GPAtlas🧭 When to suspect
Serotonin syndrome (serotonin toxicity) is a potentially life-threatening, drug-induced reaction caused by excess serotonergic activity in the central nervous system. It is defined by a clinical triad of altered mental state, autonomic hyperactivity and neuromuscular excitation, and spans a dose-related spectrum from mild, self-limiting effects through to fatal toxicity. It can follow a single drug at a therapeutic dose, but most cases arise from a combination of serotonergic drugs, a recent dose increase, or an overdose.
Onset is characteristically rapid: features usually appear within 24 hours, and about 60% within 6 hours, of starting, increasing or combining a serotonergic drug. Severe, life-threatening toxicity (rigidity and hyperthermia) almost always requires two or more serotonergic agents, one of which is often a monoamine oxidase inhibitor (MAOI). The key skill in primary care is to think of it in any patient on a serotonergic drug with new neuromuscular signs, to examine for clonus, and to diagnose using the Hunter Serotonin Toxicity Criteria rather than waiting for the full triad.
| Severity | Typical features | Action |
|---|---|---|
| Mild | Tachycardia, shivering, diaphoresis, mydriasis, tremor, mild hyperreflexia; afebrile and haemodynamically stable | Often manageable in the community: stop the agent, supportive care, review – with a low threshold to refer |
| Moderate | Above plus inducible/ocular clonus, agitation, marked hyperreflexia, temperature up to ~40°C, hypertension | Emergency hospital assessment |
| Severe | Spontaneous/sustained clonus, truncal rigidity, hyperthermia > 41°C, autonomic instability, delirium or reduced consciousness | 999 – life-threatening; requires intensive care |
| Drug group | Common UK examples (brands) |
|---|---|
| SSRIs / SNRIs | sertraline (Lustral), fluoxetine (Prozac), citalopram, escitalopram, paroxetine (Seroxat); venlafaxine (Efexor), duloxetine (Cymbalta) |
| MAOIs (incl. "hidden") | phenelzine (Nardil), tranylcypromine, isocarboxazid, moclobemide (Manerix); the antibiotic linezolid (Zyvox) and methylene blue |
| Opioids | tramadol (Zydol), pethidine, fentanyl, methadone; dextromethorphan |
| Other prescribed | triptans e.g. sumatriptan (Imigran); lithium; tricyclics e.g. clomipramine (Anafranil); mirtazapine; ondansetron/metoclopramide (weak) |
| OTC / recreational | St John's wort; MDMA ("ecstasy"), amphetamines, cocaine |
Source: Hunter Criteria · BMJ (Isbister, 2014)
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