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UnfoldingSky

Serotonin Syndrome or Serotonin Toxicity

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UnfoldingSky

ADMIN NOTE From https://psychotropical.info/serotonin-toxicity-summary/

 

"Serotonin toxicity is an iatrogenic (i.e. caused by medical treatment) toxidrome. It is still commonly referred to as serotonin syndrome. However, that is less satisfactory terminology, because it is a form of poisoning. The term toxidrome (from toxic + syndrome) is more appropriate and accurate [1].

 

Changes characteristic of increased serotonin in the central nervous system result from the archetypal serotonergic drugs, the specific, or selective, serotonin reuptake inhibitors (SSRIs). These changes are more pronounced following supra-therapeutic doses and overdoses, and they merge in a continuum with toxic effects [2-4].

 

The recently postulated spectrum concept of serotonin toxicity emphasises the role that progressively increasing serotonin levels play in mediating the clinical picture as side effects merge into toxicity. ....The dose effect relationship is the term used to describe the effects of progressive elevation of serotonin, either by raising the dose of one drug, or combining it with another serotonergic drug (which may produce an larger elevations of serotonin).

 

The serotonergic toxicity of SSRIs increases with dose, but even in over-dose is insufficient to cause fatalities in healthy adults [3]. It is usually only when drugs with different mechanisms of action are mixed together that elevations of central nervous system serotonin reach potentially fatal levels.

....

https://psychotropical.info/the-clinical-picture/

 

The reaction represents a spectrum from increasing side effects (typically– nausea, vomiting, nervousness, insomnia, headache, tremor, diarrhoea, dizziness, sweating, retarded orgasm) progressing progressing with more potent mixtures through to toxicity and, with MAOI + SRIs, to death from hyperthermia.

 

The onset of severe toxicity is usually rapid, because it results only from drug combinations, it is seen when the second serotonergic drug is introduced. The symptoms are frequently alarming and usually occur within hours of one of the first few doses of the second drug.

 

The serotonin toxic patient is usually initially alert and / or agitated, with a fine tremor and marked hyperreflexia, especially in the lower limbs. Ankle clonus and myoclonus may be present, starting in lower limbs and then becoming generalised.

 

Neuromuscular signs are typically greater in the lower limbs. Severe myoclonus may be mistaken for seizure activity. Then autonomic features become evident (fever, sweating and tachycardia). Confusion may be difficult to assess in the presence of agitation and over-excitement, but is not severe until the severe / late stage, when marked rigidity and hyperpyrexia may be present (usually only MAOI/SRI combinations).

 

Pyramidal rigidity is a late development and, when it affects truncal muscles, that may impair respiration and raise blood carbon dioxide levels.

 

Rigidity and a fever of >38.5C heralds toxicity of life-threatening degree.

 

In early cases the motor symptoms of tremor, hyperreflexia and clonus are frequently predominant. The clinical picture is determined by the potency of the combination and the stage at which the patient is observed.

....

The features of serotonergic drug overdose (ie serotonin toxicity) vs. other drugs are:–
Myoclonus / clonus
Hyperreflexia
Alertness / overactivity / agitation
Fever
Hypertonia / pyramidal rigidity
NB Pyramidal rigidity is clasp-knife progressing to fixed rigidity. Extrapyramidal rigidity in NMS is lead-pipe or cogwheel type.

 

Serotonin toxicity may be characterised as a triad of neuro-excitatory features.

 

Neuromuscular hyperactivity; tremor, clonus, myoclonus, hyperreflexia, and (in the advanced stage) pyramidal rigidity
Autonomic hyperactivity; diaphoresis, fever, tachycardia and tachypnoea.
Altered mental status; agitation, excitement and (in the advanced stage) confusion (5-20).
Agitation, suicide and serotonin toxicity


Agitation is a defining mental state characteristic of serotonin toxicity. That fact has implications for the debate concerning the increase in the risk of suicidal ideation and actions with selective serotonin reuptake inhibitors (SSRIs). Clinical experience of SSRIs over many years indicates that some symptoms of serotonin toxicity do occur at usual doses in a few patients e.g. myoclonus, sweating. Occasionally they are so pronounced that even the most determined patient is forced to cease the drug. Nocturnal myoclonus can be so severe that spouses present with multiple bruises. If the neuro-physiological substrate of “agitation” has anything to do with changes that increase the likelihood of suicidal behaviours that may help to explain this phenomenon (21-28)...."

 


 

How in the world I missed this site I will never know...Has anyone ever heard of Dr. Ken Gillman? Apparently he's one of, or maybe the, expert on serotonin toxicity. Here's his site, with contact info:

 

http://www.psychotropical.com/

 

In a number of places he criticizes Big Pharma...a must read!

Edited by Altostrata
added quotes from site

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UnfoldingSky

I just posted elswhere about a Dr. Ken Gillman, whom is an expert on serotonin toxicity living in Australia. He makes the following point about the difference between the meaning of the terms serotonin syndrome and serotonin toxicity:

 

One of the main reasons for using the term serotonin toxicity rather than serotonin syndrome is because this emphasizes that it is a form of poisoning, not an idiosyncratic syndrome: i.e. a syndrome usually implies something that occurs in some people, but not in others. Neuroleptic malignant syndrome is idiosyncratic and rarely occurs after over-dose of neuroleptics: rather it occurs in a very small proportion of patients who are taking average, or above average, therapeutic doses (4, 26). NMS is quite different to ST (26-29).

 

(from: http://www.psychotropical.com/index.php/serotonin-toxicity )

 

So technically the idea of serotonin syndrome isn't correct. Could we start phasing out the idea of serotonin syndrome here then? Dr. Gillman has written elsewhere on the site that his efforts to educate doctors via journals hasn't amounted to much as the journals wind up being overwhelmed by the mass of disinformation put out by Big Pharma. So he's taken to the net to try to reach people instead. If you have a doctor whom is remotely open-minded please consider mentioning his work to them...We need people to understand that too much of any serotonin agent is a bad thing no matter whom is taken them.

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Aria

I did read a good bit but the large print made it hard. I loved how he said Big Pharma twisted wordings to sound like something was different and there fore better when it really wasn't.

His quoting of "Alice in Wonderland" in relation to Big Pharma was right on.

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compsports

How in the world I missed this site I will never know...Has anyone ever heard of Dr. Ken Gillman? Apparently he's one of, or maybe the, expert on serotonin toxicity. Here's his site, with contact info:

 

http://www.psychotropical.com/

 

In a number of places he criticizes Big Pharma...a must read!

 

Thanks, I just bookmarked it for later reading. That looks like a fantastic site.

 

CS

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Barbarannamated

UnfoldingSky,

 

Excellent article, long overdue. It is difficult to find info on long term effects and damage of serotonin toxicity. I suspect that a less severe form is far more prevalent than literature reports (as either "syndrome" or "toxicity").

 

I didnt realize that myoclonus was related to serotonin. Very interesting.

 

Also, the triptan drugs for migraine are serotonergic and implicated in SS/ST. I may have missed that in the article.

 

Thanks for posting.

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dalsaan

Dr Gillman has interesting things to say about Mirtazapine. He argues that it has no effect on seratonin/noradrenalin and that the data supporting its use as a AD is false. He basically said there is no

data supporting seratonin toxicity for Mirtazapine in high doses and therefore the proposed mechanism of action is B***hit. On this basis, any beneficial outcomes are probably the result of the antihistamine effects on sleep - more sleep, feel better than you did before.

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Altostrata

Interesting.

 

I agree, serotonin toxicity is probably a more appropriate name.

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Altostrata

Excellent find, Unfolding. I've sent e-mail to Dr. Gillman. I also know of another researcher who might want to collaborate with him.

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dalsaan

Excellent find, Unfolding. I've sent e-mail to Dr. Gillman. I also know of another researcher who might want to collaborate with him.

 

 

Hi Alto,

 

Did you contact him by submitting a form on the website? I tried to contact him a couple of months ago, submitted info/questions etc and have had no

response.

 

I will be interested to see if he answers you

 

Dalsaan

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Altostrata

The form was broken. He put his e-mail up instead. Try again.

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UnfoldingSky

I suspect that a less severe form is far more prevalent than literature reports (as either "syndrome" or "toxicity").

 

 

 

I agree 100% Barb. I know someone whom had classic serotonin toxicity symptoms immediately after starting an AD, and they had them for (if you can believe this) sixteen years while on various ADs. Temp dysregulation and severe confusion, to the point they didn't know their own name or where they were. I probably wouldn't have believed it had I not known how ruthlessly honest the person was, and how educated. It's amazing what people can survive!

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UnfoldingSky

 

 

I didnt realize that myoclonus was related to serotonin. Very interesting.

 

 

 

I just went back and read some of the article that I must have spaced out for on the first read. Did I just understand that clonus is the sign of serotonin toxicity? Did anyone else pick that up? I'm foggy at the moment.

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Barbarannamated

*Myoclonic phenomena usually considered diagnostic of ST (apologize if I misused 'clonus') - Introduction, Paragraph 3.

 

"Another example is the quite marked muscular jerks that happen during sleep, they probably represent myoclonic phenomena which are usually considered as diagnostic of ST. (*the term side effects in this context is something of a misnomer because the effects being referred to are an inevitable consequence of the drugs main intended mechanism of action, i.e. reuptake inhibition of serotonin, resulting in increased serotonin levels. These inevitably cause, for instance, tremor, diarrhoea, retarded orgasm etc."

 

COMMENT: I *thought* that the movement disorder reactions (bruxism, myoclonus, possibly akathisia) were related to serotonin disruption of dopamine, but those 2 theories are not mutually exclusive.

 

Please correct if I'm interpreting this incorrectly! Also fogged in in California. :o

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Skyler

 

COMMENT: I *thought* that the movement disorder reactions (bruxism, myoclonus, possibly akathisia) were related to serotonin disruption of dopamine, but those 2 theories are not mutually exclusive.

 

Please correct if I'm interpreting this incorrectly! Also fogged in in California. :o

 

Barb, I don't think you are wrong. I had severe myoclonus (called Hypnic Jerks at the time) as I was going into stage one sleep from being on Elavil for a few months. This led into an episode wherein I almost had a Grand Mal seizure (I've spoken of this before). The treating doc said the symptoms I reported showed I was resistant to treatment, did not want to get better. My own rheumatologist, (who said nowww you have met the venerable doctor so and so) who had some sense and a neurologist I saw later said I could have known of the symptoms I reported. Grand Mal seizures are bad enough, but had I had one with fibro it would have led to very significant repercussions. ~S

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Barbarannamated

Barb, I don't think you are wrong. I had severe myoclonus (called Hypnic Jerks at the time) as I was going into stage one sleep from being on Elavil for a few months. This led into an episode wherein I almost had a Grand Mal seizure (I've spoken of this before). The treating doc said the symptoms I reported showed I was resistant to treatment, did not want to get better. My own rheumatologist, (who said nowww you have met the venerable doctor so and so) who had some sense and a neurologist I saw later said I could have known of the symptoms I reported. Grand Mal seizures are bad enough, but had I had one with fibro it would have led to very significant repercussions. ~S

 

"Resistant to treatment" as in PSYCHOLOGICALLY not choosing to get better??? I had to read that a few times. Amazing.

 

I dont understand what the neurologist said/meant by "you could have known..."?

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Skyler

 

"Resistant to treatment" as in PSYCHOLOGICALLY not choosing to get better??? I had to read that a few times. Amazing.

 

I dont understand what the neurologist said/meant by "you could have known..."?

 

Yup, I psychologically did not want to get better so refused to take an AD that was supposed to help with fibro.. which of course has been discredited as well. And in the process, I came up with contrived symptoms, one being a Grand Mal that came within a hair of firing off on my way to his office. The seizure was fired up by a strobe light effect of sun flashing through the trees.. thankfully my mother was driving the car. Now mind you, I made all this up!

 

Sorry.. poor edit. 'you could NOT have known' Oh for want of two letters! ~S

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Barbarannamated

The ANGER for what you (and everyone) have been told to get these harmful drugs used is intense! The ultimate kicker is knowing that THEY DON'T WORK AT ALL for some people and we then get *advanced* to cocktails for treatment-resistant patients.

 

Can you hear me SCREAMING?!?!

 

I suspect that a GOOD physician/scientist (Ill choose Dr. Giovanna Fava :) ) could look at original presentation (anergia or anxiety, for example), labwork trail, history of drugs used, significant reactions (myoclonus, bruxism), and know what the underlying physiological problem was, if any.

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Skyler

 

Can you hear me SCREAMING?!?!

 

To have a report of what was nearly a full Gand Mal summarily dismissed was shocking. At least my own rheum doc immediately took me off (the doc in question was the supposed SUPER specialist.. the expert). It really was very very scary. There was a fire storm in my head, lights loudly flashing. I instinctively ducked under the dashboard in a vain effort to block out all the light, but of course at that point it was generated in my brain. I sure found out what an aura was. My mother was dumbfounded having witnessed the episode and my terror from the driver's seat. My father is an epileptic, so we knew what almost happened.

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UnfoldingSky

 

 

COMMENT: I *thought* that the movement disorder reactions (bruxism, myoclonus, possibly akathisia) were related to serotonin disruption of dopamine, but those 2 theories are not mutually exclusive.

 

Please correct if I'm interpreting this incorrectly! Also fogged in in California. :o

 

For what it's worth it sounds correct to me, but then the fog hasn't lifted here.

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UnfoldingSky

 

Barb, I don't think you are wrong. I had severe myoclonus (called Hypnic Jerks at the time) as I was going into stage one sleep from being on Elavil for a few months. This led into an episode wherein I almost had a Grand Mal seizure (I've spoken of this before). The treating doc said the symptoms I reported showed I was resistant to treatment, did not want to get better.

 

Wow. I had a doctor insist for a month that akathisia was "agitated depression", even when I told her that it was akathisia. I thought that was bad enough...Unbelievable.

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Skyler

 

 

Barb, I don't think you are wrong. I had severe myoclonus (called Hypnic Jerks at the time) as I was going into stage one sleep from being on Elavil for a few months. This led into an episode wherein I almost had a Grand Mal seizure (I've spoken of this before). The treating doc said the symptoms I reported showed I was resistant to treatment, did not want to get better.

 

Wow. I had a doctor insist for a month that akathisia was "agitated depression", even when I told her that it was akathisia. I thought that was bad enough...Unbelievable.

 

Yeah.. He was so taken with the 'expertise' he was known to have, he did not even concern himself with malpractice. I don't know why I said he was the treating doc however, he was the doc I went to see because he supposedly knew more than my regular rheum. Rhighttt. At least I did not need to go back, but his notes of course followed, so anyone wanting know what he thought only had to ask for his records.. sigh. I did not feel truly exonerated until I saw the Tufts Medical School (Boston, MA) neuro 'top gun' who said the only way I would have known about the symptoms would have been to experience them. He also said I could never again take ADs with the exception of Wellbutrin because I had a very bad reaction to drugs that messed with seratonin. Humm, I wonder if this was part of the seratonin toxicity spectrum that was discussed in another thread. ~S

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Barbarannamated

Oh Schuyler! PLEASE tell more about the "never taking serotonin drugs again". I've considered listing that as an "allergy" or even get a med alert bracelet for that exact reason. Wellbutrin effects norepinephrine and dopamine, not serotonin. Serotonin depletes dopamine and that's what screwed me up. (VERY SIMPLIFIED version from endocrinologist)

This is why I feel the whole "serotonin = "feel good neurotransmitter/depletion = depression" is DANGEROUS.

 

Anything you can expand on from that neuro would be most appreciated.

 

FYI - A Mix of Medicines That Can Be Lethal (article)

http://survivingantidepressants.org/index.php?/topic/2621-a-mix-of-medicines-that-can-be-lethal/#entry26582

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Skyler

Oh Schuyler! PLEASE tell more about the "never taking serotonin drugs again". I've considered listing that as an "allergy" or even get a med alert bracelet for that exact reason. Wellbutrin effects norepinephrine and dopamine, not serotonin. Serotonin depletes dopamine and that's what screwed me up. (VERY SIMPLIFIED version from endocrinologist)

This is why I feel the whole "serotonin = "feel good neurotransmitter/depletion = depression" is DANGEROUS.

 

Anything you can expand on from that neuro would be most appreciated.

 

FYI - A Mix of Medicines That Can Be Lethal (article)

http://survivingantidepressants.org/index.php?/topic/2621-a-mix-of-medicines-that-can-be-lethal/#entry26582

 

Afraid the good doc retired a few years back, early onset Parkinson's. I have not taken an AD since that happened.

 

I checked out the article on Serotonin and I did not have the symptoms, though obviously there is a sensitivity. In hindsight I'm very glad not to have had

 

I am going to get a medic alert bracelet and will put that I'm allergic to benzos on it. I'm just waiting until I'm completely off (duh!.. (should not be long now)). I am also allergic to aspirin so will be putting that on the bracelet.

 

Thanks for letting me know why that one is okay, the others not.

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Barbarannamated

I wonder if his Parkinsons was the result of serotonin drugs?? The motor/movement symptoms are what I find interesting and not "classic" SS/ST. The disruption of the dopamine system by too much (or even a little) serotonin.

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Nikki

Can anyone please elaborate on it.....I have just been reading about it.  Just read that Imipramine and Nefazadone together can cause this.  I am not feeling well.  Wondering if...

 

Tapering I suppose is the antidote.

 

Thanks

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Altostrata

You have been risking serotonin syndrome all along with your combinations of antidepressants, Nikki.
 
You may wish to add any other drugs you are taking to the Drug Interactions checker below.
 
http://www.drugs.com/interactions-check.php?drug_list=1323-0,1698-0&professional=1
 

Interactions between your selected drugs

 MAJOR imipramine ↔ nefazodone

Applies to: imipramine, nefazodone
MONITOR CLOSELY: Concomitant use of agents with serotonergic activity such as serotonin reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, 5-HT1 receptor agonists, ergot alkaloids, cyclobenzaprine, lithium, St. John's wort, phenylpiperidine opioids, dextromethorphan, and tryptophan may potentiate the risk of serotonin syndrome, which is a rare but serious and potentially fatal condition thought to result from hyperstimulation of brainstem 5-HT1A and 2A receptors. Symptoms of the serotonin syndrome may include mental status changes such as irritability, altered consciousness, confusion, hallucination, and coma; autonomic dysfunction such as tachycardia, hyperthermia, diaphoresis, shivering, blood pressure lability, and mydriasis; neuromuscular abnormalities such as hyperreflexia, myoclonus, tremor, rigidity, and ataxia; and gastrointestinal symptoms such as abdominal cramping, nausea, vomiting, and diarrhea.

MANAGEMENT: In general, the concomitant use of multiple serotonergic agents should be avoided if possible, or otherwise approached with caution if potential benefit is deemed to outweigh the risk. Patients should be closely monitored for symptoms of the serotonin syndrome during treatment. Particular caution is advised when increasing the dosages of these agents. The potential risk for serotonin syndrome should be considered even when administering serotonergic agents sequentially, as some agents may demonstrate a prolonged elimination half-life. For example, a 5-week washout period may be advisable following use of fluoxetine and 3 weeks following the use of vortioxetine before administering another serotonergic agent. If serotonin syndrome develops or is suspected during the course of therapy, all serotonergic agents should be discontinued immediately and supportive care rendered as necessary. Moderately ill patients may also benefit from the administration of a serotonin antagonist (e.g., cyproheptadine, chlorpromazine). Severe cases should be managed under consultation with a toxicologist and may require sedation, neuromuscular paralysis, intubation, and mechanical ventilation in addition to the other measures.

Please note there are degrees of excessive serotonergic stimulation, leading to serotonin syndrome. In these situations, rapid reduction in dosage is justified.

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Nikki

Alto I am not sure what is happening to me.  There was too much medicine in the mix.  The plan was to get off of Celexa and Imipramine and be on 1drug.  I am off Celexa, and now on 40mgs. Imipramine and 50mgs. Nefazadone.

 

And don't know what to do....does Imipramine come in liquid?

 

If I start tapering Imipramine will I feel better or have WD?

 

I tried to do something for myself to help alleviate anxiety and now I am in the thick of it.

 

I don't know if what I experienced this week was the syndrome - or WD - or just plain insanity!

 

I know I need help.

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Altostrata

If I were you, I would not take nefazadone.

It's one of the rare cases where the FDA was actually moved to withdraw a drug from the market http://livertox.nih.gov/Nefazodone.htm
 

....Nefazodone was approved for use in moderate and severe depression in the United States in 1988, but was subsequently linked to many cases of acute liver injury, some of which were fatal, and is no longer in common use. Nefazodone is available in tablets of 50, 100, 150, 200 and 250 mg in several generic forms and formerly under the brand name of Serzone. The recommended dosage for depression in adults is 200 mg daily that can be increased in 100 mg amounts to a maximum of 600 mg daily. Common side effects of nefazodone are drowsiness, dizziness, headache, dry mouth, blurred vision, nausea, constipation or diarrhea, decreased libido, abnormal dreams, increased appetite and weight gain.

Hepatotoxicity

Liver test abnormalities occur in a proportion of patients on nefazodone, but elevations are usually modest and usually do not require dose modification or discontinuation. Soon after its general availability, nefazodone was linked to several instances of acute, clinically apparent liver injury, some of which were fatal. The onset of injury varied from 6 weeks to 8 months and the pattern of serum enzyme elevations was typically hepatocellular. Autoimmune (autoantibodies) and immunoallergic features (rash, fever, eosinophilia) were uncommon. Liver biopsy usually demonstrated an acute hepatitis with cholestasis and variable degrees of centrolobular (zone 3) necrosis. Systematic reviews suggested that the incidence of hepatic failure due to nefazodone is 1 per 250,000 to 300,000 patient-years of exposure. Because of this complication, nefazodone was withdrawn from use in many countries.

 
I question your doctor's judgment in prescribing drugs for you in combination, and in acceding to your request for nefazodone.

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Hurtingmommy

Has anyone had Serotonin Syndrome with one SSRI and been okay with another?

 

Has anyone had Serotonin Syndrome and started taking their medication again and been okay?

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UnfoldingSky

I can't answer the first question, but, I have restarted a drug that I was reacting to (I likely had a mild case of serotonin toxicity).  It got much worse after I did that.

 

Why do you ask? 

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Altostrata

I had serotonin toxicity from a too-high dose of Lexapro. I did go back to Paxil after that, but I believe the bad reaction to Lexapro added to nervous system vulnerability.

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WiggleIt

Can someone please tell me the difference between serotonin syndrome (a.k.a. serotonin toxicity) versus withdrawal?  I don't know if I had or have serotonin syndrome, especially since so many of the symptoms of it overlap with the symptoms of withdrawal.

 

Who is smart enough to diagnose serotonin syndrome?  Is it reversible?  

 

Darn it, I made a typo in the subject line!!!  How can I fix that?

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UnfoldingSky

Hi WI,

 

Serotonin syndrome, or serotonin toxicity to my understanding is caused by serotonergic agents (certain drugs) while the person is taking them.  It's a particular kind of reaction, sometimes life-threatening, to these substances. Basically a form of poisoning.  So from what I understand you'd only have this if you were on a relevant drug, or combination of the substances that cause it.  It seems conceivable though that a person might have lingering problems from having had it; however I don't know what medical authorities would say about that (given they don't know much about protracted withdrawal, if they say this can't happen they could be wrong.) 

 

One of the experts about ST is Dr. Ken Gillman.  His website is:

 

http://www.psychotropical.com/index.php/serotonin-toxicity

 

And as to your typo, I have no idea. I didn't even notice it until you mentioned it. :)

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UnfoldingSky

Actually I haven't read his site in a while, he may say that the reactions are always life-threatening.  I don't know. I've read a little about this and it seems to be hard to get a consistent definition. 

 

Also just glancing over his definition, he doesn't mention that sometimes it's said that certain plants cause it, or more specifically, combining the relevant drugs with certain plants.  I'd love to know his take on that.
 

Not that you asked about this though. :)

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UnfoldingSky

Also, even if it does cause lingering health problems, (and I am still not sure if they believe it does) that is not to say they may not heal. 

 

And I am not sure the drugs you took could even cause it, it may be that they don't.  Have a look around his site.  Or try contacting him, I haven't looked at his contact page lately but I know he used to welcome questions. 

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