February 4, 2010

How Seroquel XR Works, Part 1

When evidence based medicine results in a government sanctioned lie.

1. What is the clinical data on Seroquel's efficacy as an antidepressant?

In order to get an indication, the FDA requires at least 2 randomized controlled trials.  Both were identical in design, and nearly the same in outcome. 

Patients who were on an SSRI or SNRI, who were not improving after 6 weeks, were randomized to the addition of Seroquel XR 150mg/d, 300mg/d or placebo (along with the maintaining of their previous antidepressant at previous dose.)  The results:

seroquel xr study 7 mdd.JPG

On the basis of this, and the other similar study, the FDA approved Seroquel XR as an adjunct to other antidepressant in MDD.

2.  Is this a function of its antipsychotic properties?

No.    At 150mg/d there is very little D2 blockade; and not all antipsychotics have been able to show efficacy as an adjunct in MDD.  Some other mechanism is likely.

3.  How is Astra Zeneca and the FDA explaining the efficacy?

Not an easy question to answer.  Any proposed mechanism must be accepted by the FDA; once a mechanism is proposed and placed in the package insert (and promotional materials), it cannot be changed without resubmitting to the FDA-- even in the face of contradictory proof.  For this reason, e.g. they are vague on the mechanism in schizophrenia:

moa pi seroquel.JPG
All of Seroquel XR's promotional materials, the package insert, and the clinical trials describe the efficacy as the result of Seroquel's effect on norepinephrine and the NET.

4. What is the evidence for the proposition that Seroquel's antidepressant effect is mediated by norepinephrine?

Quetiapine is partially metabolized to norquetiapine.  Any pharmacologic (i.e. receptor) description of the Seroquel's effect must therefore include norquetiapine.

seroquel affinities.JPG
Quetiapine does not bind to the NET; but norquetiapine, its chief metabolite, is a potent inhibitor if it.  Tricyclics, Effexor, and Cymbalta all have considerable NET inhibition as well.  It's logical to conclude that when you eat a Seroquel, and it gets metabolized to norquetiapine, that it would then exert some action on the NET.

5.  At a clinically relevant dose of Seroquel, how much norquetiapine is there?

Not much.

The package insert states:

The Cmax and AUC of norquetiapine are about 21-27% and 46-56% of that observed for quetiapine.
Or, graphically (from Winter J Child Adol Psychopharm 2008):

plasma conc quetiapine and norquetiapine.JPG

Levels of norquetiapine did not differ IR vs. XR.

6.  What amount of NET inhibition occurs at 400ng/ml?  Show your work.

300ng/ml= 300ug/L

300ug/L= 0.0003g/L

MW norquetiapine = 295.4 g/mol

0.0003g/L x 1 mol/295.4g = 1.02e-6M = 1015nM

Norquetiapine's Ki for the NET inhibition is between 12-35 nM, depending on in vitro or in vivo.

At clinically relevant doses, the NET is more than completely occupied.

7.  Wow, really?

No, not really.

It appears that, in contrast to the longstanding paradigm of post-Kohut modern psychiatry, there is more to the human body than serotonin and norepinephrine receptors.  I'm as terrified as you are.  I don't know what to believe anymore.

A study measured the NET occupancy to Seroquel and norquetiapine (administered independently) in monkeys after a single dose.  Norquetiapine produced 80% occupancy of the NET at low concentrations.

However, in the nine suckers induced to participate in this other study, 300mg Seroquel XR  for 7 days generated 300nM concentrations of norquetiapine (as predicted above) and 35% NET occupancy in the thalamus.  150mg Seroquel XR-- the dose at which it functions as an antidepressant-- resulted in 19% occupancy.  That's not very much.

Consider that if Seroquel is metabolized to norquetiapine in monkeys as well, then a clinically relevant dose of Seroquel should produce clinically meaningful occupancy of NET (by the effect of its metabolite.)  It didn't.

The actual occupancy of the NET after 300mg Seroquel XR is quite low, 150mg even lower.

8.  Can you compare this to the occupancy of something I know-- like Effexor?

NET PET studies aren't as easy to do as DA studies, because many of the ligands used in the experiments bind nonspecifically and produce greater background binding.  There's also not an obvious negative to compare it to (e.g. there aren't any DAT in the cerebellum, so that becomes your control in DAT experiments.)  Radioligands specific for NET are only recently becoming used; Effexor doesn't have available PET data because now that there are such ligands for use in a study, Wyeth doesn't exist to pay for them.  Take that, unbiased research.

Understanding that the comparisons are not entirely fair, a blood assay in depressed humans found that after 8 weeks of Effexor 150mg, NET inhibition was 50%.  At 375mg, it was 60%.  Paxil, an "SSRI", blocked about 30% at 75mg.  Note that Effexor is only 55% protein bound (Seroquel is 80%) and thus in a real patient, there is more free Effexor to exert activity on the NET, which may be why it has such a larger effect on the NET despite a theoretically weak Ki (2200nM).

Despite this, the NET occupancy of a clinically efficacious dose of Seroquel XR (150mg) is likely too low to be the main cause of its antidepressant efficacy.

Part 2 here.


Ok, that's nice....but what... (Below threshold)

February 4, 2010 7:30 PM | Posted by OkieDokie: | Reply

Ok, that's nice....but what about part two of "The Cognitive Kill Switch" article?

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Looks like about a MADRS re... (Below threshold)

February 4, 2010 10:10 PM | Posted by kurlos: | Reply

Looks like about a MADRS reduction of 3! Seroquel for 3 MADRS points? As anyone knows that prescribes Seroquel, it INCREASES your appetite. This fact alone can explaine a 3 point MADRS reduction.

Did they count increased appetite as symptom reduction or side effect?

Was bedtime sedation symptom reduction or side effect?

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Um, I'm pretty new to this ... (Below threshold)

February 5, 2010 4:29 AM | Posted by Arthur Taylor: | Reply

Um, I'm pretty new to this stuff, and no scientist (musician, frankly I can only just keep the drool in). I'm also newly in treatment for the bipolar-disorder that's plagued me for most of my life, and newly on Seroquel XR (200 mg nightly so far), and it seems to be improving things. In words a guy like me can understand (and I usually understand your blog so I'm not entirely thick), is this a bad thing? I'm assuming so, so how bad? Should I mention this to my shrink? Leaves me with way more questions than answers about the drug I'm taking. Mostly my fault I'm sure!

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No, not at all a bad thi... (Below threshold)

February 5, 2010 9:58 AM | Posted by Alone: | Reply

No, not at all a bad thing. The argument here isn't that Seroquel doesn't work-- it does work, as evidenced by the clinical data (see part 2) and lots of people on it. However, the _explanation_ for the efficacy is wrong; worse, the wrong explanation is ok'd by the govt; worse, it causes something else to happen...

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If the efficacy exists, why... (Below threshold)

February 5, 2010 12:00 PM | Posted by Marques: | Reply

If the efficacy exists, why does it matter if the explanation is wrong? We already know that the FDA is incompetent, unreliable, inconsistent.
If it has an effective medicine, why would AZ want to promulgate an incorrect explanation of its efficacy? To make it easier for the drug to be approved for other uses?
Or is this a strategy by AZ to protect itself from litigation down the road?
What should I be aware of here? Excuse me if I am slow, I am interested to understand.

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I agree with Marques. What... (Below threshold)

February 5, 2010 3:58 PM | Posted, in reply to Marques's comment, by MichaelO: | Reply

I agree with Marques. What's the "explanation", for example, of how Abilify treats depression?

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<a href="http://clinpsyc.bl... (Below threshold) Why does it matter? Let's ... (Below threshold)

February 5, 2010 9:34 PM | Posted by Paul: | Reply

Why does it matter? Let's try informed consent. How does one make a decision to ingest a potentially lethal substance without knowing what the possible benefits and known risks are? Not knowing how a particular molecule generates at perceived therapeutic effect is not unimportant. I'll leave aside the question of what constitutes efficacy for a moment to leave this morsel.

Does it matter how something achieves an end? Does it matter if that end is something objective, testable, repeatable, or not? If the underlying hypothesis can be shown to be false, does it matter if a desired result is achievable? Does is matter if the decision only involves your own personal choice or is when medicating persons involuntarily?

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The only thing I can say fr... (Below threshold)

February 6, 2010 1:02 AM | Posted by Anonymous: | Reply

The only thing I can say from personal use of the drug is the dreams are fantastic. If you really need sleep for 14 hours its worth a shot. If you have a job or other responsibilities I'd stay away. :)

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It seems like this kind of ... (Below threshold)

February 6, 2010 1:16 AM | Posted, in reply to Paul's comment, by Marques: | Reply

It seems like this kind of deceit will go on forever. Who can stop it? The FDA is like the SEC, an industry entrenched stopgap that does not do its job. Similar to Wall Street and hedge fund investment schemes, this is specialized knowledge that very few people outside of the medical field understand or have the time to study and understand.
How do scientists at the FDA let this pass, why are there not more whistle-blowers? How can there be this many people - in the FDA, in pharma- with such poor values, who are corrupt (whether intentionally or not), blind, etc.?
I guess no one cares because ultimately they will not be held responsible if shit hits the fan.

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This drug almost ended my d... (Below threshold)

February 6, 2010 11:20 PM | Posted by Robin Holmes: | Reply

This drug almost ended my daughters life. The state of Tennessee mental health doctors put her on this drug. Three days later she became much more depressed and started telling me she wanted to end her life. Knowing this is a side effect I called the state and they had her meet with a not so impressive social worker. She basically told my daughter she really did not want to kill herself and my daughter agreed. On the home she started crying and again said she wanted to end her life and was becoming very angry. I decided to take her to the ER and make sure they wrote down the fact she had told me she wanted to end her life prior to the social worker meeting and after the meeting. She was hospitalized. The doctor said I had not given it enough time to work. I was so upset, but I was only a mother of a seriously ill 21 year old. She came home and two weeks later when it was totally in her blood stream she decided to take the entire bottle. During her second hospital stay this same doctor said the dose was not strong enough and against my strong wishes doubled the dosage. She came home sicker and more angry. It was a matter of time before she ended her life or had to go to a group home. The state doctors got sick of me and she got a new doctor who listened to me. Three days off this drug and on another at a very low dose she made great improvement and felt hopeful again. This goes against the fact any drug like this takes weeks to get full effect. However, her body did not like this drug very early regardless of this fact and they have recognized she responds good or bad within three or four days of a new drug. They watched it just like I did. She also gained fifty pounds in two months on this drug which was making her even more depressed. She had been a size 8. I know not every has this reaction, but it is alarming the mental health doctors don't take the side effects seriously. Wanting to kill herself was a side effect and she almost did. She is back in school and working. I am glad I did not put her in a group home and on disability as advised by every state doctor and social worker of the state of Tennessee. I have her on fish oil and she got one year of cognitive therapy given my research and her advocacy. With each doctors appointment I watched seriously over-medicated people not doing so good and my daughter improving with therapy and slow medication reduction. We both made the observation and thanked God she was not one of them again. Bottom line... Don't get mentally ill in the state of Tennessee.

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Sadly, this does not surpri... (Below threshold)

February 8, 2010 12:18 AM | Posted, in reply to Robin Holmes's comment, by The Rambling Fool: | Reply

Sadly, this does not surprise me. While I do not believe the drug is the actual problem, it was obviously the surface issue in your case. I think the deeper issue, however, is some professionals' stubborn adherence to "in theory" in spite of "in reality". In theory, this drug your daughter was on would probably rarely have these results. In reality, it did. Just as my college professor told us in regard to the H1N1, "It only has about a 1 in 1000 fatality rate... But that isn't any consolation to the 1000th person, is it?"

Obviously your daughter was affected negatively by this drug. If the doctors would have taken a minute to step away from detached statistics and approach the situation with a more human element, your daughter could have been taken off of the medicine much earlier.

But these are the professionals in control of our health.

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Jesus H, not a good story. ... (Below threshold)

February 8, 2010 2:51 PM | Posted by Arthur Taylor: | Reply

Jesus H, not a good story. Glad I'm in the UK, merely sub-standard service.

Cheers Alone, 'ppreciate it. I started to get the idea on the third read.. ;D

Have to say, four weeks in and I'm quite keen on the stuff, a massive, massive improvement on the depakote/zyprexa combo I was on a few years back that messed me up so badly I refused to go near psych-drugs again until recently. Shame about the BS, and I can see it'd not be right for everyone, it's powerful damn stuff and has some odd effects. Lucky that for me they're all pretty much enjoyable - just for a change I get something that actually bloody works.

For now. :/

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BTW, any chance of part II?... (Below threshold)

February 8, 2010 3:00 PM | Posted by Arthur Taylor: | Reply

BTW, any chance of part II? Great cliffhanger, but I need closure. :)

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Carlat talks a bit about th... (Below threshold)

February 10, 2010 4:43 PM | Posted by Sarah G: | Reply

Carlat talks a bit about the efficacy, side effects, etc. of Seroquel and Zyprexa at: http://carlatpsychiatry.blogspot.com/2010/02/lilly-execute-out-of-them.html

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I was a representative for ... (Below threshold)

February 14, 2010 12:09 AM | Posted by Bob: | Reply

I was a representative for AstraZeneca who sold Seroquel for many years. It's a shame what the company hid from the public about weight gain and other metabolic issues with Seroquel. While a useful drug for many it's the last I would take for major depressive disorder. A 5% improvement in symptoms is not worth a 20 or 30 pound weight gain.

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No wonder I was psychotic o... (Below threshold)

February 20, 2010 12:03 AM | Posted by Anonymous: | Reply

No wonder I was psychotic on that stuff.

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someone said "Does it matt... (Below threshold)

February 28, 2010 8:32 PM | Posted by Ashley O: | Reply

someone said "Does it matter how something achieves an end? Does it matter if that end is something objective, testable, repeatable, or not?" If we better understnad the chemical properties and reactions for one drug in our brain- we can better understand and anticipate it's reaction with OTHER drugs/substances. And maybe better explain the symptoms. Good god the drug company wanted to use pooh bear charcters to sell this damn drug. Helloooo commercialism is outselling our intentions for improving the quality of life for mentally ill individuals. Money money money. I wouldnt be suprised if the few positive comments i see about seroquel are actually from AZ agents. call me paranoid if you will. but im just bipolar. And the decesion to "ingest potentially lethal substances" is hard for some who are shizophrenic or suffer AUTISM which are a few of the OFF LABEL uses of this drug. gOD i feel like im arguing with an AZ lawyer. I just hope this informs people of the real metaphysical question of weather or not to take this drug. its by no means an easy decesion. but don't let people let you think that the tests don't matter. because they do. and sadly we can't even depend on those. On a personal note- i agree with the comment bout the dreams- they are TERRIFIC on this drug. I feel like i took the red pill in the matrix. im just staying in this little world ive made up for myself. haah. its great. esp if your a previous drug abuser you'll appreciate this drug like i do. And FYi to one user's comment- people won't blow the whistle because when it comes time to fire some people, that person is at the top of the list and the companies will have their excuses and top notch lawyers to defend themselves. And no one wants to lose their job making a claim that no one else is willing to back up. its a sad reality which only makes me hope that 2012 something does happen to humanity. we need a wake up call. drugs are being sold to us like candy. its not right.

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"I'm as terrified as you ar... (Below threshold)

March 15, 2010 4:39 AM | Posted by Zo: | Reply

"I'm as terrified as you are. I don't know what to believe anymore."

Where have you been all my life? How old are you? Will you marry me?

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They don't know specificall... (Below threshold)

April 27, 2010 7:49 PM | Posted by Carl: | Reply

They don't know specifically how lithium works its magic either and lithium has been in clinical use since 1948. The most effective psychotropic drugs are mysteries as to how they work their magic. We don't know how clozapine, the great schizophrenia medication works pharmacologically to do what it does with such effeciveness. It was discovered by accident as was lithium.

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Thanks for posting this inf... (Below threshold)

May 25, 2010 4:15 PM | Posted by Jen: | Reply

Thanks for posting this information. It's a little difficult to digest, given that I'm not a doctor and I have cognitive difficulties due to Schizoaffective Disorder (or Schizophrenia, depending on which doctor you ask), and I'm on a lot of medication, including 1,000 mgs of Seroquel nightly. Yeah, that's a boatload of Seroquel. This will probably come as no surprise, but given my Seroquel for the past five years along with Risperdal injections biweekly, Anafranil, and several other meds (that typically don't cause weight gain), I gained 100 pounds in three years. I blame the antipsychotics for this, and I haven't been able to lose the weight as each time I try to go off the meds, I become psychotic again. So I am stuck.

When is someone could to fund the research for a drug that will treat psychosis effectively and not lead to horrid side effects? I would really love to know.

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An article from March 200... (Below threshold)

June 2, 2010 4:44 PM | Posted by Harry Horton: | Reply

An article from March 2008, the 'journal' Neuropsychopharmacology, "Zonisamide prevents Olanzapine associated hyperphagia, weight gain, and elevated blood glucose in Rats" Wallingford et al. A quote from the article: "As indicated via c-Fos expression, we found an OLZ-induced activation in the nucleus accumbens and orexin neurons in the lateral hypothalamus. An OLZ- associated development of hyperhagia, weight gain and elevated blood glucose in the rat was found. These outcomes were attenuated and reversed in the presence of concomitant ZNS. These results suggest the hypothesis that ZNS may effectively treat or prevent weight gain or metabolic changes associated with the SGAs."
end quote. Also zonisamide is a calcium antagonist, I believe.
Another article:"A Study of Zonisamide to Prevent Olanzapine-Associated weight gain" Clinical trials gov.

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More thoughts on previous p... (Below threshold)

June 3, 2010 2:38 PM | Posted by Harry Horton: | Reply

More thoughts on previous post's addressing of zonisamide and olanzapine associated weight gain, glucose elevations and the like.... Excerpts from the March 2008 article: "Zonisamide (ZNS) a medication approved in the United States as an adjunct in the management of epilepsy, has a diverse pharmacological profile, including sodium channel blcokade, monoamine enhancement and inhibition of carbonic anhydrase. ZNS has also been reported to cause weight loss in both humans and rodents." End quote from introduction. Further areas of the article quoted: "To our knowledge, there has been no previous reports of the effect of ZNS on blood glucose alone or in attenuating an acute drug- associated effect; however, studies with acetazolamide (a cabonic anhydrase inhibitor antiepileptic) in rats have shown that the integrity of carbonic anhydrase activity is required in order to allow a normal stimulation of inuslin release by glucose. In addition, topirmate, a novel antiepileptic drug, with some similarities to ZNS, has been shown to attenuate OLZ-weight gain, decrease plasma glucose, and increase in vivo insulin sensitivity in adipocytes and skeletal muscle resulting from increase in adiponectin levels. Here, we have shown that subchronic ZNS treatment attenuates chronic OLZ- induced elevated blood glucose. We have also shown that acute ZNS administration may slightly lower baseline blood glucose levels, it has no significant effect on acute OLZ- induced elevated glucose. Therefore, the full complement of the glucose stabilizing properties of ZNS in OLZ- treated patients may require long term co-therapy, however the mechanism remains to be determined." end quote. Other random excerpted areas of the article:"The antiepileptic activity of ZNS may be mediated by a decreased production of GABA transporters, resulting in increased tissue and synaptic concentrations of GABA and enhanced GABA mediated neuronal inhibition. ZNS is also thought to potentially inhibit glutamate mediated neuronal excitation. THis may explain our finding that ZNS attenuated the degree of OLZ-associated Fos-LI in the nucleus accumbens." End quote. Also another article to read with this material is the June 2007 Anastassios PIttas study of calcium and vitamin D supplements potentially preventing diabetes II development. The article , the Pittas one that is, from an Endocrinology journal of June 2007. Zonisamide is a calcium antagonist, most likely and thus affects the area of vitamins D and calcium metabolism processes. I also believe Japan developed the drug, initially.

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Ok I've been on seroquel fo... (Below threshold)

July 21, 2010 4:27 PM | Posted by rhiannon: | Reply

Ok I've been on seroquel for about 3 weeks . I have already started gaining weight . Some days I wake up more angry than usual and other days I feel great . The doc had me on wellbutrin pristiq and seroquel and it just wasn't working . I'm torn between wanting to be happy and normal and wanting to be free of weight gain . I have also been experiencing fatigue all the time on top of constantly feeling weak andhaving constant severe hot flashes . No matter how cool it is I am sweating and miserable . I have no idea what I should be taking but I don't think my doctor knows what he's prescribing me . Has anyone actually been on anything that really works? I think its bipolar cause I've been this way since as long as I can remember, but doc calls it mdd . I'm confused as to what I'm putting into myself, but am desperate to live a normal life. Help.

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