Patient handout

Serotonin syndrome — toxidrome from serotonergic exposure (Hunter 2003 PMID 12925718; Boyer NEJM 2005 PMID 15784664); STOP serotonergic + benzo + cyproheptadine + cooling; severe → ICU + intubation + paralysis (rocuronium); AVOID bromocriptine + succinylcholine

PRODUCTION

1. Your condition

This handout is for serotonin syndrome — toxidrome from serotonergic exposure (hunter 2003 pmid 12925718; boyer nejm 2005 pmid 15784664); stop serotonergic + benzo + cyproheptadine + cooling; severe → icu + intubation + paralysis (rocuronium); avoid bromocriptine + succinylcholine. Your care team identified this based on: serotonergic agent (ssri / snri / maoi / linezolid / methylene blue / tramadol / triptan / fentanyl / dxm / mdma / st john's wort / 5-htp / lithium augmentation) initiated, dose-escalated, or added to existing regimen within 24-72 h (boyer nejm 2005 pmid 15784664).

Other reasons your team may use this plan: triad of autonomic instability (tachycardia + diaphoresis + mydriasis + hyperthermia) + neuromuscular hyperactivity (clonus + hyperreflexia + tremor — lower-extremity dominant) + altered mental status (agitation / confusion) (boyer nejm 2005); spontaneous clonus or inducible clonus + agitation / diaphoresis (hunter criteria; dunkley qjm 2003 pmid 12925718); tremor + hyperreflexia in patient on serotonergic agent (hunter criteria; dunkley qjm 2003).

2. Your medications

Take these medications exactly as prescribed. Do not stop or change a dose without talking to your provider.

Medication	Starting dose	How	When	What it does
STOP all serotonergic agents	discontinue immediately	NA	immediate	Boyer NEJM 2005 PMID 15784664 — mandatory first step; resolution within 24-48 h in 70% (Mason Medicine Baltimore 2000); without discontinuation, syndrome persists
lorazepam	1-2 mg IV q 5-10 min PRN (max 8 mg in 1 h)	IV	PRN titrated to sedation + neuromuscular control	Boyer NEJM 2005 first-line — benzodiazepine for sympatholysis + neuromuscular control + sedation; titrate to symptom control + sedation level; lorazepam preferred for predictable hepatic metabolism (no active metabolite)
diazepam	5-10 mg IV q 5-10 min PRN	IV	PRN	Boyer NEJM 2005 — alternative to lorazepam; longer half-life advantageous for sustained neuromuscular control; active metabolite (desmethyldiazepam) prolongs effect
IV crystalloid (NS or LR)	500-1000 mL bolus then maintenance 100-150 mL/h	IV	continuous	Boyer NEJM 2005 — volume + rhabdo prophylaxis; UOP target > 1 mL/kg/h; isotonic crystalloid first-line (NS or LR)
passive + active cooling (cooling blankets, ice packs, evaporative)	NA — supportive	NA	continuous until T < 38.5°C	Boyer NEJM 2005 — temperature control foundational; passive cooling (remove blankets, fans) for T > 38.5°C; aggressive cooling (ice packs, evaporative, surface cooling) + intubation + paralysis (rocuronium) for T > 41°C; mortality correlates with peak temperature

Plan: Serotonin syndrome treatment ladder — STOP serotonergic + benzo + IV fluids + cooling → cyproheptadine for moderate-severe → ICU + intubation + paralysis (rocuronium) for severe; AVOID bromocriptine + succinylcholine + droperidol (Boyer NEJM 2005 PMID 15784664; Gillman Pharmacother 2010 PMID 20429837)

3. Your action plan

Use these zones to know what to do based on how you feel.

GREEN — Doing well — on non-serotonergic alternative regimen OR on SSRI with no symptoms; chart-flag in EHR active (Boyer NEJM 2005)

If you have:

No tremor, clonus, agitation, hyperthermia (Boyer NEJM 2005)
No new serotonergic agent prescribed at any visit (Boyer NEJM 2005)
Chart-flag in EHR active and reviewed at every visit (Boyer NEJM 2005)
Stable mood + sleep + energy on alternative regimen (APA MDD 2023)
Patient + caregiver know SS warning signs (Boyer NEJM 2005)

Do this:

Take antidepressant / analgesic / migraine medication as prescribed (APA MDD 2023)
Verify SS chart-flag at every clinical visit (Boyer NEJM 2005)
Show your current med list to every new provider + pharmacist (Boyer NEJM 2005)
Avoid new OTC cold medications, supplements (St John's wort, 5-HTP) without checking with pharmacist (Boyer NEJM 2005)
Keep crisis line numbers available (988 US) (APA MDD 2023)

YELLOW — Caution — new prescription started OR mild tremor / restlessness / sweating (Boyer NEJM 2005)

If you have:

New SSRI / SNRI / tramadol / triptan / linezolid / DXM prescription (Boyer NEJM 2005)
Mild tremor or jitteriness (Boyer NEJM 2005)
Mild diaphoresis or feeling warm without fever (Boyer NEJM 2005)
Mild restlessness or agitation (Boyer NEJM 2005)
Started new herbal supplement (St John's wort, 5-HTP) (Boyer NEJM 2005)
Used recreational MDMA / cocaine / DXM (Boyer NEJM 2005)

Do this:

Call your prescriber or pharmacist within 24 h to review new medication (Boyer NEJM 2005)
Do not start new herbal supplement without checking (Boyer NEJM 2005)
Stop recreational drug use immediately (Boyer NEJM 2005)
Take your temperature q 4 h while symptoms present (Boyer NEJM 2005)
Use coping strategies + contact support person (APA MDD 2023)

Call your provider if:

New symptom persists > 24 h (Boyer NEJM 2005)
Temperature rises above 38°C (Boyer NEJM 2005)
Tremor worsening or hyperreflexia developing (Boyer NEJM 2005)
Agitation worsening (Boyer NEJM 2005)

RED — Medical alert — frank serotonin syndrome features (Boyer NEJM 2005)

If you have:

Temperature > 38°C with rigid muscles or clonus (Boyer NEJM 2005)
Severe tremor or jerking movements (clonus) (Boyer NEJM 2005)
Severe agitation, confusion, or seeing things (Boyer NEJM 2005)
Rapid heart rate + sweating + high blood pressure (Boyer NEJM 2005)
Diarrhoea + nausea + flushing in setting of serotonergic exposure (Boyer NEJM 2005)
Difficulty staying awake or breathing (Boyer NEJM 2005)

Do this:

Call 911 (US) / your local emergency services NOW (Boyer NEJM 2005)
Go to the nearest emergency department — do not be alone (Boyer NEJM 2005)
Tell the ED you have a history of serotonin syndrome — bring your med list (Boyer NEJM 2005)
Tell someone you trust what is happening immediately (Boyer NEJM 2005)
Do not take more of any medication (Boyer NEJM 2005)
Do not use any substances (Boyer NEJM 2005)

Call your provider if:

Any red zone trigger — emergency department immediately (Boyer NEJM 2005)

4. When to seek emergency care

Call 911 or go to the nearest emergency room right away if you have:

Severe SS with hyperthermia > 41°C + rigidity + rhabdomyolysis + multi-organ involvement OR refractory autonomic instability — life-threatening; ICU + intubation + paralysis (rocuronium, AVOID succinylcholine) + active cooling + benzo infusion + cyproheptadine NG (Boyer NEJM 2005 PMID 15784664)(life-threatening)
Moderate SS — T 38-40°C + clonus + agitation + persistent autonomic features after initial benzo; treatment: discontinue all offending agents + benzo IV + cyproheptadine 12 mg PO load → 2 mg PO q 2 h + monitor (Boyer NEJM 2005 PMID 15784664; Gillman Pharmacother 2010 PMID 20429837)
Hunter Serotonin Toxicity Criteria positive (Dunkley QJM 2003 PMID 12925718; sens 84%, spec 97%) — serotonergic agent exposure + ONE of: spontaneous clonus / inducible clonus + agitation OR diaphoresis / ocular clonus + agitation OR diaphoresis / tremor + hyperreflexia / hypertonia + T > 38°C + ocular OR inducible clonus — diagnostic gate
Patient on multiple serotonergic agents simultaneously — most commonly SSRI + tramadol (Werneke Pharmacopsychiatry 2016 — single most-reported trigger combination); SSRI + linezolid (FDA 2011 boxed warning); SSRI + MAOI (phenelzine / selegiline); SSRI + triptan (FDA 2006 boxed warning); SSRI + methylene blue intraoperative (FDA 2011); SSRI + DXM / MDMA / cocaine / St John's wort / 5-HTP / lithium augmentation
NMS (Neuroleptic Malignant Syndrome) converging differential — antipsychotic exposure within 1-2 weeks + lead-pipe rigidity (NOT clonus) + hyporeflexia + stupor / mutism (NOT agitation) + hyperthermia + autonomic instability + ↑↑ CK (often > 10× normal) + days-weeks onset (Strawn AJP 2007; Caroff + Mann 1993). Treatment DIFFERS critically — bromocriptine 2.5 mg PO/NG TID + dantrolene 1-2.5 mg/kg IV q 6 h for NMS, NOT for SS (bromocriptine is pro-serotonergic and WORSENS SS) — the key NMS-vs-SS pharmacological pivot(life-threatening)
Severe SS requiring intubation + paralysis — use rocuronium (non-depolarising); AVOID succinylcholine (depolarising) due to precipitation of hyperkalaemia from rhabdomyolysis (Boyer NEJM 2005 PMID 15784664)
Active serotonin syndrome — AVOID bromocriptine; the agent is pro-serotonergic (D2 agonist + indirect 5-HT release) and WORSENS serotonin syndrome; reserved for NMS rescue (the key NMS-vs-SS pharmacological pivot per Boyer NEJM 2005 PMID 15784664)
Patient on SSRI / SNRI requiring linezolid (gram-positive antibiotic) — Linezolid is a reversible MAOI per FDA 2011 boxed warning; SS risk; alternative antibiotic preferred (vancomycin, daptomycin, ceftaroline) OR 2-week SSRI washout (5-week for fluoxetine due to norfluoxetine metabolite) before linezolid initiation

5. Follow-up

Comprehensive medication review at discharge + alternative regimens (e.g., switch tramadol to non-serotonergic analgesic — paracetamol / NSAID / non-tramadol opioid; switch SSRI to bupropion if depression amenable to NDRI; switch sumatriptan to gepant — rimegepant / ubrogepant — for migraine; switch linezolid to alternative gram-positive coverage if SSRI required); psychiatry consult if depression / SI driver; pharmacy MTM for SS-prevention education; document SS in EHR allergy/ADR list + chart-flag; pain medicine consult if chronic pain driving tramadol use; if MAOI was on board, mandatory 14-d washout before reintroducing serotonergic agent (5-wk for fluoxetine due to norfluoxetine metabolite); outpatient PCP / psychiatry follow-up at 1 week + 1 month; patient + caregiver education on SS recognition + 24-h ED return precaution (Boyer NEJM 2005; APA MDD 2023)

6. Sources

Guideline: Boyer + Shannon NEJM 2005 PMID 15784664 (canonical review + management algorithm) + Dunkley QJM 2003 PMID 12925718 (Hunter Serotonin Toxicity Criteria — sens 84% spec 97%) + Gillman Pharmacother 2010 PMID 20429837 (cyproheptadine mechanism + evidence base) + FDA 2011 linezolid + methylene blue boxed warnings + FDA 2006 SSRI + triptan boxed warning + APA MDD 2023