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Serotonin toxicity is an iatrogenic (i.e. caused by medical treatment) toxidrome. It is 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. The most frequent (and perhaps the only) combination of therapeutic drugs likely to elevate serotonin to that degree is the combination of monoamine oxidase inhibitors (MAOIs) with serotonin reuptake inhibitors (SRIs). Serotonin releasers such as amphetamine and the street drug MDMA, known as "ecstasy" (3,4-methylenedioxymethamphetamine) can cause fatalities if mixed with MAOIs, usually moclobemide, which is more readily available than the old irreversible MAOIs (tranylcypromine, phenelzine, etc) (5). Note: 1) MAOIs include moclobemide and linezolid. 2) Various drugs, other than the selective serotonin reuptake inhibitors (SSRIs), have clinically significant potency as serotonin reuptake inhibitors, e.g. tramadol and sibutramine. The relative risk and severity of serotonergic side effects and serotonin toxicity with individual drugs and combinations is detailed and discussed. Drugs covered in detail include various MAOIs- selegiline, moclobemide, linezolid, and the tricyclic antidepressants (TCAs), the selective serotonin reuptake inhibitors (SSRIs), and dual action drugs duloxetine, milnacipran, venlafaxine, sibutramine, and the serotonin releasers, amphetamine, MDMA, lithium, L-tryptophan, and opioid analgesics like tramadol, pethidine, and dextromethorphan. The relative risk of serotonin toxicity provides some clues and insights about the nature and extent of drugs’ serotonergic effects. For example, it suggests mirtazapine, which has no serotonergic toxicity, has no significant serotonergic effects at all, and is not in fact a dual action drug (6). The potency of relevant drugs on the serotonergic system is examined and tabulated for reference purposes, especially the serotonin reuptake inhibitor potency of all drugs and the 5-HT 1A and 2A antagonist potency of drugs potentially relevant for treatment, and the serotonin reuptake inhibitor potency of lesser know drugs that can precipitate serotonin toxicity, e.g. opioid analgesics. An evidence-based tabulation is provided for all drugs on which data exists. In particular, Table 5 Serotonergic Drugs, has been carefully screened with substantiating references to document all therapeutic drugs with significant serotonergic effects. Note that many tables have been published in reviews that contain incorrect information (e.g., amitriptyline and mirtazapine are usually incorrectly included as serotonergic drugs). References 1. Gillman, PK, Serotonin toxicity, serotonin syndrome: 2005 update, overview and analysis. www.psychotropical.com/SerotoninToxicity.doc, 2005. 2. Whyte, IM, Serotonin Toxicity (Syndrome). in Medical Toxicology, R.C. Dart, Editor. 2004, Lippincott Williams & Wilkins: Baltimore. p. 103–106. 3. Isbister, GK, et al., Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose. Journal of Toxicology. Clinical Toxicology, 2004. 42(3): p. 277-85. 4. Whyte, IM, Dawson, AH, and Buckley, NA, Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants. Quarterly Journal of Medicine, 2003. 96(5): p. 369-74. 5. Vuori, E, et al., Death following ingestion of MDMA (ecstasy) and moclobemide. Addiction, 2003. 98(3): p. 365-8. 6. Gillman, PK, A systematic review of the serotonergic effects of mirtazapine in humans: implications for its dual action status. Human Psychopharmacology: Clinical and Experimental, 2006. 21: p. 117-25. If you wish to locate scientific papers, search using the terms serotonin syndrome and also serotonin toxicity, a term used by some researchers in the field
Diagnosis Serotonin syndrome is rare, but it is a serious, potentially life-threatening medical condition. However there is no lab test for the condition, so diagnosis is by symptom observation. It may go unrecognized because it is often mistaken for a viral illness, anxiety, neurological disorder or worsening psychiatric condition. Clinicians must differentiate between serotonin syndrome and neuroleptic malignant syndrome, which has similar symptoms. Patients taking serotonergic drugs and who have sudden onset of the below symptoms should immediately seek medical care. Serotonin toxicity is a toxidrome (i.e. a characteristic picture) caused by poisoning with serotonergic drugs. It is unique and hard to confuse with other medical conditions. Much confusion has been produced by muddling it with side effects from serotonergic drugs. These rarely, if ever, become dangerous or fatal. Dangerous toxicity is usually only ever caused by mixtures of drugs with different modes of action, most commonly monoamine oxidase inhibitors combined with serotonin reuptake inhibitors. A first step in understanding this complex topic is to appreciate the spectrum concept of serotonin toxicity (see www.psychotropical.com Serotonin toxicity: 3 Spectrum concept). reference 1. Gillman, PK, A Review of Serotonin Toxicity Data: Implications for the Mechanisms of Antidepressant Drug Action. Biological Psychiatry, 2006. 59: p. 1046-51. Signs and symptoms Symptoms may be classed into three groups: Insomnia, sleep disruption, and unrefreshing sleep are also reported symptoms, as well as itching and hives. Drugs which may contribute The combination of MAOIs and other serotonin agonists or precursors poses a particularly severe risk of a life-threatening serotonin syndrome episode. Many MAOIs inhibit monoamine oxidase irreversibly, so that the enzyme cannot function until it has been replaced by the body, which can take at least two weeks. A dangerous serotonin syndrome reaction can occur unless serotonin agonists and even serotonin precursors such as foods containing tryptophan are strictly avoided until the monoamine oxidase has been replaced. This table would benefit from being updated, and made more relevant to primary verifiable references, but I cannot see who produced the original table. However, I would comment that almost all the references are secondary or tertiary, rather than primary, this is not ideal for a verifiable account. Perhaps if they would like to contact me I could assist with sources that would increase its direct science base and topicality. Treatment There is no antidote to the condition itself, but emergency medical clinicians can administer cyproheptadine or methysergide to control the symptoms. Doing so is important as the symptoms can in severe cases be potentially life threatening. If the symptoms are not severe or life threatening, optimal treatment consists of discontinuation of the offending medication or medications, offering supportive measures, and waiting for the symptoms to resolve. If the offending medication is discontinued, the condition will often resolve on its own within 24 hours. Neuroleptic malignant syndrome and serotonergic syndrome The clinical features of neuroleptic malignant syndrome (NMS) and serotonergic syndrome are very similar. This can make differentiating them very difficult.• Features, classically present in NMS, that are useful for differentiating the two syndromes are•: | |||||||||||||||||||||||||||
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