Tuesday, March 24, 2009

Is It Still Considered Off-Label?

The FDA (Federal Douche Association), approved the barely prescribed Symbyax (1) for treatment resistant depression (TRD). You'll notice that the press release says that Symbyax is the "First Medication" approved for TRD.

This is pure marketing. Current standard of care for depression is extremely lame. Instead of acknowledging that, people spin it, creating this beast we now call treatment resistant depression.

Other's have already written about this drug (2, 3). So, I'm not going to rehash what's already been said. Many of the studies submitted to the FDA have not been published (shocker!). Here is a link to two studies that were pooled together as "supporting data" for the FDA (4). There is nothing new here to really criticise. These two studies have the same flaws as all other antidepressant studies.

Here is what I take away from the FDA approval: Zyprexa can now be advertised and prescribed for major depression without that being considered off-label. Lilly has been in a lot of trouble for pushing Zyprexa for off-label uses (5).

Symbyax has been around for a few years. Originally indicated for bipolar depression, it has not been prescribed a lot. One reason is that it is cheaper to prescribe the two drugs separately. It also gives the prescribing doctor more freedom to tweak the doses of individual drugs as opposed to the approved combination doses. Moreover, the data that is provided show that olanzapine alone was almost equal to fluoxetine alone. I'm pretty sure there are many docs out there who will use that as an excuse to prescribe Zyprexa alone for depression (they already do by the way).

Here are some questions I never hear asked: Assuming the drug actually does something, what does that say about the biological mechanism of depression? Zyprexa is a dirty drug, it kind of hits up all the major neurotransmitter systems. Does that mean no more monoamine hypothesis of depression? Has the research over the last 30 years been crap? Are bipolar depression and unipolar depression no longer distinct biological entities since they respond to the same treatment? Is the bipolar/unipolar distinction another marketing gimmick? I don't know what to believe anymore, I don't know what's black and what's white, what's right and what's wrong...I'm lost, I'm lost...


Bernard Carroll said...

This is a case study in how marketing prevails over best medical practice. This approval of the combination antidepressant-antipsychotic product Symbyax is bad for patients and may well be bad for Lilly. I told Lilly several years ago that I thought they were foolish and reckless to pursue approval of Symbyax for depression. Symbyax is Zyprexa plus Prozac.

For patients, taking the combination locks them in to a fixed ratio of the two medications, thus removing therapeutic flexibility. The side effect profile of the “atypical antipsychotic” drug Zyprexa is disturbing, and exposes patients to unnecessary risk. The worst side effect, besides the metabolic problems and diabetes, is tardive dyskinesia (TD) with long term use. Depressed patients seem to be especially susceptible to this syndrome of involuntary muscle movements in the mouth, tongue, face, and elsewhere. It can be very disfiguring. And permanent. We can put numbers on this risk of TD. In adult patients with schizophrenia the risk of TD with Zyprexa treatment is about 2.5% at 1 year. In children and adolescents treated with Zyprexa or similar “atypical antipsychotic” drugs for 6 months the risk is an alarming 6%.

So, when Symbyax is promoted early and often for depression in primary care, look for a new cohort of patients with TD and a fresh round of lawsuits against Lilly. This is a case where psychiatrist key opinion leaders have been found wanting and where patients will be damaged unnecessarily.

Here are some links.



Neuroskeptic said...

Very true, Bernard. In particular, it should be obvious that selling fixed dose combination pills serves no-one's interests but the manufacturers. They just don't make medical sense. (Except in the case of patients who can't remember to take 2 pills per day but are perfectly able to take 1, which seems unlikely in this population - if these were dementia drugs maybe there'd be a case for it.)

Regarding the neuropharmacology of atypical augmentation, it's an interesting story. There's a theory that it works by enhancing 5HT release by interfering with negative feedback loops involving 5HT2 receptors. (It's rather like the claim that pindolol synergizes with SSRIs by blocking presynaptic 5HT1A receptors, for those who know about that).

So short answer, no this isn't the end for the monoamine theory. Maybe.

Bernard Carroll said...

Thanks for your comment, Neuroskeptic.

All should keep in mind that the monoamine theory of depression that appeared in the 1960s applied to melancholic depression, not to the over-broad thing called major depression today. As Philip Dawdy remarked this week, the state of the science in clinical trials for depression is so bad that almost anything can be claimed as an antidepressant nowadays.

As for the theoretical explanation you relate, not that I think you really endorse it, I am reminded of Thomas Kuhn's description of a dying paradigm -- at the end it becomes so adorned with circumstantial exceptions and qualifications that it loses whatever explnatory power it once had.

SteveBMD said...

"Treatment-resistant depression" is one of those psychiatric pseudodiagnoses that always makes me cringe. Isn't it more appropriate to call it "medication-resistant" depression?

I mean, there are dozens, if not hundreds, of possible treatments for depression (to match the multiple conditions that we unfortunately and unapologetically lump together as "depression")-- everything from high-dose SSRIs to CBT, to yoga, to pet therapy. It always strikes me as self-righteous for the psychopharmacology industry to label a condition as resistant to only the interventions that it identifies as reasonable, conveniently ignoring other (and safer) ways to treat this condition.

I do, however, like the abbreviation. Makes me wonder why psychiatrists don't just prescribe more laxatives to get rid of their patients' TRDs.

Neuroskeptic said...

stevebMD: I believe it was David Healy who said that TRD should be renamed "inadaquately treated depression" or something similar, which I rather like...

Bernard: Actually, I think Kuhn had a point there. It's certainly possible that the monoamine theory is in danger of being "refined" to the point of being unfalsifiable. And certainly the drug companies seem to be keen on any "refinement" which gives some theoretical backing to their latest pill - but I have to say that I find the evidence about 5HT2A feedback pretty solid. Trevor Sharp and his group from Oxford have some good papers on it (not for the biologically faint-hearted).