviously there to share his expert opinion with other members of the committee.
As Carl Elliott mentioned in a piece two days ago,
“In the late 1990s, worries had emerged that patients might become dependent on the SSRIs. To combat the perception that people who stopped using Paxil might experience withdrawal symptoms – or “discontinuation” symptoms, as they were often called – GlaxoSmithKline (then still known as SmithKline Beecham) hired a public relations agency called Ruder Finn. Ruder Finn drafted letters that they planned to submit to scientific journals and that downplayed the idea that Paxil was associated with discontinuation symptoms. According to internal memos, Pollock was one of four psychiatrists whom they planned to invite to “author” the letters.
A letter from Pollock eventually appeared in the Journal of Clinical Psychiatry. Although the wording of Pollock’s letter was somewhat different from the draft written by Ruder Finn, it made all the same points. It even made them in the same order. But there was no disclosure, no mention of industry funding, no mention of “editorial assistance,” and no mention of Ruder Finn. Pollock concluded his letter by saying, “Rather than directing our efforts towards the relatively infrequent, minor and transient discontinuation symptoms associated with SSRI therapy, clinicians may be well advised to focus their energies on the greater issues of efficacy, safety, and patient outcome.” The bottom line: concerns about discontinuation symptoms were overblown.”
It gets even better. Although Pollock was on the GlaxoSmithKline advisory board, he claimed he wrote the letter to the Journal of Clinical Psychiatry himself without seeing the marketing memo that made the same points as his letter. Hey, it’scertainly possible that Pollock is being absolutely honest, but one must admit that it is odd that his letter so closely follows a PR document.
It then gets yet more better (pardon the grammar), but you’ll have to read Elliott’s piece to get the full story.
And people wonder why I was concerned that the FDA panel would avoid making any recommendations that would make a pharmaceutical product appear in a bad light.
One final note. If you go through the documents related to the PR firm and the letter sent to JCP, then you'll also notice that Charles Nemeroff was apparently slated to have his name on a letter regarding this issue. A PubMed search did not find any such letter, so I assume that he did not participate. If he was asked to stick his name on a paper he did not write and he refused, then good for him. Of course, it is possible that Ruder Finn never contacted him -- I don't know. Nemeroff's behavior has been called into question on numerous occasions on this site (here and here for a small sample), and I hope that paroxetine was a case where he got it right.
"A Food and Drug Administration federal panel Wednesday recommended the agency issue its strongest possible warning to alert patients and doctors that antidepressants can increase the risk of suicidal thoughts and behavior in young adults. The panel called for placing the so-called black-box warning on product labels and in medication guides distributed to patients.
Following the vote, FDA officials said they intended to expand the warning to include young adults."
I will need more time to think this one over, but it is certainly more than I expected. I thought nothing would happen. I am sticking with my earlier comments that the FDA review was selective in the data it included, and its trust of industry to release all relevant data was likely naive at best. Since I have not seen data that has done more than break age down into adult versus child/adolescent prior to the release of the FDA data, I really don't know what to make of it. If the data are accurate, it's certainly interesting that age has such an impact upon the drugs' propensity to sometimes cause suicidality.
My final point, for now, is that the whole panic over black box warnings is overblown. Dr. Carol Rabinowitz, president of the American Psychiatric Association, has been quoted on a few occasions saying that black box warnings will lead to less people receiving treatment, and this will increase rates of suicide. My response is that people have a right to know the risks of treatment.
For example, suppose a patient named Bill is prescribed an antidepressant. Within two weeks, he becomes agitated and suicidal. If his physician does not warn him, at the time of prescription, that there is a small chance that the drug will cause him to feel agitated and/or suicidal, then he may believe that the new feelings of suicidality are due to his depression getting worse. Now Bill is thinking, "Wow, even WITH treatment my depression is getting worse. This is hopeless." On the other hand, if Bill is warned, he may think "OK, this drug is not helping -- it might be making me feel worse. Maybe I should call my doctor and see what's happening here." Which line of thinking do you think is more apt to induce suicide?
If you've read my site with any regularity, you know what is coming next... We could sidestep the issue of suicidality, sexual side effects, and the like entirely. We could even have better long term treatment outcomes. It's called psychotherapy instead of medication for depression. Some patients might consider trying it out...
Wednesday, December 13, 2006
"Among the 1,000 people who work in the U.S. Embassy in Iraq, only 33 are Arabic speakers and only six speak the language fluently, according to the Iraq Study Group report released on Wednesday." Add this to the litany of reasons why things aren't going so hot in Iraq...
According to Merrill Goozner, there are conflicts of interest on the FDA panel which will review the link between SSRIs and suicide. Andrew Leon is one member whose links to Big Pharma seem significant, yet FDA issued him a waiver so that he can stay on the panel. Bruce Pollock will not vote, but will be on the committee, and Goozner documents that he also has significant conflicts of interest. Even the consumer advocate is reported as having significant conflicts of interest (!) in terms of her holding stock in drug companies. Apparently the FDA could not locate a consumer advocate without a significant conflict of interest – this is well past strange. For the details, check out Goozner’s post. Give the highly controversial nature of the topic, one would think that the FDA would want the committee to appear as clean as possible. The conflicts of interest do not necessarily mean that the fix is in, but at the very least, it makes for very bad PR.
Aripiprazole (Abilify) is now available in injectable form and is allegedly a great way to calm down patients quickly. Here’s a piece from the press release touting the release of this medication: “ABILIFY Injection provides rapid control of agitation in adults with schizophrenia or bipolar mania at primary endpoint (2 hours).” Let’s see if the numbers actually support this statement…
From one abstract (Andrezina et al 2006) : “At 2 h, mean improvements in PEC scores with IM aripiprazole (-8.0) were significantly greater versus IM placebo (-5.7; p less than or = 0.01).” That is a difference of 2.3 points. The Abilify group changed by 29% more than the placebo.
From another abstract (also Andrezina et al. 2006 in a slightly different study): "Mean improvement in PEC at 2 h was significantly greater for IM aripiprazole (-7.27) vs placebo (-4.78; p less than 0.001)." A difference of 2.49 points. The Abilify group changed 34% more than placebo.What is the PEC, you might wonder. It’s the Positive and Negative Syndrome Scale Excited Component, and I’m willing to venture a guess that a difference of less than three points versus placebo is not particularly compelling clinical evidence. It has five questions, each of which is scored on a 7-point scale.
But wait, there’s more! The first study I mentioned was “A sub-population analysis” of 325 patients with agitation. I’m betting that the second study was just the first study with a few more patients thrown in whose initial scores on the PEC were not as high as in the second study. Looking at the abstracts quickly, one might think they were entirely different studies, but I highly doubt this is the case. I’ll do more research and correct myself if I am wrong, although if an enlightened reader has this information readily available, please let me know.
So, coming back to efficacy, we have a large sample size, which helps make this apparently small difference between drug and placebo turn up as statistically significant. Way too many people are under the impression that statistical significance is the most important thing since sliced bread. All it shows in this case is that there really is a difference between Abilify and placebo – but it does not say if the difference was teeny-tiny or if it was gigantic. To put this in perspective, remember that the PANSS-EC is a 35-point scale. So a difference of 2.3 points is nothing to write home about.
Don’t worry, as is highly common in pharmaceutical press releases discussing research, an academic spokesperson chimed in: “"ABILIFY Injection controls agitation independent of sedation,” according to Michael H. Allen, MD, Director, Emergency Psychiatry, Associate Professor,
Thus, the question for today is as follows: Does Abilify reduce agitation to a meaningful degree more than placebo or does this marketing campaign make you significantly agitated?
Tuesday, December 12, 2006
There’s even more to this study that needs discussion…
There is a moderate effect size difference favoring the combination of risperidone and mood stabilizer over mood stabilizer plus placebo if you look at the endpoint data, which are based on taking participants’ last score and including it in the analysis. For many conditions, this analysis makes some sense. However, we know that manic episodes tend to remit with time. You don’t hear of many manic episodes lasting for several months at a time. In this study, 49% of patients dropped the study from the placebo plus mood stabilizer group versus 35% from the risperidone plus mood stabilizer. This means that the data from the placebo + ms group are coming from an earlier point in time (because the data are taken from the last observation of the patient) than the risperidone + ms group, so the risperidone plus ms group has a better chance of change, due to nothing more than being in the study longer, as manic symptoms tend to decline with time alone. So part of the difference in the endpoint analysis is due to time – we don’t know how much, but I’d bet it is substantial.
So one has to look at the differences at each week, and you’ll find a small effect size favoring risperidone plus ms at week one, a moderate effect size difference at week two, and a small difference at week three. All of these differences are smaller than the endpoint analysis.
Let’s also weigh the risks. In table 5, it can easily be seen that risperidone plus ms related to twice the incidence of somnolence, three times the frequency of an extrapyramidal disorder, and six times the incidence of dizziness compared to the mood stabilizer plus ms. If that is not enough fun for you, consider that the average weight gain for risperidone plus ms was 5.3 pounds versus 1.1 pounds for the placebo plus ms group. Oh, and the effect size for weight gain was higher than the effect size for treatment at any of the weeks. I’m willing to bet that the drug company program from which the infamous graph showing “remission” rates came from did not mention that the between group differences in weight were greater than the differences in manic symptoms.
Of course, the study discussed in this post is old news. There is only so much money to be made by using risperidone (or any other antipsychotic) for three weeks at a time. The real cash is to be made in maintaining patients on medication for as long as possible, which is of course why there is an increasing amount of attention being paid to studying the long-term use of atypical antipsychotics for mania. That, however, is a topic for another day.
The FDA sample finds that the risk for suicidality (suicidal preparation or actions) on SSRI versus placebo is increased to a non statistically significant degree. The odds ratio is 1.23, yielding a p-value of .31. The same analysis finds that suicide risk, when measured as suicidal thoughts or worse (See table 15 in the FDA report), is actually decreased to a nonsignificant degree by SSRIs compared to placebo (OR = .86, p = .16). So, case closed, eh? No evidence of increased suicide – let’s go play golf. Well, not quite. The FDA did find an enhanced risk for suicidality among individuals age 25 and under, but found a protective effect for medication among the elderly (see tables 22-27 starting on page 43).
There’s much more to this analysis, especially when placed in the context of prior research…
Based on an analysis on FDA’s database of trials, Khan et al. (2000) estimated that the risk of completed suicide was about twice as high in participants who took antidepressants versus those who took placebos. Healy (2003) noted that some of the suicides classified as occurring on placebo in trials actually occurred during a placebo washout phase, during which all participants were receiving placebo. Since nobody at the time was receiving antidepressant medication, counting placebo washout events as occurring on placebo is not justified. Healy eliminated suicide and suicidal acts that occurred during placebo washout from his calculations and determined that the rate of completed suicides on SSRIs compared to placebo was higher (Odds ratio = 3.1; 95% CI .4 – 23.1). The odds ratio for any suicidal act on SSRI versus placebo was 2.0 (95% CI 1.2 – 3.3). For readers unfamiliar with what an odds ratio means, please see here and here. For a slightly more advanced treatment of the topic, see here. For a longer post on what other meta-analyses of clinical trials comparing SSRIs to placebo have found, please go here. Suffice to say they have consistently found an elevated risk of suicidal acts and/or risk of completed suicide on SSRI compared to placebo.
Below is a discussion of problems related to the FDA’s method of data collection and how the FDA’s data differs, rather widely, from that found by another analysis.
The FDA study is based upon reports from sponsors. Thus, drug companies were trusted to provide data in an honest fashion. Given that in the cases of paroxetine, sertraline, and fluoxetine, sponsors misleadingly labeled placebo washout suicidal acts as occurring during the double-blind placebo phase, this is an issue. I am not certain if this happened in the current FDA report, but it cannot be ruled out as a possibility. I will be never be sold on the FDA data because I doubt all of these data will be released in a manner that would allow determination of when suicidal events happened in the selected clinical trials. I strongly encourage readers to examine table 14 in the FDA report (page 103) and compare it to Healy’s figures in Table 1 of this document. The rate of suicidal acts in placebo is much higher in the FDA database (0.72%) compared to Healy’s database (0.48%). In addition, the rate on SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) is 1.55% in Healy’s database versus .060% in the FDA database. In comparison to Healy, the FDA has more risk on placebo and much less on SSRIs. Yes, it is clear that the FDA database contained a larger sample of trials than did Healy’s earlier analysis. However, it is equally clear that the data in Healy’s database is likely more trustworthy, as he was able to sort out placebo versus placebo washout, whereas the FDA relied on sponsors to do the sorting out of this data. Healy’s study also appears to have utilized some uncontrolled trials and some active comparator controlled trials (trials in which a medication was compared only to another medication, not a placebo), whereas the FDA numbers are based only on placebo controlled trials. So, yes, I understand that these are different samples of studies, but it is important to note the large differences between them in terms of results. Let’s also not forget that the MHRA (roughly equivalent to the USA’s FDA) did their own analysis and found that the use of SSRIs (even excluding paroxetine, which seems related to a greatly elevated risk of suicidal behavior relative to placebo – see here and here) increased the risk of suicidality.
More will be said by people better informed than myself in the next few days and I hope to keep everyone apprised of what the FDA and others have to say publicly about these findings. The hearing is scheduled in two days (Dec. 13), so more should be forthcoming soon.
Monday, December 11, 2006
According to the AP, Neuronetics will hear word from the FDA on January 26, 2007 regarding whether its transcranial magnetic stimulation (TMS) treatment will receive FDA approval for treating depression.
You may recall that the previous date for FDA approval was delayed, as TMS was to scheduled for an FDA decision in October 2006. According to the AP, “FDA postponed the meeting due to general scheduling conflicts, according to Malvern Pennsylvania-based Neuronetics.” If you insist, we’ll buy that story.
Brief review of TMS therapy here.
First, the discussion about how much it costs to develop a new medication has been quite interesting. You may have heard that it takes an average of $800 million to bring a drug to market, and that figure seems to have been updated to $1.2 billion. Public Citizen, among others (such as Merrill Goozner), have criticized these figures as a major overestimate. Many others have been chiming in as well. Feel free to join the discussion.
In addition, there has been much discussion of Pfizer. Peter Rost, as I posted last week, has been writing some fascinating pieces on Pfizer, and John Mack at the Pharma Marketing Blog is also getting his two cents in. It’s well worth a read.
Here’s the link to the Pharma Marketing Blog. Enjoy!
Saturday, December 09, 2006
You may have thought I had nothing more to say about the ARISE-RD study, in which risperidone (Risperdal) was used as an adjunctive (add-on) treatment for depression, but, incredibly, there is more information pertinent to its discussion. If you are already familiar with the issues surrounding the authorship of the paper, please skip ahead two paragraphs.
You may recall the authorship being altered from when this study was presented in abstract form (presented at the
To quote from my earlier piece on the authorship of this paper: “What did he [Keller] do to get on the study? Keller is credited with “study concept and design,” which I would deem impossible since, if he really conceived and designed the study, he would have appeared as an author on the earlier abstract. Yet he is listed fourth on the list of people who designed the study. He is also credited, along with all of the authors, with “analysis and interpretation of the data” and critical revision of the manuscript for “important intellectual content.” Is it possible that he did a great job of helping to revise the manuscript? I suppose, but it seems there were plenty of other people who were also involved with the writing of the paper. Note that Keller was not credited with “drafting of the manuscript.” So Keller did not recruit participants, provided no administrative support, did not provide statistical expertise, and did not draft the manuscript, but apparently helped design the study after it was completed! Very impressive indeed.
So now, to the point of this post. I tracked down that this study was presented previously on two or three other occasions outside of at the ACNP conference. It was presented at the 2003 American Psychiatric Association conference (possibly in two different forms, though I am not sure on this point) as well as at the 2004 American Psychiatric Association conference and the NCDEU 2003 conference. See here on page 138 for the NCDEU reference and here for the 2003 and 2004 American Psychiatric Association references.
Both Keller and Nemeroff are conspicuously absent from the 2003 and 2004 APA and NCDEU presentations, yet both appear on the final manuscript as authors. Nemeroff appears as the lead author on the 2004 ACNP abstract for the study despite not appearing at all on prior presentations. Keller, who allegedly helped design the study, only appears on the final manuscript -- he appears on not a single presentation of the study data. To top it off, a press release touted Keller and Nemeroff as co-principal investigators on the study. Obviously, if they were really principal investigators, in any meaningful sense of the term, their names would have appeared on all earlier presentations of the data. Before doing this additional research, it seemed Keller’s contributions were minimal at best, and now it appears that Nemeroff’s work can now also be called into question, as he appears nowhere on earlier presentations prior to the ACNP presentation.
At this point, I would say the evidence is quite clear that the changing authorship of the paper had little to do with which authors were responsible for conducting the study, running analyses, and writing the paper. But it sure makes for excellent marketing when big names like Nemeroff and Keller stick their names in the authorship line. Please feel free to read the entire story, starting with a more detailed description of the authorship saga, followed by the covered-up conflicts of interest, and, finally, the tricky use of statistics.
"A senior government scientist who was a focus of a congressional probe into conflicts of interest in medical research admitted in federal court yesterday that he improperly failed to disclose payments of $285,000 he received as a consultant for the pharmaceutical manufacturer Pfizer Inc.
Pearson "Trey" Sunderland III, who was chief of the Geriatric Psychiatry Branch of the National Institute of Mental Health, pleaded guilty in Baltimore to a misdemeanor charge of violating conflict-of-interest rules...
The criminal prosecution of a researcher for violating conflict-of-interest rules is a rarity. But Sunderland's consulting arrangements, which first surfaced in 2004, were among the most egregious of the possible conflicts detailed during the probe by a congressional subcommittee."
"But members of Congress said yesterday that they found it disturbing that even after his guilty plea, Sunderland remains in his federal job, where he is a member of the Public Health Service Commissioned Corps.
"The question now becomes: Will the National Institutes of Health and the Commissioned Corps finally move to terminate Dr. Sunderland's assignment?" Rep. Bart Stupak (D-Mich.) asked in a statement. "Is a criminal guilty plea enough to, at long last, remove Dr. Sunderland from NIH?"
Gee, Bart, asking for accountability? That seems a bit harsh. A slap on the wrist should do just fine.
Of course, Sunderland HAD to be involved in psychiatry. At least he is not alone, as I've documents several other instances of ethically strange and/or scientifically dubious behavior occurring in the mental health profession over the past few months.
Friday, December 08, 2006
I noticed someone was looking under "medicare determination VNS" and stumbled upon my site. I did a little (and I mean very little, sorry) research on the topic. I noticed that Public Citizen recommends (wisely) that vagus nerve stimulation not be covered by Medicare as a depression treatment due to the meager evidence in its support. I suspect that Dr. Charles Nemeroff disagrees.
I could not find any national Medicare policy on VNS, but I found that the state of New York had the following to say: "In 2005, the FDA approved this device for the adjunctive long-term treatment of chronic or recurrent depression for patients 18 years of age or older who are experiencing a major depressive episode and have not had an adequate response to four or more adequate antidepressant treatments. However, based on review of the available scientific literature and other pertinent sources, this Local Coverage Determination (LCD) finds there is not sufficient evidence or support to pay for VNS therapy as reasonable and necessary treatment for depression."
With this sort of evidence based decision making, I have to say "I [HEART]
As Dr. Bahrick aptly points out, there is no evidence that SSRI side effects disappear. Indeed, sexual side effects can be long-lasting.
She starts out by noting “Depending on definitions of sexual dysfunction and methodology, post-market prevalence studies have found rates between 36% and 98%. The 5 to 15% rates of SSRI and SNRI-induced sexual side effects listed in the current drug-insert literature are based on information obtained in the initial trials via spontaneous reports of individuals who had been on the medications for a short time. The differences in reported rates between the pre-market trials and post-market prevalence studies are an artifact of methodology; we now know that when individuals are directly asked about their experience of sexual side effects via either a structured clinical interview or a self-report inventory, we obtain vastly different rate information than if we rely on individuals to spontaneously volunteer personally sensitive information about changes in sexual functioning.”
It was easy to NOT find sexual side effects by making sure to not look for them! Likewise, she notes that although researchers have now noted that sexual side effects occur, they have avoided asking if they persist upon treatment discontinuation. To top if off, researchers have designed measures of sexual side effects that may miss some of the most common and impairing sexual side effects. Note what Bahrick has to say about these effects, which include
“…erections that may be easily achieved and maintained yet are numb or nearly numb; orgasms that are preceded by little sense of building arousal and are experienced as pleasureless or nearly so; and genitals that respond to touch by erection or lubrication but without attendant subjective feelings of arousal. Aspects of normal sexual functioning seem to be mimicked without the attendant capacity to experience pleasure. While SSRI/SNRI-related decreased genital sensation or genital anesthesia, and decreased orgasmic intensity or ejaculatory anhedonia are reported to be uncommon, it is more accurate to say that they are uncommonly assessed. Our literature appears to be building upon the assumption that the symptoms are rare by failing to systematically include such symptoms in our instruments, and by failing to transparently report them when they are included.”
She points out that the most common measure of sexual side effects does not include an item on genital anesthesia. Additionally, “The instrument does include an item related to reduced pleasure of orgasm and its severity. However the item is not separately scored, but rather folded in with two other items related to frequency and timing of orgasm.”
Zajecka and colleagues examined these symptoms in a 1997 publication, yet the data were apparently not reported fully. According to Bahrick, there is only one study (Montejo et al., 1999) that has examined the emergence of sexual side effects after cessation of SSRI medication. In this study, patients who had experienced significant reductions in depressive symptoms in response to an SSRI were switched to amineptine (which impacts the dopaminergic system and noradrenergic systems to a much greater extent than it impacts serotonin) or to Paxil. A third group received amineptine only (they were not switched from an SSRI). Amineptine-only treatment resulted in 4% incidence of sexual dysfunction, whereas the switched-to-Paxil group had an 89% incidence of sexual dysfunction, and the switched-to-amineptine group decreased from a 100% to a 55% incidence of sexual side effects. Mind you, these treatments lasted for six months, so those who switched to amineptine, a drug that rarely induces sexual side effects, still had a high rate of sexual side effects six months after SSRI treatment discontinuation.
In Bahrick’s article, an internet community known as SSRIsex is described, in which discussion of post-SSRI discontinuation sexual side effects is prominent. Indeed, the group is reported to have coined the term Post SSRI Sexual Dysfunction (PSSD). In addition, two case reports (here and here) have been published in 2006 regarding PSSD.
In sum, there is emerging evidence from case reports, an internet discussion group, and at least one empirical study that SSRI-induced sexual dysfunction may last longer than previously thought and is causative of genital anesthesia, ejaculatory anhedonia, and decreased orgasmic intensity.
Here’s hoping that more thorough investigation of this topic will be done. I have a feeling the investigation will occur at about the same time a new antidepressant emerges that does not cause sexual side effects. Wellbutrin has gone generic, so there is no incentive for its manufacturer (Glaxo-Wellcome) to demonstrate the prevalence of long-term SSRI side effects or of the other treatment-emergent side effects mentioned above.
In fact, I’ll lay down an idea here. A drug company could make a me-too ripoff of bupropion (Wellbutrin) and then conduct these very studies on the sexual side effects of SSRIs. Wellbutrin tried to market their drug in such a fashion. Indeed, I’ll not soon forget the Wellbutrin commercial with the man getting on the horse while talking about a lack of sexual side effects. Freud must have been rolling over in his grave! Maybe Wellbutrin’s campaign did not go far enough – they should have sponsored more research on the topic. Or maybe reboxetine can be pulled off the shelf (Are you listening, Pfizer?) and run through trials for FDA approval, though one should read the following case study regarding reboxetine due to its bizarre nature. In any case, if we assume that further research would find long-term sexual side effects related to SSRI’s, there is actually money to be made by making an antidepressant that does not cause sexual side effects, so step to it! Or, God forbid, we can start referring depressed patients for psychotherapy due to its propensity to not cause sexual side effects and its better long-term performance? Nah, that’s crazy talk!
Read the full text of Dr. Audrey Bahrick’s excellent article here. Alas, this link will cease functioning at some point soon because Div. 55 of the APA apparently does not provide a permanent link to back issues of their publication. Email me if the link is broken and you’d like a copy.