July 17, 2007

No, Not Effexor, Too!? The Most Important Article On Psychiatry You'll Ever Read, Part II




In which Anne Neville agrees to believe pretty much anything anyone ever tells her, ever, and Richard discovers people are gullible idiots.

Go back and read Part I.  Hurry. 

Let's review the idea of sequential binding.  A drug with affinity for multiple receptors doesn't bind to all of them simultaneously, but rather sequentially, like an aging polygamist, starting with the system for which it has the greatest affinity.  Eventually, this maxes out, and it goes and adds the receptor system for which it has the second greatest affinity. 

Once it has maxed out a receptor system, pushing the dose doesn't get you any more of that effect (or side effects.)  You don't get less, but you don't get any more.  You know what else is like that, sort of?  Chlamydia.

Let's look at an SSRI, Celexa.  That first S stands for selective (serotonin reuptake inhibitor.) All of its clinical effect is coming from one single receptor system; this rum fountain has only one level-- and it's not that deep.  By about 20mg, you've gotten as much serotonin effect as you are going to ever get. 



Certainly, by 40mg, you're all done.  Do you expect the clinical difference from 10mg to 20mg to be significant?  Maybe.  How about 20mg to 40mg?  Not so much.  40mg to 60mg?  You woke me up for this?   Don't touch me.

In other words, there's only one level in Celexa's rum fountain, and it's pretty much filled by 40mg.  Pushing it to 60mg ("Now, with 50% more citalopram!") gets you a whole 3% more serotonin transporter binding.  Which is embarrassing.  I said don't touch me.  Do it again and I'm calling an adult.

So what about Effexor, the serotonin/norepinephrine reuptake inhibitor, invented at Wyeth Labs by Kirsten Dunst, aka Vitamin C?

From the American Journal of Psychiatry study:

la, la, la , la , la, la ,la ,la ,la ,la
la ,la ,la,la, la,la
yeah, yeah, yeah,
la, la, la, la, la, la, [repeat x 36]
we will still be friends forever [sic]


Which is exactly the point.  You don't get both S and N at all doses, it is, again, sequential: level 1 is S, maxed out by 75mg; and level 2 is N.  Guess when level 2 (N) really kicks in?  150mg.

So anything after 150mg is really two systems at once, with the N increasing from there.  300mg is the same amount of S as 150mg, but the N is more.  

Would you expect 75mg Effexor to be generally more efficacious than 40mg Celexa?  No, because they are both doing the same thing: blocking about 80% of serotonin transporters. But what about after 150mg, when you have S and N?




From  An Inconvenient Truth, 2006

This is why Effexor studies only show superior efficacy at doses above 150mg-- because at 150mg, you start adding N on top of your already maxed out S.  It's not adding more of the same drug, it is like adding a second drug.  It's not more Effexor; it's taking a maxed out SSRI, and adding a NRI.  It's like being with Princess Leia, but then adding Princess Ardala.  And if you understood that joke, you should put down Yars' Revenge and kill yourself.

Let me be clear: I'm not saying Effexor is or is not better than an SSRI.  I am saying that

  1. it would be impossible for it to be better then SSRIs, across a population, at less than 150mg.
  2. if it is going to be better, it would be better after 150mg, and only because you are adding a second system.
  3. If you are a doctor who "went all the way" up to 75mg Effexor for depression (or 300mg Seroquel for psychosis, etc, etc) and then stopped it because "it wasn't helping at all" then you should probably punch yourself in the testicles/uterus, you have missed the point.  How one responds at 75mg IS NOT AT ALL PREDICTIVE of what might happen at 150 or more (or, for Seroquel and psychosis, 500mg or more) again, and for the last time, because higher doses aren't more, they are different.(2)

You can see this most clearly if you look at an MRI:



which is self-explanatory.(3)

What you may want to ask is this: why haven't you heard this stuff before?  You think I discovered all this, in my basement lab, the one I use to create Jessica Simpson clones?  I'm the Ponce de Leon of psychiatry?(4)  Why the accepted delusion that a drug is the same, regardless of dose?  Perhaps it's because this supposedly only applies to the newer drugs?  The old ones-- Thorazine, Elavil, Pamelor, Remeron, Wellbutrin-- all blunt instruments, single receptor system drugs? 

Why do we think that an inanimate object has a fixed identity, when even a person doesn't?


Next up: Aren't Two Drugs Better Than One?


1. From the Celexa package insert: (warning: PDF-- clear your schedule)

2. Punching yourself in the testicles/uterus is not likely to help you learn this, it is more for my benefit. 

3.  It's technically an fMRI, bt the point is the same. 

4. Ponce de Leon did not actually discover psychiatry, but he was the first to make it available to the masses. 




You are a wonderful human b... (Below threshold)

July 19, 2007 4:30 AM | Posted by Shaan: | Reply

You are a wonderful human being.

Does the same go for wellbutrin?

Alone's response: No, Wellbutrin is not wonderful, he's a sneaky, evil bastard who will steal your girlfriend while she's in the bathroom. I wouldn't trust him. And he eats his own boogies.

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Ummmmm... so where does pro... (Below threshold)

July 19, 2007 7:14 AM | Posted by Wes Eades: | Reply

Ummmmm... so where does prozac fit into this picture.... what accounts for the few side-effects as we've evolved(?)... I've had a great response to 75mg of Effex... since I ain't using the N, is there something else (read "cheaper") I could take... like... maybe Rum?

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So, is there any sort of po... (Below threshold)

July 19, 2007 7:39 AM | Posted by Garrett: | Reply

So, is there any sort of pocket guide for residents with these curves for various medications? Sounds like a market niche...

Alone's Response: How much would you pay for such a guide...?

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Thanks for such a great pos... (Below threshold)

July 19, 2007 8:44 AM | Posted by Jon S.: | Reply

Thanks for such a great post. I laughed hard enough to inhale some of my breakfast and I've been coughing with watery eyes for the past few minutes.

The link to "An inconvenient truth" doesn't work for me, though.

I'm a tad confused by your graph for effexor though... Since there are two different chemical systems affected shouldn't there be two lines? And, secondly, at what point does the NRI rum fountain fill up?

And lastly, what is that snippet about the dogs dying from? There's no reference to it from the article (and I can't tell if that was on purpose or not).

Alone's response: First of all, I suck. Link fixed, and that beagle footnote comes from the Celexa package insert, which I forgot to reference (now fixed also.) But the graph for effexor shows only the S, and how it maxes out. you are correct, there should be an N line as well, but the authors of that study were only looking at S effects. And yes, the N will eventually plateau also, but it appears to be after 300mg.

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What causes the hyperhidros... (Below threshold)

July 19, 2007 8:53 AM | Posted by Steve: | Reply

What causes the hyperhidrosis seen with Cymbalta?

Alone's response: SSRIs are known causers of sweating (>10%) and apparently this can be minimized with cyproheptadine or clonidine. However, there are Effexor related sweating case reports that responded to cogentin (and apparently the SSRIs don't respond to cogentin.) So there may, in fact, be two pathways to sweating, an S and an N, so you may have to try both treatments to see what works (under the care of your doctor, etc,etc).
But if it were me, I'd take the guy off the Cymbalta.

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"Next up: The Existential P... (Below threshold)

July 20, 2007 1:02 AM | Posted by Stephany: | Reply

"Next up: The Existential Problem of Psychiatry "

Why do you appear to be the only psych that has read my notes?

Alone's response: Soon, soon, there's a reason I'm called "Alone..."

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"So there may, in fact, be ... (Below threshold)

July 20, 2007 1:07 AM | Posted by Stephany: | Reply

"So there may, in fact, be two pathways to sweating, an S and an N".
So true.

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i think i'm in love with yo... (Below threshold)

July 20, 2007 8:52 AM | Posted by anonymous mom: | Reply

i think i'm in love with you.

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Alone's response: No, We... (Below threshold)

July 20, 2007 5:36 PM | Posted by Jon S.: | Reply

Alone's response: No, Wellbutrin is not wonderful, he's a sneaky, evil bastard who will steal your girlfriend while she's in the bathroom. I wouldn't trust him.

That's the reason she dumped me? For wellbutrin? Imagine if I hadn't sta.... *reminisces for 5 seconds* On second thought, wellbutrin can have her.

Oh, and you are quite far from "sucking."

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The Last Psychiatrist:... (Below threshold)

July 20, 2007 10:51 PM | Posted by AK: | Reply

The Last Psychiatrist:

Seemingly hardboiled attitude, has a profound sense of fairness, retains enough faith in humanity to keep on teaching, and is capable of writing humorously about statistics and psychopharmacology.

And likes a good glass of rum.

Someone could write a series of detective novels, with a forensic psychiatrist (LP)as a protagonist.

But it would be a tough assignment--the writer would have to have mastered the detective/crime novel genre, and at the same time write about medicine as skillfully as Berton Roueche.

Alone's response: thank you for thinking it is only one glass...

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Alone, is it safe to assume... (Below threshold)

July 21, 2007 6:19 PM | Posted by J: | Reply

Alone, is it safe to assume that most psychiatrists know this sort of thing and it's only other docs one must worry about?

I don't trust anyone who can smile and frown at the same time or who uses the term "mental fitness", but this looks like a decent and comprehensive run-down (incl. Wellbutrin): http://www.askdrjones.com/2005/02/23/best-antidepressants/ It lacks the snark, but admittedly I giggled a bit when he referred to the "'poop out' effect" (used as both a noun and a verb). What must ESLers think of us?

Lastly, is there any data on whether M&M's antidepressant effects level off at some point due to weight gain? Or is the therapeutic dose low enough that this is not a problem?

Alone's response to the comment, "is it safe to assume most psychiatrists know this.." No. I used to give this (more formally) as CME lectures, with associated articles, slides (not by Atari)-- and I have yet to meet one psychiatrist who had heard this before. But I have had internal med and neurology docs come and "correct" me on some technical points (I try to simplify certain aspects. It's a difference in education. Psychiatrists are almost exclusively taught by Pharma, and so they learn drug effects by name; neurologists often use the same drug for different purposes and so learn them by dosage effects. (consider dopamine, the pressor drug.)

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Alone,WOW! I hate ... (Below threshold)

July 22, 2007 5:54 PM | Posted by Carrie: | Reply


WOW! I hate having depression. I hate even worse that my doctor(s) don't know what they are doing. I don't think that I'm well enough to monitor what they are doing to me...


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Finally someone that can pr... (Below threshold)

July 22, 2007 9:10 PM | Posted by NimishS: | Reply

Finally someone that can present a topic that is very easy to understand with some humor. Absolutely great and interesting...I keep wanting to read more articles but I am getting sleepy...just one more Cuba Libre!

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" Psychiatrists are almost ... (Below threshold)

July 22, 2007 11:56 PM | Posted by Stephany: | Reply

" Psychiatrists are almost exclusively taught by Pharma"

If only everyone understood what this means.
Cheers. Who needs a glass.

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Let us suppose that the res... (Below threshold)

July 23, 2007 11:21 PM | Posted by jt: | Reply

Let us suppose that the residents in the audience are in fact willing to pay for a guide with curves for various medications. Does such a guide exist? Has someone collected these graphs in a central location? Could that person be persuaded to make said graphs available?

Alone's response: Such a guide does not exist, nor will anyone (other than me) ever write it. Too much work, learning curve is too steep. It's so much easier to take the Pharma line (each med is different) or the cynic line ("Pharma says Geodon is good for everything, so therefore it must be good for nothing! Don't you hate Pharma, too!?") Or maybe I'm just bitter.

Maybe I'll get around to it.

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Ha ha! I just got the Vita... (Below threshold)

July 24, 2007 4:16 PM | Posted by technically well: | Reply

Ha ha! I just got the Vitamin C/Kristen Dunst joke, boy, that's an obscure reference. Do you spend all your day watching TRL?

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Man, I know I'd buy that bo... (Below threshold)

July 26, 2007 11:34 AM | Posted by jbeyermd: | Reply

Man, I know I'd buy that book. As a psych intern, right now what I need is clinically RELEVANT information, not BS in a Box. That is what these past two articles have been, as well as a lot of stuff you've written on this site in the past.

I'd buy that damn book. And I'd pay a good chunk of change for it if I had to. Or tip you some of my personal fave, Bombay Sapphire. The big bottle, of course.

Alone's response: Gin? Gin? You're not a communist, are you?

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I just stumbled onto your b... (Below threshold)

July 27, 2007 11:16 PM | Posted by austinshrink: | Reply

I just stumbled onto your blog; very informative.
Certainly the Effexor info is well known by most shrinks that I know (below 150mg it's an SSRI and at 150mg it acts as a SNRI).
The saturation info is great in theory, but it doesn't always pan out in my practice. I have a large number of patients that didn't have a complete remission on Celexa until I raised their dose to 80mg. Placebo-effect or fast metabolizers?
I don't know and I don't care as long as they are happy.

theories are great, but practice makes perfect.

Alone's response: and here we have the main criticism: how come some people do get better going from 60mg to 80mg? Or, how come I'm still getting massive increases in sedation even going from 750 to 800mg Seroquel?

An easy answer would be to say that these people are fast/slow metabolizers. Except that actually is only trivially relevant-- drug-drug interactions, which we generally ignore, have a much greater effect.

The answer actually is that these graphs represent either individuals, or averages of individuals. So I can say that, on average, Celexa maxes out at 40mg, or, across a population, Seroquel doesn't get significant D2 until 500mg. But every person will be different-- bell curve of humanity-- and some won't hit saturation of 5HTT until Celexa 200mg. (etc).

But here's why knowing these graphs is still relevant: because when someone walks into the office, you have nothing else to go on except the average. Knowing nothing else, you have to assume it takes about 500mg Seroquel to kick in; or after 40mg of Celexa, you're finished. OR, to say it in the reverse: if you give up at Seroquel 200mg even though the guy tolerates the med, you have wasted that much time, that much chemical, and that much money.

My motto always is: if you are at dose X, and there is no efficacy but no side effects, you keep going. When you finally get efficacy, you win; but if you get intolerable side effects first, it's time to switch. Note that my motto does not require you to know the value of X.

Welcome, as my hero says, to the real world.

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Jbeyermd and austinshrink,<... (Below threshold)

July 30, 2007 10:17 PM | Posted by Herb: | Reply

Jbeyermd and austinshrink,

Its good reading that there is a couple of docs willing to go the distance for their patients and also looking at the clinical side of things.

I must say after 44 years of battling my spouse’s MDD we’ve been fortunate to have been associated with a number of MDs and researchers willing to think outside the box. One such professor had my spouse up to 900 mg a day on Effexor XR some 9 years ago which my spouse was able to tolerate reasonably well. Most amazingly she maintained a reasonable degree of wellness for almost a continuous year which was unheard of in her case history. Then the refractory issue once again raised its ugly head.

After trying to maintain my spouse’s wellness for several years this professor recognized the fact that all the years of meds were not going to do the trick for her and it was at that time that I presented my research to him relating to VNS Therapy which he felt was worth a try and through his efforts and his professional relationships my spouse was enrolled and one of the earliest study subjects in the MDD studies. To make a long story short her results with this unique and innovative therapy has been “pretty remarkable” also adding of note that the first 3 continuous years she was depression free solely utilizing this unique therapy without the use of any psychotropic medications for purposes of depression.

While the therapy is not a panacea it is exhibiting efficacious responses for a percentage of those who are probably the most difficult patient population suffering from MDD to treat and more amazingly a percentage of these same individuals are obtaining long-term remissions not exhibited with any other therapies. So despite the seemingly poor D-02 study results the clinical reality is patients are benefiting and despite some medical non-psychiatric professionals and their claim of “placebo effect” I’d like these same medical professional’s to cite medical references to continuous multi-year placebo effects.

The fact is there is a large population of these disenfranchised patients who are the worst of the worst needing newer and innovative therapy and approaches to achieving wellness and the fact is; drugs ain’t doing it and dressing up the old drugs with a slight cosmetic makeover also ain’t going to do it either.



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I understood the part about... (Below threshold)

August 2, 2007 2:40 PM | Posted by pastabagel: | Reply

I understood the part about Dr. Dre and chlamydia, but what the hell happened to Black Manta? This is a trilogy, right? Aren't the bad guys always supposed to gain the upper hand in part 2 of a trilogy, only to have their dastardly plans foiled by muppets in part 3?

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Look, taking enough SSRI wi... (Below threshold)

August 6, 2007 7:07 PM | Posted by Uhh: | Reply

Look, taking enough SSRI will provoke serotonin syndrome immediately. I don't think the receptors "saturate" in the way you think.

Think of it like this: the syndrome is the result of excess serotonin, not excess SSRI. SSRIs prevent serotonin from being reuptook (that's right, I made it up, bite me), but don't cause you to have more serotonin in your system. Mixing it with an MAOI, however, which prevents the catabolism of serotonin... or Imitrex (see https://thelastpsychiatrist.com/2006/11/imitrex_sumatriptan_is_not_goo.html ) or adding it to amphetamines or ecstasy, etc...

As a historical note, serotonin syndrome was first diagnosed in 1950, when a tuberculosis patient on meperidine and phenelzine (and l-tryptophan, I think) got it, and died. It was her death that prompted the first wave of changes in residency hours and workloads (less) and staffing (more.)

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Could you please elaborate ... (Below threshold)

August 15, 2007 4:28 PM | Posted by Nick: | Reply

Could you please elaborate on Effexor vs. Wellbutrin? Is Wellbutrin worse? I am having "dead brain" or "flatbrain" symptoms on 75mg of Effexor. So 150mg will sort of juice up my mind? Or should I go with Wellbutrin?

Alone's response: standard disclaimer: I'm not your doctor, consult with your doctor, etc. That said, no one can predict whether going to 150mg will help or hurt or do nothing. NO ONE. ANYONE WHO SAYS OTHERWISE IS OF SATAN. However, I can confidently say that 150mg Effexor is _different_ than 75. For example, if the flatbrain is the result of serotonin, perhaps 150 would be helpful, or at least not more harmful. But if it is due to something else-- for example, the first inklings of norepinephrine-- then it would be worse. This probably wasn't as helpful as you'd like, but I did get to write SATAN in capital letters. No other psych blog has done this.

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From my own clinical trial ... (Below threshold)

September 6, 2007 7:44 AM | Posted by Aden: | Reply

From my own clinical trial in the treatment of depression, Effexor is definitely a two stage medication. No symptom relief was experienced until after norepinephrine levels were being modified.

Gradually increasing dosage over a 6 month period from 75MG to 300MG, no change was experienced until the after the norepinephrine levels were being affected above the 150MG mark. Efficacy was reached at 300MG.

In the treatment of patients with depression symptoms contributed to by norepinephrine levels, wouldn’t attention-deficit/hyperactivity disorder medications such as Ritalin/Concerta, Dexedrine, or Adderall be more targeted/useful for treatment then an SSRI with NRI abilities?

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Since Seroquel appears to b... (Below threshold)

November 27, 2007 7:50 PM | Posted by Edmond O`Flaherty: | Reply

Since Seroquel appears to be sedating due to blocking the histamine receptors do you know if adding a non-sedating antihistamine could be used to reduce this effect.

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Correction...who do you thi... (Below threshold)

January 23, 2008 8:53 PM | Posted by Anonymous: |