Serotonin Syndrome and Neuroleptic Malignant Syndrome
Summary
Serotonin Syndrome (SS) and Neuroleptic Malignant Syndrome (NMS) are serious, potentially life-threatening drug-induced conditions characterised by Hyperthermia, Altered Mental Status, Autonomic Instability, and Neuromuscular Abnormalities. Although they share some clinical features, they have different aetiologies and distinct presentations. Serotonin Syndrome results from Excess Serotonergic Activity (Usually from serotonergic drug combinations or overdose), presents acutely within hours, and is characterised by Neuromuscular Excitability (Hyperreflexia, Clonus, Tremor, Myoclonus). Neuroleptic Malignant Syndrome is an Idiosyncratic Reaction to Antipsychotics (Dopamine Antagonists) or Dopamine Agonist Withdrawal, develops over days, and is characterised by "Lead-Pipe" Muscular Rigidity and a slower onset. Early recognition and supportive management (Stopping the offending drug, Cooling, Hydration) are critical. Specific treatments include Cyproheptadine (SS) and Dantrolene/Bromocriptine (NMS). Both conditions can cause Rhabdomyolysis, DIC, Multi-Organ Failure, and Death if untreated. [1,2,3]
Clinical Pearls
"Hunter Criteria for Serotonin Syndrome": More sensitive and specific than Sternbach criteria. Requires serotonergic agent + specific neuromuscular findings.
"Clonus = Serotonin Syndrome, Rigidity = NMS": SS has neuromuscular excitability (Hyperreflexia, Clonus). NMS has "Lead-pipe" rigidity.
"SS is Fast (Hours), NMS is Slow (Days)": SS develops within 24 hours (Often less than 6 hours). NMS develops over 1-3 days.
"Stop the Drug": For both conditions, Discontinuing the offending agent is the first and most critical step.
| Feature | Serotonin Syndrome (SS) | Neuroleptic Malignant Syndrome (NMS) |
|---|---|---|
| Cause | Serotonergic drugs (Excess 5-HT) | Dopamine antagonists (Antipsychotics) OR Dopamine agonist withdrawal |
| Incidence | More common | Less common |
| Onset | Rapid: Hours (Usually less than 24h, Often less than 6h) | Slow: Days (1-3 days to 2 weeks) |
| Duration | Resolves quickly (24-72h) after drug stopped | Prolonged (Days to weeks) |
| Mental Status | Agitation, Confusion, Hypervigilance | Encephalopathy, Stupor, Catatonia |
| Neuromuscular | Hyperreflexia, Clonus (Inducible/Spontaneous), Myoclonus, Tremor | "Lead-Pipe" Rigidity (Generalised, Cogwheeling) |
| Autonomic | Tachycardia, Hypertension, Hyperthermia, Diaphoresis, Mydriasis, Diarrhoea | Tachycardia, Labile BP, Hyperthermia, Diaphoresis, Pallor, Sialorrhoea |
| Hyperthermia | Usually less than 40°C (Unless severe) | Often >40°C |
| Reflexes | Hyperreflexia | Normal or Decreased (Due to rigidity) |
| Bowel Sounds | Hyperactive | Normal or Hypoactive |
| Treatment (Specific) | Cyproheptadine | Dantrolene ± Bromocriptine/Amantadine |
Aetiology
| Drug Class | Examples |
|---|---|
| SSRIs | Fluoxetine, Sertraline, Citalopram, Paroxetine |
| SNRIs | Venlafaxine, Duloxetine |
| TCAs | Amitriptyline, Clomipramine |
| MAOIs | Phenelzine, Tranylcypromine, Moclobemide |
| Opioids | Tramadol, Pethidine (Meperidine), Fentanyl |
| Triptans | Sumatriptan (Rare, Low serotonergic activity) |
| Linezolid | Antibiotic with MAOI activity |
| Recreational Drugs | MDMA (Ecstasy), Amphetamines, Cocaine |
| Others | St John's Wort, Dextromethorphan, Lithium |
Common Precipitants: SSRI + MAOI (High risk). SSRI + Tramadol. SSRI dose increase. Overdose.
Pathophysiology
- Excess stimulation of 5-HT1A and 5-HT2A receptors in CNS and PNS.
- Leads to neuromuscular excitability, Autonomic dysfunction, Altered mental status.
Clinical Features (Hunter Criteria – More Specific)
| Criteria |
|---|
| In the presence of a Serotonergic Agent, ONE of the following: |
| 1. Spontaneous Clonus |
| 2. Inducible Clonus AND (Agitation OR Diaphoresis) |
| 3. Ocular Clonus AND (Agitation OR Diaphoresis) |
| 4. Tremor AND Hyperreflexia |
| 5. Hypertonia AND Temperature >38°C AND (Ocular Clonus OR Inducible Clonus) |
Clonus is Key: Spontaneous, Inducible (Ankle), Ocular (Slow, Continuous, Horizontal eye movements).
Management
SEROTONIN SYNDROME SUSPECTED
(Serotonergic drug + Clonus/Hyperreflexia + Autonomic features)
↓
STOP ALL SEROTONERGIC AGENTS
↓
SUPPORTIVE CARE
- ABCDE
- IV Fluids
- Continuous monitoring
↓
SYMPTOM-SPECIFIC TREATMENT
┌──────────────────────────────────────────────────────────┐
│ **AGITATION/SEIZURES** │
│ - Benzodiazepines (Diazepam, Lorazepam, Midazolam) │
│ - Avoid physical restraint (Worsens hyperthermia, │
│ Rhabdomyolysis) │
│ │
│ **HYPERTHERMIA (≥39.5°C)** │
│ - Active Cooling (Ice packs, Cooling blankets, Evaporative)│
│ - Consider intubation + Paralysis (Non-depolarising NMB)│
│ for severe hyperthermia. Abolishes muscle activity. │
│ - **Avoid antipyretics** (Not effective – hyperthermia │
│ is due to muscle activity, Not hypothalamic reset) │
│ │
│ **AUTONOMIC INSTABILITY** │
│ - Treat hypertension: Short-acting agents (Esmolol, │
│ Nitroprusside) │
│ - Treat hypotension: Fluids, Direct-acting vasopressors │
│ (Noradrenaline) │
└──────────────────────────────────────────────────────────┘
↓
SPECIFIC ANTIDOTE
┌──────────────────────────────────────────────────────────┐
│ **CYPROHEPTADINE** (5-HT2A Antagonist) │
│ - Loading: 12mg PO/NG │
│ - Then 2mg every 2 hours until improvement (Max 32mg/day)│
│ - Maintenance: 8mg every 6 hours │
│ - Only available orally/NG │
│ - Sedating │
└──────────────────────────────────────────────────────────┘
↓
MONITOR FOR COMPLICATIONS
- Rhabdomyolysis (CK, Fluids)
- DIC
- Renal failure
- Respiratory failure
Aetiology
| Drug Class | Examples |
|---|---|
| Typical Antipsychotics | Haloperidol, Chlorpromazine, Fluphenazine. Higher risk with high-potency, IM depot. |
| Atypical Antipsychotics | Risperidone, Olanzapine, Clozapine, Quetiapine. Lower risk but still occurs. |
| Antiemetics (D2 Antagonists) | Metoclopramide, Prochlorperazine |
| Dopamine Agonist Withdrawal | Abrupt cessation of Levodopa, Bromocriptine in Parkinson's disease. |
| Others | Lithium, Tetrabenazine |
Risk Factors: High dose, Rapid dose escalation, IM administration, Dehydration, Exhaustion, Agitation.
Pathophysiology
- Dopamine D2 receptor Blockade in:
- Hypothalamus: Impaired thermoregulation.
- Nigrostriatal pathway: Rigidity, Extrapyramidal features.
- Mesocortical pathway: Altered mental status.
- Leads to hyperthermia (From muscle rigidity and hypothalamic dysfunction), Rigidity, AMS.
Clinical Features
| Feature | Notes |
|---|---|
| Hyperthermia | Often >40°C. |
| Muscle Rigidity | "Lead-Pipe" rigidity. Generalised. May have cogwheeling. |
| Altered Mental Status | Confusion, Encephalopathy, Mutism, Stupor, Catatonia. |
| Autonomic Instability | Tachycardia, Labile BP (Hyper or Hypo), Diaphoresis, Tachypnoea, Pallor, Sialorrhoea, Urinary incontinence. |
| Laboratory | Elevated CK (Rhabdomyolysis – Often >1000, Can be >100,000). Leucocytosis. Metabolic acidosis. Elevated LFTs. |
Onset: Typically 1-3 days after starting/Increasing antipsychotic, But can be up to 2 weeks. Can also occur after dopamine agonist withdrawal.
Management
NEUROLEPTIC MALIGNANT SYNDROME SUSPECTED
(Antipsychotic + Rigidity + Hyperthermia + AMS)
↓
STOP ALL ANTIPSYCHOTICS / CAUSATIVE AGENT
(If due to dopamine agonist withdrawal – REINSTATE)
↓
SUPPORTIVE CARE
- ABCDE. High dependency / ICU.
- IV Fluids (Aggressive – Rhabdomyolysis risk)
- Continuous monitoring
↓
SYMPTOM-SPECIFIC TREATMENT
┌──────────────────────────────────────────────────────────┐
│ **HYPERTHERMIA (Critical)** │
│ - Active Cooling (Ice packs, Cooling blankets, Cold IV │
│ fluids) │
│ - Consider intubation + Paralysis (Non-depolarising NMB)│
│ for severe rigidity and hyperthermia │
│ - **Avoid antipyretics** (Ineffective) │
│ │
│ **RHABDOMYOLYSIS** │
│ - Aggressive IV fluids (Maintain urine output) │
│ - Monitor CK, Renal function, Potassium │
│ - RRT if AKI refractory │
│ │
│ **AUTONOMIC INSTABILITY** │
│ - Treat as above (SS) │
└──────────────────────────────────────────────────────────┘
↓
SPECIFIC TREATMENTS
┌──────────────────────────────────────────────────────────┐
│ **DANTROLENE** (Muscle Relaxant – Ryanodine Receptor │
│ Antagonist) │
│ - 1-2.5 mg/kg IV. Repeat every 5-10 mins as needed. │
│ - Max 10 mg/kg/day. │
│ - For severe hyperthermia and rigidity. │
│ │
│ **BROMOCRIPTINE** (Dopamine Agonist) │
│ - 2.5-5 mg PO/NG every 6-8 hours. │
│ - May speed recovery. │
│ - Alternative: Amantadine. │
│ │
│ **BENZODIAZEPINES** │
│ - For agitation. │
│ │
│ **ECT (Electroconvulsive Therapy)** │
│ - Consider for refractory NMS. Safe and effective. │
└──────────────────────────────────────────────────────────┘
↓
MONITOR FOR COMPLICATIONS
- Rhabdomyolysis → AKI
- DIC
- Respiratory failure (Aspiration, Chest wall rigidity)
- VTE (Immobility)
- Death (~10% mortality)
| Complication | Notes (Both SS and NMS) |
|---|---|
| Rhabdomyolysis | From muscle hyperactivity. Elevated CK. Risk of AKI. |
| Acute Kidney Injury (AKI) | From rhabdomyolysis and dehydration. |
| Disseminated Intravascular Coagulation (DIC) | |
| Seizures | More common in SS. |
| Respiratory Failure | Aspiration, Chest wall rigidity (NMS). |
| Cardiac Arrhythmias | |
| Multi-Organ Failure | |
| Death | SS ~less than 5% with treatment. NMS ~5-10% with treatment. |
| Factor | SS | NMS |
|---|---|---|
| Duration | Resolves within 24-72 hours after drug cessation (Longer with long-acting agents like Fluoxetine). | Days to weeks (Mean ~7-10 days). Longer with depot antipsychotics. |
| Mortality | less than 5% with early treatment. | ~5-10% with treatment. Higher historically. |
| Full Recovery | Most patients recover fully. | Most recover fully. Some have persistent neurological sequelae. |
Key Principles
- Early Recognition: Both are clinical diagnoses.
- Stop the Offending Drug: Paramount.
- Supportive Care: ICU for severe cases.
- Specific Treatments: Cyproheptadine (SS), Dantrolene/Bromocriptine (NMS).
What are Serotonin Syndrome and Neuroleptic Malignant Syndrome?
These are rare but serious reactions to certain medications.
Serotonin Syndrome happens when there is too much serotonin (A brain chemical) in your body, Usually from taking certain antidepressants, Painkillers, Or combinations of these medications.
Neuroleptic Malignant Syndrome is a rare reaction to antipsychotic medications (Used for mental health conditions like schizophrenia).
What are the symptoms?
Both can cause:
- High temperature (Fever).
- Fast heartbeat.
- Sweating.
- Confusion or agitation.
- Muscle stiffness or twitching.
What should I do if I think I or someone has this?
This is a medical emergency. Call 999 or go to A&E immediately. Bring a list of all medications if possible.
How is it treated?
- Stopping the medication that caused it.
- Cooling the body.
- Fluids through a drip.
- Sometimes specific medications to reverse the effects.
Primary Sources
- Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112-1120. PMID: 15784664.
- Dunkley EJC, et al. The Hunter Serotonin Toxicity Criteria. QJM. 2003;96(9):635-642. PMID: 12925718.
- Strawn JR, et al. Neuroleptic malignant syndrome. Am J Psychiatry. 2007;164(6):870-876. PMID: 17541044.
Common Exam Questions
- Differentiating Feature: "What clinical finding differentiates SS from NMS?"
- Answer: SS = Clonus/Hyperreflexia (Neuromuscular excitability). NMS = Lead-Pipe Rigidity.
- Onset: "How does the onset of SS differ from NMS?"
- Answer: SS = Rapid (Hours). NMS = Slow (Days).
- SS Antidote: "What is the specific antidote for Serotonin Syndrome?"
- Answer: Cyproheptadine (5-HT2A antagonist).
- NMS Treatment: "What specific treatments are used for NMS?"
- Answer: Dantrolene (Muscle relaxant) ± Bromocriptine/Amantadine (Dopamine agonists).
Viva Points
- Hunter Criteria: Serotonergic agent + Specific findings (Clonus, Hyperreflexia, Tremor, Hypertonia).
- Avoid Antipyretics: Hyperthermia is from muscle/Hypothalamic dysfunction, Not infection.
- Paralysis for Severe Hyperthermia: Non-depolarising NMB. Stops muscle activity.
- Fluoxetine = Long Half-Life: SS may take longer to resolve.
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