Friday, October 01, 2010

Cymbalta and Effexor: Hype Over Science
Remember the hype around the serotonin-norepinephrine reuptake inhibitors (SNRIs)? Effexor and Cymbalta impact both serotonin and norepinephrine, so they should be more effective than SSRI’s in treating depression? Mind you, that’s not a high bar to clear - it’s not like SSRI’s are much better than placebo. So get the hell outta the way, Prozac and Paxil, because Cymbalta and Effexor will unleash their incredible efficacy onto the world of psychiatry. Doubt me? Read this 2009 article regarding the wonders of Pristiq (son of Effexor) and learn about how “The emergence of the selective serotonin reuptake inhibitor (SSRI) and serotonin norepinephrine reuptake inhibitors (SNRI) antidepressants has improved the treatment of MDD.” Or this press release from Wyeth. Or Dr. Danny Carlat’s experience selling Effexor to his peers. I don’t think anyone who has followed drug marketing would deny that both Wyeth and Lilly tried to pimp Effexor and Cymbalta as working better because of their SNRI properties.

But is that actually true? A team of German researchers examined the data and concluded that neither Effexor nor Cymbalta really work better than SSRIs. They actually found a small advantage for Effexor over SSRIs for treatment response (but not depression remission), but they also found that the manufacturer was hiding studies from them (and the rest of the world). I haven’t said this for a while, but enter Charles Nemeroff. To understand the research by the Germans, we first need to recall that a 2008 study (lead author: Nemeroff) found

...the pooled effect size across all comparisons of venlafaxine versus SSRIs reflected an average difference in remission rates of 5.9%, which reflected a NNT of 17 (1/.059), that is, one would expect to treat approximately 17 patients with venlafaxine to see one more success than if all had been treated with another SSRI. Although this difference was reliable and would be important if applied to populations of depressed patients, it is also true that it is modest and might not be noticed by busy clinicians in everyday practice. Nonetheless, an NNT of 17 may be of public health relevance given the large number of patients treated for depression and the significant burden of illness associated with this disorder. [my emphasis]

As I wrote then, the benefit to public health claim is ridiculous. To understand the reasons why this is so laughable, please check out my prior post on the topic. This meta-analysis included a bunch of data from Wyeth that was previously unpublished...

Which leads to the freshly published meta-analysis on how Effexor compares to SSRIs. The German researchers requested unpublished data from Wyeth and only got some of it - you’d think that just maybe Wyeth sent them the “good news” data and maybe held back on some of the “bad news” data. So when an ever-so-small benefit emerged for Effexor (5% high treatment response rate), well, call me crazy, but I ignored it. We’re not playing with a full dataset because the manufacturer wants to keep some of it hidden, so shame on Wyeth and let’s look at Effexor with a little bit of suspicion. So Effexor vs. SSRIs - no difference. Except that more people drop out of clinical trials on Effexor due to side effects compared to SSRIs (about 3% more). So even if you believe that Wyeth’s hidden data really doesn’t impact these findings, we’re left with a very small advantage for Effexor that is probably negated by its slightly higher dropout rates.

Cymbalta. It had a 3% higher dropout rate due to adverse events and the same efficacy as SSRIs. So nothing to write home about, except that it costs a boatload more than generic SSRIs and is harder to tolerate. But Cymbalta has been marketed to the gills and is clearing $3 billion a year in sales. Hey, this is the company marketed Zyprexa for dementia (oops), and for, well, lots of other stuff (1, 2). So it’s not surprising at all that they can take a mediocre antidepressant like Cymbalta and turn it into a big moneymaker - the wonders of a good marketing department. But Depression Hurts and Cymbalta is a painkiller. Well, that’s fine and dandy until you actually look at the data which show Cymbalta doesn’t do much for pain in depression.

It’s time to get over the hype surrounding SNRIs. The next “advance” in antidepressants, well, who knows what it will be - but let’s hope it’s something a little more substantial than SNRIs. But I’m not hopeful. And no, I don’t want to hear anything more about agomelatine.

I know it’s been a long time between posts. So pardon me if my writing is more awful than usual. And it doesn’t mean I will be posting regularly. Thanks to the multiple readers who sent me a copy of this article.

Citation to new meta-analysis of Effexor and Cymbalta:
Schueler, Y., Koesters, M., Wieseler, B., Grouven, U., Kromp, M., Kerekes, M., Kreis, J., Kaiser, T., Becker, T., & Weinmann, S. (2010). A systematic review of duloxetine and venlafaxine in major depression, including unpublished data Acta Psychiatrica Scandinavica DOI: 10.1111/j.1600-0447.2010.01599.x

Friday, May 14, 2010

Eli Lilly: Our Drug Failed, So it Has Serious Potential
These folks at Lilly must think we are exceptionally stupid. As in can't tie our own shoes. A study in the Journal of Psychiatric Research recently found that their experimental antidepressant LY2216684 was no better than placebo. Here are a couple of quotes from the abstract:
LY2216684 did not show statistically significant improvement from baseline compared to placebo in the primary analysis of the Hamilton depression rating scale (HAM-D17) total score. Escitalopram demonstrated significant improvement compared to placebo on the HAM-D17 total score, suggesting adequate assay sensitivity.
On the primary outcome measure, the experimental drug failed whereas Lexapro worked to some extent. I know what you're thinking - "the sample size was probably too small to find a significant effect." Um, you're wrong. How about 269 people on the Lilly drug, 138 on placebo, and 62 on Lexapro.

But wait, here comes the good news...
Both LY2216684 and escitalopram showed statistically significant improvement from baseline on the patient-rated QIDS-SR total score compared to placebo... The results of this initial investigation of LY2216684’s efficacy suggest that it may have antidepressant potential.
The good news for Lilly is that most people who claim to "read journal articles" really just browse the abstract without actually looking at the full text of the paper. For the select few who have nothing better to do than read Lilly propaganda, take a look at Table 2. A total of 12 secondary outcome measures are listed. The Lilly drug beat placebo on... ONE of them. Lilly doesn't say much about how much better their drug was than placebo on the QIDS-SR measure beside throwing around that often meaningless term of "statistically significant." People on the drug improved by 10.2 points whereas placebo patients improved 8.3 points. So about a 20% difference. If you bother to calculate an effect size, it is d = .24, which is quite small and clinically insignificant. So on the ONE measure where the drug was better than placebo, it was by a small margin, and it missed the mark on 11 other secondary measures as well as on the primary outcome measure. But "it may have antidepressant potential." Hell yes, I've never been so exited about a new drug.

By the way, Lilly is apparently trying this wonder drug out in at least five trials. The journal in which this article appeared has published other dubious Eli Lilly research in the past. The editorial review process is clearly working wonders over at the Journal of Psychiatric Research. Sad, really. The journal publishes some really good work, but then runs this kind of junk as well.

Depression Self-Report Sidebar: The self-reported measure on which the drug had an advantage, the Quick Inventory of Depressive Symptoms (QIDS) - it's really awesome, according to Lilly. Remember, it's the only measure on which their experimental failure drug had an advantage over placebo. So the authors wrote "Self-reported depression symptoms, such as those obtained by the QIDS-SR, may be more sensitive than clinician-administered scales for signal detection in clinical studies of depression."

What does Bristol-Myers Squibb think? In three trials of Abilify for depression, self-reports of depression were unfavorable. So the publications for these studies made sure to downplay these depression self-reports by saying that these measures were not sensitive, that they weren't picking up improvements in depression.

So if a self-report provided positive results, then BAM, it's an awesome measure of depression. But if it provided negative results, then it's a horrendously inaccurate measure and should never have been used in the first place.

Citation below. Yes, one of the authors' last names is Kielbasa.

Dubé, S., Dellva, M., Jones, M., Kielbasa, W., Padich, R., Saha, A., & Rao, P. (2010). A study of the effects of LY2216684, a selective norepinephrine reuptake inhibitor, in the treatment of major depression Journal of Psychiatric Research, 44 (6), 356-363 DOI: 10.1016/j.jpsychires.2009.09.013

Friday, April 02, 2010

Charles Nemeroff, Consultant Extraordinaire

The key opinion leader of key opinion leaders. Or Boss of Bosses, if you prefer. In any case, take a peek at the following from Charles Nemeroff's page on the University of Miami's website. Seems like something must have happened in 2006 to slow down Chuck's momentum...

What? This is old news? Yeah, I know. But I just hadn't written much about our friends in the world of drug sales/"academics" lately, so I just had to do this.

Pharmaceutical and Clinical Research Company Scientific Advisory Boards

Abbott Laboratories
- Consultant, Abbott Laboratories, Diagnostics Division, 1986-1992.
- Research and Education Advisory Board for Psychiatry
- Member, 1990 - 2006
- Executive Board, 1991 - 1993, 2003 - 2006
-Antidepressant Advisory Board, 1991 - 1992

ACADIA Pharmaceuticals Clinical Advisory Board
- Member, 2000 - 2006.

AstraZeneca Pharmaceuticals
- Psychiatry Advisory Board, 1997 - 2001.
- Chairman, 1999 - 2002.
- Neuroscience Scientific Advisory Board, 1999 - present.

- Antipsychotic Advisory Board, 2003 - 2006.
- Antidepressant Advisory Board, 2003 - 2006.
- EMSAM Advisory Board - Chairman, 2005-2006.

Cephalon Pharmaceuticals
- Scientific Advisory Board, 2002

Comprehensive Neuroscience, Inc.
- Scientific Advisory Board, 1999 - 2004.

- Scientific Advisory Board, 2001 - 2006

- Scientific Advisory Board, 2002 - 2006.
- Chair, Mechanism of Action Board, 2003 - 2006.

Cypress Biosciences, Inc.
- Board of Directors, 2001 - 2004
- Consultant, 2004 - 2006

Eli Lilly and Company
- Psychiatry Advisory Board, 1990 - 2000.
- Bipolar Advisory Board, 1998 - 1999.
- Consultant, 2002 - 2003.
- Global Neuroscience Advisory Board, 2005 - 2006.

Forest Laboratories
- Citalopram Clinical Advisory Board, 1997 - 2002.
- Psychiatry Scientific Advisory Board, Chairman, 1999 – 2008.

GlaxoSmithKline Advisory Board of Psychiatrists
- Chairman, 1991 - 2004.

Janssen Pharmaceuticals
- Mood Disorders Advisory Board, Member and Chairman, 1998 - 2004.
- Topiramate Advisory Board, Member and Chairman, 1999 - 2001.
- Antipsychotic Advisory Board, Member, 1999 - present.

Johnson & Johnson Scientific Advisory Board, 2007- present.

- Consultant, 2006

Merck Sharp & Dohme Research Laboratories
- Consultant, Neuroscience Research Center, 1994.
- Mood Disorders Advisory Board, 1999 - 2003.

Merck-MedCo Mental Health Advisory Board
- Member, 1996 – 1998

Mt. Cook Pharma
- Board of Directors, 2007 - Present

Neurocrine Biosciences
- Scientific Advisory Board, 1994 - 2004.

- Scientific Advisory Board, 2006

Novadel Pharma
- Board of Directors, 2003 - present
- Chair, Scientific Advisory Committee
- Member, Compensation Committee
- Member, Nominating Committee

Novartis Pharmaceutical Company
- Bipolar Advisory Board Chairman, 2001 - 2003.
- Pediatric Bipolar Advisory Board, 2002 - 2003.
- Antidepressant Advisory Board, 2006.

Organon Pharmaceuticals Psychiatry Advisory Board
- Member, 1997 - 2004.

Otsuka Psychiatry Advisory Board
- Chairman, 2003 - 2006.

- Scientific Advisory Board, 2006 – present.

Pfizer Pharmaceuticals
- Clinical Neuroscience Advisory Board, 2004 - 2006.
- Chair, Antipsychotic Advisory Board, 2004 - 2006.

Quintiles Scientific Advisory Board, 2004 - present

- Stockholder

Roche Laboratories, a Division of Hoffman-LaRoche, Inc.
- Mania Advisory Board, 1993.
- Pharmocogenomics Advisory Board, 2006

- Psychiatry Advisory Board, 2002 - 2005.

- Scientific Advisory Board, 1999 - 2003.

Solvay Pharmaceuticals Psychiatry Advisory Board
- Member, 1991 - 1999.
- Chairman, 1991 - 1999.
- Antipsychotic Advisory Board, 2005 - 2006.

Somerset Pharmaceuticals Psychiatry Advisory Board
- Chair, 2000 - 2004.

Vela Pharmaceuticals
- Scientific Advisory Board, 2001 - 2002.

Wyeth-Ayerst Psychiatric Advisory Board
- Chairman and Member, 1995 - 2002.

Tuesday, March 16, 2010

Research Blogging Awards 2010

Research Blogging Awards 2010

Holy cow, I've been nominated for an award?!? Under the category of best health blog, with eight other nominees. Voting is already closed, and I can pretty much guarantee I didn't win, but it's an honor to have been nominated.

Editorial Support, CME, and the Primary Care Companion

By now, everyone who has been paying attention should know that a journal article which lists "editorial support" is an article that was ghostwritten. Yet the average reader of these articles is apparently uninformed enough to not care. Why else would so many articles get published which feature "editorial support provided by [insert name of ghostwriter here]." One my my favorite journals, under the "so bad, it's good" category, is the Primary Care Companion to the Journal of Clinical Psychiatry. Good articles certainly make their way into the journal, perhaps by accident, but the journal can always be counted on to provide a steady supply of utter garbage.

Here's the acknowledgements section from one recent piece in the journal: "Editorial support was provided by George Rogan, MSc, Phase Five Communications Inc, New York, New York. Mr. Rogan reports no other financial affiliations relevant to the subject of this article." And in case you're wondering, "Funding for editorial support was provided by Bristol-Myers Squibb." If you've somehow guessed that this is an advertorial for Abilify, you win. Other ghostwritten pieces of fluff paid for by BMS include an article discussing the safety profile of Abilify in depression. It states that "In conclusion, this post hoc analysis extends previous findings demonstrating that aripiprazole is safe and generally well tolerated as an augmentation strategy to standard ADT in patients with MDD with a history of an inadequate response to antidepressant medication." But Abilify caused akathisia in a quarter of patients - I think that's a problem.

But wait... there's more. An article based on data from two trials, which showed (allegedly) that Seroquel improves anxiety in patients with bipolar disorder. This piece also acknowledges that it was ghostwritten. And we know that AstraZeneca, manufacturer of Seroquel, has cooked the books on Seroquel in the past. Feel free to look through the journal every month and have a giggle at some of the ridiculous pieces that make their way into print.


You can get your continuing medical education (CME) from the Primary Care Companion as well. One particularly awesome piece of medical wisdom pimped Abilify educated physicians about the best ways to manage resistant depression. This one is a beauty. It was supported by cash from BMS, which features prominently in the "treat aggressively" message of the piece. The article features none other than Michael Thase as the leading discussant. The same guy who was the leading author on a paper which allegedly showed the wonders of Abilify for depression - despite the pesky fact that patients said it didn't work.

Back to the CME.. Thase starts off by stating that only a third of patients achieve remission of depressive symptoms during treatment. Given that Abilify is being marketed for treatment-resistant depression, this is a perfect way to start off this infomercial educational piece. He adds that failure to achieve remission increases the risk of suicide and puts people at risk for more depression, worse psychiatric outcomes, and all sorts of other bad things. So we better get rid of all symptoms of depression. Thase suggests that clinicians should closely monitor patients to see if their symptoms are remitting.

In particular, "Relying on the global statement “I’m definitely better” from the patient overlooks persistent, minor, or residual symptoms. Dr Thase recommended using a standardized symptom assessment measure and keeping track of the patient’s levels of symptom burden." So even if the patient says he or she is much better, don't believe it. Have the patient fill out rating scales and if any symptoms at any level are present, keep treating. In Thase's words, "If the current treatment is well tolerated and the individual has made significant symptom improvement but is still experiencing residual symptoms, then it may be necessary to adjust the treatment dose, add another medication, or combine pharmacotherapy and psychotherapy." Note that adding psychotherapy comes after adding another medication.

Then a series of other objective, expert psychiatrists chime in. Dr. Gaynes offers his wisdom, which includes "Dr Gaynes concluded that incomplete remission requires aggressive identification and management." Don't be afraid - be aggressive. The unspoken message: Hey, using an antipsychotic like Abilify for depression may seem freakin' crazy. But don't worry, you need to be aggressive. Dr. Trivedi then comments about using rating scales to measure side effects. I don't have much to say about his section, but things get worse momentarily...

Dr. Papakostas then checks in. "A meta-analysis of randomized, double-blind, placebo controlled studies found that augmentation of various antidepressants with the atypical antipsychotic agents olanzapine, risperidone, and quetiapine was more efficacious than adjunctive placebo therapy. In addition, Dr Papakostas noted that the atypical antipsychotic aripiprazole was recently approved by the US Food and Drug Administration (FDA) for use as an adjunctive therapy to antidepressants in MDD. Augmenting with atypical antipsychotics has so far been the best studied strategy for managing treatment-resistant depression, said Dr Papakostas." Dr. P was the coauthor of a meta-analysis that provided "considerable evidence" regarding the wonders of antipsychotic therapy for depression. The only problem was that the analysis actually did not find convincing evidence that the drugs were particularly effective, which I discussed in December 2009.

Next comes Dr. Shelton. Time to be aggressive, again: "Thus, said Dr Shelton, the long-term management of depression should be viewed in the context of acute treatment and the need for early aggressive management to get the patient as well as possible." Be aggressive by adding Abilify to the antidepressant regimen. If not, your patient won't achieve full remission and will suffer needlessly... "Dr Shelton advised clinicians to be aggressive in treatment and stay active over time, asking themselves if everything has
honestly been done to help the patient." Psychotherapy is given a brief mention in this section, but let's face it -- most physicians think of "be aggressive" as upping the dosage and/or adding medications - not as "let's be aggressive by adding psychotherapy."

Then there's the exam at the end. Write up your answers, mail them in, and get your medical education credit. Here's one of the questions...
3. Scores on both patient- and clinician-rated scales found that Ms B is still experiencing residual depressive symptoms. You optimize her current SSRI dose, which produces some improvement. She has not reported any problems with side effects. What course of action to improve her outcome has the most comprehensive efficacy data?
a. Increase the dose of her current SSRI again
b. Augment her current SSRI with another SSRI
c. Switch her to a serotonin-norepinephrine reuptake inhibitor
d. Augment her current SSRI with an atypical antipsychotic

If you guessed that D is the correct answer, you're one step closer to CME credit. And one step closer to writing a prescription for Abilify despite the fact that it is as likely to induce akathisia as to induce remission of depressive symptoms. Or that its advantage over placebo is small on several measures and nonexistent on a patient-rated measure of depression. But D is still the "correct" answer.

The offending educational piece is cited below:
Thase, M., Gaynes, B., Papakostas, G., Shelton, R., & Trivedi, M. (2009). Tackling Partial Response to Depression Treatment The Primary Care Companion to The Journal of Clinical Psychiatry, 11 (4), 155-162 DOI: 10.4088/PCC.8133ah3c

Wednesday, March 03, 2010

If You Don't Learn Your Lesson the First Time

I'm short on time, so I apologize for the lack of details. The short of it: A researcher at the University of Sheffield (Guirong Jang) submitted research findings regarding Procter & Gamble's osteoporosis medication Actonel. However, Sheffield had a contract with P & G to only release Actonel data with the permission of P & G. So Dr. Jang is in BIG trouble - as Sheffield wouldn't want to offend its corporate sponsor by releasing any potentially unflattering data. More can be found here.

P & G, Actonel, and trying to effectively manage data to best suit the needs of Actonel's marketing. Hey, wait, this sounds familiar. You may recall the case of Aubrey Blumsohn - a researcher at the same university investigating the same drug, followed by all sorts of strange happenings. Read more on the Blumsohn story here.

Wednesday, February 10, 2010

Say Hello to Temper Dysregulation Disorder with Dysphoria

The buzz around the new version of the DSM is already starting. The draft version is now online and it features a new condition with the ungainly moniker of "Temper Dysregulation Disorder with Dysphoria." That's a friggin' mouthful, so let's try T-Triple D for short. WTF is this disorder? Well, according to my first look, it closely resembles the bad-behavin' kids who have been labeled as bipolar for the last few years. The symptoms are below, and can also be found on the official DSM-V website:

A. The disorder is characterized by severe recurrent temper outbursts in response to common stressors.

1. The temper outbursts are manifest verbally and/or behaviorally, such as in the form of verbal rages, or physical aggression towards people or property.

2. The reaction is grossly out of proportion in intensity or duration to the situation or provocation.

3. The responses are inconsistent with developmental level.

B. Frequency: The temper outbursts occur, on average, three or more times per week.

C. Mood between temper outbursts:

1. Nearly every day, the mood between temper outbursts is persistently negative (irritable, angry, and/or sad).

2. The negative mood is observable by others (e.g., parents, teachers, peers).

D. Duration: Criteria A-C have been present for at least 12 months. Throughout that time, the person has never been without the symptoms of Criteria A-C for more than 3 months at a time.

E. The temper outbursts and/or negative mood are present in at least two settings (at home, at school, or with peers) and must be severe in at least in one setting.

F. Chronological age is at least 6 years (or equivalent developmental level).

G. The onset is before age 10 years.

H. In the past year, there has never been a distinct period lasting more than one day during which abnormally elevated or expansive mood was present most of the day for most days, and the abnormally elevated or expansive mood was accompanied by the onset, or worsening, of three of the “B” criteria of mania (i.e., grandiosity or inflated self esteem, decreased need for sleep, pressured speech, flight of ideas, distractibility, increase in goal directed activity, or excessive involvement in activities with a high potential for painful consequences; see pp. XX). Abnormally elevated mood should be differentiated from developmentally appropriate mood elevation, such as occurs in the context of a highly positive event or its anticipation.

I. The behaviors do not occur exclusively during the course of a Psychotic or Mood Disorder (e.g., Major Depressive Disorder, Dysthymic Disorder, Bipolar Disorder) and are not better accounted for by another mental disorder (e.g., Pervasive Developmental Disorder, post-traumatic stress disorder, separation anxiety disorder). (Note: This diagnosis can co-exist with Oppositional Defiant Disorder, ADHD, Conduct Disorder, and Substance Use Disorders.) The symptoms are not due to the direct physiological effects of a drug of abuse, or to a general medical or neurological condition.

I've not given this a lot of thought yet. The committee that examined the topic has some discussion of T-Triple D/bipolar here and here. The committee takes a couple of digs at the the child bipolar diagnosis. So if this new disorder is adopted, we're going to have yet another name for children who behave badly. Fortunately, the criteria appear to require much worse behavior than what has been passing for "bipolar" according to some child psychiatrists. The diagnostic threshold is higher and should theoretically lead to fewer kids being unnecessarily diagnosed. But even if the current criteria are adopted without any changes - look for a movement to diagnose "subthreshold" cases of T-DDD, as untreated subthreshold T-DDD will be found to cause untold psychological and physical damages across the world. Damages that can only be mitigated through aggressive treatment using [insert name of latest patented tranquilizer here]. So whatever antipsychotics or "mood stabilizers" are hot in 2013 when the DSM-V is released... they will be the "cure" for T-DDD or bipolar or whatever the hell we decide to label kids with behavior problems.

That's my first impression. This is definitely going to be a hot-button topic. There is apparently some mechanism to send comments to the DSM-V folks, since this is only a draft version - feel free to comment here or send your ideas to the DSM-V posse.

Tuesday, January 05, 2010

Do You Have Mild, Moderate, or Severe Depression? Here, Take This Placebo, er, Antidepressant

Yet another meta-analysis with the same damn result -- antidepressants for most cases of depression are placebos. This is in a paper with authors including Jay Amsterdam, Richard Shelton, and Jan Fawcett, who are not exactly cut from the Peter Breggin mold. This was based on six studies which compared antidepressant to placebo in patients who had a wide range of depression severity. Key results:
  • Mild to moderate depression: Effect size of d = .11, which is tiny (and was not statistically significant)
  • Severe depression: Effect size of d = .17, which is pretty darn small (and not statistically significant)
  • Very severe depression: Effect size of d = .47, which is moderate.

Hmmmm. Not looking so hot. Of course, anyone who has paid attention to the clinical trial literature on antidepressants over the past 10 years or so already knew this. But now it's in JAMA, so a wider audience may now pay attention. Or ignore it. Good marketing usually beats science, so maybe this won't make any difference.

Antidepressants for all but very severe depression: All the benefits of placebo plus the added bonus of side effects. Sign me up! To quote the authors: "What makes our findings surprising is the high level of depression symptom severity that appears to be required for clinically meaningful drug/placebo differences to emerge, particularly given the evidence that the majority of patients receiving ADM in clinical practice present with scores below these levels." In other words, most people who receive antidepressants would likely have done just as well on placebo (without the side effects).

A few other posts on the topic:
I've linked the abstract of the latest JAMA study here. Enjoy.