Serotonin syndrome: the combinations that cause it, and the Hunter criteria

Serotonin syndrome (serotonin toxicity) is a dose-dependent excess of serotonergic activity, not an idiosyncratic allergy. It is a predictable drug interaction, which is why knowing the combinations matters. The classic triad - Neuromuscular: clonus (especially inducible and ocular), hyperreflexia, tremor, rigidity. - Autonomic: hyperthermia, tachycardia, sweating, dilated pupils. - Mental status: agitation, confusion. The Hunter Serotonin Toxicity Criteria A serotonergic agent plus any one of: spontaneous clonus; inducible clonus with agitation or diaphoresis; ocular clonus with agitation or diaphoresis; tremor plus hyperreflexia; or hypertonia with temperature >38 C and clonus. The Hunter criteria (Dunkley et al., QJM 2003) are more specific than the older Sternbach criteria. The dangerous combinations - MAOI + any serotonin releaser or reuptake inhibitor (SSRIs, SNRIs, MDMA, meperidine/pethidine, dextromethorphan, tramadol). This pairing causes the most severe, sometimes fatal cases. - Two serotonergic agents stacked (e.g. SSRI + tramadol, SSRI + linezolid, which is itself a weak MAOI). - The washout matters: fluoxetine's long half-life means weeks, not days, before starting an MAOI. Onset is usually within hours of the interacting dose — that speed distinguishes it from neuroleptic malignant syndrome, which builds over days. The Libby Zion case thread on Case Reports works a real, fatal example (meperidine + phenelzine). Neurotransmitter mechanism: https://wiki.soapbox.community/wiki/Monoamine_Oxidase_Inhibitors_and_Neurotransmitter_Systems