July 10, 2007

The Most Important Article On Psychiatry You Will Ever Read




I'm warning you.


Let's begin with a simple drive down a country road, say, I10.


The Three Problems of Psychiatry:

You know those white dashed lines separating the lanes in a highway?  How long are they?  Answer: _____________  Most people I ask say 3 feet.  The real answer is 10 feet.  Surprised?  And that’s the first problem in psychiatry: perspective.  Your perspective is always driving at 60mph, so they look 3 feet long.  Unless you change your perspective, you never get to see the truth.  Worse, much worse, you go through life confident they are three feet. 

Which brings us to the second problem: closed mindedness.  Even though I’ve told you the truth, you still don’t believe it—that’s how powerful your perspective is.  “He must be talking about some other lines, maybe in France?”  Unless you change your perspective, you will never be open to the truth, to the discovery that what you have thought, for your entire life, is wrong.  Unless you get out of your car and measure those lines, you’ll never accept the truth. 

Which brings us to the third problem: if you do try and change your perspective, get out and measure those lines, you will be quickly dispatched by a minivan to the face for your lack of faith.




 The irony of it all was not lost on Paris.  Or was it coincidence?  Irony?



Here is a picture of a molecule of Seroquel:


seroquel molecle

It’s a single molecule. Count them.

Seroquel, like all atypical antipsychotics, binds to multiple receptor types.  Seroquel blocks, with varying affinity, histamine (H1), alpha 1 (a1), dopamine (D2), etc, etc.  You can imagine a molecule having different spokes to it, that each bind to different receptors.  Here’s a graphical representation of this, made famous by Steven Stahl, MD, at the University of California, and formerly with Styx:

seroquel graphic

Consult your doctor if you are at risk for esophageal rupture

The other way this is often represented is with a pie chart:


Seroquel and its chaotic brother Fredo 

From the video Serocool (Styx, 1981)

A typical understanding of this pie chart is that the various sizes represent “amounts” of blockade.  So, here, Seroquel is very antihistaminergic—so it causes a lot of sedation.  It is moderately an alpha1 blocker—which is what causes orthostasis (lightheadedness/dizziness/grogginess).  And much less of a D2 blocker, which is what actually provides the antipsychotic effect.  You can also see that Seroquel’s H1 section is bigger than Zyprexa’s, which explains why Seroquel is more sedating than Zyprexa.  (1)

One molecule gets you H1, a1, 5HT2a, D2


Two molecules gets you twice as much H1, a1, 5HT2a, D2












So this is so easy to visualize that anyone can understand it.  But unfortunately this representation is misleading, it leads you to think something that is not completely accurate, in the same way that looking at Nancy Pelosi makes you think of that guy in Raiders of the Lost Ark:





One of the central themes of the postmodern critique of our values is that aesthetics must trump truth as long as aesthetics remains undefined.  That’s the semiotic conundrum, why psychiatry is politics: the truth is demanded only when it supports a preset ideology.


Nothing.  Let’s move on.

The mistake is that those pie chart sections aren’t amounts, they are affinities.  They are preferences.  Here's a metaphor.  Imagine you have only one molecule of Seroquel.  Where does one single molecule  prefer to go?  It can’t go to four different places, right?  It has to "choose."  And most likely it chooses to go to H1.  The spokes don't cause the effect-- the spokes fit into  receptors-- the receptor causes the effect.  So if it binds to H1 receptor, the other spokes remain unused.

Let’s say you are a gentleman, and as such prefer blondes by virtue of their fair hair, lithe contouring, and receptiveness to new ideas.  If you’re in a room with 10 brunettes and two blondes, do you go to everyone, equally?  (Assume for this gedankenexperiment you have only the one, non-mechanical penis.)  No, you make a bee line for the blondes.



who do you choose?

Tom was thankful he was sober enough to avoid the ugly one



This is a safe bet.  Sadly, since not every blonde will support your ideas for a ménage, you’ll have to settle for the brunettes.  Painful, I know.  I can call you in a script for Viagra. 

So one molecule goes to H1.  What about two molecules?  Or three? Or 13 gazillion? 

Think how sedating 25mg of Seroquel is (trust me, it's sedating.)  Why isn't 32 times more-- 800mg-- lethal?  Certainly 32mg of Xanax is more than a short nap, so what's the difference?


Instead of thinking that the drug binds to all receptors simultaneously, a better analogy would be a champagne fountain, like at a wedding.  Except I hate champagne, so pretend it is a rum fountain.  Rum fills the top level, overflows into the second level, then that overflows into the third, etc.  You can't get anything into level 3 until you fill levels 1 and 2. And, once you've filled level 1, you can't put anything more into it.




Get it?  So level one can be labeled H1, level two is alpha 1, and level 3 is D2. (2)

So you can see that, at some dose, there is no more increasing sedation with Seroquel. You've filled up level 1-- the H1 section. Going from 25mg to 50mg is a big jump in sedation (level 1), but going from 400mg (level 3) to 800mg is not felt to be an increase in sedation. It's the same amount of sedation, because by the time you hit 400mg, you were all full up. (3)

But there’s a dark side to my analogy, and it isn’t the rum fits.  Here’s the thing: if one molecule of Seroquel goes to H1, and not to D2, then can it have any antipsychotic effect? No.  One molecule binds to H1, so it isn't an antipsychotic, it's an antihistamine.

Yes, it does.  Weird, isn’t it?

Until this drug is blocking a significant number of D2 receptors, it is not functioning as an antipsychotic.  Important: the antipsychotic effect of one molecule of Seroquel isn't so weak you just can't see it-- it is exactly and precisely zero.

The drug can't be called an antipsychotic unless it is behaving as an antipsychotic, regardless of the product labeling.



At some amount of D2 blockade, these things will be antipsychotics.  What amount?  Theories abound, but look at it this way: 10mg of Zyprexa blocks a certain number of D2 receptors.  How much Seroquel, Risperdal, or Geodon does it take to block the same number?  Answer:

10mg Zyprexa = 500mg Seroquel = 3mg Risperdal= 120mg Geodon. (4)

This is the problem so many doctors have.  “I tried him on Seroquel, it didn’t work.”  Really?  At what dose?   Because higher doses aren’t stronger—they are completely different.  The behavior of Seroquel at 100mg is completely different than the behavior and effects at 500mg.  500mg is an antipsychotic; 100mg is not an antipsychotic.  I know it looks like it’s five times more, but it’s not—it’s the addition of a completely new level.  It's like adding a new “drug.”  Just because the FDA calls it an antipsychotic, and that word is printed on the box, doesn't mean it is. 



So you weren’t listening.

Reducing these doses by half pretty much extinguishes the D2 blockade.  Reducing the dose puts you into a different "level."  They’re not half as good as they were, they’re completely different.

The drug isn't a tease.  It doesn’t give you a little bit of efficacy at a low dose, “oh, it’s working a little bit—he must be a Seroquel responder—I’ll just increase the dose to get more efficacy.”  Another way of saying it is this: the absence of efficacy at 250mg is in no way predictive of what might happen at 500mg, because the two doses are working at different receptors.

So, yes, 5mg Zyprexa is equal to 250mg Seroquel for psychosis, in the same way that an academic psychiatrist is like a certain Congresswoman from California: they all do nothing.  ZING! (5)

Next up: Oh, No, Not Effexor, Too?


1.  The pie chart is wrong, wrong in the same way that Pamela Anderson is wrong, i.e. right in  many ways.  This is an in vitro pie chart, derived from affinities of receptors ripped out of the cadaverous remains of former tax attorneys.  It may not represent what happens in an actual human body when confronted with unequal distribution of drug and receptors, number, and subtypes of receptors.  It also doesn’t account for competition from other endogenous chemicals, drugs, or ice picks in the skull.  All this notwithstanding, they are still usefully inaccurate.  And all this is just a metaphor anyway.


2. This is not technically accurate.  Receptor systems don’t fill up, i.e. become saturated, before the next system is impacted.  More accurately, there exists a certain level of binding at one receptor such that it then becomes equally likely that it goes elsewhere.  So my rum fountain should be more accurately labeled “the effects from H1 blockade” and “the effects from alpha 1 blockade.”  Those effects do “max out.”  Also, a drug’s maximal effect can occur well before 100% saturation of a system; for example, 10% H1 blockade may be all that is necessary to get maximal sedation, such that increasing binding to 20% doesn’t get you more effect.  Nor might a drug be able to bind to more than 10%.  So while binding saturation is often used interchangeably with maximal effect, they are not the same.


3. Drugs bind to specific receptors, but also nonspecifically (i.e. everywhere else.)


Note that binding is related to the rates of the binding (Kd=Koff/kon) 


If you want a real world example, look at Zyprexa, below-- a real human in a real PET scanner eating real Zyprexa:

Kapur 2001

If you increase the dose from 5mg to 30mg, serotonin binding increases from 95% to 100%.  Do you expect to “feel” much difference?  But D2 binding goes from 55% to 85%.  That you’ll feel.)










4. Be careful: these are the equivalents for D2 blockade—for antipsychosis.  If you are using Zyprexa for, say, anxiety, then maybe D2 isn’t the relevant system.  Maybe it’s the serotonin that’s relevant.  (I have no idea; NO ONE HAS ANY IDEA.)  So the conversion doesn’t hold.  Do you understand?  If you are using 10mg Zyprexa tablets to clog a toilet in some heroin fueled Consumer Reports product test down at the American Standard offices, you don’t need 500mg Seroquels to get the same clogging action.  Ok?   

5. Actually, this isn’t true either.  250mg Seroquel has trivial D2 blockade, but Zyprexa 5mg still has some (55%).  So 5mg Zyprexa is more likely to treat psychosis than 250mg Seroquel.  The equivalences are really to be used the other direction: if you needed 15mg of Zypexa, you will likely need more than 600mg Seroquel… 




Well that one's getting a l... (Below threshold)

July 13, 2007 7:11 PM | Posted by Garrett: | Reply

Well that one's getting a link and a bookmark :)

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Fantastic article--enlighte... (Below threshold)

July 13, 2007 7:44 PM | Posted by J: | Reply

Fantastic article--enlightening even though I have no experience in medicine, but hilarious too. (Would like to say though, the fact that 2/3rds of your jabs at powerful female Democrats were based on their beauty...not only is it mean-spirited and low-hanging fruit to call average/semi-attractive-yet-assertive women ugly, but it's so obviously chauvinistic and it's an insult to all ambitious women.)

Anyway, maybe I wasn't listening, but what exactly causes the affinity? Relative number of binding sites for each receptor? Or, if I recall chem well enough, does it depend on how exothermic the rxn is? (Or something else?) I assume it's the relative reactivity of the receptor and the binding site on the drug, but the reason behind the 3rd sentence of caveat #2 wasn't really explained. Is it just diminished availability, and this equality is the point at which the relative reactivity cannot overcome the dearth of the favored receptor and must "settle?"

PS: Agreed on the rum. I doubt you could saturate me to the point where I would start drinking champagne.

Alone's response: First, regarding the jabs at powerful female Democrats. You do realize that's Margaret Thatcher and Black Manta? But, that notwithstanding, the joke wasn't about female democrats who are powerful; it was about a specific female democrat who has proven herself nearly completely useless. (And it's a joke about Sandra Oh, as well-- follow the arrow...)

Regarding the reason for the "settling" for a different receptor system: in most cases, it isn't a lack of available receptors. Many drugs do not 100% (or even close) saturate a receptor system (hence the point about receptor reserve.) Sometimes they do (D2 saturation is common.) This is further complicated by local, physical factors; in the pituitary (outside the BBB) binding may be very different than in the striatum (inside the BBB) and recpetor distribution may be different, etc. Hence my point about the in vitro pie charts-- they don't necessarily reflect what goes on inside the body, or even what goes on in side specific regions of the body.)

All this aside, rather than trying to predict where the drug goes next and at what dose, people have done actual human experiments, so I can tell you with good accuracy where it is at what dose-- see the Zyprexa binding curve in footnote 3.) (But, again, this is binding in the absence of other drugs, in a single dose experiment, and doesn't describe binding in differing areas (striatum vs. pituitary, etc.) But it's better than nothing.

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Are psychiatrists supposed ... (Below threshold)

July 13, 2007 9:24 PM | Posted by Jack Coupal: | Reply

Are psychiatrists supposed to be funny?

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So are you saying that one ... (Below threshold)

July 13, 2007 9:58 PM | Posted by the lone wolf: | Reply

So are you saying that one molecule of drug can't bounce around between receptors and just spend more time on a histamine receptor than a dopamine receptor before it gets metabolized? In other words, the action of the drug may not require "blockade" of dopamine for a long time, maybe it just needs to brush up against the receptor and move on.

Alone's response: It's even more complicated than that-- I'll get to it in the next installment, but you're asking two different questions. One is about "fast dissociation"--- i.e. how long a drug needs to block a receptor (in this case D2) in order to exert its actual effect (e.g. antipsychosis.) The answer is that it is a short time, relative to half life or other parameters. In other words, how long the drug lingers in the blood is not the relevant consideration. The other question you are asking is whether amount of binding to a receptor is related to the speed of association or dissociation, i.e. related to the rate of the binding. And it is, as given by the equation I just added in footnote 3 (the new graph.)

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Last Psychiatrist wrote:</p... (Below threshold)

July 14, 2007 9:17 AM | Posted by AK: | Reply

Last Psychiatrist wrote:

"At some amount of D2 blockade, these things will be antipsychotics."

Would it be more accurate to re-write the sentence as 'these things will *become antipsychotics* or "begin-to-exhibit-anti-psychotic-effects" (?)

I too am bookmarking this article. And I am gonna bring a hard copy of it to my therapist. He's a smart cookie LCSW who works collaboratively with prescribing psychiatrists.

PS What kind of rum do you like? My stepdad swore by Saint James. It was good enough that it was best delivered in small quantities, sipped slowly and contemplatively, as one does with fine brandy.

Alone's response: You're not going to get all dasein/existenz on me? Bu you are right: "begin's to exhibit antipsychotic effects" is most accurate. More on this in Part II.

And yes, I was drinking rum when I wrote it-- Zaya. And I drink it neat.

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Yeah, Pelosi is a dud, but ... (Below threshold)

July 14, 2007 9:41 AM | Posted by AK: | Reply

Yeah, Pelosi is a dud, but it isnt just her. (I say this with pain because I voted for her)

How to inject courage into a group that is still tiptoing around, using polite, decorous language when dealing with the gang of sharks that infest the White House, a crew that shows no respect for anyone who isnt a member of their tiny, sleazy club?

Its not like the rest of Congress is over-endowed with courage these days.
Why cant someone in Congress stand up and say, “Have we become a dictatorship? Have we all become subjects instead of citizens?’

Most of these elected representatives are already millionaires. What’s the point of being millionaire-rich if it doesn’t free you up to say and do the right thing?

And these people are physically hardy. They withstood the stress test of running for office. Its not like they’re going to collapse from chronic fatigue or come down with crippling stress related cardiac arryhytmias if the White House says nasty things to them after they dare take a stand.

These folk thrive on turmoil or they’d not be in Congress anyway.

Come on, Congress! Show some remembrance of noblisse obliege. FDR and Adlai Stevenson were old fashioned guys who operated from that non-PC principle and they’re way better than the crew we have today

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Linked and commented on. I... (Below threshold)

July 14, 2007 10:06 AM | Posted by resonance: | Reply

Linked and commented on. I like the rum fountain metaphor as a visually and conceptually intuitive way of describing something fairly confusing otherwise.

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Fascinating! I came here vi... (Below threshold)

July 14, 2007 1:37 PM | Posted by Meredith: | Reply

Fascinating! I came here via resonance, and as someone on Geodon (for anti-psychotic value) with a friend looking to Seroquel for anxiety and insomnia but questioning the value of taking an anti-psychotic for those issues, this is a great way to explain it to her.

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Can you provide us with the... (Below threshold)

July 14, 2007 3:44 PM | Posted by jt: | Reply

Can you provide us with the source for the second graph in footnote 3? It would be interesting to view the graphs for other antipsychotics if available.

Alone's response: didn't I reference it? Maybe you have to hover over the image. In any case, it comes from Kapur's article in Am J. Psych 2001, something like "Fast Dissoctiation of D2 receptors." (search by name.)

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I'll take rum vs. Seroquel ... (Below threshold)

July 14, 2007 5:14 PM | Posted by Stephany: | Reply

I'll take rum vs. Seroquel any day, what a great post. I linked to it.

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awesome, awesome post.... (Below threshold)

July 14, 2007 10:15 PM | Posted by jon: | Reply

awesome, awesome post.

that's all i had to say :).

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Another great blog! The ru... (Below threshold)

July 25, 2007 11:20 PM | Posted by Therapist4Chnge: | Reply

Another great blog! The rum fountain and weaving line between the pictures were two of my favorite parts (though the explanations were decent too)

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Okay, I'm really interested... (Below threshold)

October 19, 2007 12:22 PM | Posted by Nate: | Reply

Okay, I'm really interested in figure 3b. It's at the heart of what you're talking about, and it goes against common sense. Not that nothing true is ever unintuitive.

I mean, it's not like zyprexa molecules have little flagella, driving them towards open receptors. There's just a bunch of the molecules swimming around first in your bloodstream and then in your brain, locking on wherever they hit something in the right orientation (and with the right ambient energy?), right?

I mean, it'd make sense that dopamine binding went from 33 to 55 during the same interval that serotonin binding went from 50 to 75, but the numbers suggest something more than that.

The only explanation that I can come up with is that receptors are more intricate than we currently know, which doesn't seem like a ridiculous idea to me. Weren't there, like, four neurotransmitters fifteen years ago? So maybe when we talk about serotonin, we're talking about serotinin alpha and serotonin beta and serotonin beta four and serotonin gamma etc.

But that idea, in the absence of really detailed info about the drugs we're talking about, totally ruins your anti-polypharm thesis, because we haven't got a very good idea of exactly which undiscovered variant receptors are affected by a specific drug-- we don't look at PETs, because they can't catch what we don't know, we just look at behavior and use our intuition. Which is exactly what the polypharm Rxers you're describing, you're complaining about, do.

Sorry, I'm probably pretty uneducated and speaking too strongly, and, I realize, a little unclearly-- really looking forward to your explanation(s).

Alone's response: no, you have it right, but there are two issues. Using a single molecule is only to show the idea of affinity. A better model would be to consider probability, i.e. the probability that a drug will go to receptor/cup A is 10x greater than receptor B. But after enough drug has bound to enough receptor As, then it becomes more likely that it goes to B (say, 3x); then later 1x. etc. Think of a gunshot at a target-- most hits the center, but some scatter on other parts...

But what you're getting at-- that the receptors are more complex, or even that the drug itself is more complex, has affinities for other receptors, doesn't diminish these points. Sure, maybe 5HT2a binding is more complex, and maybe 5HT2a receptors actually have another site which binds glutamate or something. So perhaps mixing Zyprexa and Risperdal does have some logic (though prolixin and haldol, both "pure" D2 blockers, would not.) But you can't predict this, you can't assume it. No one's knowledge of pharmacology allows them to make any predictions AT ALL about what the effective result of Zyprexa + Risperdal will be. They may as well mix Zyprexa with a blood pressure pill.

So one might say, "but if it works, why not?" Because it's risk/reward. If you've failed monotherapy a few times, ok, it's time to get creative-- but let's accept that it's intuition, not some science. But it is bad medicine to just open up with polypharmacy simply because you've seen it work before; I can't promise two drugs will be better than more of one drug, but I can guarantee that it's twice as much chemical, with more side effects, etc.

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Can you suggest which med w... (Below threshold)

December 18, 2007 3:38 PM | Posted by Gary: | Reply

Can you suggest which med will help me the best.

I'm 39 y.o. WM, married, 2 young kids. I lost my brother last year who was just 39 y.o at the time. He died from an internal bleed unexpectedly in front of my eyes. I'm an RN and couldn't save him. Since this occured, I developed GAD. It's just over a year now, and I've been out of work for almost 9 mos. mostly due to anxiety. I've been on Serzone 400mg x 8 years or so. I also take klonopin 1mg bid, and metoprolol 12.5mg bid. The reason I was on the above meds was to treat panic attacks I started getting at age 18. They were under control and I functioned as an RN x 14 years just fine. So now I have this GAD and an underlying depression due to losing my brother. SSRI's interfere with the Serzone putting me into pre-syndrome. Wellbutrin gave me bad side effects as well. Just tried Lamictal x 9 days, but had to stop as it really made my anxiety 3 times worse and I found myself taking more Xanax. It did seem to elevate my mood, but so did Lexapro in the beginning. I also was getting short of breath on the Lamictal, so I called it quits. Xanax doesn't seem to be working so great anymore despite increasing my dose from 0.5mg/day to 0.5mg tid. I just started on Lyrica today and we will see how that goes. I have tried to wean down off the Serzone, but I get severe Akastasia at even a 25mg drop. This occurs roughly within 72hrs of dropping the Serzone. I'm thinking its the lowering of the 5HT2a that is causing these side effects. So how the heck do I get off the Serzone. Should I block it with Abilify, Zyprexa, or Seroquel? I really want off this med so I can take a real SSRI. I would appreciate and input on this. Thank you so much in advance.....Gary

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Hey mate this is bloody fas... (Below threshold)

March 25, 2008 3:19 AM | Posted by Alex: | Reply

Hey mate this is bloody fascinating stuff..
Particularly interested on the seroquel side of things with respect to its affinity for the receptors it binds to.

I was prescribed Remeron and Seroquel for insomnia, and I understand that Remeron (like Seroquel) has a high affinity for the H1 histamine receptor.

I was taking 30 mg of Remeron, 50mg of Seroquel.

Could you tell me if because of the Remeron, this low dose of Seroquel actually started to function as an anti-psychotic (since the H1 receptors were already occupied)??

Also where does one come across the specific data for a drug's affinity for certain receptors and at what dosages the "levels" become full??

Any information would be very much appreciated in understanding how I felt whilst on the meds.

Cheers again, Alex.

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How much Seroquel must one ... (Below threshold)

June 12, 2008 4:48 AM | Posted by Anonymous: | Reply

How much Seroquel must one take before it starts working on Serotonin?

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You explained Seroquel (and... (Below threshold)

June 18, 2008 9:10 AM | Posted by CAMSMD: | Reply

You explained Seroquel (and Zyprexa)'s mechanism of action better than my pharmacology professor could ever do... even better than the consulting psychiatrists when I did pre-residency for Psychiatry. You should write a book on Psychiatric drugs. I promise I'll buy your book instead of Stahl's. =)

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Now I know why in the 90's ... (Below threshold)

June 30, 2008 3:05 PM | Posted by attitude: | Reply

Now I know why in the 90's the art in the Stahl was so much fun. Because I had too much time on my hands in 1981. You rock!

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Speaking as a layperson, th... (Below threshold)

January 15, 2009 10:37 AM | Posted by La BellaDonna: | Reply

Speaking as a layperson, this was an extraordinarily eye-opening explanation of the way certain drugs act. It also illustrates, brilliantly, why it's so dangerous for a patient to self-medicate - if the patient decides that "less medicine is needed" and reduces a dose without consulting his/her physician, the patient may wind up experiencing, not a reduction of Effect A, but a totally different result - Effect B, C or D. If a reduction of Effect A is what's needed or desired, then a totally different medication may be required to achieve that.

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This is an amazing post... ... (Below threshold)

March 1, 2009 1:53 AM | Posted by Jake: | Reply

This is an amazing post... Unfortunately I've been on antipsychotics for several years now! Although, its been very low doses; according to your descriptions above.

I was on risperdal 2.5mg's max... Then I was on seroquel 600mg's max. But I was at about 300mg's for seroquel and 2mg's of risperdal max... I can, however; see what you mean about the comparisons of drugs. And I appreciate you explaining it, because it allows me to see things more clearly - and it even justifies some of my doctor's decisions on my behalf - pertaining to the drugs they prescribed me.

Thanks again.

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Amusing post this one. When... (Below threshold)

May 5, 2009 7:26 AM | Posted by abysmal musings: | Reply

Amusing post this one. When I was psychotic last year they stuck me on Seroquel - but the sedation was such (we'd just had a new baby) that I refused to ramp it up to the 300+ (thinking 2x = 2x etc). So I was basically taking an anti-hystamine. And hey, that can INCREASE dopamine - perhaps why on an anti-psych I went extra-psych. My psychs needed shooting. I'm lucky to be here. Extraordinarily interesting and useful post this one. atb D

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wtf... (Below threshold)

May 10, 2009 10:09 PM | Posted by Anonymous: | Reply


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It seems to me that a table... (Below threshold)

September 29, 2009 12:32 PM | Posted by Psynospy: | Reply

It seems to me that a table with the affinities of different psychotropic drugs AND a table of the side effects of the neurotransmitters activated by those drugs (the kind of information you gave about the seroquel and the H1, D2 and a1)would be the most precisious information in order to empower the patients and in order to help the doctors to make their choice of medicie. I tried to find that information on the net without much success. Too bad.

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Thank you. I get it. Ive be... (Below threshold)

October 5, 2009 11:51 PM | Posted by Anonymous: | Reply

Thank you. I get it. Ive been on seroquel for years and never understood how it works, neither does my doc apparently. What other drugs can you break down? I like how you explain things.

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Nice article, yes. But as f... (Below threshold)

November 21, 2009 2:35 PM | Posted by Marian : | Reply

Nice article, yes. But as far as I know, dopamine doesn't cause "psychosis", it "causes" cognition, motivation, pleasure, etc. etc. So, IMHO, "anti-psychotics", even the part of them that binds to dopamine receptors, don't act "anti-psychotic", but simply by enhancing stupidity and indifference. Isn't it a bit of a misleading euphemism to call such an effect "anti-psychotic"? Well, maybe it depends on the perspective...

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This is a really good read ... (Below threshold)

December 29, 2009 6:16 PM | Posted by Cassi Nenno: | Reply

This is a really good read for me, Must admit that you are one of the best bloggers I ever saw.Thanks for posting this informative article.

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My personal favorite is blo... (Below threshold)

March 25, 2010 4:45 AM | Posted by Andrew Glynn: | Reply

My personal favorite is blood tests for Lamictal. Nobody knows how Lamictal works, never mind what is an 'optimal' blood level.

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I guess you wrote part 4 th... (Below threshold)

April 15, 2010 11:37 PM | Posted by Anonymous: | Reply

I guess you wrote part 4 three years ago.

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After reading the article a... (Below threshold)

September 1, 2010 10:13 PM | Posted, in reply to La BellaDonna's comment, by John Q: | Reply

After reading the article and flowing down through the rum fountain, one should arrive at a frantic realization that even the best educated doctor should never prescribe and/or adjust these meds. While problematic and unreadable charts have driven even the straight and narrow docs to drinking entirely too much from the fountain, it doesn't change the fact that no one knows which receptor will be effected by noted chemicals.

Getting psychosis from the rum fountain is almost impossible, and the dosing factor is much more fun.

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last sentence, 1st graf:<br... (Below threshold)

September 1, 2010 11:07 PM | Posted, in reply to John Q's comment, by spelling: | Reply

last sentence, 1st graf:
affected by noted chemicals, not effected.

also, how do you explain then when the medicines work?
And what brand of rum would you recommend?

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If you are ever an expert w... (Below threshold)

September 2, 2010 10:09 AM | Posted by Mike B: | Reply

If you are ever an expert witness at a trial for these drugs please make it known. The cross-examination will be worth the travel time.

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This article is brilliant. ... (Below threshold)

September 2, 2010 11:57 AM | Posted by name: | Reply

This article is brilliant.

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My thanks to you for gainin... (Below threshold)

September 2, 2010 2:40 PM | Posted, in reply to spelling's comment, by John Q: | Reply

My thanks to you for gaining the knowledge of language. One can have a known existence or bring about a false existence through foreign matter. To that end, you decide which style applies to my application of writing.

It can not be explained because it is a fallacy. Therapy works best with no lingering side effects. No rum fountain required.

Without punch.

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Great job of explaining the... (Below threshold)

September 3, 2010 5:23 PM | Posted by Guzzo: | Reply

Great job of explaining these concepts in an easy-to-understand and entertaining format.

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As someone who was diagnose... (Below threshold)

September 17, 2010 10:04 PM | Posted by Jack: | Reply

As someone who was diagnosed as Bipolar, put on 300mg, then put on 400mg, then on 500... all because of different symptoms estabilishing (which later led to a whole new diagnosis...) you've re-affirmed what I thought!

On low doses (building up to the 300mg) it was a real effort to wake-up, the kinda sleep that makes you put a cigarette and an energy drink beside your bed for the morning! Even though you wont wake up in the morning - it'll be long after the morning!

On 300mg I found it would actually keep me awake for a few hours (and on 500 still find this!) but had a much better reaction.

I began having flash-backs, nightmares and intrusive/alarming thoughts and images.. this led to it going up to 400mg. This seemed to do nothing else so they put it on 500mg. This was better I guess.

I was then diagnosed with PTSD, and put on clonazepam of all things! Ended up abusing that as I'm an idiot, and nearly ODing - but then it explained all of the flashbacks and later onset symptoms... did they rectify the higher seroquel dosage? Nope! Still on that for some reason...

However, you've put the science behind a theory I've long had - the affects aren't multiplied by dose, but are completely different. Now if only someone could explain that to my psych...

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You, Doctor are my new hero... (Below threshold)

October 6, 2010 1:34 PM | Posted by Hamed Mokhtari: | Reply

You, Doctor are my new hero! Your knowledge is worthy for others to read and acknowledge. I for one will refer your blog and articles to those who I think could benefit from this information. For one, my old quack of a psychiatrist (anti-depressants; all he ever thought was the answer) and my respected family doctor.

Thanks you for taking the time and writing this exceptional paper, and I am going to read many more of your articles to come in the few days.

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How do I send you rum?... (Below threshold)

December 21, 2010 10:48 PM | Posted by izrik: | Reply

How do I send you rum?

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I was taking 25 mgs....yes ... (Below threshold)

March 10, 2011 11:47 AM | Posted by Ja Wheeler: | Reply

I was taking 25 mgs....yes you read that right, only 25 mgs, for about 3 months. I gained some weight, dropped the seroquel, and my whole body has been itching. I mean, itching like I will scratch off my arm with this fork and smile while I'm doing it, kind of itching. Could the seroquel be resopnsible for this strange side effect? I'm at my wits end. No, I do't have psychosis, never have and never had allergies either.

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What's the dose of the top ... (Below threshold)

March 20, 2011 9:42 AM | Posted by Doug: | Reply

What's the dose of the top level (H1) before it overflows into the 2nd level (Alpha 1)?

Thanks for your time!

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I wonder since it states:</... (Below threshold)

April 14, 2011 4:40 AM | Posted by Pharma_student: | Reply

I wonder since it states:

"(e.g. generalized anxiety disorder,[10] panic disorder,[11] post-traumatic stress disorder);[12] however, olanzapine has not been rigorously evaluated in randomized, placebo-controlled trials for this use and is not FDA approved for these indications. Other common off-label uses of olanzapine include the treatment of eating disorders (e.g. anorexia nervosa) and as an adjunctive treatment for major depressive disorder without psychotic features. It has also been used for Tourette syndrome and stuttering.[13] Olanzapine is also used in many addiction clinics as a sleep aid (usually 2.5–5 mg) due to its low abuse profile and zero addictive properties.[14]"

- In my opinion the off-label use for this medication still does not outweigh the side-effects.
I wonder what you guys think if some one who use it for a reason or more of the off-label use would not benefit from a once or twice daily dosage of

clondine- Catapres.
Stated for such reasons:

It has been prescribed historically as an antihypertensive drug. It has found new uses, including treatment of some types of neuropathic pain, opioid detoxification, sleep hyperhidrosis, anaesthetic use, and off-label, to counter the side effects of stimulant medications such as methylphenidate or amphetamine. It is becoming a more accepted treatment for insomnia, as well as for relief of menopausal symptoms. Clonidine is increasingly used in conjunction with stimulants to treat attention-deficit hyperactivity disorder (ADHD), for which it is administered in late afternoon or evening for sleep, Clonidine can be used in the treatment of Tourette syndrome.[2]
Clonidine is also a mild sedative, and can be used as premedication before surgery or procedures.[4]
This medication may also be used to ease withdrawal symptoms associated with the long-term use of narcotics, alcohol and nicotine (smoking). In addition, clonidine has also been used for migraine headaches and hot flashes associated with menopause.[5][6]
On October 4, 2010, the Food and Drug Administration approved the used of clonidine hydrochloride to be used either as an adjunct to traditional stimulant therapy or as a monotherapy in the treatment of attention deficit hyperactivity disorder (ADHD). It is being manufactured by Shionogi Pharma under the brand name Kapvay. Clonidine is regularly prescribed to help alleviate opiate withdrawal symptoms. It is mainly used to combat the sympathetic nervous system response to opiate withdrawal, namely tachycardia and hypertension, in the initial days of withdrawals.[7] It helps take away the sweating, hot/cold flashes, and general restlessness. The sedation effect is also useful although its side effects can include insomnia, thus exacerbating an already common feature of opiate withdrawal.[8]
Clonidine also has several off-label uses, and has been prescribed to treat psychiatric disorders including stress, sleep disturbances, and hyperarousal caused by post-traumatic stress disorder, borderline personality disorder, and other anxiety disorders.[9][10][11][12][13][14][15][16][17]
Clonidine along with Methylphenidate has been studied for treatment of ADHD.[18][19

The only side-effect I notice at .4 mg a night is dry mouth... and it helps my sleep hyperhidrosis (night sweats) and insomnia. And the next day I am not groggy at aall. It has alaso retained its sedative properties for sleeping after 6 motnhs now. None could be said about any benzo or even many antihistamines like hdryoxyzine or olnaz, or sero, or respiridone for all that matter.

does thsi make sense to anyone who is thinking about off-label use of olnazipine compared to offlababel use of clonidien with my personal experience being positive on clondine by far. It just makes more sense, few side-effects, hunger and dry mouth (at frist hunger) then a few times constipation at first, then dry mouth in mornings.

Curious why it isnt used more often; Clonidine that is... physcicians dont udnerstand the potential for such a drug. So strong, relatively safe in low no more than .4 at a time use for sleep.

anyone can shed their opinion on this thought?

-^ Pollack MH, Simon NM, Zalta AK, Worthington JJ, Hoge EA, Mick E, Kinrys G, Oppenheimer J. (2006). "Olanzapine augmentation of fluoxetine for refractory generalized anxiety disorder: a placebo controlled study.". Biol Psychiatry. 59 (3): 211–5. doi:10.1016/j.biopsych.2005.07.005. PMID 16139813.
^ Sepede G, De Berardis D, Gambi F, Campanella D, La Rovere R, D'Amico M, Cicconetti A, Penna L, Peca S, Carano A, Mancini E, Salerno RM, Ferro FM. (2003). "Olanzapine augmentation in treatment-resistant panic disorder: a 12-week, fixed-dose, open-label trial.". J Clin Psychopharmacol. 107 (5): 394–6. PMID 16415705.
^ Jakovljević M, Sagud M, Mihaljević-Peles A. (2006). "Olanzapine in the treatment-resistant, combat-related PTSD—a series of case reports.". Acta Psychiatrica Scandinavica 26 (1): 45–9. doi:10.1111/j.1600-0447.1951.tb10961.x. PMID 12752037.
^ Stuttering Foundation of America - A look at genetic and neurological correlates of stuttering
^ "Antiphyscotic used as sleeping pill". Forbes. 0028–0836. Retrieved 2005-12-11.


^ National Institute of Neurological Disorders and Stroke (2002). "Methylphenidate and Clonidine Help Children With ADHD and Tics".
^ Schapiro NA. "Dude, you don't have Tourette's": Tourette's syndrome, beyond the tics. Pediatr Nurs. 2002 May-Jun;28(3):243-6, 249-53. PMID 12087644
^ Patel SS, Dunn CJ, Bryson HM (1996). "Epidural clonidine: a review of its pharmacology and efficacy in the management of pain during labour and postoperative and intractable pain". CNS Drugs 6 (6): 474–497.
^ Fazi L. A comparison of oral clonidine and oral midazolam as preanesthetic medications in the pediatric tonsillectomy patient. Anesth Analg. 2001 Jan;92(1):56-61. PMID 11133600
^ "Clonidine Oral Uses". Web MD.
^ "Clonidine". Drugs.com.
^ . AJ Giannini. Drugs of Abuse--Second Edition. Los Angeles, Practice Management Information Corporation,1997.
^ AJ Giannini, I. Extein,MS Gold, ALC Pottash, S. Castellani. Clonidine in mania. Drug Development Research. 3:101-105,1983.
^ Ziegenhorn, A.; Roepke, S.; Schommer, N.; Merkl, A.; Danker-Hopfe, H.; Perschel, F.; Heuser, I.; Anghelescu, I. et al. (2009). "Clonidine improves hyperarousal in borderline personality disorder with or without comorbid posttraumatic stress disorder: a randomized, double-blind, placebo-controlled trial". Journal of clinical psychopharmacology 29 (2): 170–173.

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Earlier comment was mine as... (Below threshold)

April 14, 2011 5:06 AM | Posted by Hamed Mokhtari: | Reply

Earlier comment was mine as well sir. Can you email me at the following email, would love to talk about medication. I am only 23 but my knowledge and experience can be valuable; won't be a waste of your time!

Give me the time, [email protected]

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"This is a really good read... (Below threshold)

June 11, 2011 12:22 PM | Posted by BND: | Reply

"This is a really good read for me, Must admit that you are one of the best bloggers I ever saw.Thanks for posting this informative article." [2]

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Third-rate crap, at its ver... (Below threshold)

October 15, 2011 6:53 PM | Posted by reader: | Reply

Third-rate crap, at its very best... or maybe first-rate crap, if you please...

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This is really great!... (Below threshold)

December 2, 2011 2:36 AM | Posted by SuperRyu: | Reply

This is really great!

I remember I was having serious cognition problems along with my psychosis during that time. I was talking to my psychiatrist whyyy?? Why can't increasing seroquel make my understanding of things better since I feel it will??? why is is that I feel that if you increase it more I will understand more in my studies?? This inexperienced psychiatrist was not understanding me. I later switched to a more experienced psychiatrist, that psychiatrist looked at the info of seroquel and just followed the "usual effective dosage" and presto!! gotten better.

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i have been using Antipsych... (Below threshold)

March 27, 2012 11:50 AM | Posted by angelo van beersum: | Reply

i have been using Antipsychotics for about 10 years now,
just after the psychose , iused Syprexa, Abilify, Leponex, finally with the use of Risperdal, i had no more psychotic feelings and so on, but i was very depressed, 5 years, in that tim a started to use less Risperdal ,from 6 to 4mgr. bafter 4 or 5 months i stsrted to get back certain psychotic sensations, oke, the i went on Seroquel 500mgr. XR, less and less psychotic moments, but i felt drugged, slow in my head , certain normal feelings i didnt'feel anymore,
so last year i started to cut down on the Seroquel, that was oke ,till 300mgr. i started to get paranoid, so i raised it to 400mgr.I feel reasonable oke. I want to give peole one advise, if the are long on Antipsychotica. if you want to use less, take time,
for 10years of use, take a coople of years, and very helpful is to do holistic psychotherapy
to every body
God bless
Angelo van Beersum from the Netherlands

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In June 2001 I was prescr... (Below threshold)

March 27, 2012 2:30 PM | Posted, in reply to Pharma_student's comment, by Harry Horton: | Reply

In June 2001 I was prescribed 1/2 to 1 miligram of risperdal to treat paranoid schizophrenia and bi polar. I put on twenty to thirty pounds and went right into a serious metabolic disturbance that altered insulin resistance in my liver and screwed up my carb sugar and fat fuel consumption utilization order in my metabolism. I developed a premature form of diabetes. I remember this terrible rash breaking out across my face with immune injury that came with the drug and three months later after that initial rash a sand flea rash that stretched from July to September with immune function weakening. THough the doctor could have had the best intentions in the world for all I know, I was startled to find such a low dose of the antipsychotic could take one into this metabolic disturbance state so swiftly. Hopefully over the past nine years the conditions has improved, the facial rash has disappeared, as in some cases the body tries to recorrect and return to a previous normal status of health. And research out of Korea suggest that in animal studies the metabolic disturbance was reversed and good health was reconstituted. At least in mice. But I have not seen the specifics on that research report.

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Hi Angelo, Nice post, good ... (Below threshold)

March 27, 2012 6:23 PM | Posted, in reply to angelo van beersum's comment, by Anonymous: | Reply

Hi Angelo, Nice post, good to hear from a patient, I'm one too. I hope your medication changes are being helped along by a supportive psychiatrist, they have access to all the latest information and they know certain things that are valuable, like that a person shouldn't split the time-release medications in half to taper themselves down...also psychiatrists have access to very small doses because of starter packs, which can help with tapering down....I hear they have a new antipsychotic out now too...
I think a holistic approach is best too. Have you heard of the recovery movement, not the one for alcohol and drugs, but the one for mental health, it is pretty cool, check it out. Good luck.

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I think I know what you're ... (Below threshold)

March 27, 2012 6:31 PM | Posted, in reply to Harry Horton's comment, by Anonymous: | Reply

I think I know what you're talking about. People gain weight and get diabetes and high cholesterol and maybe high triglycerides and maybe their blood pressure starts to get bad and all that? Metabolic syndrome, is that what it's called? I'm not an expert, but when this happens to people who are not on antipsychotics, there are things you can do to help the situation, like exercise and diet. My friend did it and he even went off his diabetes medicine, he got so healthy. Ask your doctor if that might help you too. With diet and exercise, even small changes are good. You don't have to get radical.
And stay away from those sand fleas, they itch. :-)

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TLP: Ok then genius tell me... (Below threshold)

March 28, 2012 4:50 AM | Posted by Anonymous: | Reply

TLP: Ok then genius tell me how cl-OH!-zapine works.

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anonymousare you ask... (Below threshold)

March 28, 2012 6:41 AM | Posted by angelo van beersum: | Reply

are you asking how Clozapine or Leponex works?

Angelo van Beersum

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hello evrybody on teh other... (Below threshold)

April 29, 2012 7:08 PM | Posted by angelo van Beersum: | Reply

hello evrybody on teh other site of the ocean
rember I Am using Seroquel XR for 4 years now, all the time aI used it all at once before going to sleep, I don"t know in time, but my daily rithum changed, I woke up drunk, gallons of coffee and I kept a low profile during the day and in the evening I started sort of living, I changed psychiatrist and we desited to take 200mgr. in the morning and 200 mgr. in the evening, well, I feel at least awake during the day, not totally balanced yet , but it is a start, how about that? I hope that anybody on Seroquel XR is doing that already, if not, you should give it a thought
I"keep in touch with you, I might have something very good for all the people who are getting overweighted because of Antipsychotics
god bless everybody
Angelo van Beersum, the guy from the Netherlands

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That's great taking it twic... (Below threshold)

April 29, 2012 10:46 PM | Posted, in reply to angelo van Beersum's comment, by Anonymous: | Reply

That's great taking it twice a day is working! :-)

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You need to take Seroquel X... (Below threshold)

April 30, 2012 7:17 PM | Posted, in reply to angelo van Beersum's comment, by ERU: | Reply

You need to take Seroquel XR (the whole dose) at dinnertime to avoid feeling drunk and/or comatose the following morning. Short-acting Seroquel can be taken at bedtime. The 1/2-life on the extended release arcs so you're getting hit with the "bedtime" peak dose when it's just about time to start your day if you take it at 10pm, which can be avoided if you take it at about 5 or 6pm (maybe 4pm if you're espeically sensitive). Shifting it back this way will allow you to switch back to your normal daytime schedule. Easy to do, works beautifully. May want to swich psychiatrists again...

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Thanks for a very informati... (Below threshold)

April 30, 2012 11:08 PM | Posted by anon: | Reply

Thanks for a very informative article. Can you tell me what is the equivalency for D2 blockade for abilify is?

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goodday everybodyfor... (Below threshold)

May 20, 2012 4:34 AM | Posted by angelo van Beersum: | Reply

goodday everybody
for about a month I am taking my Seroquel 400mgr. XR spread over the day, at noon 200mgr. and at 00.00hour at night 200 mgr.
I feel great by it, I live fully now, but there 2things though, my nap in the afternoon, Ihave to put an alarm , oyherwise I "ll sleep for 2 and a half hour, oke , so I set an alarm, at night I have difficulties with going to bed , I take med. at 00.00hours, but I go to bed at about 02.00in the morning, I am just awake, I slepp for about 6 hours,
now I was thinking, what if I take 150 mgr. at noon, and 250 mgr. at 00.00 hour at night, does anybody have an idea about it? please mail
I might have something for people with an overweight because of Antipsychotics
3months ago I weighted 144 kg.now Iweight 132kgr. and a bit
this is how I did it:
I detoxed myself with Chaga , a fungus ,I find that on a Burch tree
while doing yhat , my taste changed, I stopped using sugar, in the coffee in the tea,and so on, about 6 weeks ago, my Niece , a Nutricion Therapist, put me on a diet with the use of Hemppowder,
a very much protein with Omegas, everything, I was eating to many sugars in the food, bread, pasta"s potatoes, trhe moment I started with the Hemppowder I stopped, snacking and spoiling myself with cookys, peaces of cheese, you name it, I felt for the firsttime Satisfied with the food I eat, I must say that I feel motifated to eat good food because of the info now on internet
try a consult with a Nutricion Therapist , it might do miracles
I"ll keep in touch
god bless

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Could you please do a simil... (Below threshold)

June 29, 2012 11:21 PM | Posted by Anonymous: | Reply

Could you please do a similar treatise with alcohol, a drug most of us is familiar with? It binds to GABA and the NMDA receptors, but that's not a very good explanation of its effects. Other NMDA antagonists such as ketamine cause wild psychotic stuff, and though alcohol causes quite wild stuff, it doesn't quite cause *that* wild stuff.

It may be that the GABA effects of alcohol somehow cancel the NMDA blocking stuff, but I'm not sure... I'd like to see a good analysis on how alcohol affects GABA and NMDA according to the dose.

On another note, I think the schizophrenia researchers should look more to glutamate and the NMDA receptors instead of just the plain old dopamine. Just in case.

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Hello everybodyI def... (Below threshold)

July 1, 2012 2:57 PM | Posted by Angelo van Beersum: | Reply

Hello everybody
I defenitly have something for the overweight because of Antipsychotics in April 16 Istarted with Hemppowder(natural protein)
changed my diet more in raw veggies with a natural chickpee dip
and up till now I last 13 kgr.well, of course spreading the Seroquel over the day gives me more lust for live, and I love to be busy
You have to check your diet its essentual, I love what I eat, there are so many good reccepies
god bless
Angelo from Holland

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Hello again,I post... (Below threshold)

October 5, 2012 10:29 PM | Posted by SuperRyu: | Reply

Hello again,

I posted last December 2011. Just wanted to tell that i'm already down to 0mg of seroquel XR. It was a real hard battle and I pray it continue. I had been taking antipsychotics and antidepressants for about 14 years since age 18... and now I'm 34 years old.

I did natural foods, exercise, praying and meditation and also some vitamins and fish oil.

I believe nothing is impossible if you want it and are determined...

There is hope....

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I'd say a sense of humor wo... (Below threshold)

October 15, 2012 3:48 PM | Posted, in reply to Jack Coupal's comment, by Dave H: | Reply

I'd say a sense of humor would come in very handy. They must encounter a lot of drama in their work.

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I might be put on new AP, s... (Below threshold)

November 2, 2012 5:09 PM | Posted by 2mg: | Reply

I might be put on new AP, so I really need some info:

1.) Does Zyprexa exert the same histamine/dopamine receptor occupancy at 5mg like Seroquel below 100mg - is Zyprexa really an antipsychotic at 5mg?

2.) Where could one find histamine/dopamine/dose related occupancy tables on the Internet? What keywords/sites to search? I'm not getting much results...

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I honestly don't know what ... (Below threshold)

December 8, 2012 6:30 PM | Posted by frank: | Reply

I honestly don't know what you are trying to say in this article. You are all over the place. A few responses to some of the random points you made are....a) the NE reuptake efficacy of the norquetieptine metabolite might offset the sedating effects of H1 blockade. b) how can you say that nobody knows if 5-ht2a blockade is linked to anxiolysis and yet d2 blockade is unequivically linked to antischizophrenic action. c) the clinical efficacy of the drug dictates at which dose the drug has effect in psychcosis. An antipsychotic does not behave in a binary way. It can start to reduce symptom sevarity at lower (ie 100mg) doses and then become more effective in higher doses. Some patients don't experience full symptom relif regardless of dose. d) yes some d2 occupancy occurs at any dose. e) that the drug isn't an antipsychotic (by your definition) in 'lower doses' is obvious. The drug is being used for anxiety, it cannot reduce psychotic symtpoms that don't exist. However, it can exert (in any individual) side effects that are linked to d2 blockade. As such, I think it is fair to call any dose an antipsychotic. Just because you don't have pain, doesn't mean you aren't ingesting a painkiller. f) seroquel is not harmless. Take hydoxyzine if you just want a high potency h1 blocker (with some 5-ht2a blockade). At least it has not been linked to blood sugar problems, cataracts, cardiovascular issues etc.

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"Rum fills the top level, o... (Below threshold)

December 19, 2012 5:53 PM | Posted by kate: | Reply

"Rum fills the top level, overflows into the second level, then that overflows into the third, etc. You can't get anything into level 3 until you fill levels 1 and 2. And, once you've filled level 1, you can't put anything more into it... But there’s a dark side to my analogy, and it isn’t the rum fits. Here’s the thing: if one molecule of Seroquel goes to H1, and not to D2, then can it have any antipsychotic effect? No."

I read this, redirected from two separate websites, both thinking they now completely understand receptor affinities and making it very clear that they didn't get past this line to your no. 2 footnote. I'm a pharmacist and this is totally inaccurate, which you basically acknowledged at 2 when you consider competitive binding of endogenous ligands, concentrations of receptors and the fact that the molecule can dissociate from say, H1 and bind with another receptor, such as D2 if it is in high proximity - it is just less likely. Maybe instead of tossing that little paragraph in right at the end where everyone obviously stopped reading because they saw the "rum chart" and thought I GET IT NOW!! you should make it clear that there WILL be some binding, and due to the factors mentioned above, possibly some effect at a number of receptors despite the high affinity for H1. And of course, the clinical effect can't necessarily be predicted with simple binding studies - though as you've shown above, it does give a good indication of why some effects don't increase above a certain dose.

I understand that this isn't a scholarly article, but a lot of people have taken the concept of "all receptor --> next receptor" and run with it so I think it's important to make this clearer.

Maybe a better analogy would be one of those fountains with the little holes in each tier so that the MORE full the upper tier becomes the more likely it is to drip to the next. Or something. :P

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I would really like to get ... (Below threshold)

February 14, 2013 6:26 AM | Posted by Ira : | Reply

I would really like to get to know more about you and read more of your work. Do you have any means to communicate individually?

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He's irrelevant. Focus on t... (Below threshold)

February 14, 2013 9:22 AM | Posted, in reply to Ira 's comment, by Anonymous: | Reply

He's irrelevant. Focus on the words.

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This article was posted ove... (Below threshold)

March 7, 2013 12:23 AM | Posted, in reply to kate's comment, by Too late: | Reply

This article was posted over 5 years before your comment... do you understand?

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thank you frank and kate.</... (Below threshold)

March 19, 2013 6:19 PM | Posted by polypharmacist: | Reply

thank you frank and kate.

Alone/TLP... couldn't there be a reason for, maybe, filling a higher level (for example 5ht) in the champagne fountain with one pill, and a lower level (for example dopamine) with a different pill?

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So,,, Are you sugesting tha... (Below threshold)

April 15, 2013 11:26 AM | Posted by one student: | Reply

So,,, Are you sugesting that if Abilify or some other anti-psychotic is given say 15-30 minutes after an an H1 blocker... It will work more efficiently (as an antipsychotic)... and maybe this could reduce the dose amounts ofd the antipsychotic? Perhaps straight up H1 blockers have a stronger affinity to the H1 receptors and can minimize this inconvenient interaction also? Any takers? Thx.

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Hi!!!Thank you for... (Below threshold)

May 21, 2013 12:49 PM | Posted by Anonymous: | Reply


Thank you for this great article!!!!!

I take 0.5 mg of Risperdal. I think that the most of the receptors that it touch is dopamine right? then it is a real low antipsychotic? I'm a person a bit anxious and I've fallen sicker because I felt pression from my dad. Big history, I'm a bit TDA trouble deficit of attention WITHOUT hyperactivity (sorry I'm a french person, my english is not perfect). When I was young, child and people laugh about be because they found I was slow or something likw that. I find myself a bit nevrotic. My doctor don't think I'm in psychose, but she was just scared that I would become. Because I suddently fallen sicker because of my dad (and my perseptions a but higher than reality). The pression to be like others, to find works like others and about my professionnal futur. When I fallen sicker, I developped a alimentation mania (first try to eat alacalin foods for my vagina problems and after, because of the meat an other stuffs that are acidifiants, I fallen vegetarian and after vegetalian. And after without gluten and after all raw and after just fruits-legumes and some nuts = frugivore). Now I eat meat, gluten, but not everyday. My doctor gave me risperdal because she was scared that I would developp a psychose. I was sometime scared to call or response to phone thinking about talking to my father. He is a good father, but for a girl that has difficult, too much pression just pushced me downer. One day, when my alimentation was a bit more normal, but my anxety was higher about my father, I went to hospital by myself to be far from problems and be securised. It was because the summer was approached and he told me about summer work. I never worked and I'm 25. My dad is very functionnal but not me. I'm dreamer and artistic. I like to study very much. I'm in university. But to fall down made me stop temporally my study. To someone like me, study is more difficult that other, but I have a lot of volontarism. To come back to the reason I've fallen sick, it was because I was scared to talk to my dad and say that I'm too sick to work, I felt I needed to slow down myswlf in summer. And I was on a move in few months to go in Montreal. I've always lived in suburbs around Montreal, quebec. But me and my boyfriend wanted to move on to the main city. I was scared about to say that I would take money from school to pay a bigger place (we were living in a 1 and a half). I think it is better for mood and my study to live there. I talked about it to my father and he approve. He is more comprehensive now. And for work, there are many organisms that help people with mental problems to find jobs. I will have help. I finished my test with the neuropsychologist and I will have my diagnostic in a few weeks.

Now is the point. About seroquel. When I went to hospital to relax a bit, they gave me seroquel 25mg. It was really working on me. The next day, I felt good, yes I felt the sedative effets, but it calm down my nevrotics thoughts. my head and nervs seem like always on a bit high. Not like a hyperactive person. I look like a slow person because my head and nerves are maybe a bit too activated and it slow down me. It is all the day long. I would like to be more relax. It is difficult to be in my head I find. I'm gonna see my doctor in a few weeks and talk to her about seroquel. In facts, when I saw her back some weeks after hospitalization, I told her I stopped the medication (risperdal) because it slow down my hand and felt a bit depressed. And she saw that without this medication, I become by myself better. I am reasonable with alimentation and I don't have any problems with my dad (wich was a big problem for me). Then, I didn't have any crisis. But, I'm always like before, a anxious and nervous person. My head is always a bit hypervigilence. Always running thoughts. My doctor was happy to see that I was better and thought I maybe would not need any medication because I wasn't in a crisis anymore. But I will tell her about who I am when i'm not in crisis. She saw the summit of the iceberg, but now that there is no more summit, there is the base that is in the water, the base that was my sensibolity to fall down. I wonder if seroquel 25 would be good for me. I read a lot of good comments on 25mg for anxiety. Now, I read that if a take seroquel 25, it would be just a sedative antihistamine. maybe I just need to slow down my head and my nerves. She gave me an antipsychotic risperdal 0.5mg just because she was scare about me to fall down into a real psychose. But when she saw me again, she didn't think so anymore. But because the real problem wasn't resolved, I took again risperdal. I am now on it. I think this is now for me antipsychotics. I feel like the foward part of my brain is a bit heavy and hurt a bit, like a headache. I'm not used to have headache. I feel it block to much things in my head, but it don't help with my problems. This is my 10e day on it. Maybe it it not long enough to know if it's working on me. But seroquel was working well on me. my thoughts was a bit clearer. My nerves was calmed down. I must to say that I never had bad acts like verbal violences, angry things, etc. I'm too much kind. I cannot defend myself, I'm too kind. I wanted to add this to my profile for you to knowm me better. Then, what do you think about antihistamine seroquel 25mg on my symptoms? I read so much good comments about seroquel 25mg or 50 on anxious people that had a bit problems like me!!!!!!

Anyway, thx to reply me :) Thank you to make me approach to happyness and serenity!!!!!!!!!!!!!!!!!!!!!! All this will change my life in a better may :)



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I wish I found this article... (Below threshold)

May 21, 2013 5:11 PM | Posted by Josh: | Reply

I wish I found this article months ago. They should have a "Newbie" guide to psych meds for all patients and explain how drugs like Seroquel, Zyprexa, etc. work

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Reading these articles writ... (Below threshold)

May 21, 2013 10:48 PM | Posted by Anonymous: | Reply

Reading these articles written 6 years ago and then comparing them with the articles from 2013, it seems that Alone has become much more cynical over the years. From these articles, I couldn't help but notice a tone of sincerity and that the author is trying to preach to his readers. The tone in the more contemporary articles are more sarcastic and shows someone who has been hardened by the harshness of reality and has given up in trying to be sincere. Poor Alone

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We always inadvertently mis... (Below threshold)

September 25, 2013 12:21 AM | Posted by abc: | Reply

We always inadvertently missed a lot of good things, have to cherish. After the well will be more wonderful.

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hey Angelo. how was your ex... (Below threshold)

December 3, 2013 1:45 PM | Posted, in reply to angelo van Beersum's comment, by alhexone: | Reply

hey Angelo. how was your experience with leponex (clozapine), and how much? I have been on it for about 12 years. For me its fantastic! (300 mg. and a blood level of around .12)
just curious!

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Yes, considering how much h... (Below threshold)

January 11, 2014 6:12 PM | Posted, in reply to Jack Coupal's comment, by name: | Reply

Yes, considering how much harm they can inadvertently cause to people they should not take themselves so seriously as to ignore potential errors in diagnosis.

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Treating mysterious conditi... (Below threshold)

February 17, 2014 11:44 AM | Posted by WhatAJoke: | Reply

Treating mysterious conditions with mysterious medications.

If a person consumes a well meaning fortune cookie thirty minutes before the onset of a psychotic episode...(insert more bullshit here)...they will reduces symptoms by 32%

Pseudoscience much?

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OMG you are so funny and I ... (Below threshold)

March 13, 2014 6:10 PM | Posted by Pisnicants: | Reply

OMG you are so funny and I love you. Great article too.

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Great explanation of how th... (Below threshold)

June 17, 2014 3:24 PM | Posted by flapacor: | Reply

Great explanation of how these antipsychotics actually work. My mom (she has Alzheimer's and lives in a care home) had been on Seroquel for about 6 years but recently started being agitated and paranoid so they tried increasing the dosage which didn't work (I now understand why from this article) and has now been put on Risperidone. She was too sedated so they lowered the dose - she is back to her "content" self but I still think she's too sedated.
Could the writer of this great blog write a similar article about Risperidone. It would be great to understand that too.

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How then do you withdraw fr... (Below threshold)

September 2, 2014 8:51 PM | Posted by Rachel: | Reply

How then do you withdraw from an antipsychotic? Is it ok then to stop it completely at a certain dose, rather than keep tapering it, or is a very slow taper best?

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I'm no psychiatrist, but gi... (Below threshold)

September 2, 2014 9:53 PM | Posted by Anonymous: | Reply

I'm no psychiatrist, but given that TLP's post is factual, I understand it like this:

Let's say you suddenly stop taking seroquel after tapering off it through the anti-psychotic dose range (D2), so that you instantly cut the H1 and a1 effects without any tapering. My understanding is that while this may drastically affect sleeping habits and other mental activity, it wouldn't directly lead to the re-emergence of psychotic symptoms associated with stopping typical anti-psychotic meds cold-turkey. But it may indirectly lead to the re-emergence of psychotic symptoms due to effect of removing a1 and H1 activity on sleeping habits and other mental activity.

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Oh, for God's sake.... (Below threshold)

September 3, 2014 11:49 AM | Posted, in reply to Anonymous's comment, by Anonymous: | Reply

Oh, for God's sake.

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300-400mg of quetiepine is ... (Below threshold)

September 18, 2014 10:30 PM | Posted by Anon: | Reply

300-400mg of quetiepine is awesome to get some sleep after a 11-day meth binge.....

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I have a question for you.<... (Below threshold)

October 20, 2014 1:18 PM | Posted by NewBipo: | Reply

I have a question for you.

You say Seroquel has no Dopamine occupancies at doses lower than 150mg.

I understand that Tardive Diskinesia is caused by dopamine depletion... How can someone on a dose of 100 get TD?

Would love to hear from you

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What makes seroquel great i... (Below threshold)

November 9, 2014 11:10 PM | Posted by joe: | Reply

What makes seroquel great is its touch and go nature at dopamine receptor. Do your own research this is just this guys analysis above

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I find these articles very ... (Below threshold)

February 26, 2015 12:48 PM | Posted, in reply to Garrett's comment, by Anonymous: | Reply

I find these articles very informative, but who is writing them? what is the qualification and accuracy, I am considering increasing my dose of venaflaxine, I am currently at 75mg and just came across the info that states I may not be getting the noephrenine or the dopamine I need at the current dose

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Then you talk IN PERSON to ... (Below threshold)

February 27, 2015 10:12 PM | Posted, in reply to Anonymous's comment, by Anonymous: | Reply

Then you talk IN PERSON to someone who is licensed for the purpose of assisting you in that decision.

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can anyone tell me if they ... (Below threshold)

March 21, 2015 8:10 AM | Posted by Ed: | Reply

can anyone tell me if they are taking Zyprexa and how long it took before it worked

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