Evidence For Abilify & Bipolar Disorder Is Debated
7 CommentsBy Ed Silverman // May 4th, 2011 // 10:04 am
Was the evidence used for prescribing Abilify to combat bipolar disorder skimply? That’s the contention in a new paper, which argues the justification for using the Bristol-Myers Squibb drug as maintenance treatment was based on one long-term, controlled trial that had numerous limitations. Moreover, the paper maintains these limitations were not identified in many of 104 subsequent review articles and treatment guidelines. For its part, Bristol-Myers disagrees (keep reading).
The original trial was published in the American Journal of Psychiatry in 2003 and compared the safety and efficacy of Abilify with placebo for treating bipolar patients. The study concluded that the pill had “significantly greater efficacy than placebo for the treatment of bipolar disorder patients in acute manic or mixed episodes and was safe and well tolerated” (this is the abstract and there are two subsequent papers that different phases of the trial, which you can read here and here).
But a paper published today in PLoS Medicine finds fault. Here is a synopsis: First, the authors write that the duration of the trial was too short to show Abilify was helpful in maintaining an initial benefit or preventing mood swings over the long haul. Second, few participants completed the entire study. Third, the trial was based on a select few subjects who demonstrated an initial response, which made it difficult to extrapolate findings more widely to patients with bipolar disorder.
And in the fourth observation, the trial was designed in such a way that patients assigned to a placebo were abruptly taken off Abilify given during a previous “run-in” phase and reassigned to placebo. Consequently, any differences in the risk of a relapse seen between trial arms may also reflect the potentially harmful effects of rapid drug withdrawal in patients given placebo (read the PLoS paper here).
The pill “has FDA approval for maintenance treatment of bipolar disorder, (although what this actually means is debatable. Our FOIA info shows that the FDA meant relatively short-term maintenance of acute anti-manic effects), and is aggressively marketed for this indication based on one flawed trial which, when examined closely, does not appear to show a long-term benefit of Abilify over placebo,” Nicholas Rosenlicht, one of the PLoS authors and a clinical professor of health sciences in the psychiatry department at the University of California, San Francisco School of Medicine, writes us.
“Yet this trial has been cited, virtually uncritically, as evidence supporting this use by a large number of subsequent reviews and treatment guidelines. It appears that marketing forces, rather than science, has driven the rapid adoption of Abilify as an accepted agent for the long-term treatment of bipolar disorder.”
Asked about the PLoS paper, a Bristol-Myers spokeswoman writes us this: “A total of five long-term studies of Abilify in a maintenance setting for Bipolar I Disorder were conducted and have been either published in peer-reviewed journals or presented during medical meetings, including the American Psychiatric Association annual meeting.
“These studies were conducted in accordance with good clinical practice and represent designs that were endorsed by leading researchers in Bipolar I Disorder. Two of these studies led to FDA approval…as maintenance treatment for Bipolar I Disorder as monotherapy and adjunctive therapy to either lithium or valproate.” We asked the spokeswoman to point us to these specific studies and will update you accordingly with the info.
UPDATE: The Bristol-Myers spokeswoman has written back to say two studies are currently unpublished, but offered links to three studies – here and here. She also pointed to the two papers that we have linked to above (see here and here). Rosenlicht maintains these describe extensions of the original trial. We have, however, asked him to comment about the links sent us by the drugmaker.
Rosenlicht responds: 1. We obtained the NDA information from the FDA under the FOIA (described in our paper), which shows, contrary to BMS’s assertion, this one trial was used to justify the added indication of maintenance treatment. Their statement is incorrect.
2. Our study examined the firm evidence, the kind that would guide FDA approval and good clinical practice: Double-blind, placebo or active med controlled studies for the use of Abilify monotherapy in the maintenance treatment of bipolar disorder (which is what they claim it is useful for). The two studies that are linked (directly above) are for ADJUNCTIVE, or add-on treatment treatment, and do not address whether Abilify itself protects against disease relapse, and thus do not bear directly on the question of whether aripiprazole is useful itself in this indication (as claimed in the ads).
Also, one is open-label and the other is single-blind in the initial stages. And in both only a select minority of patients that responded to the added-on Abilify are included. And those in the placebo arm are abruptly switched away from a treatment that was working for them (again, a select minority). Not surprisingly they relapse in higher numbers (this effect is discussed in our paper).
3. The Keck study we examine is the only study found meeting the criteria we set out…There is one other study, that was never published, that we discuss in our paper. Since it was never published there is not enough data or information to adequately examine it, but the sparse data that are available showed that twice as many Lithium treated subjects completed the study as those treated with Abilify. Small surprise that they elected not to publish it.
4. The abstracts we found (after an extensive search described in the paper) use the same study data and are just a pre-hash of what they published later. This is mentioned in our paper. If there are other abstracts (I highly doubt it) we’d be glad.
pic thx to purpleslog on flickr
keiner
Maybe some of those: ;-)
Assessment of safety, tolerability and effectiveness of adjunctive aripiprazole to lithium/valproate in bipolar mania: a 46-week, open-label extension following a 6-week double-blind study.
Vieta E, Owen R, Baudelet C, McQuade RD, Sanchez R, Marcus RN.
Curr Med Res Opin. 2010 Jun;26(6):1485-96.
________________________________________________
Aripiprazole as adjunct to a mood stabilizer and citalopram in bipolar depression: a randomized placebo-controlled pilot study.
Quante A, Zeugmann S, Luborzewski A, Schommer N, Langosch J, Born C, Anghelescu I, Wolf J.
Hum Psychopharmacol. 2010 Mar;25(2):126-32.
________________________________________________
Acute treatment of pediatric bipolar I disorder, manic or mixed episode, with aripiprazole: a randomized, double-blind, placebo-controlled study.
Findling RL, Nyilas M, Forbes RA, McQuade RD, Jin N, Iwamoto T, Ivanova S, Carson WH, Chang K.
J Clin Psychiatry. 2009 Oct;70(10):1441-51.
________________________________________________
Aripiprazole monotherapy in acute mania: 12-week randomised placebo- and haloperidol-controlled study.
Young AH, Oren DA, Lowy A, McQuade RD, Marcus RN, Carson WH, Spiller NH, Torbeyns AF, Sanchez R.
Br J Psychiatry. 2009 Jan;194(1):40-8.
________________________________________________
Beneficial acute antidepressant effects of aripiprazole as an adjunctive treatment or monotherapy in bipolar patients unresponsive to mood stabilizers: results from a 16-week open-label trial.
Mazza M, Squillacioti MR, Pecora RD, Janiri L, Bria P.
Expert Opin Pharmacother. 2008 Dec;9(18):3145-9.
________________________________________________
Aripiprazole monotherapy in the treatment of acute bipolar I mania: a randomized, double-blind, placebo- and lithium-controlled study.
Keck PE, Orsulak PJ, Cutler AJ, Sanchez R, Torbeyns A, Marcus RN, McQuade RD, Carson WH; CN138-135 Study Group.
J Affect Disord. 2009 Jan;112(1-3):36-49. Epub 2008 Oct 2.
________________________________________________
Aripiprazole monotherapy in patients with rapid-cycling bipolar I disorder: an analysis from a long-term, double-blind, placebo-controlled study.
Muzina DJ, Momah C, Eudicone JM, Pikalov A, McQuade RD, Marcus RN, Sanchez R, Carlson BX.
Int J Clin Pract. 2008 May;62(5):679-87. Epub 2008 Mar 25.
________________________________________________
Aripiprazole therapy in 20 older adults with bipolar disorder: a 12-week, open-label trial.
Sajatovic M, Coconcea N, Ignacio RV, Blow FC, Hays RW, Cassidy KA, Meyer WJ.
J Clin Psychiatry. 2008 Jan;69(1):41-6.
________________________________________________
A prospective, open-label study of Aripiprazole mono- and adjunctive treatment in acute bipolar depression.
Dunn RT, Stan VA, Chriki LS, Filkowski MM, Ghaemi SN.
J Affect Disord. 2008 Sep;110(1-2):70-4. Epub 2008 Feb 12.
________________________________________________
Aripiprazole monotherapy in nonpsychotic bipolar I depression: results of 2 randomized, placebo-controlled studies.
Thase ME, Jonas A, Khan A, Bowden CL, Wu X, McQuade RD, Carson WH, Marcus RN, Owen R.
J Clin Psychopharmacol. 2008 Feb;28(1):13-20. Erratum in: J Clin Psychopharmacol. 2009 Feb;29(1):38.
________________________________________________
Aripiprazole monotherapy for maintenance therapy in bipolar I disorder: a 100-week, double-blind study versus placebo.
Keck PE Jr, Calabrese JR, McIntyre RS, McQuade RD, Carson WH, Eudicone JM, Carlson BX, Marcus RN, Sanchez R; Aripiprazole Study Group.
J Clin Psychiatry. 2007 Oct;68(10):1480-91.
________________________________________________
Efficacy and safety of aripiprazole in subpopulations with acute manic or mixed episodes of bipolar I disorder.
Suppes T, Eudicone J, McQuade R, Pikalov A 3rd, Carlson B.
J Affect Disord. 2008 Apr;107(1-3):145-54. Epub 2007 Sep 27.
________________________________________________
An open-label trial of aripiprazole monotherapy in children and adolescents with bipolar disorder.
Biederman J, Mick E, Spencer T, Doyle R, Joshi G, Hammerness P, Kotarski M, Aleardi M, Wozniak J.
CNS Spectr. 2007 Sep;12(9):683-9.
________________________________________________
A randomized, double-blind, placebo-controlled 26-week trial of aripiprazole in recently manic patients with bipolar I disorder.
Keck PE Jr, Calabrese JR, McQuade RD, Carson WH, Carlson BX, Rollin LM, Marcus RN, Sanchez R; Aripiprazole Study Group.
J Clin Psychiatry. 2006 Apr;67(4):626-37.
________________________________________________
Aripiprazole in the treatment of acute manic or mixed episodes in patients with bipolar I disorder: a 3-week placebo-controlled study.
Sachs G, Sanchez R, Marcus R, Stock E, McQuade R, Carson W, Abou-Gharbia N, Impellizzeri C, Kaplita S, Rollin L, Iwamoto T; Aripiprazole Study Group.
J Psychopharmacol. 2006 Jul;20(4):536-46. Epub 2006 Jan 9.
________________________________________________
Effectiveness of aripiprazole v. haloperidol in acute bipolar mania: double-blind, randomised, comparative 12-week trial.
Vieta E, Bourin M, Sanchez R, Marcus R, Stock E, McQuade R, Carson W, Abou-Gharbia N, Swanink R, Iwamoto T; Aripoprazole Study Group.
Br J Psychiatry. 2005 Sep;187:235-42.
________________________________________________
A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania.
Keck PE Jr, Marcus R, Tourkodimitris S, Ali M, Liebeskind A, Saha A, Ingenito G; Aripiprazole Study Group.
Am J Psychiatry. 2003 Sep;160(9):1651-8.
Don
You are correct – the FDA DID mean short-term “maintenance” for manic symptoms. But one would never know it, the way the atypicals have been marketed. If a person actually has real manic depression, lithium is it. Cheap, effective, and no lethal, multi-system side effects.
I’m wondering why the FDA (if they actually did) approve the atypicals in addition to the SSRIs, for depression…
A terrible, wasteful (in human lives and health, let alone costs) class of drugs.
M Helm, MD
There is a simple way to learn the best method of relapse prevention. It is comparison of actual patient results from administrative databases. I would take an administrative claims study over an open label study any day of the week. I don’t believe we have seen that study.
It is not useful to know how a psyciatric (or any other) drug performs for any condition in comparison to placebo. Patients with real medical, psychiatric or behavioral problems are not treated with placebo. Real world patients tend to have more complex mix of conditions than those who qualify for clinical trials. Certainly aripiprazole has been around long enough, and marketed heavily enough that a large population of patients with bipolar disorder could be compared to other treatments across a number of important administrative measures.
Personally, I am having trouble imaging that any honest comparative study would ever reveal aripiprazole to be a cost-effective option relative to other available treatments.
Lithium should be the comparator against which other bipolar maintenance medications are measured. All the above citations don’t amount to a hill of beans, though I’m sure it represents a significant investment in advancing the BMS marketing message for aripiprazole.
Doc
BMS is concerned with profits first and foremost, make no mistake about it.
Don
The docs are right. Read crackerjack science writer Robert Whitaker’s “Anatomy of An Epidemic” for outcome studies that tell the truth (as in people who have or have had mental health crises and issues being gainfully employed and/or not on the SSI/SSDI rolls). For example (p.245)”The prescribing of psychotropic drugs to two-year-olds and three-year-olds began to be commonplace about a decade ago, and, sure enough, the number of severely mentally ill children under six years of age receiving SSI has tripled since then, rising from 22,453 in 2000 to 65,928 in 2007″.
Duane Sherry, M.S.
Abilify.
Any antipsychotic drug is dangerous.
Period -
http://breggin.com/index.php?option=com_docman&task=cat_view&gid=27&Itemid=37
More than one person commenting gave reference to Lithium… the “gold standard” according to some.
Lithium has fallout as well. Lots of fallout. At the end of the day, it’s not safe to put 1,000 mg/day of toxic salt in the body -
http://google2.fda.gov/search?q=lithium+carbonate&x=9&y=12&client=FDAgov&site=FDAgov&lr=&proxystylesheet=FDAgov&output=xml_no_dtd&getfields=*
Duane Sherry, M.S.
http://discoverandrecover.wordpress.com
Walter
The author of this paper neglected to include the most relevant article supporting the opposite side of the issue in his references. When confronted with this, he tries to trivialize it, even though the study was peformed not just in “responders” as he implies, but entirely in patients who failed to respond to lithium.
He’s either lazy and careless or dishonest. In either case he sounds like a real jerk.