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. This paper reviews the animal and human evidence for the dose effect relationship in detail, especially in relation to the important newly available HATS data from Professor Ian Whyte’s group in Newcastle, Australia. 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 like amphetamine and the street drug MDMA, 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, eg 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, and 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 [1, 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 eg 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).

Tables of data in full version
Table 1 SRI affinity of antidepressants
Table 2 Serotonin toxicity and side effects with various drugs
Table 3 Pharmacological Profile for 5-HT release and 5-HT uptake inhibition
Table 4 Serotonin toxicity signs
Table 5 Serotonergic Drugs
Table 6 5-HT transporter affinity antidepressants
Table 7 5-HT transporter affinity of opioid analgesics
Table 8 Antidepressant drugs 5-HT transporter affinity: comparison
Table 9a 5HT2A antagonism neuroleptics and others
Table 9b 5HT2A antagonism antidepressants and others
Table 10 5-HT2A / 1A antagonists: human Cloned Data
The clinical picture of serotonin toxicity is detailed from the latest data from Professor Ian Whyte’s group in Newcastle, and other sources [2, 3, 7-9]. Whyte’s more reliable data supersedes previous information that was, perforce, based on unsatisfactory case report data. There are some symptoms that are typical of serotonin toxicity, but which may not help in distinguishing it from other toxidromes (eg mydriasis); and there are other symptoms that are characteristic of serotonin toxicity and differentiate it reliably from other toxidromes and conditions (viz. clonus, hyperreflexia).

The duration of an episode of serotonin toxicity is dependant on the type of drugs that precipitate it. Since many have durations of action (elimination half-lives) less than 24 hours, side effects or toxicity will subside steadily over times determined by elimination half-life, without specific treatment, if one or all of the offending drugs are reduced or (more usually) ceased completely.

Thus far, there is no evidence that there can be permanent or long-term neurological effects or damage from an episode of serotonin toxicity (unless there are secondary complications).

General physicians may note that for therapeutic drugs the only cases that have been life-threatening or fatal, as a result of serotonin toxicity, have resulted from combinations of a monoamine oxidase inhibitor (MAOI) and a serotonin reuptake inhibitor (SRI) but not from other combinations of serotonergic drugs (eg monoamine oxidase inhibitors combined with lithium or L-tryptophan or nefazodone or mirtazapine, nor from SSRIs with anything other than MAOIs).

Serotonin toxicity typically exhibits [10] (in approximate order of importance):–

Neuromuscular hyperactivity; tremor, clonus, myoclonus, hyperreflexia (and only late / severe stage rigidity, which may effect truncal muscles causing > PaCo2).
Altered mental status; excitement, agitation and (only late stage / severe) confusion
Autonomic hyperactivity; diaphoresis, fever (pyrexia / hyperpyrexia), mydriasis, tachycardia moderately elevated blood pressure and tachypnoea.
The usual clinical picture is one of rapid onset; the patient is hypervigilant or agitated, with tremor and hyperreflexia. Clonus and myoclonus start in lower limbs and may become generalised. Pyramidal rigidity is a late development (usually it only occurs with MAOI + SRIs) and may impair respiration if it affects truncal muscles. Rigidity and a fever of >38.5C and rising Pa CO2 indicate serious toxicity.

Examples of drug combinations that may produce severe toxicity, and may require life-saving treatment are:–

An irreversible MAOI (in normal dose) plus any serotonin reuptake inhibitor in normal dose. Such as:
Tranylcypromine (or phenelzine) + clomipramine or venlafaxine or any SSRI
Tranylcypromine (or phenelzine) + tramadol or pethidine
Any RIMA (reversible inhibitor of monoamine oxidase-A) like moclobemide in high doses of 600 – 1200 mg+) plus any serotonin reuptake inhibitor in normal dose. Eg moclobemide (or linezolid) + clomipramine or venlafaxine or any SSRI or SRI analgesic like tramadol
Note: the mixture of MDMA, ecstasy (3,4-methylenedioxymethamphetamine) with moclobemide (but not SSRIs) is likely to precipitate potentially fatal serotonin toxicity.

In Whyte’s series of moclobemide + SSRI over-doses 25% (6/21) suffered severe serotonin toxicity which might have been fatal without treatment.

The spectrum concept of serotonin toxicity assists in predicting the severity of toxicity, and therefore management.

Key information is:

The quantity and type of drugs ingested
The symptoms and their rate of change
Individual patient characteristics: weight, age, and disease.
One of the oddest aspects of the history of serotonin toxicity is the repeated uncritical reiteration of the proposition that 5-HT1A receptors are responsible. One of the very earliest reports of serotonin toxicity that established evidence for a dose effect relationship was a neurological investigation by Oates using L-tryptophan. This was the first to postulate the basic mechanism of elevated intra-synaptic serotonin levels as the essential cause of the changes. The notion that 5-HT1A receptors are responsible was first widely promulgated by Sternbach in his seminal 1991 review [11]. However, it is noteworthy that he observed it was a speculation derived from rat work, and he cautioned against extrapolation to humans. This was a wise caution, especially because he was probably unaware of the extensive body of animal research detailed herein that supported the involvement of 5-HT2A receptors much more strongly. Subsequent authors have quoted a this speculation uncritically, as if it were fact. In almost every instant there has been a failure to quote any original animal research to support the argument. Ironically, not only was the argument always weak, but the evidence against its has accumulated and is now so extensive that the evidence supporting the involvement of 5HT2A receptors is difficult to repudiate [12, 13].

It is important for clinicians to understand that there is persuasive evidence that clinically effective 5HT2A antagonists are life-saving in severe serotonin toxicity.

The risk of serotonin toxicity with moclobemide (and linezolid) is evaluated in detail; especially because of ongoing debate about moclobemide + selective serotonin reuptake inhibitors (SSRIs) as a safe and / or effective treatment strategy [14]. When both an MAOI (including RIMAs such as moclobemide) and an SRI have been co-ingested (even in low doses) severe serotonin toxicity exhibiting rapid deterioration is well documented [14].

In cases where MAOIs in any form have been co-ingested with SRIs of any kind, the earliest possible consultation with an experienced toxicologist is strongly recommended. It is these combinations that are most likely to require intensive medical intervention, possibly including intensive care admission, cooling, 5HT2A antagonists, endotracheal intubation and neuromuscular paralysis. Cyproheptadine is effective for the milder cases, but only if activated charcoal has not already been given. For severe toxicity IM or intra-venous chlorpromazine has been used with good effect and may be life-saving. More detailed references are provided in the individual sections [13, 15].

Keywords
Serotonin syndrome, serotonin toxicity, 5-HT toxicity, drug interactions, drug combinations, drug toxicity, fatal, death, risk, morbidity, severity, side effects, agitation, tremor, clonus, myoclonus, trismus, diaphoresis, hyperreflexia, hyperthermia, fever, pyrexia, hyperpyrexia, SSRI, MAOI, RIMA, TCA, tranylcypromine, phenelzine, isoniazid, iproniazid, selegiline, linezolid, moclobemide, toloxatone, venlafaxine, duloxetine, sibutramine, tramadol, pethidine, meperidine.

Suggested significant references, by year of publication
2005 [1, 6, 9, 12, 16, 17]
2004 [2, 3, 7, 14, 18-23]
2003 [4, 10, 24-30]
2002 [31-33]
2001 [34-37]
2000 and earlier [13, 15, 38-43]