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:
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:
Consult your doctor if you are at risk for esophageal rupture
The other way this is often represented is with a pie chart:
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:
BUT HOW CAN COLOR PICTURES BE WRONG?
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.
WHAT THE HELL ARE YOU TALKING ABOUT?
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.
Tom was thankful he was sober enough to avoid the ugly one
WHAT IF ALL THE BLONDES ARE TAKEN?
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.
DOESN’T THE BOX CLEARLY SAY ANTIPSYCHOTIC?
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.
ARE YOU SAYING THE FDA ARE A BUNCH OF UNSCIENTIFIC ASS-MONKEYS?
What?
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.
DOES THAT MEAN 5mg ZYPREXA = 250mg SEROQUEL?
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?
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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:
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…
IF YOU LIKE IT, DIGG IT-- OR REDDIT IT-- OR SEND ME MONEY-- OR RUM--
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July 13, 2007 7:44 PM | Posted by : | 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.
July 13, 2007 9:58 PM | Posted by : | 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.)
July 14, 2007 9:17 AM | Posted by : | 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.
July 14, 2007 9:41 AM | Posted by : | 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
July 14, 2007 10:06 AM | Posted by : | Reply
Linked and commented on. I like the rum fountain metaphor as a visually and conceptually intuitive way of describing something fairly confusing otherwise.
July 14, 2007 1:37 PM | Posted by : | 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.
July 14, 2007 3:44 PM | Posted by : | 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.)
July 14, 2007 5:14 PM | Posted by : | Reply
I'll take rum vs. Seroquel any day, what a great post. I linked to it.
July 25, 2007 11:20 PM | Posted by : | 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)
October 19, 2007 12:22 PM | Posted by : | 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.
December 18, 2007 3:38 PM | Posted by : | 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
March 25, 2008 3:19 AM | Posted by : | 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.
June 12, 2008 4:48 AM | Posted by : | Reply
How much Seroquel must one take before it starts working on Serotonin?
June 18, 2008 9:10 AM | Posted by : | 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. =)
June 30, 2008 3:05 PM | Posted by : | 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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