August 3, 2011

4 Unintended Consequences of Seroquel's Adjunct to Antidepressants Indication


cutting edge research on this drug should be coming any day now

Part 3 here-- short refresher.

In 1998, I discover something is red.  "It's red."  Sweet.

In 2010, I discover that same thing is also hard.  "It's hard."  Nice.

The question is: what is its primary attribute?  Is it a Red thing that's hard, or a Hard thing that's red? 


Imagine you did it the other way around: in 1998 you discover it is hard, then in 2010 it's found to be red.  Does that change things?  Is the primary attribute based on history, or something else?

"I guess it all depends on what you use it for."  You guess?


Seroquel is that thing, discovered first to be efficacious in schizophrenia (translation: "antipsychotic") and now found to be efficacious in depression ("antidepressant").

So is it an antipsychotic that treats depression, or an antidepressant that treats psychosis?

"I guess it all depends--"  Shut it.  Scientists are talking.


You might think it doesn't much matter what you call it but rather how you use it, but it matters.  If you call it an antidepressant, regardless of mechanism of action, price, or data it gets slapped with a suicide warning.  If you call it an antipsychotic you forever battle a diabetes warning regardless of the truth of it (see Geodon, Latuda.)  And call it the wrong thing, or the right thing at the wrong time, and your company gets to pay $1B to the government.


Seroquel is a special case study in the semiotics of psychiatry, because much of the naming was intentional.

1.  Excessively high dosing.

One can't fault the FDA for striking a balance between safety and efficacy.  They voted nearly unanimously "Yes" on its monotherapy efficacy in GAD and MDD-- they agreed it worked; but they didn't want it being used as commonly as Prozac, so voted unanimously "No" on safety.  So no monotherapy approval. 

Recall that one of the monotherapy trials of Seroquel showed efficacy at 50mg.   However, because the FDA chose to go with the adjunct indication for safety reasons, it can only approve the doses used in those adjunct trials: 150mg.  Three times higher than the "minimally" efficacious dose in a monotherapy trial.

So in choosing an indication out of safety concerns, it tripled the doses used.

The reps are not allowed to suggest you use 50mg, or tell you that those studies exist; indeed, they aren't told about those studies themselves.

2.  Reinforcement of an erroneous mechanism of action.

The FDA wants to "protect the public". They know docs will generalize the indication of one drug to others in the class.  Hence, the FDA's and AZ's interests run in parallel: not all antipsychotics are antidepressants.

So AZ avoids all talk about mechanisms of action which are shared by all atypicals (dopamine or serotonin antagonism) and settles on a mechanism which is specific to
Seroquel-- the NET inhibition.

However, as I hope is clear, from part 3, the NET probably has nothing to do with it.

3. Reinforcement of the cult of polypharmacy.

It worked fine as monotherapy; but it's indicated as an add on to drugs (SSRIs/SNRIs) that failed for over 100 days at high doses.

If the combination works, what then?  Was it the Seroquel alone that did it?  Was it the SSRI just taking longer to kick in? Or some kind of synergy?  The FDA answer is that since you don't know,  you use both.

But you do know: Seroquel worked as monotherapy in at least two FDA trials.  Given this, it would be most logical to taper off the SSRI after a while, because you don't know two drugs are better than one drug, but I can promise they are twice as toxic and twice as expensive. But you won't find that recommendation in the PI or any academic journal.   The FDA is causing psychiatry to move backwards: more polypharmacy; less safety; greater costs. 

4. Pharma/academic focus on "bipolar depression."

Seroquel isn't indicated as monotherapy for MDD, but it is indicated as monotherapy for bipolar depression.  Fortunately, 1) bipolar depression looks exactly like major depression during the episode; 2) it's indicated at 300mg, so you can be guaranteed to get heavier.

From the company perspective, the obvious marketing strategy is to push for "awareness and detection of bipolar depression" (read: "recurrent major depression is probably bipolar disorder"), and "incentivize" the reps to have their scripts skew towards 300mg.  Farewell, depression, again.

For example, if Seroquel is truly an "antidepressant" then the competition would be Prozac.  But it isn't; it's Geodon.  Reps aren't measured against SSRIs, only against atypicals, which, in theory, they're not really competing against.

VI.  Should we worry about any of this?

Nope.  Once Seroquel goes generic, the impact of all of this nonsense will be minimal.  Then no one will care how you use it, at what dose; whether you use it monotherapy or in combination with nine other drugs none of which anyone cares about either.  Do a Pubmed search on Zyprexa research in the last year.  Anything?

Granted, there's probably patients who do care.  But.