March 14, 2010

Swallow This: How Seroquel XR Works, Part 3

3d message.JPG
if you could only see the truth


Part 1
Part 2



Now let's stop asking how, and ask what: what does this drug actually do?

FDA:

Major Depressive Disorder sNDA Submission
The FDA approval of SEROQUEL XR for MDD was based on a supplemental new drug application (sNDA) comprising findings from two Phase III, placebo-controlled studies that assessed the efficacy and safety of once-daily treatment with SEROQUEL XR as adjunctive treatment in patients with MDD.

Note the word adjunctive.  Two trials showed its efficacy as an adjunct.   Like Abilify, Seroquel is only indicated for use as a supplement to a failed/failing antidepressant.  Maybe it's a necessary combination of a serotonergic effect plus (a non-existent) noradrenergic effect, or some other synergistic mechanism; but it's an add-on, so get adding.


An adjunct-- to what?


study 2 seroquel mdd.JPG
There's your data, it's one of the two trials the FDA used to grant the indication.  The other trial's data was nearly identical.  (1)

Seroquel was tested as an add-on to SSRIs, and also Effexor and Cymbalta.  (The top line is placebo + SSRI/SNRI.)  If we believe that at the doses used Effexor and Cymbalta are blocking the NET, and Seroquel at 150mg is doing the same, then why would we expect the addition of Seroquel to be of any use?  They're both fighting for the same site, only one can bind, so?  You wouldn't mix Paxil and Zoloft, would you?

So either the NET isn't relevant here; or, if it is, then those patients on Effexor/Cymbalta + Seroquel will not show greater improvement (e.g. as compared to Celexa + Seroquel).  And the pooled data you see above will appear less impressive because the Effexor and Cymbalta patients dragged the overall average down.

Or, more simply: if they did the study only with SSRIs, maybe the augmentation results would have been even better!

So either the FDA is wrong you shouldn't mix it with Effexor/Cymbalta, or you should because the FDA is wrong about the mechanism.  Good luck, have a drink.  Your next patient is the dumpster guy from Mulholland Drive.


You're frightening me with your talk of dumpsters and intimations of rum.

Drink up.

This is from the promotional slide deck that Astra Zeneca uses to detail doctors, showing the results of the two trials.


seroquel xr 6 and 7.JPG


Take a good look at this slide, and compare it to the one above, from which it came.  Do you see anything weird?  Take minute. 

Stop looking at the data curves.  Stop looking at the p values.  What do you expect to see there?  You already know it's going to beat placebo or else they wouldn't have made a slide.  Do you really think you're going to discover something there?

This slide is an illusion like the impossible fork, you want to see this as a representation of something else instead of seeing it for what it is.

I'll give you a hint:

seroquel xr 6 and 7 redacted.JPG

What happened to studies 1-5?


Undoubtedly, your first thought will be that AZ hid the data.  I wish that was true.

This is a promotional slide.  The purpose of it is to push Seroquel.  That means that nothing on it is not either compelled by the FDA or on purpose to get you to believe.  They are accurately labeled studies 6 and 7 so that  there so doctors ask about the other 5 studies.  Why do they need doctors to ask?  Because the FDA forbids them from mentioning them.   So strict is this ban that the AZ reps are not even told by the company there are 5 other studies, so that they don't accidentally mention them.  I am not exaggerating.  The reps don't know.

You know what makes me happiest?  When the government considers certain information so disruptive that it not only doesn't it tell the citizens, it doesn't even tell other members of the government.  So that the only people who know are the heads of the government, and the heads of a for-profit corporation.

There's a word for that kind of thing.  But anyway.

So what were studies 1-5?


Studies 1-5 were all monotherapy studies-- specifically, 4 acute trials and one 6 month maintenance study.  And all but one acute study worked.(2)

More importantly, two of the trials that worked used 50mg.

In fact, AZ also submitted 5 other studies-- all positive-- to the FDA showing efficacy in GAD at doses starting at 50mg.


So this drug is efficacious as monotherapy in depression and anxiety?

Apparently so, and apparently at doses less than 150.  Of course, since the adjunct trials were only done using 150 and 300, those are the doses that get approved.  Safety, to the FDA, means they'd rather you get 3x to 6x the necessary dose-- along with a probably irrelevant drug-- than reveal that it worked as monotherapy. 


Wait a second-- if there's very little NET inhibition at 150mg, doesn't that probably mean there isn't any at all at 50mg?

Oops.


Why would Astra Zeneca want to convince us that the mechanism of antidepressant effect was NET inhibition, when there is so much evidence (that presumably they are aware of) that it isn't?

Astra Zeneca doesn't want to convince us of that: the FDA does.


----

Coming soon: Part 4



1. Note that 300mg was not better than 150mg.  And why would it be?  The higher the dose, the more dopamine blockade your getting, which isn't relevant to depression otherwise we'd be augmenting with Haldol, which we aren't.  (NB: which is why Abilify augmentation stays below 15mg.)

2.
Seroquel 150 vs. Celexa 20 vs. placebo: no difference.


---
http://twitter.com/thelastpsych




Comments

We know psychiatry can mani... (Below threshold)

March 15, 2010 1:24 AM | Posted by Ron: | Reply

We know psychiatry can manipulate people to have different emotion with drugs, chemical, etc...but mental illness itself is bogus. Even psychiatrists commit suicide and murder. Why didn't they "cure" themselves. There is a solution to schizophrenia.
Checkout this site on mental illness: www.destroypsychiatry.org

Vote up Vote down Report this comment Score: -45 (57 votes cast)
William James had nitrous o... (Below threshold)

March 15, 2010 2:09 AM | Posted by Asshole: | Reply

William James had nitrous oxide among other things and Freud had coke. The problem with psychiatry isn't a failing of science any more than science fails in any other field of medicine. The problem is the purpose of the science, are you trying to treat or are you trying to make a buck? If you want to make a buck you just iterate slight changes to drugs and hope the new one works for something and just have a replacement lined up for when the patent expires.

If you are depressed enough to need a drug you are depressed enough to get an MAOI. Otherwise get a smooth doctor to tell you the placebo is something more and get a fucking puppy. Psychiatry isn't evil, it is just partners with the laziest companies brazen enough to pretend to the title of innovators.

Vote up Vote down Report this comment Score: 1 (19 votes cast)
So how does Seroquel work f... (Below threshold)

March 15, 2010 2:21 AM | Posted by acute_mania: | Reply

So how does Seroquel work for anxiety?

Vote up Vote down Report this comment Score: 2 (2 votes cast)
Same way it works for anyth... (Below threshold)

March 15, 2010 2:57 AM | Posted by Buddy D: | Reply

Same way it works for anything else: we don't know.

Vote up Vote down Report this comment Score: 6 (8 votes cast)
"psychiatry isn't evil, it ... (Below threshold)

March 15, 2010 5:25 AM | Posted by Re: Asshole: | Reply

"psychiatry isn't evil, it is just partners with the laziest companies brazen enough to pretend to the title of innovators."

you are lazy company my friend.

sinking a billion dollars into creating a new drug is not "lazy"
abilify is not the same as lithium. its an innovation.

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Go to 'ell Ron. Transparen... (Below threshold)

March 15, 2010 7:32 AM | Posted by Arthur Taylor: | Reply

Go to 'ell Ron. Transparent you are.

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This is a great analysis. T... (Below threshold)

March 15, 2010 9:01 AM | Posted by medsvstherapy: | Reply

This is a great analysis. This is what academics should be throwing out there in the journals to stimulate discussion, thought, and discovery.

Vote up Vote down Report this comment Score: 9 (9 votes cast)
wow that was a challenge. I... (Below threshold)

March 15, 2010 9:24 AM | Posted by medsvstherapy: | Reply

wow that was a challenge. I won't spoil it for anyone else, but it is there. "Y....E" with 28 characters total (not counting spaces). the wolf, the dolphin, and the mermaid jump right out. but words are really hard to perceive.

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Ah...now this is starting t... (Below threshold)

March 15, 2010 11:15 AM | Posted by Nadia: | Reply

Ah...now this is starting to make sense to me. Only took three posts.

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"There is a solution to sch... (Below threshold)

March 15, 2010 6:20 PM | Posted, in reply to Re: Asshole's comment, by Depik Moriz: | Reply

"There is a solution to schizophrenia.
Checkout this site on mental illness: www.destroypsychiatry.org"

Maybe schizophrenia is a lie. Did anyone test out the method? What is the point of drugs like abilify when it does absolutely nothing to cure the patient. Where is the innovation? It is all about making money from the clueless.

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I think I am looking in the... (Below threshold)

March 15, 2010 10:54 PM | Posted by Mike M: | Reply

I think I am looking in the right place. Thank you TLP.

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Go on, spoil it for me-how ... (Below threshold)

March 16, 2010 1:30 AM | Posted, in reply to medsvstherapy's comment, by Les: | Reply

Go on, spoil it for me-how do you see? I'm hopeless at these sort of things!!
Maybe why I was given a diagnosis of schizophrenia.....though funnily enough I did recover when I dropped the meds! Intially I thought seroquel had given me my life back but think it was only had less disabling/visible side effects than all the others I had tried as once used to it wasn't so doped. Gave me a bit of space to understand that as I reduced my dose I could do even more for myself by actually experiencing emotions that for years had been medicated out of existence. Worth the hard work but had struggle to get good support. Am in UK and I found it outside of Psychiatry funnily enough....

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Les: like i said: the coyot... (Below threshold)

March 16, 2010 8:29 AM | Posted by medsvstherapy: | Reply

Les: like i said: the coyote and the dinosaur pop out easily. but you have to spend a lot of time to see text. like ten minutes. it goes from nothing, to horiz lines, to horiz tubes, to dramatic-relief horiz lines, then text begins to appear. first one character or word, then it is kind of down hill from there. it honestly takes time and optimism.

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OK: here is an FDA drug reg... (Below threshold)

March 16, 2010 5:22 PM | Posted by medsvstherapy: | Reply

OK: here is an FDA drug reg question where I don't know the answer: If a drug has FDA approval as an adjunctive with another drug that has FDA approval as monotherapy for the same indication, can you manufacture a combo pill with each at its approved dose, etc., without specific FDA approval for the combo drug itself?

I think I get the picture, but it depends on efficacy data showing augmentation is better than monotherapy. It looks like a problem is that at 50 mg quetiapine, you cannot get the separation between monotherapy of SSRI and SSRI-augmented with quetiapine - since they will be equally efficacious since working on the same receptor set; however, if you overpower the quetiapine, maybe you get additional "benefit" for quetiapine through another pathway.

But this sceanrio would involve the data that quetiapine works at 50 mg monotherapy for depression, but SSRI plus quetiapine requires a dose of 300 mg quetiapine, so it requires two pathways, one main one bloacked by the SSRI, allowing the effect of the second pathawy to come into play.

The benefit is you can combo with more than one mon-SSRI: if you cannot beat them, join them.

I don't know the receptor info well enough to evaluate how strange this stratgey is.

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50mg of Seroquel is an anti... (Below threshold)

March 16, 2010 6:56 PM | Posted, in reply to medsvstherapy's comment, by Anonymous: | Reply

50mg of Seroquel is an antihistamine, like Benadryl.

Vote up Vote down Report this comment Score: 1 (5 votes cast)
"But this sceanrio would in... (Below threshold)

March 16, 2010 6:59 PM | Posted, in reply to medsvstherapy's comment, by Anonymous: | Reply

"But this sceanrio would involve the data that quetiapine works at 50 mg monotherapy for depression."

Not FOR depression...FOR lowering a scale that features a variety of symptoms, not all of which are mood. ANYTHING that improves sleep will lower MADRS scores, which will then be declared a treatment FOR depression.

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OK - I see that part. Like ... (Below threshold)

March 17, 2010 2:29 AM | Posted by Anonymous: | Reply

OK - I see that part. Like this post I had, about Lilly maximizing placebo-sensitive items on a depression scale...

http://www.medsvstherapy.com/2009/11/lilly-publishes-study-on-how-to-measure.html

Now: to look back on Alone's old post about antihystamine receptors...the champaign fountain analogy...

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ouch. the kosmix link leads... (Below threshold)

March 17, 2010 8:46 AM | Posted by Anonymous: | Reply

ouch. the kosmix link leads to their search results on the madras - including an NHLBI review, in 2005, of dep measures in trials; the madras does not fare well. looks like it was developed to include somatic and other items that are very responsive to pharmacotreatment. the nhlbi committee included an all-star line-up, including helena kraemer who is very prominent in trial methodology issues. one hand - the fda - does not benefit from what the other hand - nhlbi - has figured out.

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ouch. the kosmix link leads... (Below threshold)

March 17, 2010 8:47 AM | Posted by medsvstherapy: | Reply

ouch. the kosmix link leads to their search results on the madras - including an NHLBI review, in 2005, of dep measures in trials; the madras does not fare well. looks like it was developed to include somatic and other items that are very responsive to pharmacotreatment. the nhlbi committee included an all-star line-up, including helena kraemer who is very prominent in trial methodology issues. one hand - the fda - does not benefit from what the other hand - nhlbi - has figured out.

Vote up Vote down Report this comment Score: -2 (2 votes cast)
..."OR lowering a scale tha... (Below threshold)

March 17, 2010 10:59 PM | Posted by Paul: | Reply

..."OR lowering a scale that features a variety of symptoms, not all of which are mood. ANYTHING that improves sleep will lower MADRS scores, which will then be declared a treatment FOR depression."

What else do one need to know? This is the problem with using questionnaires as a substitute for objective measures. It truly baffles me how we continue to think that we can develop a well characterized molecular entity yet pretend we have any idea as to how it works or whether it does anything at all. Is sedation a valid treatment for depression or anything else other than sleep?

This really bugs me.

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Sedation is a good treatmen... (Below threshold)

March 18, 2010 9:31 AM | Posted by medsvstherapy: | Reply

Sedation is a good treatment for some things. Apparently, it may be a good treatment for some cases / flavors of depression.

Coincidentally, the Am J Psychiatry JUST published a methods-issue letter noting that it is a challenge to detect the supposed effects of quetiapine, above and beyond expectancy effects due to broken blinding when the drug causes such sedation: this letter notes a study that found, post-hoc, results differing by whether the pt experineced this sedation or not (reference 7 Calabrese in the letter)...

Roy H Perlis, Michael Ostacher, Maurizio Fava, Andrew A Nierenberg, et al. Assuring That Double-Blind Is Blind. The American Journal of Psychiatry. Washington: Mar 2010. Vol. 167, Iss. 3; pg. 250, 3 pgs.

My guess? You could trial diphenhydramine as an antidepressant, and use the MADRAS, and get a decent result.

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"You wouldn't mix Paxil and... (Below threshold)

March 18, 2010 11:03 AM | Posted by Hollyluja: | Reply

"You wouldn't mix Paxil and Zoloft, would you?"

*sigh*

I worked in a pharmacy for a few years and yes, in fact, you would.

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"Even psychiatrists commit ... (Below threshold)

March 18, 2010 5:17 PM | Posted by Mario: | Reply

"Even psychiatrists commit suicide and murder. Why didn't they 'cure' themselves. There is a solution to schizophrenia.
Checkout this site on mental illness: www.destroypsychiatry.org"

I loved these sentences. Oncologists have cancer and, surprisingly, cardiologists have heart attacks! Why don't we create websites such as destroyoncology and destroycardiology?

About Seroquel and sedation, let's pay attention to the new idea of mixing two antidepressants (one of them being Mirtazapine) in order to achive a bigger remission (does the sedative effects of Mirtazapine means something?). When Andre Nierenberg (one of the guys behing STAR-D and STEP-BD) came to Brazil, where I live, and told us about the possible benefits of the two-antidepressants treatment, I should have asked him about switching Mirtazapine for low-dose Amitriptyline, with the same sedative properties. But I didn't ask, sorry.

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Interesting bit: extended-r... (Below threshold)

April 16, 2010 12:19 PM | Posted by syntaxfree: | Reply

Interesting bit: extended-release brand-name "Seroquel XRO" has been available in Brazil for quite a while. I took it for a while, more than eight months before your Seroquel XR approval series started. I'm pretty sure Seroquel XRO was introduced here before Seroquel XR in the US.

Somehow, the approval process in Brazil must be more lax (maybe they let Seroquel XRO pass blind because Seroquel was already approved; I take an extended-release version of trazodone, believe it or not) but it'd still be interesting to know what kind of story AZ told the brazilian authorities. Actually, it'd be interesting to do that kind of comparative study with more drugs. On what grounds did they reject Prozac in Germany again?

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Interesting review...have b... (Below threshold)

April 28, 2010 12:03 AM | Posted by jesse : | Reply

Interesting review...have been on seroquel for BP1. I have noticed absolutely zero antidepressant effects. In fact, it made me more depressed and I'd relapse b/c I'd stop taking it. It's good for stopping a manic episode and sleep. Lamictal has been far superior to this medication (for me). I'm at 50mg serqouel now and can't wait to be off this nasty medicine! I feel so much better now, less depressed, more energy, etc...I'm not surprised by the deception by the FDA and big pharma. In fact, I expect this and this is why I read stuff like this article.

Thanks for posting this analysis, it's helpful for patients to have this kind of guide, so they can start thinking critically about treatment options. I really appreciate your work!
Jesse

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Some articles centering o... (Below threshold)

June 16, 2010 1:54 PM | Posted by Harry Horton: | Reply

Some articles centering on weight loss, diabetes cures, and other metabolic syndrome features. "The Skinny on TRPV1- Cioffi 100 (7) 934 - Circulation. Excerpt from the article: "TRPV1 is a member of the transient receptor potential superfamily of proteins. It is a non selctive cation channel with high calcium permeability and is activated by noxious stimuli including chemicals in the vanilloid class (eg capsaicin and resiniferatoxin), elevated temperatures and protons. TRPV1 is highly expressed in sensory neurons ...and other tissues..." end quote. Further TRPV1 Cioffi article quotes: "In the current study, Zhang et al detected TRPV1 for the first time in mouse embryo 3T3-L1 preadipocytes as well as in human and mouse visceral adipose tissue. Induction of adipogensis was accompanied by a concomitant decrease in TRPV1 expression and decreased capsaicin- mediated calcium influx. In the presence of capsaicin, TRPV1 downregulation was no longer observed, the capsaicin induced cytosolic calcium increase was maintained and adipogensis was prevented. Surprisingly the prolonged capsaicin treatment (8days) did not desensitize TRPV1 channels...Collectively, data in that this study provide evidence for activation of TRPV1 and increased cytosolic calcium in the prevention of adipogenesis." end quote. Another study to be read along with the above Cioffi one is "John Fenzel: Science" Add in also "TRPV1 diabetes Toronto Sick Childrens Hospital" in search engine title. This report from this blogger relates the stunning cure in mice with daibetes I and II. This scientific article on thie TRPV1 oriented study from Toronto was further related in the "journal" Cell December 15, 2006, edition. A third article: "Tunable Calcium Current through TRPV1 Receptor Channels" Samways et al. Content from this article is relevant to information from the previous two listed articles in this post.

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The following article fro... (Below threshold)

July 27, 2010 4:01 PM | Posted by Harry Horton: | Reply

The following article from Science Daily, July 22, 2010: "Could diabetes be in your bones? Link between metabolic disease, bone mass; breakdown of bone keeps blood sugar in check" Excerpts from the article: "Mice whose bones can't respond to insulin develop high blood sugar and insulin resistance, both hallmarks of diabetes. Those symptoms are tied to a drop in osteocalcin, or perhaps a drug that targets bone, might hold promise in fighting the global epidemic of type 2 diabetes, according to researchers."
..further info from article...."Our study reveals a key molecular link between bone remodelling and metabolism" said George Karsenty of COlumbia University...further continued info from the article..."Still, Clemens said he was surprised by what they saw after developing a mouse lacking insulin receptors only in their osteoblasts> "The mice started to get fat" he said. They showed changes in their biochemistry that were consistent with insulin resistance. They also had low osteocalcin levels and fewer osteoblasts to produce less bone."...further quoed material from the article..."Scientists also had evidence that osteoblasts might respond to insulin in important ways. Osteoblasts bear insulin receptors and when treated with insulin show signs of collagen synthesis and take up more glucose, Clemens team notes. People with type 1 diabetes due to lack of insulin can also develop weakened bones." End quote. The information is interesting in that the development of fat comes from the insulin receptors in combination with osteoblasts while the Cioffi article: "The Skinny on TRPV1" relates fat and adipogenesis occurs with capsaicin stimulation of TRPV1.

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correction of previous co... (Below threshold)

July 28, 2010 2:31 PM | Posted by Harry Horton: | Reply

correction of previous comment post. "The final sentence should read: "The Skinny on TRPV1" relates fat and adipogenesis occurs without or absence of capsaicin stimulation of TRPV1."

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I'm on Seroquel for a BP1 d... (Below threshold)

August 12, 2010 12:30 AM | Posted, in reply to jesse 's comment, by Sara: | Reply

I'm on Seroquel for a BP1 diagnosis (which I don't really identify with even if I may seem to match the pattern) and I could also swear that it puts me in a state that might be called depression. I feel emotionally numb, disconnected and unmotivated, my creativity is gone, and I can't move forward with my life. It's like I'm not even really alive. It's just something they give me in the hospital to take the mania away, and then leave me on to languish.

I'm curious to know what's happening to my neurotransmitters at 250 mg/day of Seroquel XR so I can know what to compensate for if I try to come off of it again. I keep wondering if to what extend it's having an anti-adrenergic, anti-cholinergic, anti-dopaminergic or other effects.

At this point even the immediate-release version doesn't put me to sleep, either! It actually gives me crazy anxiety after I take it at night, but I just switched to XR and I feel more zombified during the day.

I had a much better life before I was on "maintenance meds" - any of them, Seroquel, lithium, divalproex, etc. I could actually live and feel like myself even if things got crazy sometimes - and sometimes the craziness even had a meaning to it, if that makes sense to anyone.

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

October 9, 2010 5:15 AM | Posted by iPhone Cases: | Reply

so good .Thanks for the information you post.

Thanks for posting this.iPhone Cases

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Benadryl is also a mild SRI... (Below threshold)

November 4, 2010 12:21 PM | Posted, in reply to Anonymous's comment, by someone: | Reply

Benadryl is also a mild SRI. That's where they got they idea for prozac.

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This has been a very reassu... (Below threshold)

March 5, 2014 8:36 PM | Posted by Evan Kearney : | Reply

This has been a very reassuring read for me, long-time (necessary evil given the DEA's closed system mechanics) patient and extreme skeptic of contemporary "five minute visit" psychiatry.

The last page was simply the best, for the following obvious reason:

If AZ let out that 50 mg Quetiapine mono therapy "improved" affect (measured on scales that really don't directly ask how the patient feels), then SOMEONE out there might realize that this simply proves that these people could reach the same "improvements" but TAKING BENADRYL for six weeks.


I love it!

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Part 4, what, never?... (Below threshold)

March 6, 2014 1:58 AM | Posted by Anonymous: | Reply

Part 4, what, never?

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