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), 197-206Read More...
Furious Seasons has a rather distressing piece of news from a recent Bristol-Myers Squibb conference call. To sum it up quickly, BMS claims that 10.6% of depressed patients are now receiving atypical antipsychotics. Of those 10.6%, 21.7% are taking Abilify. So that would mean roughly 10-11 in 100 depressed patients are taking antipsychotics and 2 of them are on Abilify. I shudder to think how many are on Seroquel. Or Zyprexa. It made me think of a post I wrote a few weeks ago in which I described the marketing of Abilify for depression. A huge market of depressed people just ripe for the picking.
Going along with this, BMS is pushing back on the issue of akathisa, the side effect that has garnered the drug much bad publicity (at least in the blog world; 1, 2, 3) via a medical journal article that distracts attention from Abilify as an akathisia-inducer. More on that to come soon. Ghostwriters, ignoring contradictory evidence; basically, an attempt to completely obscure the evidence on the topic. It's not the first time BMS has successfully placed a study with major flaws into a medical journal (1, 2). Details will be forthcoming.
"The results are extremely unimpressive; they just squeak by," says Massachusetts psychiatrist Daniel Carlat, editor of the respected Carlat Psychiatry Report. For a clinician or a patient's family, the difference between those on Abilify and those who took a placebo "would be hard to actually see," he adds.
Dr. Carlat is referring to the comparison between Abilify and placebo in the treatment of depression, a topic I have discussed in depth previously (1 , 2 , 3, 4). The above quote comes from a Melissa Healy piece in the Los Angeles Times that throws a damper on Abilify's parade through depression.
Another Melissa Healy piece from the LA Times starts off as follows:
About a year ago, patients began trooping into the office of UCLA psychiatrist Andrew Leuchter, asking whether an antipsychotic drug called Abilify "might be right for them." Few appeared to be delusional, plagued by hallucinations or suffering fearsome mood swings. Mostly, they were depressed or anxious, and frustrated by the pace of their recovery.
Leuchter wondered what was up: Depressed patients didn't usually seek out drugs used to quell psychiatry's most disturbing symptoms.
What was up, he soon discovered, was spending on a new advertising campaign touting Abilify as an "add-on" treatment for depression. For the first time since the arrival of a new generation of antipsychotic medications -- six drugs called the "atypicals" because they work differently from the earlier generation of antipsychotic drugs -- the makers of one, Abilify, had been granted the legal right to market to a vast new population of patients beyond those with schizophrenia or bipolar disorder.
Here's Bristol-Myers Squibb's advertisement for the drug:
This is classic. BMS notes that two-thirds of depressed patients who take antidepressants will still have symptoms after a course of antidepressants. And they have a point: Antidepressants ain't exactly miracle pills. So the commercial implies that Abilify must be really helpful... But if patients add Abilify to their treatment regimen, then only about 25% of them experience remission of depressive symptoms. Isn't it a bit strange that Abilify is appealing to the two-thirds of patients who still have depressive symptoms after taking an antidepressant and offering them a treatment that will lead to remission for only one-quarter of them? Of course, no studies have compared adding Abilify to adding another antidepressant, adding psychotherapy, adding an exercise routine, or adding anything except a placebo. Oh, and given that Abilify led to remission of symptoms in about 25% of patients, while placebo led to remission in about 15% of patients, um, that's a pretty small difference. And keep in mind that the studies were designed in a manner that was almost sure to find a benefit for Abilify, as I have noted previously.
If Abilify was generally benign, then a relatively small benefit over placebo is acceptable. But, as I mentioned previously, the side effects are troubling. I took issue with a BMS-funded journal article/puff piece that tried to spin side effect data on Abilify:
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."
You gotta like any drug that induces akathisia at the same rate that it induces symptom remission. Psychiatrist Doug Bremner had a similar take on Abilify as showing a poor cost-benefit ratio. For a few descriptions of akathisia, see comments at this post on Furious Seasons.
Given the unimpressive scientific data regarding Abilify for depression on one hand and the drug's exploding sales on the other, I was sure glad to see a big paper such as the LA Times note that there really is a controversy here. And if Seroquel receives official FDA approval as an add-on treatment for depression, get ready for the marketing machine to reach a fever pitch. Viva Zyprexa, anyone? Melissa Healy covers the expansion of atypical antipsychotics from schizophrenia and bipolar disorder into depression in an article that y'all simply must read. I'll close with a sad-but-true quote from Yale psychiatry professor Robert Rosenheck:
The story's pretty clear, and pretty embarrassing for the profession of psychiatry, which has allowed itself to be led by marketing," says Robert Rosenheck, a psychiatrist at Yale University who has studied the effectiveness and expanded use of the atypical antipsychotics. "We know now what these companies' strategies are: The number of people with schizophrenia is limited, so the road to profitability goes through soccer moms. They need to market these drugs to ordinary people who have dissatisfactions in life.
I was very pleased to have been acknowledged in a recent story in the St. Paul Pioneer Press. The reporter, Jeremy Olson, wrote the following in his story:
An Internet psychiatry blog first raised questions March 2 about the research Schulz presented at the APA conference and why it lacked any of the company's findings."It raises troubling questions when an independent academic author presents results that are in direct opposition to the underlying data," wrote the blogger, an anonymous academic.
He didn't cite my blog by name -- the unwieldy long name which I stupidly chose for the site may be responsible for that -- but I'm nonetheless grateful that my site was acknowledged for its work on this story. He is referencing my post in which I noted that a University of Minnesota psychiatry professor (Charles Schulz) had stated in a press release that Seroquel was "more effective" than Haldol. This was based upon his analysis of data comparing Seroquel to the much older antipsychotic drug Haldol in the treatment of schizophrenia. Yet an internal AstraZeneca analysis found that Haldol was actually more effective than Seroquel. Both the Pioneer Press and the Star Tribune, the two big papers in the Minneapolis-St. Paul area ran stories on the controversy.
When asked about his lavishing of praise on Seroquel in the press release, the Pioneer Press said:
In an interview with the Pioneer Press last week, Schulz defended his research and presentation of Seroquel as accurate and ethical. However, he acknowledged the corporate press release from his APA presentation might have exaggerated in calling Seroquel "significantly superior."
"You know," he said, "I can't disagree with that."
Schulz said the following in the Star Tribune:
In an interview this week, Schulz said the pharmaceutical company never shared its doubts about Seroquel, which went on to become a blockbuster, with annual sales of $4.5 billion today. "I don't recall anybody calling up and saying, oh my goodness, we have this problem," he said. At the same time, Schulz acknowledged that his own study did not really show that Seroquel was more effective than the older drug. "That's a bit of a misunderstanding," he said. "I think the overall message is that it works about the same."
Thanks to a helpful reader, I was able to track down what appears to be Schulz's presentation from 2000. It says "...quetiapine was clearly statistically significantly superior to placebo as well as to haloperidol..." This appears to contradict his statement that Haldol and Seroquel "work about the same." Again, the data from Schulz's presentation don't match AstraZeneca's internal analysis. Schulz is obviously backing away from his earlier praise for Seroquel, for which he deserves some credit. The problem was that Schulz, along with a laundry list of researchers in psychiatry were caught in a tidal wave of unbridled enthusiasm for the atypical antipsychotics, first as wonder drugs for schizophrenia, then as the Next Big Thing in bipolar, then moving into the world of depression and anxiety disorders in the absence of decent supportive evidence.
Interesting sidenote: While Schulz was presenting on the wonders of Seroquel, he was likely quite unaware that AstraZeneca has conducted a study (Study 15) which had found that Seroquel compared unfavorably to Haldol in preventing psychotic relapse among patients with schizophrenia who began the study in full or partial symptom remisison. Furious Seasons has some additional reporting on this study. It is a near certainty that Schulz was not informed about this study's results, as this could have changed his lofty opinion of Seroquel. This points to the problem of researchers relying on data collected by drug companies -- how are researchers to know they are receiving all of the data?
Note to key opinion leaders: If you don't realize it by now, you are pawns. You are being used to place an academic veneer on the marketing of drugs. The drugs that you are marketing as major breakthroughs typically offer little to no benefit over existing treatment and may cause a slew of nasty side effects. Decide if you want to be a scientist or a marketer. Don't try to do both at the same time, because the odds are pretty good that your scientific credentials will end up being tarnished. Just ask this guy. Now that the media are paying much closer attention to the conflicted interests and skewed science that sadly underlie much of psychiatry these days, it would be a good idea to maintain appearances.
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 Management Experienced 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
Jim Edwards at BNET dug through the Seroquel documents and found many instances of AZ employees noting that Seroquel causes weight gain. Yet the company seemed bent on keeping this information hidden. As I mentioned last week, this sure seems a lot like Zyprexa redux, except with more sex scandals and perhaps more buried data. I suggest that everyone head over to BNET and see the details.
Despite all the bad news, AZ is pressing onward with its application for FDA approval for Seroquel in both generalized anxiety disorder and depression. Yikes. I broke the story earlier this week about the "scientific literature" claiming that Seroquel worked better than Haldol in the treatment of schizophrenia, yet internal company data showed Haldol as superior to Seroquel in reducing schizophrenia symptoms. Between discrepant data, the apparent hiding of negative clinical trials and trying to keep doctors distracted from data indicating that Seroquel caused weight gain, I think that Seroquel's luck may have ran out -- my bet is that the FDA won't approve the drug for depression or GAD. But I've been wrong before; the FDA did approve Abilify as an add-on treatment for depression based on pretty flimsy evidence.
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 small
There was no advantage on the patient-rated measure
Due 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), 156-165Read More...
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 
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