Serotonin syndrome treatment

[393656]

I was curious to get all of your expertise and experience in approaching serotonin syndrome. The 2 main methods that I have used and seen were

1. Risperdal (or other atypicals as second choice) due to its high 5Ht2A affinity
2.Cyproheptadine-5ht2a affinity

However both of these have some downside.
1.If you believe that serotonin syndrome is in the spectrum of malignant catatonia (not NMS) then the strong D2 blockade of risperdal always to me is a risk of throwing someone into autonomic instability and malignant catatonia. However it helps with the delirium aspect and the serotonin toxicity
2.Cyproheptadine has so much anti-cholinergic effects that it causes so much delirium and confuses the picture IMO. Its hard to track progress in mental status if you are causing confusion along the way.

One thought I had that you never see is Hydroxyzine with its potent 5HT2A antagonism, no anti-cholinergic and no D2 blocking- I was trying to find Ki values for hydroxyzine's 5ht2A affinity to see just how it compared to risperdal and cyproheptadine but could not..

any thoughts guys?

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[NJWxMan]

I've learned that sometimes doing nothing, but supportive care, can be the best way to go. It's the same idea with NMS. You can throw around Dantrolene, etc., but in the end, IV hydration and time are the best way to go. Why cloud the picture more?

 

[nitemagi]

Agreed. Just like delirium, the first step is treat the underlying condition (removing offending agent). Next step is supportive care (IVF, cooling blankets). Then can try other meds. I don't think there's hugely great data on anything for treatment since it's relatively uncommon.

I always liked this NEJM review article -
http://www.nejm.org/doi/full/10.1056/NEJMra041867

 

[393656]

Thanks-great link! I totally agree with you guys as similar to delirium you sometimes are throwing meds at something that may resolve on its own with treatment of underlying condition.

I guess where medication intervention tends to come up is when the delrium is getting in the way of getting any solid information from the patient or there is not one clear reason for the delirium. You may suspect serotonin syndrome but cannot necessarily get an entire history and a few other things are suspicious. Then you start to think its probably multifactorial and as you guys know as well as I do-treating the underlying cause is often just not a reality. I think more often then not I see multifactorial causes that do not have a clear underlying problems.

So in those cases I guess I go to medicine to try to clarify the picture more quickly so I can take the correct steps and treat the right disease.

Great thoughts though and totally agree!

I guess more hypothetically does anyone have thoughts on hydroxyzine for this use? I really cannot get over how many people reccomend cyproheptadine since its more potent anti-cholineric than benadryl is and will make someone delirious real quick. You would have to be sure you were treating 100 percent serotonin toxicity in someone young who is not susceptible as much to ach blocking. To me it confuses things even more.

thanks guys!

 

[nitemagi]

Agreed that treatment and evaluation is often not easy. That's one of my favorite parts of C/L - the detective work.

Cyproheptadine I believe is more recommended d/t being a serotonin antagonist, though of course it's an antihistamine too. So I'm not really sure why other antihistamines would be useful. I'd love to see other data if people know some studies on this.

This is a nice pharm paper on anticholinergic aspects of antihistamines.
http://www.ncbi.nlm.nih.gov/pubmed/15627436

Hydroxyzine apparently has in vitro anticholinergic effects, but none in vivo. So as far as avoiding anticholinergic delirium, I say

Risperdal, like many atypicals, is used for its 2A blockade effects.

PDSP for hydroxyzine (3H-Mepyramine) only has H1 blockade listings. Seems like there's no data on it as a serotonin blocker.

 

[393656]

Yes sorry I was not clear. It would not be due to its anti-histamine effect but rather it is a quite potent 5HT2A antagonist similar to cyproheptadine, remeron, trazodone or the atypicals and agomelatine (well 5ht2C in its case but still relevent for SS)

That is the thought behind using it for anxiety over other anti-histamines-is its 5ht2a blockade effects. Also for sleep over benadryl as it offers properties of both 5ht2a block and anti-histamine which are both helpful for sleep structure and increasing slow wave sleep--anyway off topic!

But yes the key would be to find out the Ki of cyproheptadine and hydrosyzine and compare each to see which is more potent at the serotonin receptor.

As you know none of this is an exact science! CL is detective work and some shots in the dark-great stuff!

I hate citing wiki but here is a good list of some other onesn you dont commonly think of as having 5ht2 action-
http://en.wikipedia.org/wiki/5-HT2A_receptor

 

[Manicsleep]

Adjuntive use of remeron to avoid serotonin syndrome?

 

[393656]

Adjuntive use of remeron to avoid serotonin syndrome?

No no I was just listing other 5HT2A antagonists if you are referring to my post. BUT you probably could treat SS with remeron with good effect. People mistakenly think remeron (and less so trazodone) is a big risk for SS when thrown in with other serotonergic drugs. Fact of the matter is its inherent potentn 5ht2A antagonism will block a fair amount of serotonin at the receptors that produce toxicity. Its alpha 2 blockade ramps up NE and some serotonin however these mechanisms take days-weeks. The 5ht2a is instanteous. Therefore in SS starting remeron for a few days is probably equally effective as anything else. You would have a hard time doing it because 99 percent of physicians do not know enough pharm and to be honest with other treatments I am not saying it is better by any means. Except it does lack anti-cholinergic so I personally prefer it to cypraheptadine.

Trazodone is the same deal. Low doses have potent 5ht2a and only hte higher doses get signifigant SSRI. Therefore trazodone at lower doses is really not going to cause any SS and higher doses is also pretty unlikely. Starting it in a trazodone naive patient at 50-100 also would do a great job at treating SS with its lack of anti-cholinergic properties. Again preferable to cypraheptadine but no real reason to use it IMO with things like risperdal and hydroxyzine.

Just my .02-

 

[Manicsleep]

Talk to some hardcore psychopharmacologists about remeron.
The remeron for serotonin syndrome prophylaxis thing isn't so far fetched.

Max out on prozac etc? Add remeron! Especially if you have tramadol or some other risk factor on board. I have seen it.

 

[393656]

Talk to some hardcore psychopharmacologists about remeron.
The remeron for serotonin syndrome prophylaxis thing isn't so far fetched.

Max out on prozac etc? Add remeron! Especially if you have tramadol or some other risk factor on board. I have seen it.

Oh believe me my friend I have grilled as many as I could and have done as much research as I could my first year of residency since I heard this but nobody could show me any data and that always pisses me off. I realized nobody really knows. Its one of those speculated points unfounded on any data. To be honest I am sure there is a factor both ways. The only way to really prove this is starting remeron at 45mg. Come to think of it why start at 15 ever? I think next time I use it I will just shoot right to 45 and test this hypothesis as the pt hopefully will have better time tolerating it.

The tramadol is the silent killer since you mentioned it. Half of the SS cases I have seen are tramadol with an SSRI and often effexor (with many docs thinkings its purely a NRI and do not know its more potent SSRI at most usable doses. All comes down to knowing your pharm.

Good thoughts-thanks everyone for the input on this thread-appreciate it! I like to know I am on the same page or atleast in the same ballparks as some very intelligent colleages cross country!

 

[nitemagi]

I've only seen one case of serotonin syndrome (caught it on call),

a borderline on heavy polypharmacy. Some of the meds may have been preventing, but ultimately, as all too happens with borderlines, people keep adding meds and steadily maxing out doses. Was on an SNRI, buspar, seroquel, a triptan, and if memory serves either remeron or trazodone.

 

[393656]

I've only seen one case of serotonin syndrome (caught it on call),

a borderline on heavy polypharmacy. Some of the meds may have been preventing, but ultimately, as all too happens with borderlines, people keep adding meds and steadily maxing out doses. Was on an SNRI, buspar, seroquel, a triptan, and if memory serves either remeron or trazodone.

That will do it-good catch! For some reason I have seen many serotonin toxicity spectrum presentations. Probably one classic SS. The problem is like all else in consult psychiatry-too many complicating factors. For one the variation in sensitivity to serotonin is so extreme, extremely effected by poor/fast metabolizer's and the population that is on BP meds that interfere with autonomic signs of instability make the overall diagnosis of classic SS pretty rare and tricky.

Still cool to talk about and be aware of for sure. I feel strongly people often miss the forest for the tree-the tree being classic SS and the forest being the large spectrum of toxicity with subtle presentations of subtle myoclonus or twitches that unless you look for it wouldnt otherwise see. These are the people that you can catch before it progresses but sadly lpeople either see black or white. Same with catatonia--malignant catatonia and the interplay with NMS. Many consults want an answer whether "is it this.. or is it this.. " Almost every CL patient is a big pot of soup with too many ingredients to count. I am big on spectrum of all things-mood, psychosis and medical presentations. I feel strongly you can catch and treat subclinical presentations more quickly and effective than full blown symptoms of the disease.

Sorry that was a bit off topic--

 

[Manicsleep]

I have seen it more than once but the worse I saw was a patient complaining of anxiety/restlnessness while on paxil and the resident added effexor and then gradually kept upping it. Turned out to be serotonin syndrome.

Speaking of triptans and synthetic opiates...anyone ever seen problems with linezolid or is this some urban myth? Please don't post an article, I want to know if anyone has witnessed this.

 

[393656]

I have seen it more than once but the worse I saw was a patient complaining of anxiety/restlnessness while on paxil and the resident added effexor and then gradually kept upping it. Turned out to be serotonin syndrome.

Speaking of triptans and synthetic opiates...anyone ever seen problems with linezolid or is this some urban myth? Please don't post an article, I want to know if anyone has witnessed this.

I think its not as common as people seem to suspect. Its such a weak MAOI and have seen many people on tons of serotonin drugs with linezolid and never has been a problem. Just like someone can get SS on low doses of two serotonergic drugs v. someone else it takes 3 drugs at high doses, of course it is possible and not sure how you would differentiate it based on "have you seen it" Its impossible to tell because linezolid alone obviously does not cause it which means they would have to be on another serotonergic drug/drugs-so it would be impossible to tell if linezolid contributed unless the timeline was crystal clear which never happens.

Bottom line from what I seen its not anywhere near the risk of the "true" MAOI's

 

[nitemagi]

Challenge of a selection bias though. Serotonin syndrome isn't all that common, is probably missed a lot of the time. So not having clinical experience with linezolid causing it doesn't seem like a consolation to me.

Conceptually one shouldn't see serotonin syndrome without excess dose of a single SSRI over a long period of time, or multiple serotonergic drugs simultaneously, since with reuptake inhibitors it should take some time to build up an excessive amount of serotonin. I did see a case report recently of an OD on a massive amount of Paxil XR that led to death, despite use of cyproheptadine.

 

[393656]

Challenge of a selection bias though. Serotonin syndrome isn't all that common, is probably missed a lot of the time. So not having clinical experience with linezolid causing it doesn't seem like a consolation to me.

Conceptually one shouldn't see serotonin syndrome without excess dose of a single SSRI over a long period of time, or multiple serotonergic drugs simultaneously, since with reuptake inhibitors it should take some time to build up an excessive amount of serotonin. I did see a case report recently of an OD on a massive amount of Paxil XR that led to death, despite use of cyproheptadine.

That is about the most stupid thing you could give to someone on a massive dose of paxil. Probably gave them anti-cholinergic toxicity with paxil's potent anti-cholingic activity and cypro's VERY potent AC activity-they probably died of an arrythmia. That is when people do not think and they just do something because "that is what you use for SS." Here is a classic example of where risperdal or any other 5HT2 blocker as discussed above would be a much smarter choice.

At the very least some short acting achesterase inhibitor if you are going to throw cypra at him. However if someone was using cypra clearly they are not aware of this problem and thus wouldn't known to even think of this. Sad

 

[firedoor]

Risperdal, like many atypicals, is used for its 2A blockade effects.

Is there anything special about 5-HT2A in the pathophysiology of SS?

 

[393656]

Yes it mediates many of the ill-effects of serotonin toxicity along with a smaller componnent of 5HT1A.

 

[Yeti37]

This is a nice pharm paper on anticholinergic aspects of antihistamines.
http://www.ncbi.nlm.nih.gov/pubmed/15627436

Awesome information

 

[393656]

Yes more evidence cyproheptadine is a horrible treatment for SS and unfortunately has penetrated even most textbooks and practice. That is the risk of just following what is written without thinking about it and understanding why something is used. There are better alternatives to cyprohepatidine as discussed that would not complicate the delirium which is crucial to making the diagnosis often and getting the patient better.

 

[firedoor]

1.If you believe that serotonin syndrome is in the spectrum of malignant catatonia (not NMS) then the strong D2 blockade of risperdal always to me is a risk of throwing someone into autonomic instability and malignant catatonia. However it helps with the delirium aspect and the serotonin toxicity
2.Cyproheptadine has so much anti-cholinergic effects that it causes so much delirium and confuses the picture IMO. Its hard to track progress in mental status if you are causing confusion along the way.

One thought I had that you never see is Hydroxyzine with its potent 5HT2A antagonism, no anti-cholinergic and no D2 blocking- I was trying to find Ki values for hydroxyzine's 5ht2A affinity to see just how it compared to risperdal and cyproheptadine but could not..

any thoughts guys?

First, a question: Could you please explain the distinction you're alluding to between malignant catatonia and NMS (and malignant hyperthermia as well)?

Secondly, I would be reluctant to use an antipsychotic except as a last resort due to the reason you mentioned (a hypothetical SS-"NMS" spectrum), and also because of the risk of exaberating an existing NMS-spectrum entity when the clinical picture is unclear (frequently) or polypharmacy is involved.

Also, as has been suggested, I'd not want to use cyproheptadine due to its anticholinergic effects.

Remeron, as discussed, sounds reasonable, but I'd still be nervous using it.

Hydroxyzine actually sounds like a really good possibility. I'm curious what others think?

Methysergide has been mentioned in the literature but is not on the market in the US.

Inderal also has antiserotonergic properties, so I guess Vistaril, Remeron and Inderal seem the most attractive to me based on the limited knowledge available on the treatment of SS.

???

 

[nitemagi]

I have to disagree. While there's at least a little data on atypicals and mirtaz, and as much of a fan of vistaril as I am for anxiety, the idea of using vistaril as first line seems far-fetched. Does anyone have any papers showing vistaril actually has anti-serotonergic effects? It seems at best theoretical.

Furthermore the only study I found that mentioned it seems to involve a delirium case in a pt taking vistaril plus linezolid:
http://www.ncbi.nlm.nih.gov/pubmed/15940417

 

[393656]

There are no controlled trials of anything in serotonin syndrome as its too uncommon. Cyproheptadine all stemmed from theoretical benefit being serotonin antagnoistic.

There is in vitro and vivo proof of hydroxyzine binding to the serotonin 5ht2 receptor so that is not in question. It is hard to compare it against cyproheptadine as many other facts come into play.

Again this would be a harm reduction model. With cyproheptadine IMO you are doing more harm than good. With hydroxyzine you are not adding any harm and potentially doing some good.

Keep in mind most SS needs no treatment aside from supportive care so any added benefit without adding harm is a reasonable option.

What distinction between NMS and malignant catatonia are you looking for? I would reak fink's book on the topic-by far the best out there.

NMS is just one type of malignant catatonia. A type caused by neuroleptics or a type where neuroleptics atleast were a large contributory to proceeding to malignant catatonia. MC is the broad category of a set of symptoms we call catatonia that have progressed to have further instability in vitals, temp, autonomic etc.

More often than not you see cases of catatonia from a variety of other causes who were given neuroleptics for "delirium" and this pushed them over the edge into a malignant catatonia but people than label this stricly NMS while really the neuroleptic was simply a contributing factor.

Not sure what you are asking however in regards to distinction. They are not mutally exclusive. By definition if you have NMS than you have malignant catatonia.

Malignant hyperthermia is a set of symptoms and presentation induced by halothane anasethestics. This is in its own category and not the same as malignant catatonia although it has several similar features. Receptor wise it probably also involves a similar set of subcortical and cortical gaba, dopamine and other receptors but it is not in the "spectrum" of catatonia--malignant catatonia. IMO atleast and Finks

 

[nitemagi]

There are no controlled trials of anything in serotonin syndrome as its too uncommon. Cyproheptadine all stemmed from theoretical benefit being serotonin antagnoistic.

There is in vitro and vivo proof of hydroxyzine binding to the serotonin 5ht2 receptor so that is not in question. It is hard to compare it against cyproheptadine as many other facts come into play.

Again this would be a harm reduction model. With cyproheptadine IMO you are doing more harm than good. With hydroxyzine you are not adding any harm and potentially doing some good.

I wouldn't say there are NO trials. Maybe no human trials.
At least some animal studies to support use of an atypical or mirtazapine.
http://www.ncbi.nlm.nih.gov/pubmed/20655983
http://www.ncbi.nlm.nih.gov/pubmed/20456331

But I'd need to see any data on hydroxyzine having ANY serotonergic antagonism. At this point the only data I've seen is as an antihistamine.

 

[9point75]

Intravenous Thorazine is the answer

 

[393656]

Intravenous Thorazine is the answer

Ya a potent anti-cholinergic is another good idea We have just re-hashed the entire point of the thread that cyproheptadine is not good due to this same reason. Way to dress up the same idea in leopard print.

Regarding hydroxyzine here are a few citations and comments on it-regarding its 5ht2a antagonism-no offense but if you do pubmed you can find multiple articles, reviews etc on pharmacology of hydroxyzine. These are the 2 first ones that popped up on googscholar and pubmed
http://books.google.com/books?id=qu...=en#v=onepage&q=hydroxyzine serotonin&f=false

Cochrane Database Syst Rev. 2010 Dec 8;(12):CD006815.
Hydroxyzine for generalised anxiety disorder.

Guaiana G, Barbui C, Cipriani A.
Source

Department of Psychiatry

 

[9point75]

It's for the 5-HT antagonism in an IV form for the critically ill patient. If you can still take PO, you're not critical enough to warrant anything other than supportive measures IMHO. I'll be waiting to hear about how Thorazine doesn't have activity at the 5-HT's.

 

[nitemagi]

Ya a potent anti-cholinergic is another good idea We have just re-hashed the entire point of the thread that cyproheptadine is not good due to this same reason. Way to dress up the same idea in leopard print.

Regarding hydroxyzine here are a few citations and comments on it-regarding its 5ht2a antagonism-no offense but if you do pubmed you can find multiple articles, reviews etc on pharmacology of hydroxyzine. These are the 2 first ones that popped up on googscholar and pubmed
http://books.google.com/books?id=qu...=en#v=onepage&q=hydroxyzine serotonin&f=false

Cochrane Database Syst Rev. 2010 Dec 8;(12):CD006815.
Hydroxyzine for generalised anxiety disorder.

Guaiana G, Barbui C, Cipriani A.
Source

Department of Psychiatry

Not trying to be oppositional, but the evidence still seems skimpy. The book chapter mentions mild 5HT-2A antagonism without a citation. The cochrane article doesn't mention serotonin at all aside from that's the mechanism by which the antidepressants hydroxyzine is being compared to works. Not strong enough data IMHO to warrant first line use. I welcome citations of primary papers showing its use in serotonin syndrome, or showing the level of its anti-serotonin effects. WS, I like your style of stirring up discussion on so many topics, but I'm also picking up a trend of weighing anticholinergic problems as trumping all others.

 

[393656]

Ok show me any data for cyproheptadine in a primary paper citing anything other than theoretical benefit because of its 5ht2 antagonism.

By all means, it sounds like you are just another conformer and if you want to treat a delirious SS patient with strong anti-cholinergics than you are the same as many psychiatrists.

My point is to those open to actually thinking about things, there is a better couple options including risperdal and hydroxyzine as a second line agent that is going to be safe with no downside as far as worsening the delirium.

I wont go through it again but harm reduction approach does not include giving someone a drug that can worsen their problem-cyproheptadine. Believe it or dont-up to you.

Same reason people like you would hesitate to use trazodone or remeron for SS ( I would not at all). Not that it would be a first choice but if there was a scenario you have to think outside the box. Most would just assume "they increase sesrotonin-that is bad" when in reality they block serotonin by ht2a initially and become serotonerigc after days-weeks. So ST use is just one other better option than cyproheptadine.

If you wait for primary papers on new lines of thinkoing on rare situations you will always be a sheep and conformer. If you have some forward thinking with good reasoning and a low harm approach v. benefit, than you will be ahead in whatever field you are in.

 

[393656]

Sure it has potent 5ht2 antagonism but if someone is that unstable than using an anti-psychotic is a stupid dangerous idea that puts them at risk for progression further into malignant catatonia. If they are that delirious and out of it than they are prime targets for being on their way to malignant catatonia and no longer just SS. Especially with potent IV adminstration.

Not to mention as mentioned the anti-cholinergic effects which are really a bad move in malignant catatonia since you will kill your ability to thermoregulate and your fever will potentially get out of control.

SS already has autonomic instability-you do not want any further anti-cholinergic activity as is-

Keep up the good work putting patients at risk though.

 

[9point75]

Wallstreet... It seems like you would make a truly awesome neurologist. I respect your knowledge of all things academic. You would have been an awesome psychiatrist in the 90's as a forerunner Of the biologic movement. I worry that your talents might be wasted in the field as it stands today though

 

[nitemagi]

Ok show me any data for cyproheptadine in a primary paper citing anything other than theoretical benefit because of its 5ht2 antagonism.

By all means, it sounds like you are just another conformer and if you want to treat a delirious SS patient with strong anti-cholinergics than you are the same as many psychiatrists.

My point is to those open to actually thinking about things, there is a better couple options including risperdal and hydroxyzine as a second line agent that is going to be safe with no downside as far as worsening the delirium.

I wont go through it again but harm reduction approach does not include giving someone a drug that can worsen their problem-cyproheptadine. Believe it or dont-up to you.

Same reason people like you would hesitate to use trazodone or remeron for SS ( I would not at all). Not that it would be a first choice but if there was a scenario you have to think outside the box. Most would just assume "they increase sesrotonin-that is bad" when in reality they block serotonin by ht2a initially and become serotonerigc after days-weeks. So ST use is just one other better option than cyproheptadine.

If you wait for primary papers on new lines of thinkoing on rare situations you will always be a sheep and conformer. If you have some forward thinking with good reasoning and a low harm approach v. benefit, than you will be ahead in whatever field you are in.

Whoa there cowboy. Way to get defensive. Before you start pointing fingers at "people like me," go back and read the post. All I asked was for actual citations studying 5HT-2A antagonism with hydroxyzine. Without that, the evidence seems light.

Funny you're getting all defensive about this and calling me a conformer. Conformer to what exactly? Standard of care? Asking for evidence before changing the standard of care? Trying to have an intelligent discussion about clinical choices rather than be reactionary?

Dial it down and come back to the land of rational discussion.

I never said cyproheptadine was benign. But at least I have solid evidence on its serotonin antagonism. I haven't seen as such for hydroxyzine. While anticholinergic effects is always a problem, it isn't the problem that kills people from SS. I'm on board with non-cyprohep approaches such as remeron or atypicals. Hydroxyzine just seems a reach.

 

[Suedehead]

Wallstreet... It seems like you would make a truly awesome neurologist. I respect your knowledge of all things academic. You would have been an awesome psychiatrist in the 90's as a forerunner Of the biologic movement. I worry that your talents might be wasted in the field as it stands today though

is this code for 'work on your people skills?'

 

[9point75]

Tact? Code? WTD? ;-)

 

[billypilgrim37]

I've seen three SS cases in the ICU. One of them the primary team treated entirely supportively. The other two were quite agitated, so to treat the agitation and for strong 5ht2a antagonism, I used Zyprexa. Things went well in each of these cases.

 

[Ceke2002]

nm....

 

[Ceke2002]

I wish I knew/could remember exactly what I was given as a treatment protocol for the one and only time I had serotonin syndrome (combo high dose Tramadol with Effexor). I mentioned in another post on this that I was pretty out of it by the time I actually got to hospital, at which point I was treated as a priority one emergency as soon as they actually took my vitals, but apart from being given fluids and having a vague recollection of someone saying they were giving me Diazepam, I have no idea what else was pushed through the lines I had in (just that they were pushing other meds as well). I assume because my blood pressure had skyrocketed that one of them had to be some sort of anti-hypertensive. I think it's general practice here as well to give cypropheptadine in severe cases, not sure if I was severe enough to have been given that, or whether they managed to get me stabilised quick enough with other treatments/medications.

From the very limited access to guidelines for medical students doing Psych rotations in Adelaide that I've been able to read at least, treatment protocols seem to be IV fluids, benzos, and external cooling for immediate treatment/stabilisation of vital signs, cypropheptadine to be considered in severe cases, and temperature above 41C indicates patient should be intubated.