Tuesday, February 19, 2008

Why I Love the Discussion Section

A recent study in the Journal of Clinical Psychopharmacology found that aripiprazole (Abilify) offered no benefit over placebo in treating biploar depression. Well, at least that's what the results showed, but the discussion section told a bit of a different story. At the end of eight weeks, Abilify failed to beat placebo on either the Montgomery-Asberg Depression Rating Scale or the Clinical Global Impressions -- Bipolar Severity of Illness Scale.

It is rare that an industry-sponsored article reports negative results and it would be nigh-impossible to find a published industry-sponsored study that failed to put a happy spin on the negative results. Sure, the results were negative in this study, but if the dosing was different, the treatment could have worked. There's always a loophole, some possibility that results would have been dandy if something were different. Check this out:
It is possible that the dosing regimen used in the current studies may have been too high for this patient group, or that titration was too rapid. Specifically, the unexpectedly high rates of discontinuation caused by any reason or because of AEs suggest that the aripiprazole starting dose (10 mg/d) may have been too high and that the dose titration (weekly adjustments in 5-mg increments according to clinical response and tolerability) may have been too rapid...

However, because preliminary data indicate that aripiprazole may have a potential value as adjunctive therapy in patients with bipolar depression, future studies that focus on the use of aripiprazole as adjunctive therapy using a better-tolerated dosing schedule with a more conservative escalation may be of greater value for the treatment of patients with bipolar depression...
And my favorite part...
Although the improvements in MADRS total scores in the current aripiprazole studies did not separate statistically significantly from placebo at end point, the significant effects observed with aripiprazole monotherapy within the first 6 weeks are clinically meaningful and similar to the effects seen with olanzapine monotherapy and lamotrigine monotherapy in patients with bipolar depression.
OK, so the argument is that while treatment did not work at the end of 8 weeks, the effects after 6 weeks were really super-duper impressive. Gimme a break. The authors did not present the actual numbers on the MADRS (the primary manner in which depression was assessed); rather, the data were presented in figures. Um, isn't science supposed to be based on numbers -- shouldn't they be provided in the text of the paper? At 6 weeks, the difference in scores between Abilify and placebo looks to be a little more than 2 points on the MADRS, a rating scale that spans from 0 to 60. And if a drug makes a person 2 points better relative to placebo, then the findings are "clinically meaningful"? Keep lowering that bar, fellas. While the discussion reaches out to rescue the reputation of Abilify, it does (to be fair), also point out on a couple occasions that Abilify was not particularly efficacious at the end of 8 weeks and was related to a worse safety/tolerability profile than placebo. In fact, relative to some other studies I've dissed regarding their sunny presentation of unimpressive results (like this one), the current Abilify article is a model of fair discussion.

Side note: Akathisia was reported by about a quarter of patients taking Abilify. The funny thing about akathisia is that it is not well-defined in this study or in many others. Is it a problem with movements, mental tension, something else, or what? It would seem important to know, given that Abilify apparently causes akathisia in droves. Do a Pubmed search for aripiprazole and akathisia and you'll see what I mean. A couple descriptions of akathisia follow:
  • Increased tenseness, restlessness, insomnia and a feeling of being very uncomfortable
  • On 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 cancelled
  • Another: A movement disorder characterized by a feeling of inner restlessness and a compelling need to be in constant motion as well as by actions such as rocking while standing or sitting, lifting the feet as if marching on the spot and crossing and uncrossing the legs while sitting. People with akathisia are unable to sit or keep still, complain of restlessness, fidget, rock from foot to foot, and pace.


Anonymous said...

I can attest to the akathisia induced by Abilify. I can't stand the jaw clenching tension, and restlessness. To compound the issue, the akathisia makes me very irritable. If the pdoc doesn't do something to remedy the problem I will discontinue the Abilify on my own.

Anonymous said...

I have just been started on Abilify. Well, slowly ramping up. I think I felt better on the lowest dose but the pdoc wants to keep increasing because I still have irritability issues.
I have just in the last few days started experiencing the akathisia. And it is an awful feeling. An inner restlessness defines it pretty well for me. I can't get comfortable and I can't sit still. The feeling is mostly in my legs. I feel like I constantly need to move. I'm not liking it one bit and it may lead me to quit the medication.