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).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).
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?
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.
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