February 22, 2010

How Seroquel XR Works, Part 2

warren commission.jpg
The ongoing story of a government cover-up

Part 1 was here. 

Let's assume it did bind to the NET, how much of the efficacy should we attribute to norepinephrine?

In the pre/frontal cortex there are no pure dopamine transporters (DAT), and the NET is primarily responsible for dopamine's reuptake.  So the NET, which norquetiapine fully occupies/barely touches, transports about 50/50 norepinephrine and dopamine.

So even if the NET is inhibited, the ultimate effect in the frontal lobe may be related to dopamine.

Are there any other better explanations for Seroquel's antidepressant efficacy?

It's odd that while the FDA has chosen to be unsure about the mechanism of action in psychosis, it is confident in the MOA in depression.  Here are some equally/more likely explanations for the antidepressant effect:

H1 antagonism: sure, why not?  6 points on a Hamilton for sleep, another 2 for weight gain...

Partial agonism at 5HT1a
:  Think Buspar.

a2 antagonism:  (inhibitory autoreceptors.)  Blocking these would increase serotonin and norepinephrine release, etc.

Unfortunately,  a2 antagonism is a property only of quetiapine, not norquetiapine.

Why is that unfortunate?

Because if norquetiapine is marketed as a new drug...


But if norquetiapine does actually inhibit the NET, wouldn't that at least be a plausible mechanism for its efficacy?  Since Effexor and Cymbalta work...


I'll grant that it is evident Effexor and Cymbalta work; but who are you asking to tell you why they work?  Wyeth and Lilly?  That's like asking your future wife's ex-boyfriends to write her a letter of recommendation.  "She's so awesome, she'll make you really happy." Oh, I guess I should go shave my back then.

That's a very disturbing visual, Backbeard.

Let's do an abbreviated analysis for Effexor.  According to this non-porn site, the Ki for the SERT is 80nM and NET 3000nM (1000-6000).  This means it "prefers" to go to the serotonin transporter (SERT).

Consistent with this is PET data showing high SERT binding in striatum:

effexor sert.JPG


This is a comforting graph, and shows the "fountain" approach to understanding a "dirty" drug's effects. But note that the line isn't flat, it still trends upwards.  If the affinity for the SERT is 200-600 times that for NET,  then clinically meaningful effects on NET would have resulted in serotonin overload.

But that's speculation.  You've already shown that the Ki's are unreliable guides of in-vivo affinities and effects.

Ok:

What you want is a direct test of the operation of the NET in the human body.

If you inject tyramine into your friend, it will be taken up into the presynaptic NE terminal by the NET, where it will cause the release of norepinphrine.  The blood pressure then reliably goes up.

If you block the NET, this effect will also be blocked, since tyramine can't get in.  Nortriptyline, a tricyclic and "norepinephrine reuptake inhibitor" blocks the tyramine effect almost completely.(1)

What about Effexor?  If Effexor is an NRI, it should also block the blood pressure elevation.  Zoloft, not an NRI, should not block it-- the BP should go up.


tyr30.JPG 
This is ratio of post/pre blood pressures; >1 means tyramine caused BP to go up, <1 means tyramine couldn't get BP to go up.

What you see is that 75mg of Effexor was no more an NRI than Zoloft; and maprotiline (the NRI) turned Effexor 375mg into a cuckold.

But surely Cymbalta has impressive clinically relevant NRI effects?

What dose of tyramine is needed to make the BP go up 30mmHg?  That's called the PD30.  If a drug blocks the effect (like desipramine, an NRI, would) than it would take more a higher dose of tyramine:


 TYR PD30 (mg)
 Day 7Day 8
Placebo (n=12)7 [4-14]6 [5-9]
Duloxetine 80 mg (n=5)9 [5-8]7 [4-7]
Duloxetine 120 mg (n=6)6 [5-9]4 [4-7]
Desipramine 100 mg (n=11)30 [22-82]18 [12-31]

Well that's unfortunate. (2)


But then how can they claim Cymbalta is an NET?


1.  By ki, the SERT/NET ratio is about 10, versus Effexor's 200, so in that sense you get the norepinephrine "earlier" in the dosing cycle;

2. If it blocks the NET, then it should also decrease the cycle of norepinephrine turnover (since it isn't being taken back up and degraded.)  So there should be less NE and its metabolites in the urine.  And that's certainly what this study finds (abstract:)

Urinary and cardiovascular measurements suggest that duloxetine has an effect on NE synthesis and turnover, indicative of NE reuptake inhibition.
"Suggest?"


NE metabolites cymbalta.jpgCompare the NRI desipramine (DMI) to placebo, note the decrease in urine NE and metabolites.  You can see that while the levels of NE and its metabolites decreased in the urine, Cymbalta resulted in a decrease in only the metabolites, but not NE itself.  Do you know why?  No one else does either. 

On the basis of this study we can reasonably conclude only that duloxetine is spelled with an x.


So you're saying that they arbitrarily decided on the mechanism of action of Seroquel by its barely detectable similarity to Effexor and Cymbalta, which themselves don't generate their efficacy the way they say they do and Seroquel hoped they did?

At this point, someone in the room should probably say "oops."


-----

Part 3.  (You mean there's a Part 3?)
----

1. One interesting conclusion of this is that it would therefore be safe to mix an MAOI with Pamelor.  THAT IS NOT A CLINICAL RECOMMENDATION.

2. If you want to make a gazillion dollars, perform the TYR30 test with Seroquel and norquetiapine.  Residents: I just gave you a treasure map.








Comments

So why give others a treasu... (Below threshold)

February 22, 2010 10:09 PM | Posted by Josh: | Reply

So why give others a treasure map rather than just find the treasure yourself?

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He's Blackbeard - he alread... (Below threshold)

February 22, 2010 10:40 PM | Posted by Anonymous: | Reply

He's Blackbeard - he already has treasure.

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Fckn A. Why did it take so... (Below threshold)

February 23, 2010 12:58 PM | Posted by Cousin Larry Appleton: | Reply

Fckn A. Why did it take so long for you to post this? Some people were waiting a long time to read this while it was languishing in your saved documents file.

When are you coming to Chicago? There are many people here who want to hear you speak. Please have your publicist put together a speaking tour- it could be a nice change of pace for you. I realize that you might have to reveal your identity, but perhaps you could work around that.

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I have read this post.It is... (Below threshold)

February 24, 2010 3:18 AM | Posted by Aion kinah: | Reply

I have read this post.It is very good.

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So is the sleepiness and we... (Below threshold)

February 24, 2010 4:57 PM | Posted by acute_mania: | Reply

So is the sleepiness and weight gain from Seroquel/norquetiapine enough to account for the 3-point reduction in the MADRS score?

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Quick question for Alone:<b... (Below threshold)

February 25, 2010 8:21 AM | Posted by jack: | Reply

Quick question for Alone:
How is that "it is evident Effexor and Cymbalta work." Aren't the recent studies, or metanalyses, saying that antidepressants are no better than placebo? I think Effexor was specifically one of the drugs they looked at.

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You write very enjoyable ar... (Below threshold)

February 25, 2010 1:02 PM | Posted by Spencer: | Reply

You write very enjoyable articles that are a pleasure to read. Thank you for your insight and wit.

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My brain just blew. I love... (Below threshold)

February 25, 2010 1:31 PM | Posted by KD: | Reply

My brain just blew. I love these kind of posts.
I sense this will not change the niche created for Cymbalta as "Effexor Lite".

Re nor/quetiapine. Seroquel for depression is like giving anesthesia for a sucking chest wound. I can get why it might be tried before mirtazapine (H1 antagonism plus notable antidepressant action) in bipolar depression, but in MDD it just strikes me as booze plus copay minus grapefruit juice. You can get sleepiness and weight gain from rum, too, but Bacardi doesn't make it into the PDR.

Re footnote 1. I do know one person who has been on 40mg tranylcypromine in the morning and 10mg nortriptyline at night for over a decade. Dosages and timing being critical to the safety of that, I suppose.

jack: at least the most recent meta-analysis looked at only paroxetine and imipramine. They cut out an enormous number of studies. And meta-analyses in general can fall prey to confirmation bias; they don't always agree with large RCTs.
Granted, the drug companies have been quite talented at not publicizing the studies showing lack of efficacy in milder depression.

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Any substance that induces ... (Below threshold)

February 25, 2010 2:53 PM | Posted by Anon: | Reply

Any substance that induces sleep can "treat" depression at a stastistically significant level.

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So is norepinephrine irrele... (Below threshold)

February 26, 2010 1:03 AM | Posted by Anonymous: | Reply

So is norepinephrine irrelevant or it is relevant but no drugs do it? And what you wrote abot the norepinephrine transporter transporting dopamine just blew me away

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Why does blood pressure dro... (Below threshold)

February 26, 2010 10:43 AM | Posted by acute_mania: | Reply

Why does blood pressure drop below baseline in the people taking effexor and maprotiline? Doesn't that suggest that the drugs themselves have hypotensive effects in addition to/rather than simply blocking the effect of tyramine?

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Since you seem to take requ... (Below threshold)

February 26, 2010 3:14 PM | Posted by TheUnderwearBandit: | Reply

Since you seem to take requests. Any chance you can finish your Autism series? (Perhaps I missed installment three, but a search of autism and imprinting on your site only brings up that piece.)

The mainstream media, i.e. The New york Times, continues to butcher this issue.

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Excellent post. Amusingly I... (Below threshold)

March 2, 2010 4:20 AM | Posted by Neuroskeptic: | Reply

Excellent post. Amusingly I am getting a page full of Scientology adverts along with it.

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I love to read comments fro... (Below threshold)

March 5, 2010 12:46 AM | Posted by Anonymous: | Reply

I love to read comments from people (including the original author) that are smarter than anyone else (including FDA regulators). Try solving this dilema: The words "love" and "like" both have 4 letters, but mean 2 different things altogether. In the meantime, continue to practice medicine by the seat of your pants while inserting all of your own wisdom into the equation.

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I took seraquel for the fir... (Below threshold)

March 6, 2010 8:46 PM | Posted by onedoseonly: | Reply

I took seraquel for the first time. One high dosage made me sleep a whole weekend.

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What rubbish. If you actual... (Below threshold)

June 6, 2010 12:49 PM | Posted by metafunj: | Reply

What rubbish. If you actually tried effexor you'd be able to feel the increase in norepinephrine right off the bat. Sure its not nearly as potent as its effect on serotonin, but it doesn't need to be for many people. Who said that the levels had to be equal. One does of desvenlafaxine increase norepinephrine 400 percent, a similar increase is seen with cymbalta. I'm sure the NRI aspect of norquetiapine plays a role in how it works. I don't think the tyramine pressor effect is an accurate way to determine the way a drug will effect mood.

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Methodology and objectivity... (Below threshold)

June 6, 2010 2:18 PM | Posted by acute_mania: | Reply

Methodology and objectivity be damned! You can actually FEEL the the norepinephrine at work when you take Effexor.

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Yup, you can. You feel you... (Below threshold)

June 6, 2010 2:41 PM | Posted by metafunj: | Reply

Yup, you can. You feel your heart rate go up and cant sleep the first few nights. SSRIs don't do that. It fades after a couple weeks but its undoubtable it increases norepinephrine. Don't believe me just look at in vivo test in rats NE levels. It increases NE despite the low affinity for the transporter. You have to look at more than binding affinities.

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Here's a post regarding big... (Below threshold)

June 9, 2010 7:48 PM | Posted by vv111y: | Reply

Here's a post regarding big pharma bad behaviour,, including seroquel:

http://www.nakedcapitalism.com/2010/06/guest-post-predatory-pharma-%E2%80%93-an-end-to-too-big-to-nail.html

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As a grad student in pharma... (Below threshold)

June 20, 2010 3:37 PM | Posted by N: | Reply

As a grad student in pharmacology, I find this fascinating. As a grad student experiencing depression, I find it irritating. What the hell drug should I be taking? Celexa 20 mg + Wellbutrin XL 150 mg is barely getting me out of bed in the morning.

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so good .Thanks for the inf... (Below threshold)

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iPhone Cases

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Any studies comparing seroq... (Below threshold)

April 10, 2012 11:35 PM | Posted by billy marivate: | Reply

Any studies comparing seroquel ir to seroquel xr clinically ?

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