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Serotonin Toxicity - Detailed

INTRODUCTION

Serotonin toxicity is often known as serotonin syndrome. It is not, in fact, a true discrete syndrome but represents a spectrum of serotonergic effects, many of which can be seen at therapeutic doses of serotonergic agents while some are only seen with toxicity.(1-3) For many years it was thought that serotonin toxicity was mediated through 5-HT1 receptors.(4) It is now much clearer that the predominant receptors involved in toxicity in man are 5-HT2 and that 5-HT1 receptors are responsible for the therapeutic effects of the serotonergic antidepressants.(5;6) Severe serotonin toxicity may be life-threatening with hyperthermia, increased tone that may lead to respiratory failure, and secondary rhabdomyolysis.(7) These features should be preventable with sedation, good supportive care and judicious use of 5-HT2 blocking agents but occasionally more aggressive intervention with muscle paralysis, supported ventilation and active cooling measures may be required.

HISTORY

Oates first suggested serotonin excess as a problem in 1960.(8) This was in patients who developed symptoms after receiving tryptophan while on therapy with a monoamine oxidase inhibitor. In the 1980’s, animal work suggested that the previously documented interaction between meperidine (pethidine) and the irreversible monoamine oxidase inhibitors was due to excess serotonin. Insel et al are often quoted as describing the serotonin syndrome(9) although the features had clearly been described by Oates and others previously.(10)

PATHOPHYSIOLOGY

Serotonin (5–hydroxytryptamine or 5–HT) is a neurotransmitter, discovered in 1948, and thought to have a major role in multiple states including aggression, pain, sleep, appetite, anxiety, depression, migraine, and emesis. Serotonin in the body is derived from dietary tryptophan, which is converted to 5–hydroxytryptophan by tryptophan hydroxylase and then to 5–HT by a non-specific decarboxylase. 5–HT is then transported into cells by a specific transport system and is degraded mainly by monoamine oxidase both within the cell and after release. Monoamine oxidase A is more significant than monoamine oxidase B in this process. The breakdown products are excreted in the urine as 5–hydroxyindole acetic acid (5–HIAA).

Serotonin predominantly causes excitation of central nervous system neurons, but can also produce inhibition of some subsets. It also stimulates peripheral nociceptive nerve endings and has a variety of vascular effects. Serotonin increases gastrointestinal motility, both directly via an action on smooth muscle and indirectly via enteric neurons. It causes contraction of other smooth muscle as well. Peripherally, serotonin is thought to have a role in peristalsis, vomiting, platelet aggregation and haemostasis. It may also be involved as an inflammatory mediator and in microvascular control. Centrally, serotonin is thought to be involved in the control of appetite and have important roles in sleep and mood maintenance. Serotonin excess has been associated with hallucinations and stereotypical behavior and in normal amounts has a role in central pain perception. There are at least 7 serotonin receptors that have been identified in man and animals, and several of these have subtypes. The most important receptor groups are 5–HT1 and 5–HT2. Both of these receptors are typical G-protein linked receptors with 7 transmembrane domains. 5–HT1 is thought to be important in the anxiolytic and antidepressant actions of serotonin. 5–HT2 is a phospholipase-C dependent receptor which is thought to be related to the hallucinogenic effects of excess serotonin and appears to be the main receptor involved in the neuroexcitatory (and thus toxic) effects of serotonin.

Receptor mechanisms

The best available evidence supports serotonin toxicity as being primarily mediated by the 5-HT2A receptors(6;11-13) and not by 5-HT1A as originally suggested by Sternbach.(4)

Early animal models of serotonin toxicity suggested it was mediated by 5-HT1 receptors. However, many of the features described were not seen in man or were not features that were of clinical concern. In a more recent rat model, when 5-hydroxy-L-tryptophan and clorgyline are given, the animal becomes tremulous with hyperthermia, resembling human serotonin toxicity, and eventually dies from the effects.(11) Studies have demonstrated that this progression is not reversed by dopamine D2 antagonists such as haloperidol(11) or propranolol,(6) a 5-HT1A receptor antagonist. The toxicity is reversed by high doses of nonspecific 5-HT2 receptor antagonists (e.g., cyproheptadine, chlorpromazine) and by the potent 5-HT2A receptor antagonist ritanserin. (6) Risperidone, also a 5-HT2A receptor antagonist,(14) has been shown to reverse the hyperpyrexia and death of these animals with serotonin toxicity.(11)

In man, there is evidence that cyproheptadine and chlorpromazine (5-HT2 antagonists) are effective in the treatment of moderate to severe serotonin toxicity.(5;12;15)

ETIOLOGY

Serotonergic drug interactions

Serotonergic drug interactions, particularly of those that act through different mechanisms (see Table 1), are common causes of serotonin toxicity.(16) Any combination of the drugs in the table may lead to increased serotonergic effects.

Table 1: Serotonergic drug interactions

Drugs Mechanism
L-Tryptophan, S-adenyl-L-methionine, 5-hydroxytryptophan, dopamineSerotonin precursors
SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline), venlafaxine, ChlorpheniramineInhibit serotonin reuptake
TCAs (clomipramine, imipramine)Inhibit serotonin reuptake
TramadolInhibits serotonin reuptake
Fenfluramine, p-chloramphetamine, bromocriptine, dihydroergotamine, gepirone, eltoprazin, quipazineSerotonin agonists
MAO Inhibitors (clorgyline, nialamide, pargyline, phenelzine, tranylcypromine)Inhibit metabolism of serotonin
RIMAs (brofaramine, befloxatone, toloxatone, moclobemide)Inhibit metabolism of serotonin
LithiumUnknown
Opioids (dextromethorphan, pentazocine, pethidine)Inhibit serotonin reuptake
LSDPartial serotonin agonist
CocaineInhibits serotonin reuptake
Ecstasy (MDMA)Increases serotonin release and inhibits reuptake

Overdose

Pure SSRI overdose causes clinically significant serotonin toxicity (sufficient to warrant consideration of specific therapy) in around 16% of cases.(17;18) In an overdose context the combination of an SSRI and a MAOI or RIMA is much more likely to result in serotonin toxicity and produces the most severe toxicity.

CLINICAL PRESENTATION

In 1991, Sternbach collected 38 cases from 10 case reports and 2 case series of drug interactions.(4) Of the 38 cases, the proportion of cases with a particular clinical sign ranged from 42.1% for confusion or hypomania to 13.2% for ataxia or incoordination with the proportion having a fever not recorded. From these cases, Sternbach suggested some diagnostic criteria for the serotonin syndrome.

  1. Coincident with the addition of or increase in a known serotonergic agent to an established medication regimen, at least three of the following clinical features are present
    • mental status changes (confusion, hypomania)
    • agitation
    • myoclonus
    • hyperreflexia
    • diaphoresis
    • shivering
    • tremor
    • incoordination
    • fever
    • serotonin_syndrome_figure2.jpg
  2. Other aetiologies (e.g. infectious, metabolic, substance abuse or withdrawal) must have been excluded.
  3. A neuroleptic had not been started or increased in dosage prior to the onset of the signs and symptoms listed above.


In the context of drug overdose, however, many of these signs may be present without any serotonergic drug being involved. Thus, serotonin toxicity is better characterized(19) as a spectrum of neuroexcitation with a triad of

  1. Neuromuscular hyperactivity
    hyperreflexia, clonus, myoclonus, tremor and rigidity
  2. Autonomic hyperactivity
    hyperpyrexia, tachycardia and diaphoresis; and
  3. Altered mental status
    agitation, anxiety, hypomania and confusion

Initially, the serotonin toxic patient is alert, often hypervigilant, with a fine tremor and marked hyperreflexia (especially in the lower limbs). There is clonus demonstrable at the ankle and there may be myoclonus, which can be generalized. Severe myoclonus may be mistaken for seizure activity, which is rare in serotonin toxicity. As toxicity increases, the autonomic features become more evident with hyperpyrexia, sweating and tachycardia. Rigidity, initially in the lower limbs, is a late sign. Characteristically, the neuromuscular signs are predominantly in the lower limbs but become more generalized as the toxicity becomes more severe. As the rigidity increases in truncal muscles, respiration becomes impaired and this, in conjunction with a rapidly rising temperature heralds life-threatening toxicity.

DIFFERENTIAL DIAGNOSIS

The condition most often confused with serotonin toxicity is neuroleptic malignant syndrome (NMS). While both conditions have autonomic hyperactivity and altered mental status, NMS has neuromuscular hypoactivity and they are, in fact, two very different conditions that have very different etiologies (serotonin excess versus dopamine blockade) and are easily distinguished by simple physical examination. Serotonin excess (serotonin toxicity) has a relatively rapid onset after a serotonergic drug and responds to serotonin blockade with drugs such as cyproheptadine and chlorpromazine. Dopamine blockade (Neuroleptic Malignant Syndrome) has a relatively slow onset after a neuroleptic drug and responds to dopamine agonists such as bromocriptine. Clinical features that distinguish between the two conditions are shown in Table 2.

Table 2: Clinical features of serotonin toxicity and neuroleptic malignant syndrome

Serotonin excess (serotonin toxicity) Dopamine blockade (Neuroleptic Malignant Syndrome)
Onset relatively rapid onset after a serotonergic drugrelatively slow onset after a neuroleptic drug
Therapy responds to serotonin blockade with cyproheptadine, chlorpromazineresponds to dopamine agonists such as bromocriptine
Mental status
Agitation+++
Restlessness++++
Confusion+++++
Hypomania+-
Motor system
Inducible clonus+++-
Spontaneous clonus+++-
Ocular clonus++-
Myoclonus+++-
Tremor+++¤++
Shivering++-
Hyperreflexia+++++
Hypertonia/rigidity++¤++++
Bradykinesia-+++
Other CNS
Akathisia-++
Nystagmus++-
Ataxia/incoordination++
Coma-+
Oculogyric crisis-+
Opisthotonus-+
Seizures--
Autonomic system
Autonomic instability++++
Diaphoresis+++++
Tachycardia+++++
Flushing+++
Mydriasis+++
Diarrhoea+-
Lachrymation--
Other features
Rhabdomyolysis++++
Fever+++++
  • Action¤
  • Extrapyramidal¤¤
  • Pyramidal¤¤¤

REFERENCES

See also Serotonin toxicity: a practical approach to diagnosis and treatment
Download this file pdf isb10375_fm.pdf

1. Whyte I. Serotonin syndrome complicating treatment of recurrent depression. Current Therapeutics 1999;40(10):6-7.
2. Gillman PK. Serotonin syndrome: history and risk. Fundam.Clin.Pharmacol. 1998;12(5):482-91.
3. Isbister GK, Dawson AH, Whyte IM. Serotonin syndrome and 5-HT2A antagonism. Ann.Pharmacother. 2001;35(9):1143-4.
4. Sternbach H. The serotonin syndrome. Am.J.Psychiatry 1991;148(6):705-13.
5. Gillman PK. The serotonin syndrome and its treatment. J.Psychopharmacol. 1999;13(1):100-9.
6. Nisijima K, et al. Potent serotonin (5-HT)(2A) receptor antagonists completely prevent the development of hyperthermia in an animal model of the 5-HT syndrome. Brain Res. 2001;890:23-31.
7. Lane R, Baldwin D. Selective serotonin reuptake inhibitor-induced serotonin syndrome: review. J.Clin.Psychopharmacol. 1997;17(3):208-21.
8. Oates J, Sjoerdsma A. Neurologic effects of tryptophan in patients receiving a monoamine oxidase inhibitor. Neurology (Minneap) 960;10:1076-8.
9. Insel TR, Roy BF, Cohen RM, Murphy DL. Possible development of the serotonin syndrome in man. Am.J.Psychiatry 1982;139(7):954-5.
10. Oates J, Sjoerdsma A. Neurologic effects of tryptophan in patients receiving a monoamine oxidase inhibitor. Neurology (Minneap) 1960;10:1076-8.
11. Nisijima K, Yoshino T, Ishiguro T. Risperidone counteracts lethality in an animal model of the serotonin syndrome. Psychopharmacology (Berl) 2000;150(1):9-14.
12. Graudins A, Stearman A, Chan B. Treatment of the serotonin syndrome with cyproheptadine. J.Emerg.Med. 1998;16(4):615-9.
13. Kapur S, Zipursky RB, Jones C, Wilson AA, DaSilva JD, Houle S. Cyproheptadine: a potent in vivo serotonin antagonist [letter]. Am.J.Psychiatry 1997;154(6):884.
14. Richelson E, Souder T. Binding of antipsychotic drugs to human brain receptors: Focus on newer generation compounds. Life Sci. 2000;68:29-39.
15. Gillman PK. Successful treatment of serotonin syndrome with chlorpromazine. Med.J.Aust. 1996;165(6):345-6.
16. Chan BS, Graudins A, Whyte IM, Dawson AH, Braitberg G, Duggin GG. Serotonin syndrome resulting from drug interactions. Med.J.Aust. 1998;169(10):523-5.
17. Whyte IM, Dawson AH. Relative toxicity of venlafaxine and serotonin specific reuptake inhibitors in overdose. J.Toxicol.Clin.Toxicol. 2001;39(3):255.
18. Whyte, I. M. and Dawson, A. H. Redefining the serotonin syndrome. Journal of Toxicology - Clinical Toxicology 40(5), 668-669. 2002.
19. Isbister GK, Whyte IM. Serotonin toxicity and malignant hyperthermia: role of 5-HT2 receptors. Br.J.Anaesth. 2002;88(4):603-4.


wikitox/serotonin_toxicity_detailed_article.txt · Last modified: 2018/09/01 09:01 (external edit)