thelastpsychiatrist.com - 4 Unintended Consequences of Seroquel's Adjunct to Antidepressants Indication. Adnotated.

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

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?

II.

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 attributeⁱ based on history, or something else? "I guess it all depends on what you use it for." You guess?

III.

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

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

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

IV.
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.^vii

V.
Seroquel is a special case study in the semiotics of psychiatry^viii, 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^ix "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.^x

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^xi'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.^xii

But you do know: Seroquel worked as monotherapy in at least two FDA trials^xiii. 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^xiv 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^xv; 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.^xvi

1. There's no such thing as a "primary attribute". Attributive primacy is not a matter of ontology. [↩]
2. Seroquel is not efficacious in schizophrenia ; at least, not anymore than "fuel economy magnets" are efficacious : in winter, when a colder engine makes the heat->energy conversion slightly more efficient, it's not entirely inconceivable one might "show" them to be "efficacious". [↩]
3. There is no such thing as the medical condition of "depression" ; at least not anymore than the medical condition of "not buying enough winning scratch lottery tickets", or "always getting a flat at an inconvenient moment in time". [↩]
4. For the same money he could have said the moon is a celestial essence that treats the medical condition of "female hysteria" ; historically they have. Or I guess une crise de foie, or any other item off the lengthy list of historical "diseases" constructed in the same manner by the same kinds of people.

   Come to think of it, you could attempt to treat love sickness. It absolutely must be a legitimate sickness, it even has "sickness" right in the name! Who can argue with that ? [↩]

5. Is the result of dividing four by zero greater or smaller than the result of adding two and the square root of minus one ?

   That's exactly the mental process involved : the result of dividing by zero might look, superficially, to the naive observer, like a real. It isn't! And the thing you feed a schizophrenic may look, superficially, like medicine. But... it isn't! You may appear to be acting exactly like someone giving sulpha to a girl with UTI -- yet you aren't doing anything even remotely similar.

   From the other side : comparing complex numbers to reals may look, superficially, like you're engaging in a comparison. You aren't. "Treating" depression may look, superficially, like any other treatment. It isn't. [↩]

6. Oh, right, the scientists making the science "America runs on". With scientists like these it's inconceivable anyone'd need priests for anything. [↩]
7. The problem with this view is that "the corporation" and "the government" are in no sense distinct ; not only is the supposed "payment" so much thin air, but more importantly the only reason Inca under his aspect of "the company" even has "a billion" to pay Inca under his aspect as "the government" is because "the government" gave it to "the company" in the first place.

   The whole exercise in wordage reduces to something quite like "getting a flat tire at an inconvenient moment results in your left coat pocket sending a piece of scribbled paper to your right pants pocket". O noes, I guess ? [↩]

8. Rather, the psychiatry of pseudoscience, but whatevers. [↩]
9. A point sufficiently well established by now : "consensus" votes aren't. [↩]
10. Right, right, because this is science we're talking about here, a methodical approach, proceeding rationally from empirical observation on the basis of a few self-evident truths, or however that went.

    Nuts. [↩]

11. Astra Zeneca, the "company". Private company, might I underscore, it's owned by "pension funds" which consist of the money "the government" gave to "the people" so as to... spend it... wisely... on owning "the company". Why do you not see the rationality immanent in the scientific system "America runs on" ? Hm ? [↩]
12. The answer is, you're not a doctor, you're a bureaucrat. [↩]
13. Everything worked to the same standard of working-ness, including the Ptolemaic planetary model. [↩]
14. It is improbable two drugs given together are merely twice as toxic as the average toxicity of each of them in isolation. [↩]
15. And exactly like "female hysteria" at all other times. Go ahead, write the differential diagnostic manual for "depression" and "female hysteria", it'll be fun to watch ; and no, you don't get to walk out of it with weakass "do we still have to do this". Of fucking course you still have to do it, that's what the fuck science even is. I never heard of a mathematician unable to cross the Pons Asinorum waving his hands and "do I still have to do this"-ing himself all over the landscape.

    Science, rite ? [↩]

16. Fifty or so years of this, that's exactly how the whole thing ended itself. [↩]