CL Psych

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  • October 1, 2010
  • 03:19 PM
  • 654 views

Cymbalta and Effexor: Hype Over Science

by CL Psych in Clinical Psychology & Psychiatry

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 ... Read more »

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  

  • May 14, 2010
  • 01:22 PM
  • 749 views

Eli Lilly: Our Drug Failed, So it Has Serious Potential

by CL Psych in Clinical Psychology & Psychiatry

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... Read more »

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  

  • March 16, 2010
  • 09:43 AM
  • 785 views

Editorial Support, CME, and the Primary Care Companion

by CL Psych in Clinical Psychology & Psychiatry

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. CMEYou 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 hashonestly 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 againb. Augment her current SSRI with another SSRIc. Switch her to a serotonin-norepinephrine reuptake inhibitord. Augment her current SSRI with an atypical antipsychoticIf 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:... Read more »

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  

  • December 16, 2009
  • 04:08 PM
  • 779 views

Atypical Antipsychotics For Depression: Now With "Considerable Evidence"

by CL Psych in Clinical Psychology & Psychiatry

I've been wanting to write about this for months. Here goes. We know that antipsychotics are the new panacea for all things mental health-related, including depression (1, 2, 3). But critics kept pointing to a pesky lack of evidence that such treatments actually worked. Bristol-Myers Squibb, manufacturer of Abilify, has been running a disinformation campaign in medical journals to tout its drug as an antidepressant. Their attempts to paint a positive picture of Abilify's antidepressant properties and its allegedly fantastic safety/tolerability profile have been simultaneously tragic and amusing (1, 2, 3).We're now moving on to something bigger... It ain't just Abilify, folks. It's all the atypicals. They are all antidepressants. According to the authors of a recent meta-analysis, for atypical antipsychotics: "At present, this body of evidence is considerably larger than that for any other augmentation strategy in the treatment of major depressive disorder." In other words, if you are not prescribing atypicals for your patients who don't show adequate response to antidepressants, you are not practicing evidence-based medicine. You are a [bleeping] cowboy who is willfully disregarding science. You are denying your patients the best possible treatment. The authors don't actually say any of those things, but those are the implications. If the evidence for using antipsychotics is "considerably larger" than the evidence for anything else, then the implications are clear-cut. And this is exactly how this study will be cited. Salespeople, from drug reps to academic psychiatrists, to practitioners looking to earn a few thousand extra bucks on the side through pharma speaking gigs, will discuss this study as if it were a landmark finding.Response and Remission: But the "evidence" is not all that convincing. Here's why... The authors pooled together the results of 16 randomized controlled trials. In these studies, patients had failed to respond adequately (using various definitions) to an antidepressant. Patients were then assigned to receive either an atypical antipsychotic or a placebo in addition to their antidepressant. Outcomes were then tabulated somewhere between 4 and 12 weeks later. The results seem clear cut -- if your brain is turned to "off" -- the response rates for atypicals was 44% compared to 30% for placebo. The remission rates were 31% for atypicals and 17% for placebo. The advantage for atypicals is statistically significant. Well, there you have it. Done deal. Ask your doctor about Abilify/Zyprexa/Seroquel today...But the most important thing in a treatment outcome study is... the outcomes. The authors of the meta-analysis did not bother to actually measure change in scores on rating scales. Instead, they only used response and remission rates. There is absolutely no good reason for doing this. It's potentially quite misleading. Doctors like remission and response rates because they provide the illusion that we are measuring depression exactly. A "responder" got a lot better and is functioning reasonably well whereas a "non-responder" is in bed 12 hours a day while spending the rest of her time watching the E! Network, eating Bon-Bons, and sobbing constantly. But it's not nearly that scientific. A "responder" is usually defined as someone who got 50% better on his or her depression rating score during the study period. So Bob's depression rating score improved by 52% (he's a responder), but Amy's score only improved by 48%, so she's a nonresponder. Is this 4% difference really meaningful?Let's look at the following dataset for 20 participants in a fictional study...Improvements in depression over course of 10 week studyDrugPlacebo40%30%55%60%50%45%55%48%52%48%60%55%60%55%10%25%20%10%25%30%Using a 50% improvement to determine if a patient is a "responder", we get a 60% response rate on drug and a 30% response rate on placebo. Lazy logic says: Oooh -- the drug is twice as effective as placebo. But is we take the average for each group, we get an average improvement of 42.7% on the drug compared to 40.6% on placebo. See the problem with response and remission rates? Similar arguments have been made by smarter people than myself.Putting outcomes into convenient little categories makes good sense when the categories themselves make sense - events like having a heart attack, getting pregnant, or dying. If the death rate on a drug is 4% compared to 2% on a placebo, then the drug really reduced death by 50%. But if the "remission rate" or "response rate" for depression is 40% on drug compared to 20% on placebo, that does not mean the drug is twice as effective as placebo in treating depression. If you need to score a 7 or below on a depression rating scale to be "in remission", but you score an 8, are you really much worse off than the person who scored a 7?Am I saying that the drugs really just squeaked by placebo in these studies? Well, I've read the Abilify studies and posted on them previously - in those studies, Abilify barely beat the placebo. And in the opinion of the patients themselves, Abilify didn't beat placebo at all. And the studies were designed to benefit Abilify, not to actually see if the drug worked. As I noted previously...Patients were initially assigned to receive an antidepressant plus a placebo for eight weeks. Those who failed to respond to treatment were assigned to Abilify + antidepressant or placebo + antidepressant. Those who responded during the initial 8 weeks were then eliminated from the study. So we've already established that antidepressant + placebo didn't work for these people -- yet they were then assigned to treatment for 6 weeks with the same treatment (!) and compared to those who were assigned antidepressant + Abilify. So the antidepressant + placebo group started at a huge disadvantage because it was already established that they did not respond well to such a treatment regimen. No wonder Abilify came out on top (albeit by a modest margin).Here's an analogy. A group of 100 students is assigned to be tutored by Tutor A regarding math. The students are all tutored for 8 weeks. The 50 students whose math skills improve are sent on their merry way. That leaves 50 students who did not improve under Tutor A's tutelage. So Tutor B comes along to tutor 25 of these students, while Tutor A sticks with 25 of them. Tutor B's students do somewhat better than Tutor A's students on a math test 6 weeks later. Is Tutor B better than tutor A? Not really a fair comparison between Tutor A and Tutor B, is it?I've not read the other antipsychotics for depression studies. I'll even give them the benefit of the doubt and assume they were not designed in the same biased manner as the Abilify trials. It is, however, worth noting that the "benefit" of Abilify, in terms of response and remission rates compared to placebo, was about the same as for the other atypicals. Which leads me to think that the other atypicals probably show similar marginal benefits for depression.But now, based solely on potentially quite misleading response and remission rates, an article appears in the American Journal of Psychiatry - a piece that has the potential to ramp up the prescribing of antipsychotics for depression to ... Read more »

Nelson, J., & Papakostas, G. (2009) Atypical Antipsychotic Augmentation in Major Depressive Disorder: A Meta-Analysis of Placebo-Controlled Randomized Trials. American Journal of Psychiatry, 166(9), 980-991. DOI: 10.1176/appi.ajp.2009.09030312  

  • October 30, 2009
  • 09:42 AM
  • 888 views

Transcranial Magnetic Stimulation for Depression: Not so Effective, but FDA Approved

by CL Psych in Clinical Psychology & Psychiatry

Apparently, the FDA will approve just about anything as an antidepressant. Despite patients indicating that they don't perceive Abilify to work as an antidepressant, the FDA approved it, likely leading to tens of thousands of Americans being able to enjoy a taste of akathisia while getting all the psychological benefits of a placebo. Good work, FDA. The shift of antipsychotics into antidepressants has been documented in many places and is, ironically, very depressing (1, 2, 3, 4).The FDA's "anything goes" attitude regarding antidepressants apparently extends to mediocre medical devices. In 2007, a paper in Biological Psychiatry presented results from a large trial comparing TMS to sham TMS. The article concluded that the treatment was a fantastic option for depression. Well, close to that anyway. That actually wrote that "Transcranial magnetic stimulation was effective in treating major depression with minimal side effects reported. It offers clinicians a novel alternative for the treatment of this disorder."Before all of us poor depressed souls get in line for some sweet magnetic stimulation, maybe we should, like, look at the evidence. On the primary measure of outcome, the Montgomery-Asberg Depression Rating Scale, the results weren't quite statistically significant. So the sponsor tried to convince the FDA Neurological Devices Panel that the secondary measures showed super-impressive results. The problem: They didn't. The FDA review panel thought a few things (as can be seen in its entirety here):The Panel’s consensus was that the efficacy was not established; some stated that the device’s effectiveness was “small,” “borderline,” “marginal” and “of questionable clinical significance.” The Study 01 endpoint with a p value of 0.057 per se was not considered a fatal flaw in the study analysis. The Panel did not believe that clinical significance was demonstrated with these results.In general, the panel believed that the analyses of the secondary effectiveness endpoints did not contribute significant information to help establish the effectiveness of the device.The Panel agreed that unblinding was greater in the active group, and considering the magnitude of the effect size, it may have influenced the study results. (35.8% of people receiving TMS reported pain at the application site compared to only 3.8% in the sham TMS group. This is a quick way to make a study unblind, as people experiencing pain could logically surmise that they were receiving TMS).The Panel stated that there were too many non-random dropouts to reliably interpret these results. The Panel’s consensus was that the Week 6 data was of limited value and did not provide supportive data for establishing effectiveness. (After week 4, patients who did not show adequate improvement were given the option to quit the double-blind study; over half of patients departed the study after week 4).One more doozy. A quote follows from a letter to the editor in Biological Psychiatry in which TMS is taken to task.The authors note that some patient outcome measures were collected in the trial but omitted from the article. Of the 15 secondary end points the authors included in the paper, 11 were statistically significant. Of 11 secondary end points not included, 2 were statistically significant. Thus, the published end points were three times more likely to be statistically significant than the unpublished ones.TMS was denied FDA-approval in January, 2007. But in October 2008, the FDA had a change of heart, approving the device. I'm not quite sure what changed the mind of the FDA. The following disclaimer on the device's website is a bit funny:NeuroStar TMS Therapy has not been studied in patients who have not received prior antidepressant treatment. Its effectiveness has also not been established in patients who have failed to receive benefit from two or more prior antidepressant medications at minimal effective dose and duration in the current episode. So it's only demonstrated (weak) efficacy in people who have failed one (not zero, not more than one) antidepressant trial. Impressive, eh? To summarize, the sponsor and its affiliated academics wrote a paper in a major psychiatry journal in which positive outcomes were three times as likely to be reported as negative outcomes. The efficacy data were unimpressive according to an FDA panel -- and these panels are not known for being particularly choosy about efficacy data. It seemed that TMS was dead in the water, only to be resurrected in the form of a surprising FDA approval. And if being resurrected from the grave doesn't make for a great Halloween post, then what does?Offending Study:O’Reardon, J., Solvason, H., Janicak, P., Sampson, S., Isenberg, K., Nahas, Z., McDonald, W., Avery, D., Fitzgerald, P., & Loo, C. (2007). Efficacy and Safety of Transcranial Magnetic Stimulation in the Acute Treatment of Major Depression: A Multisite Randomized Controlled Trial Biological Psychiatry, 62 (11), 1208-1216 DOI: 10.1016/j.biopsych.2007.01.018Letter to Editor:Yu, E., & Lurie, P. (2009). Transcranial Magnetic Stimulation Not Proven Effective Biological Psychiatry DOI: 10.1016/j.biopsych.2009.03.026... Read more »

O’Reardon, J., Solvason, H., Janicak, P., Sampson, S., Isenberg, K., Nahas, Z., McDonald, W., Avery, D., Fitzgerald, P., & Loo, C. (2007) Efficacy and Safety of Transcranial Magnetic Stimulation in the Acute Treatment of Major Depression: A Multisite Randomized Controlled Trial. Biological Psychiatry, 62(11), 1208-1216. DOI: 10.1016/j.biopsych.2007.01.018  

Yu, E., & Lurie, P. (2009) Transcranial Magnetic Stimulation Not Proven Effective. Biological Psychiatry. DOI: 10.1016/j.biopsych.2009.03.026  

  • June 9, 2009
  • 07:21 AM
  • 932 views

Abilify for Depression: Patients Give it an Oh-For-Three

by CL Psych in Clinical Psychology & Psychiatry

Abilify for depression: you've seen the ads. You've hopefully read this blog (1, 2) and the excellent series in the LA Times from Melissa Healy. The advantage over placebo is nothing to get particularly excited about. Especially from the patients' point of view. As I have mentioned previously, the two studies that were touted by key opinion leaders are supporting the efficacy of Abilify for depression suffered from a number of problems. Most germane to this post, the patient self-report rating scales did not indicate a significant advantage for Abilify in either study. Well, yet another Abilify for depression study is out in CNS Spectrums and guess what... Still not a significant advantage over placebo according to patients. So in each of three large studies, Abilify has failed to beat a placebo according to patients' self-report. These three trials are the basis for the massive marketing campaign and an FDA approval. Abilify started off as an also-ran antipsychotic. But times have changed. Bristol-Myers Squibb's CEO prophetically stated in 2004 after Abilify's approval as a treatment for bipolar disorder:This approval underscores our commitment to delivering innovative solutions that address unmet needs for a broad spectrum of patients with mental illness, as well as their families and health care providers. He could as easily have stated: "This approval underscores our commitment to rebranding our unpopular antipsychotic as a Swiss Army Knife/broad spectrum psychotropic that treats everything under the sun. If I can get the FDA and the public to believe that this akathisia-inducing bottom feeder can treat depression, then I'll be LOADED, BWAAH, HA HA HA HA!!!" OK, maybe he didn't actually say any of those things, but his "broad spectrum" comment was literally right on the money. Just don't ask those pesky patients what they think; they might tell you it's no better than a damn sugar pill. Yes, I'm aware that on some other rating scales, Abilify was rated as superior to a placebo, but I'm thinking that if the patient self-report of depression is consistently not favorable for Abilify, then who are we kidding by calling it an antidepressant?Robert M. Berman, Maurizio Fava, Michael E. Thase, Madhukar H. Trivedi, René Swanink, Robert D. McQuade, William H. Carson, David Adson, Leslie Taylor, James Hazel, & Ronald N. Marcus (2009). Aripiprazole Augmentation in Major Depressive Disorder: A Double-Blind, Placebo-Controlled Study in Patients with Inadequate Response to Antidepressants CNS Spectrums, 14 (4), 197-206... Read more »

Robert M. Berman, Maurizio Fava, Michael E. Thase, Madhukar H. Trivedi, René Swanink, Robert D. McQuade, William H. Carson, David Adson, Leslie Taylor, James Hazel.... (2009) Aripiprazole Augmentation in Major Depressive Disorder: A Double-Blind, Placebo-Controlled Study in Patients with Inadequate Response to Antidepressants. CNS Spectrums, 14(4), 197-206.

  • May 7, 2009
  • 01:53 PM
  • 1,078 views

Phase V, Abilify, and Vanishing Akathisia

by CL Psych in Clinical Psychology & Psychiatry

If you've been reading about Abilify for depression on this site, you've probably noticed that I've been down on Abilify for causing akathisia in a frighteningly high percentage of patients. In two recent trials, akathisia occurred in 25% of Abilify patients compared to 4% of placebo patients. What, exactly, is akathisia? That's still a matter of some debate. Let's turn to a recent Journal of Clinical Psychiatry article on the topic. Entitled "Akathisia: An Updated Review Focusing on Second-Generation Antipsychotics," the paper purports to provide "a review of the literature on the incidence of drug-induced akathisia associated with the use of second-generation antipsychotics (SGAs) and first-generation antipsychotics (FGAs)."It provides a few different characteristics associated with acute akathisia, including:"Intense dysphoriaAwareness of restlessnessComplex and semipurposeful motor fidgetiness"It mentions "...suicidal behavior has been described in patients with akathisia in case reports, both in patients receiving antipsychotic medication and in patients receiving selective serotonin reuptake inhibitors (SSRIs)."A couple of descriptions from another journal:Increased tenseness, restlessness, insomnia and a feeling of being very uncomfortableOn the first day of treatment he reacted with marked anxiety and weepiness, on the second day felt so terrible with such marked panic at night that the medication was cancelledSo we can all agree that akathisia does not sound like fun.Now back to the Journal of Clinical Psychiatry review article. What did the authors conclude? "The comparative incidence of akathisia among the newer antipsychotic agents remains poorly characterized." And "...SGAs are generally associated with a lower propensity for movement disorders compared with their FGA counterparts, an emerging body of comparative literature shows that second-generation medications are not completely free from inducing akathisia."The authors go through a long list of second-generation antipsychotic medications. The drug that receives the least attention is aripiprazole (Abilify). The authors conclude that "in studies comparing aripiprazole with placebo, akathisia rates in the aripiprazole arm were similar in some studies, and higher in others. As with other SGAs, akathisia rates with aripiprazole were lower than those of FGAs." So Abilify causes less akathisia than older medications and it's unclear if it causes more akathisia than placebo. But, wait, wasn't akathisia related to much higher rates of akathisia than placebo in treating depression? Fortunately, the authors had a little trick to erase that inconvenient piece of evidence; they only examined trials trials involving people diagnosed with schizophrenia or bipolar disorder. So the depression studies -- POOF -- vanished, along with their damning data.Why would the authors want to censor negative data about Abilify? Well, one author is an employee of Otsuka America Pharmaceutical, Inc., and another is an employee of Bristol-Myers Squibb, companies that market Abilify. And the other authors: All but one of them have a financial relationship with Bristol-Myers Squibb. The best part:Editorial support provided by Maria Soushko, Ph.D., Phase Five Communications, Inc., New York, N.Y., with funding provided by Bristol-Myers Squibb.So a paper that excludes the most inconvenient evidence regarding akathisia on Abilify had major parts of the writing done by... a medical writer hired by Bristol-Myers Squibb. If one goes to Phase Five's website , the first animation that pops up says "Spinning Your Science Into Gold." I'd say that this article was indeed 24 karat gold. I hereby nominate all authors of the study for a much coveted Golden Goblet Award.Citation Below:Kane, J., Fleischhacker, W., Hansen, L., Perlis, R., Pikalov, A., & Assunção-Talbott, S. (2009). Akathisia: An Updated Review Focusing on Second-Generation Antipsychotics The Journal of Clinical Psychiatry DOI: 10.4088/JCP.08r04210... Read more »

Kane, J., Fleischhacker, W., Hansen, L., Perlis, R., Pikalov, A., & Assunção-Talbott, S. (2009) Akathisia: An Updated Review Focusing on Second-Generation Antipsychotics. The Journal of Clinical Psychiatry. DOI: 10.4088/JCP.08r04210  

  • March 10, 2009
  • 07:46 AM
  • 1,117 views

Abilify, Depression, and the Memory Hole

by CL Psych in Clinical Psychology & Psychiatry

The Primary Care Companion to the Journal of Clinical Psychiatry has a piece on Abilify for depression that illustrates many of psychiatry's woes. Full text of the article is here. The journal published an article titled "Examining the efficacy of adjunctive aripiprazole in major depressive disorder: A pooled analysis of two studies." The paper combines data from two previously published studies which examined the addition of Abilify to existing antidepressant treatment (1, 2). One of psychiatry's big-name academics, Michael Thase, signed on as lead author. I'm hoping that he didn't actually write the paper. Actually, there are eleven authors of the paper, which seems a little ridiculous given that the paper is an analysis of data which had already been collected for two previously published clinical trials. Seven of the authors are employees of Bristol-Myers Squibb (BMS) or Otsuka, which both market Abilify. Wait... If you look closely, you can see my favorite disclosure... In the fine print on the first page...In case you can't read the fine print: In defense of Thase and the other academic authors, they may have not actually written any of the paper. Much or all of the writing appears to be creditable to Ogilvy Healthworld Medical Education. On their site, they note that they perform:Clinical Development and Publications ManagementExperienced medical writers work closely with authors, editors and publishers to provide our clients with a full range of publishing options.Whatever BMS/Otsuka paid you for this one simply was not enough. Why? Because whomever wrote this thing did an admirable job of focusing on the positive and completely ignoring the negative.Erasing the Patient's Opinions: Remember, the article's title states that it examines the efficacy of adjunctive Abilify (adding Abilify to existing antidepressant treatment). So you'd think the article would mention all of the relevant depression data from the two relevant studies. Well, no. In the two stuides which are discussed in the article, patients were assessed on depression using the following measures:Montgomery Asberg Depression Rating Scale (MADRS)Inventory of Depressive Symptoms-Self Report Scale (IDS)Quick Inventory of Depressive Symptoms Self-Report Scale (QIDS)Using the MADRS, the authors conclude that adding Abilify to antidepressant treatment is more effective than adding placebo to antidepressant treatment. OK, fine, though it's not by a particularly huge margin. Mysteriously, the authors do not even mention that the self-report scales (IDS and its subscale, the QIDS) were used in the two trials. And why would they? In both trials, Abilify was not significantly better than placebo on these measures. A letter to the editor pointed out this glaring weakness in Abilify's claims of efficacy, the response to which was weak:Noting that Abilify did not outperform placebo on the self-report measure in the trial, he wrote that "this may be due to the lower sensitivity" of the measure. So the drug wasn't the failure -- blame the rating scale instead. The people at BMS picked the scale and when it doesn't give results they like, then suddenly it's a poor measurement of depression. I bet Dr. Berman would not have complained about the instrument had it yielded results in favor of Abilify.In the publications of each of the two clinical trials, the authors tried to downplay the fact that Abilify was no better than placebo according to patient self-reports. Then, when publishing an analysis that combined the results of the two trials, the authors go a step further by not even mentioning that patients completed a self-report. Right down the memory hole. In my opinion, any reasonable academic author writing about such research would want to note the strengths and limitations of Abilify in treating depression. The lack of benefit on patient-rated measures is a major weakness. Yet several big-time academics signed off on this paper despite its complete scrubbing of negative data. For that, I hereby nominate each author for a coveted Golden Goblet Award. And I credit the ghostwriter at Ogilvy with a fantastic job of serving his/her corporate clients. You, sir or ma'am, deserve kudos for a marketing job well-done.The instructions for authors who submit to the Primary Care Companion to the Journal of Clinical Psychiatry state: "Conclusions should flow logically from the data presented, and methodological flaws and limitations should be acknowledged." Um, does completely scrubbing negative data count as failing to acknowledge limitations? I can see that the peer reviewers and/or editor really paid close attention to this paper.Safety: The authors note that "adjunctive aripiprazole is relatively well-tolerated in patients with MDD." Relatively? Relative to what -- being hit with a baseball bat repeatedly? They note that akathisia occurred in 25% of patients on Abilify compared to 4% of patients on placebo. Restlessness: 12% vs. 2%; insomnia: 8% vs. 3%; fatigue: 8% vs. 4%; blurred vision: 6% vs 1%. The authors report that akathisia resolved in 52% of patients by the end of the study, which would also mean that for 48% of patients with akathisia, they were stuck with it at the end of the study. But don't worry, it's "relatively well-tolerated."Overall, another example of a "research" publication being little more than a puff piece in favor of a drug. With big-name academics signed on as authors to add credibilty and just a fine print mention of a ghostwriter. I thank an anonymous reader for alerting me to this study.Citation:Thase ME, Trivedi MH, Nelson JC, Fava M, Swanink R, Tran Q, Pikalov A, Yang H, Carlson BX, Marcus RN, Berman RM (2008). Examining the efficacy of adjunctive aripiprazole in major depressive disorder: A pooled analysis of 2 studies Primary Care Companion to the Journal of Clinical Psychiatry, 10, 440-447... Read more »

Thase ME, Trivedi MH, Nelson JC, Fava M, Swanink R, Tran Q, Pikalov A, Yang H, Carlson BX, Marcus RN.... (2008) Examining the efficacy of adjunctive aripiprazole in major depressive disorder: A pooled analysis of 2 studies. Primary Care Companion to the Journal of Clinical Psychiatry, 440-447.

  • January 27, 2009
  • 08:52 AM
  • 1,189 views

Abilify For Depression: I'm Not the Only Skeptic

by CL Psych in Clinical Psychology & Psychiatry

In April 2008, findings were published in the Journal of Clinical Psychopharmacology which claimed that the atypical antipsychotic aripiprazole (Abilify) was an effective add-on treatment for depression. I heartily disagreed with the study's conclusions, noting that the patient-rated depression measure did not demonstrate an advantage over placebo, an inconvenient result that the authors tried to explain away as if was unimportant. I also pointed out that the study design was biased in favor of Abilify:Study Design. Patients were initially assigned to receive an antidepressant plus a placebo for eight weeks. Those who failed to respond to treatment were assigned to Abilify + antidepressant or placebo + antidepressant. Those who responded during the initial 8 weeks were then eliminated from the study. So we've already established that antidepressant + placebo didn't work for these people -- yet they were then assigned to treatment for 6 weeks with the same treatment (!) and compared to those who were assigned antidepressant + Abilify. So the antidepressant + placebo group started at a huge disadvantage because it was already established that they did not respond well to such a treatment regimen. No wonder Abilify came out on top (albeit by a modest margin).Here's an analogy. A group of 100 students is assigned to be tutored by Tutor A regarding math. The students are all tutored for 8 weeks. The 50 students whose math skills improve are sent on their merry way. That leaves 50 students who did not improve under Tutor A's tutelage. So Tutor B comes along to tutor 25 of these students, while Tutor A sticks with 25 of them. Tutor B's students do somewhat better than Tutor A's students on a math test 6 weeks later. Is Tutor B better than tutor A? Not really a fair comparison between Tutor A and Tutor B, is it?Some commenters agreed with my take on the matter while others did not. Two letters to the editor published in the latest Journal of Clinical Psychopharmacology raised concerns about the study. Alexander Tsai, from UCLA, wrote that he was concerned that the advantage for Abilify was small (2.8 points on the Montgomery-Asberg Depression Rating Scale ) and that the study design was biased in favor of Abilify (agreeing with my earlier point).Dr. Bernard Carroll, wrote in his letter that:The advantage of Abilify over placebo was smallThere was no advantage on the patient-rated measureDue to the notable side effect profile of Abilify, clinical raters could likely distinguish patients who were taking Abilify from those who were taking placebo, which could have biased their ratings. Thus, he questions if the study was truly double-blind.The authors did not report whether the occurrence of several side effects were more common on Abilify than placebo. Dr. Carroll calculated that akathisia, fatigue, restlessness, and insomnia were all significantly more common on Abilify and wondered why the authors did not include such data in their report.The authors did not note the relationship between akathisia (severe restlessness/tension) and suicide, which is concerning given that Abilify produces akathisia in droves.The Defense: Robert Berman from Bristol-Myers Squibb wrote back to defend the study. His points were not impressive. Noting that Abilify did not outperform placebo on the self-report measure in the trial, he wrote that "this may be due to the lower sensitivity" of the measure. So the drug wasn't the failure -- blame the rating scale instead. The people at BMS picked the scale and when it doesn't give results they like, then suddenly it's a poor measurement of depression. I bet Dr. Berman would not have complained about the instrument had it yielded results in favor of Abilify.Adverse Events: As for not reporting adverse events, well, there's a perfectly good explanation hidden somewhere in here......we have clearly reported rates of spontaneously reported treatment-emergent events that occurred at a rate of 5% or greater in any treatment group. As this study is not designed to collect adverse events in a systematic manner, statistical comparison between treatment groups is not appropriate. So let me get this straight. They discussed "spontaneously reported" events, which would refer to the events reported by the patients without much questioning. Everyone knows that spontaneous reports are a joke because most side effects are not spontaneously reported. Based on spontaneous report, the rate of sexual side effects in SSRI's is quite low. But when you bother to ask people taking SSRIs questions about their sexual functioning, the rates of sexual problems increase drastically. So when Dr. Berman goes on to write that no suicide-related adverse events were reported in the study, keep in mind that the study investigators were not asking about such events. So it may be more accurate to say that nobody committed suicide during the study, but nobody was tracking suicidal ideation unless patients reported such problems themselves. Yes, suicidal ideation was covered a little bit by measures used in the study, but a more systematic assessment would have been helpful. To give the authors credit, at least they did include a couple measures of extrpyramidal symptoms, from which we gathered that akathisia happened in 25% of patients. Yikes.Saying that the study was not designed to collect adverse event data in a systematic manner is frightening. If adverse event collection was not systematic, then the authors writing in the study report that "adverse events were generally mild to moderate" is meaningless. You can't say that adverse event data were not collected in any sort of systematic manner then also say that the study is "safe," as the authors claim in their paper. This is the definition of duplicitous. In any case, the authors should have reported that several adverse events were significantly more likely to occur on Abilify than placebo rather than making the ridiculous claim that comparing adverse event rates between treatment and placebo is not appropriate. Dr. Berman does not address the less than 3-point benefit for Abilify over placebo. There is also no real explanation to address the concerns of Dr. Tsai and myself, who noted that the study design was biased in favor of Abilify. Kudos to Dr. Caroll and Dr. Tsai for taking the time to write excellent letters which addressed quite problematic issues in this study. Every time I see a commercial pimping Abilify for depression, I cringe. It's good to know that some people in the medical community are seeing through the weak research that "supports" the use of Abilify as an antidepressant. Citation for the offending study below:Ronald N Marcus et al. (2008). The Efficacy and Safety of Aripiprazole as Adjunctive Therapy in Major Depressive Disorder Journal of Clinical Psychoopharmacology, 28 (2), 156-165... Read more »

Ronald N Marcus et al. (2008) The Efficacy and Safety of Aripiprazole as Adjunctive Therapy in Major Depressive Disorder. Journal of Clinical Psychoopharmacology, 28(2), 156-165.

  • January 7, 2009
  • 01:11 PM
  • 886 views

Sowing the Seeds of Lexapro

by CL Psych in Clinical Psychology & Psychiatry

I'm reading an article with my jaw completely agape and I thought I'd share the pain. The good people at Forest Pharmaceuticals have put together a tragic waste of journal space. The editorial board at the journal Depression and Anxiety should call an emergency meeting to see how this thing got published. Any peer reviewer who put a stamp of approval on this should be forced to listen to Michael Bolton's Greatest Hits at maximum volume for 12 hours straight.OK, so what am I having a fit about? Here's what happened in this so-called study. 109 primary care doctors were recruited to participate, for which they were doubtlessly paid a decent chunk per patient (not discussed in the manuscript). The lucky depressed patients of these physicians then received escitalopram (Lexapro) for six months. The manuscript mentions that the "investigators" (the primary care docs) "were not required to have previous clinical research experience to be selected for this study." Yeah, no kidding.There was no control group, and there had already been dozens of studies on the effects of Lexapro in depression, so how are we getting any new info out of this study? Maybe because this is investigating Lexapro in primary care settings; maybe there was no research on that beforehand. Well, no. The manuscript writes that "The efficacy and tolerability of escitalopram in MDD have been extensively evaluated in primary-care settings," citing four relevant studies. So the study is actually not an attempt to answer a scientific question. So what, exactly, is this study?Looks and smells like a seeding trial, about which Harold Sox and Dummond Rennie wrote:This practice—a seeding trial—is marketing in the guise of science. The apparent purpose is to test a hypothesis. The true purpose is to get physicians in the habit of prescribing a new drug. Why would a drug company go to the expense and bother of conducting a trial involving hundreds of practitioners— each recruiting a few patients—when a study based at a few large medical centers could accomplish the same scientific purposes much more efficiently? The main point of the seeding trial is not to get high-quality scientific information: It is to change the prescribing habits of large numbers of physicians. A secondary purpose is to transform physicians into advocates for the sponsor’s drug. The company flatters a physician by selecting him because he is “an opinion leader” and incorporates him in the research team with the title of “investigator.” Then, it pays him good money: a consulting fee to advise the company on the drug’s use and another fee for each patient he enrolls. The physician becomes invested in the drug’s future and praises its good features to patients and colleagues. Unwittingly, the physician joins the sponsor’s marketing team. Why do companies pursue this expensive tactic? Because it works.So these primary care doctors now feel like "researchers," even though their investigation had essentially zero scientific merit. That probably makes these "investigators" feel important -- and the association between feeling important/scientific and Lexapro is a feeling Forest was banking on to increase Lexapro prescriptions in Canada.Findings: So what did this extremely important piece of seeding, er, research find? Get ready... Lexapro is safe and effective. To quote the authors: "Escitalopram was well tolerated, safe, and efficacious. Escitalopram can be used with confidence to treat patients with MDD in Canadian primary-care settings." And "As adherence to antidepressant treatment is paramount to achieving long-term recovery, the present results suggest that escitalopram should be considered among the first-line choices of antidepressant used in primary care." So with no control group, we can determine that a Lexapro prescription should be among the first things that come to mind when treating depression. This is mind-boggling. This journal often published good work, but this is among the most uninformative pieces of research I have read. Unless one is thinking about marketing, in which case it is very enlightening.Citation: Pratap Chokka, Mark Legault (2008). Escitalopram in the treatment of major depressive disorder in primary-care settings: an open-label trial Depression and Anxiety, 25 (12) DOI: 10.1002/da.20458... Read more »

Pratap Chokka, & Mark Legault. (2008) Escitalopram in the treatment of major depressive disorder in primary-care settings: an open-label trial. Depression and Anxiety, 25(12). DOI: 10.1002/da.20458  

  • December 4, 2008
  • 09:29 AM
  • 939 views

Lamictal: Break Out the Shovel

by CL Psych in Clinical Psychology & Psychiatry

ormal {margin:0.0pt; margin-top:0.0pt; margin-bottom:0.0pt; margin-left:0.0pt; margin-right:0.0pt; text-indent:0.0pt; font-family:"Times New Roman"; font-size:10.0pt; color:Black; font-weight:normal; } H1 {margin:0.0pt; margin-top:0.0pt; margin-bottom:6.0pt; margin-left:0.0pt; margin-right:0.0pt; text-indent:0.0pt; font-family:"Arial"; font-size:18.0pt; color:Black; font-weight:bold; } H2 {margin:0.0pt; margin-top:0.0pt; margin-bottom:6.0pt; margin-left:0.0pt; margin-right:0.0pt; text-indent:0.0pt; font-family:"Arial"; font-size:16.0pt; color:Black; font-weight:bold; } H3 {margin:0.0pt; margin-top:0.0pt; margin-bottom:6.0pt; margin-left:0.0pt; margin-right:0.0pt; text-indent:0.0pt; font-family:"Arial"; font-size:14.0pt; color:Black; font-weight:bold; } GlaxoSmithKline, manufacturer of lamotrigine (Lamictal), the antiepileptic drug used widely for bipolar disorder, happily hid clinical trial results which found Lamictal was no better than a placebo. Given recent findings about how often pharmaceutical companies selectively push positive results to publication in medical journals while suppressing negative results, this can hardly be considered a surprise. It is nonetheless instructive to examine how the published data on Lamictal paint a much rosier picture of the drug's efficacy compared to unpublished data. Nassir Ghaemi, a psychiatrist at Tufts University Medical Center, dug through GSK's online database of information, and found that several negative Lamictal studies (studies which failed to show a benefit for Lamictal over placebo on the primary outcome measure) were quietly residing on the site. Why did GSK post such information on their site? Not out of the goodness of their hearts; rather, because they were forced to post data about clinical trial outcomes as a result of a legal agreement. Here's what Ghaemi found in GSK's database:Acute mania: Two studies compared lithium, Lamictal, and placebo. Both found that Lamictal did not beat a placebo. Neither study was published.Acute bipolar depression: Three studies were conducted. All three showed negative results. Two were not published. On one study, there was a positive result for Lamictal on a secondary outcome measure, and the results of the study were written to emphasize the positive outcomes, as in stating "Lamotrigine monotherapy is an effective and well-tolerated treatment for bipolar depression."Rapid cycling bipolar: Two studies were completed; both were negative on the primary outcome. However, one study showed favorable outcomes for Lamictal on several secondary measures. The obviously negative study was not published while the study that showed a number of benefits for Lamictal was published.Prophylaxis (Prevention of future episodes): Two studies were conducted, both of which showed that patients on Lamictal went longer between episodes than did placebo patients. Both studies were published.Well, I'm shocked, shocked, that GSK would simply bury a slew of negative data on their product. Who woulda thunk it? So what does this mean for Lamictal? Dr. Ghaemi was interviewed by Dr. Daniel Carlat (of Carlat Psychiatry Blog and the Carlat Psychiatry Report). There were many pieces of Ghaemi's interview that were interesting (see February 2008 issue of Carlat Psychiatry report; sorry, no link available), but the most interesting piece was:Carlat: My understanding is that you wrote up your discovery of the negative Lamictal data and submitted the paper to some journals. What has been the response? Ghaemi: I first submitted to JAMA because I knews they were sympathetic to this kind of critique. Their reaction was, "We already publish many papers like this; this is old news; there is nothing new here." They recommended that I send it to a psychiatric journal. So then I sent it to the American Journal of Psychiatry, but they rejected it as well, saying that they were doubtful that this type of negative publication bias was common among other companies marketing medications for bipolar disorder. Carlat: Do you think there is much suppressed negative data about other drugs? Ghaemi: It's very hard to get this information. Companies are not required to disclose it. And if they do publish it, they will sometimes delay publication for two or three years, and then publish it in an obscure journal that it less likely to be read. Ghaemi also did some digging on other drugs used for bipolar disorder and found that negative studies for Seroquel and Abilify were also lurking in the unpublished zone. However, it appears that Lamictal is the worst offender of the bunch. Is it just me, or is anyone else getting flashbacks to GSK's handling of suicide data regarding its antidepressant Paxil? Thanks to an anonymous reader for helping to track down relevant information on this and an upcoming post on this topic. The forthcoming post will deal with the misleading scientific literature on Lamictal. Key opinion leaders will likely be mentioned. The usual stuff, just on a different drug and plugging in the names of other academics who apparently deemed it acceptable to mislead their fellow physicians about the efficacy of lamotrigine. GSK worked the system expertly and it paid off. S. Nassir Ghaemi, Arshia A. Shitzadi, Megan Filkowski (2008). Publication bias and the pharmaceutical industry: The case of lamotrigine for bipolar disorder Medscape Journal of Medicine, 10 (9), 211-211... Read more »

S. Nassir Ghaemi, Arshia A. Shitzadi, & Megan Filkowski. (2008) Publication bias and the pharmaceutical industry: The case of lamotrigine for bipolar disorder. Medscape Journal of Medicine, 10(9), 211-211. DOI: http://www.medscape.com/viewarticle/579046  

  • September 30, 2008
  • 01:14 PM
  • 895 views

Gabitril Goes Down

by CL Psych in Clinical Psychology & Psychiatry

Gabitril (tiagabine) is an antiseizure medication from Cephalon, which just forked out a cool $425 million to settle charges that it marketed several drugs for unapproved conditions, including Provigil and Gabitril. Government investigators claimed that Gabitril was marketed as a treatment for anxiety, which is too bad considering that it struck out in three clinical trials against a placebo. Each study found no evidence that Gabitril was better than a sugar pill.Gabitril was also allegedly marketed as a treatment for pain. I was unable to locate a single controlled study examining the efficacy of Gabitril for pain, though there were a small number of uncontrolled (i.e., not very useful) studies suggesting that maybe Gabitril could be used to treat pain. Regarding sleep, the placebo-controlled trials I located did not suggest that the drug was particularly effective (1, 2). So we're looking at a drug with essentially no controlled evidence of efficacy being pushed for pain, sleep, and anxiety. Well-done, Cephalon.Some of the supporting evidence about the off-label marketing cases came from a sales rep who wore a wire to collect evidence on the company's marketing practices. Apparently a total of four company whistleblowers were involved. Shades of Peter Rost?Read more about the case at the Philadelphia Inquirer.PS. Cephalon published the negative anxiety Gabitril trials in June 2008. As is well-established, companies often fail to publish negative data about their products, so why is Cephalon being so open? A skeptic might note that with the legal case againt Cephalon gaining steam, it would look even worse if Cephalon was sitting on negative data. So perhaps knowing that bad publicity was coming due to the lawsuit led Cephalon to allow the negative anxiety results to be published, as they could state "Look at how open and honest we are." I'm just saying that it's a possibility.Reference for anxiety trials:Mark H. Pollack, Jane Tiller, Fang Xie, Madhukar H. Trivedi (2008). Tiagabine in Adult Patients With Generalized Anxiety Disorder Journal of Clinical Psychopharmacology, 28 (3), 308-316 DOI: 10.1097/JCP.0b013e318172b45fUpdate: Also read a related post at Health Care Renewal. It mainly discusses Cephalon's opiate-laced "perc-o-pops" (Actiq) approved to treat cancer pain, but marketed in a much broader manner. Follow-up mini-rant: Let's not excuse the physicians who jumped on board. Docs need to do a much better job of checking the evidence base, though when some of the evidence base consists of publishing the same data repeatedly and when negative trials are often not published, what kind of "evidence base" are we really talking about?... Read more »

Mark H. Pollack, Jane Tiller, Fang Xie, & Madhukar H. Trivedi. (2008) Tiagabine in Adult Patients With Generalized Anxiety Disorder. Journal of Clinical Psychopharmacology, 28(3), 308-316. DOI: 10.1097/JCP.0b013e318172b45f  

  • September 8, 2008
  • 10:39 AM
  • 1,246 views

Atypical Antipsychotics for All, Oregon Chapter

by CL Psych in Clinical Psychology & Psychiatry

Oh boy. Here we go again. A study published online ahead of print at the Journal of Clinical Psychiatry notes that among Oregon Medicaid patients who received a prescription for an atypical antipsychotic: 52% had a depression diagnosis34% had an anxiety diagnosis15% had a PTSD diagnosis But only 15% had a schizophrenia diagnosis and 27% had a bipolar diagnosis. So... the majority of atypical scripts were written off-label. Seroquel was the most frequently prescribed atypical, followed by Zyprexa, then Risperdal. Doses less than what are typically given to treat schizhophrenia or bipolar disorder (subtherapeutic dosing) were quite common. As in 86% of Seroquel scripts were subtherapeutic, 59% of of Risperdal scripts, and 48% of Zyprexa prescriptions. Wait, am I calling for higher doses of these drugs? That doesn't sound like me at all, right? Don't worry, I haven't lost my mind (I think). Here's the deal. The authors suspect that a lot of these low-dose prescriptions are being written to manage agitation and as sleep aids. The authors note that there are likely less expensive/more effective medications for such conditions. Not to sound too cavalier, but one could also recommend behavioral treatment to help with sleep as well. Nah, that's crazy talk -- not enough money to be made in that. Primary care docs were more likely than psychiatrists to dish out low-dose antipsychotics. I guess that the Viva Zyprexa marketing blitz was a success after all. Thanks to Daniel Hartung and collagues for their study, which provides another insight into the wonderful world of atypical antipsychotics as a treatment for everything imaginable. Sorry to beat a dead horse with my zillionth post about the topic of atypicals, but isn't this getting just a teeny bit out of control? Daniel M Hartung, Jennifer P Wisdom, David A Pollack, Ann M Hamer, Dean G Haxby, Luke Middleton, Bentson H McFarland (2008). Patterns of atypical antipsychotic subtherapeutic dosing among Oregon Medicaid patients Journal of Clinical Psychiatry DOI: ej07m03658... Read more »

Daniel M Hartung, Jennifer P Wisdom, David A Pollack, Ann M Hamer, Dean G Haxby, Luke Middleton, & Bentson H McFarland. (2008) Patterns of atypical antipsychotic subtherapeutic dosing among Oregon Medicaid patients. Journal of Clinical Psychiatry. DOI: ej07m03658  

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