Key references:--(1-6)

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.

Whyte and colleagues at the Hunter Area Toxicology Service (HATS) have systematically recorded prospective data in detail concerning all cases of drug overdose and toxicity over a number of years and published various findings in relation to drug toxicity and serotonin toxicity. This systematic approach has produced an improved quality of data, both clinical examination and recording of data, by a team of doctors experienced in drug toxicity. This avoids the selection bias and imprecise documentation from case reports and similar sources which makes case reports of limited scientific value, and worse, frequently misleading. See especially:--

The clear picture of features that are associated with serotonin toxicity specifically, as opposed to features that are shared by other drug intoxications (“toxidromes”) has emerged from analysis of the HATS database.

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.

  1. Neuromuscular hyperactivity; tremor, clonus, myoclonus, hyperreflexia, and (in the advanced stage) pyramidal rigidity
  2. Autonomic hyperactivity; diaphoresis, fever, tachycardia and tachypnoea.
  3. 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).


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