Tuesday, April 01, 2008

Abilify for Depression: Second Round a Lot Like the First Round

In July 2007, I posted about a very strangely designed study that claimed to show Abilify was an effective treatment for depression when added to antidepressant medication. Here is what I wrote about it then...
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?
Well, these experts in study design decided that once was just not enough, so they ran the same exact study twice. Same huge design flaw. Similar results. The results are posted in the Journal of Clinical Psychopharmacology. By a statistically significant, though not overwhelming margin, those on Abilify + antidepressant improved more than those on antidepressant + placebo. Or did they?

Dear Patients: We Don't Care What You Say. On depression measures rated by clinicians, patients did modestly better on Abilify. But on measures completed by the patients, there was no statistically significant difference between Abilify + antidepressant vs. placebo + antidepressant. So the patients didn't actually perceive themselves as being less depressed -- um, shouldn't the opinion of the patients matter? The message that the authors are trying to make is that the opinion of the clinical raters matters much more than the opinions of patients, which strikes me as ludicrous. These people are depressed, not floridly psychotic, so I think they would have a pretty decent idea as to their mental health status.

The authors attempted to explain this inconvenient finding away as follows:
These [patient-rated] scales were included for exploratory purposes, and the lack of emphasis on these ratings may have contributed to increased variance. The corresponding clinician-rated versions were not included, which may have hindered patients in responding accurately to the self-rated version.
I'm really confused here -- what do they mean that a "lack of emphasis" resulted in increased variance? And as for accusing the patients of not completing the ratings accurately, that just sounds like sour grapes to me. If there was a significant difference favoring Abilify, you can bet your life savings that the authors would not have accused the patients of reporting inaccurately. Only if a drug is shown to not work can we accuse patients of inaccurate reporting because all new drugs must work; such is the dogma of modern day psychopharmacology gone wild.

The authors close their paper with the following jewel:
Given the public health challenge of antidepressant nonresponse, this is a significant clinical finding.
We're getting knee-deep in bogus public health claims these days. Even though patients don't perceive that they improved any more on Abilify relative to a placebo, this is a significant benefit to public health? You bet. If someone has a defense for designing a study in such a manner, I'm all ears, but this really looks like a blatantly biased study that still managed to find no benefit (according to patients) in using Abilify.

15 comments:

DrJ said...

I would think the goal here is to just have a study published that MIGHT indicate some kind of benefit. It doesn't have to be that meaningful...only meaningful enough to justify the addition of an antipsychotic medication. That way, psychiatrists can feel more comfortable (i.e., no longer have to prescribe off-label because they can cite two-count them-two studies pointing to a benefit). It's published in a journal for goodness sakes. Ahhh. You mean now we don't have to message the diagnosis to prescribe antipsychotics?? I was going to call this major depression with psychotic features, but now I can just call it Major Depression Moderate!!

Doesn't happen you say... It happens every day and is quite freqent. I worked in a mental health center for 2+ years and found myself scratching my head about the psychiatrists' diagnoses until I noticed what meds were prescribed.

Anonymous said...

I agree with previous poster that the FDA hurdles only increase every year to get approval and that Abilify was approved for augmentation in Major Depression based on these trial designs, that's good enough for me. Have you asked the company for a response to your concerns?

CL Psych said...

Anon,

I'm not sure where you would get the impression that the FDA hurdles are getting more difficult with time. It appears that your statement that FDA approval is good enough for you means that you don't care about the strength of the data underlying FDA approval. Some drugs that have strong evidence of efficacy are approved and some drugs have rather meager evidence of efficacy (like Abilify for depression), and they are also approved. If you're unwilling to look at the data from clinical trials, then I sincerely hope you are not a physician.

The company, like most companies I discuss, visits my site on a regular basis. I would welcome any comment from BMS.

DrJ said...

Anon's response confirms what I was thinking (especially if he/she is a psychiatrist or drug rep). I wasn't saying this is a good thing that psychiatrists will have to message their diagnoses less, I'm simply saying that psychiatrists will use this as justification for prescribing antipsychotics for depression even more than they do now. And drug reps will tout these studies to psychiatrists when pitching the drugs to psychiatrists. Regardless, it's not uncommon for difficult patients to be on every class of medication (no matter what the diagnosis--antipsychotics, antidepressants, mood stabilizers, and benzodiazepines). If I could choose one that I wish didn't exist, it would be the benzos. They make the patients I see much harder to treat. CLPsych...maybe you could write some on benzos??

Anonymous said...

this is a great article. it really shows that drug companies start with a goal (get X drug approved for Y) based on monetary concerns and then will do ANYTHING to make the research prove that.

IMNSHO there should be a law that does not let them rate the "efficacy" of these drugs when they cannot measure it in a scientific way. It should be up to the patients to say whether they are depressed or not.

I also think that even "psychotic" individuals can tell if they are improving. They don't like the drugs becuase they don't work and cause nasty side-effects. If they worked and didn't cause side-effects, people would be lining up to get them.

Anonymous said...

Hi all,

While I agree with some of your statements, particularly those about the patients responses, my concern is that you are misunderstanding the point of the study.

There are a substantial number of depressed folks out there who are only able to get some partial benefit from conventional meds such as SSRIs. If there is a recognized benefit, even a small one, from adding a drug with a different MOA, don't you agree it would be worthwhile making it available?

To take your analogy, its unfair to talk about directly comparing Tutor A and Tutor B, and its certainly wrong to say that 'Abilify came out on top' - there was no competition involved. The two tutors have different teaching styles, and a percentage of students do better with both teaching techniques, as opposed to just Tutor A alone. While no-one would say that Tutor B is qualified to teach students alone (and aripiprazole is not suitable for monotherapy in depression), Tutor B clearly provides a way for a group of students to improve their math scores if taught by both tutors, when they have perhaps struggled with Tutor A's teaching style. Not perfect, but then neither is the analogy.

The issue that you should be looking at in this blog is one of the relevance of the added efficacy. The two studies have come up with, frankly, remarkably identical findings as regards percentage remission when aripiprazole is used as an augmentation agent in depressive disorders. The issue at stake is whether that very modest improvement is worth the FDA approval as adjunctive therapy? I would be interested to hear you comment on that.

And I think it is also worth bearing in mind the point that was made in passing by DrJ. The unfortunate truth is, many of these patients are sometimes on cocktails of drugs for their spectrum of psychiatric disorders, regardless of whether the agent is FDA-approved or not. Will BMS' revenue from abilify increase as a result of the new indication? I am sure there will be as modest an increase as the results in these studies - ie, not much, but the only difference is who is now paying them for the drug? Many docs have been prescibing atypical antipsychotics as adjunctives for a while (risperidone augmentation was described in 1999, and olanzapine in 2001), and I am sure that most psychiatrists will not be changing prescribing practices for the bulk of their patients just because of the new indication.

And if you want to express concerns with trial design for this type of trial, I think you are aiming slightly off-target - the precedent for all of these trials was set by STAR-D, and as such that is the benchmark for all augmentation studies now. If BMS or any other company wants the augmentation indication, that's what they need to pay attention to where the FDA is concerned. I'm afraid comparing yourself to Tutor A may be the only way to go as far as our oversight body is concerned.

CL Psych said...

Anonymous,

Very good comments. I have no issue with augmentation being studied. Obviously, there are a subset of people with depression who respond poorly to antidepressants and thus require alternative treatments.

The issue I have is with the design:
A. One group of people was shown to not respond to antidepressant plus placebo for an eight week period.
B. Some of the nonresponders continue on a treatment already shown to not work.
C. Some of the nonresponders get Abilify rather than placebo. Since they are doing something different than the treatment that failed them for eight weeks, then of course they should improve more than group B.

You are correct that the FDA buys into such designs as being legitimate, which is certainly a big part of the problem. If the FDA sets a very low bar, then why would a company waste time trying to reach a more impressive standard?

It's a good question as to the extent to which FDA-approval is relevant. After all, much prescribing is already off-label and with new "reforms" in order allowing for even more off-label promotion, it is likely that even more off-label marketing will occur.

"If there is a recognized benefit, even a small one, from adding a drug with a different MOA, don't you agree it would be worthwhile making it available?"

Very good question. As I mentioned above, in the case of antipsychotics for depression, they will be available whether they are FDA-approved or not. But what about the fact that patients themselves perceived no statistically significant (much less clinically significant) benefit? I find that quite concerning.

And I also perceive that many physicians, upon learning of a drug's FDA-approval courtesy of drug reps, reprints, CME, and the like, are not going to be hearing the straight dope: At best, marginally better than a placebo in studies designed in a biased manner. Rather, the impression given by marketers is more likely to overplay the benefits and hide from any discussion surrounding akathisia, or that the patients didn't perceive themselves as less depressed.

Psychiatrists? Sure, they might change their practices a but. If Seroquel gets FDA-approved for depression, then that is more ammo for the idea that antipsychotics in general are also antidepressants. Monotherapy with antipsychotics... We'll see; I believe Seroquel may be pursuing such an indication. And who says that general practice docs will not be targeted with "education" and marketing regarding the new benefits of "broad spectrum psychotropics" like Abilify and its brethren?

Not sure if I answered all of your questions...

Dr J: As for benzos, I haven't written much about them, mostly because they are out of the marketing limelight. If you have a specific issue you'd like me to tackle, please let me know.

Stephany said...
This comment has been removed by the author.
Marissa Miller said...

Thanks for the analogy. I'm quite weak with statistics.

CL Psych said...

Don't worry about being weak with stats -- you can apparently publish a study in a medical journal based on completely misinterpreting your stats these days. Just ask the authors of this study of Abilify used to treat dementia.

Michelle (the beartwinsmom) said...

Great analogy. I'm in graduate school and no matter how many times I read those darn stats, I still need something concrete to help me put it in focus.

I found your blog from Marissa (@ depression introspection). Looks like I'll have to bookmark your blog for some good reading. I have much to research for my upcoming psychiatrist appointment.

Warm regards,
Michelle aka The Beartwinsmom

Anonymous said...

Very interesting post. I came here because I heard about someone prescribed JUST abilify for depression. First SSRI+abilify, then abilify alone. This is the slippery slope.

I read the abstract if the article you linked to, and noticed several questionable things. First, patients were all on different SSRI's,chosen by their doctor, so the study was comparing apples and oranges and bananas and grapes. Moreover, different people respond differently to the same SSRI.

Also it concludes Abilify is "safe and effective." Woah -- one of the problems with the new antipsychotics is that they have many health dangers, including developing diabetes.

For all we know some of the patients weren't helped by antidepressants because they were on the wrong one, or they had a lousy talk therapist. The whole idea that an antipsychotic on top of something else will help someone who is not psychotic is bizarre on its face.

You're hearing this from someone prescribed Seroquel and Zyprexa for INSOMNIA. What next, hiccups? They really are the new benzos. I look forward to reading more of your blog.

Roy said...

>>"C. Some of the nonresponders get Abilify rather than placebo. Since they are doing something different than the treatment that failed them for eight weeks, then of course they should improve more than group B."

Not sure I agree with your logic here. Why should they necessarily improve just because they're doing something different? If what they're doing is just randomly different, they should be equally likely to improve more than group B as they are to improve less (and on average the two groups should improve by the same amount). But they did improve more. Why should we not attribute that to Abilify?

CL Psych said...

Roy,

It's not "randomly different." One group continues to receive treatment that clearly does not work for them. Another group gets to switch to something notably different (Abilify). If there had been a comparison group that added another antidepressant, lithium, exercise, psychotherapy or some form of active treatment -- and if Abilify had beaten that group, then I'd change my tune.

INSATIABLE GIRL said...

I don't know if this post is too old to comment on, but I need help. I have been seeing a counselor for months. In order to get medications prescribed, I had to see the therapist/psychologist DR, something. I have Borderline Personality Disorder. The DR wanted to write for Seroquel. I was concerned about the weight gain, since I lost over 100 lbs after severe depression caused major weight gain. My biggest problem was severe mood swings, minutes apart, mostly causing anger and violent rages. The DR said I could take abilify if I wanted, at my own suggestion. It has helped, its helped completely balance my moods, I feel almost like my old self. The most annoying thing is the feeling of being unsettled. I am restless, but the Aderall that I also take helps even things out. But, would or should Abilify help balance my mood for Borderline OR since it has worked, does it mean I am psychotic? I do not take any depression meds. Thanks!