Serotonin Syndrome
Definition
- Serotonin Syndrome (SS) is a potentially life-threatening condition caused by excess serotonin activity in the central nervous system due to the use of serotonergic medications.
- Characterised by a triad of autonomic dysfunction, neuromuscular excitation, and altered mental status.
Medical emergency requiring immediate discontinuation of serotonergic drugs and supportive management.
Causes & Risk Factors
Pathophysiology
- Increased Serotonin Levels in the CNS → Overstimulation of 5-HT1A & 5-HT2A Receptors.
- Results in Autonomic Dysfunction, Hyperthermia, Neuromuscular Excitation.
Severe Cases Lead to Multi-Organ Failure, Rhabdomyolysis, and Death.
Common Causes of Serotonin Syndrome
|
Category |
Examples |
|
Selective Serotonin Reuptake Inhibitors (SSRIs) |
Fluoxetine, Sertraline, Citalopram, Escitalopram. |
|
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) |
Venlafaxine, Duloxetine. |
|
Tricyclic Antidepressants (TCAs) |
Amitriptyline, Clomipramine, Imipramine. |
|
Monoamine Oxidase Inhibitors (MAOIs) |
Phenelzine, Tranylcypromine, Linezolid. |
|
Serotonin-Modulating Analgesics |
Tramadol, Fentanyl, Tapentadol, Pethidine. |
|
Migraine Medications (Triptans) |
Sumatriptan, Rizatriptan. |
|
Illicit Drugs |
MDMA (Ecstasy), LSD, Cocaine. |
|
Herbal Supplements |
St John’s Wort, Ginseng. |
🔹 SS occurs when multiple serotonergic drugs are taken together or if a single serotonergic drug is overdosed.
Clinical Features
|
Category |
Common Symptoms |
|
Autonomic Dysfunction |
Hyperthermia, Hypertension, Tachycardia, Sweating. |
|
Neuromuscular Excitation |
Hyperreflexia, Clonus (Spontaneous or Inducible), Myoclonus, Tremor, Rigidity. |
|
Altered Mental Status |
Agitation, Confusion, Anxiety, Hallucinations, Coma. |
Additional Symptoms Based on Severity
|
Severity |
Symptoms |
|
Mild |
Tachycardia, Tremor, Hyperreflexia, Anxiety. |
|
Moderate |
Hypertension, Hyperthermia, Myoclonus, Clonus, Agitation. |
|
Severe (Life-Threatening) |
Seizures, Rhabdomyolysis, Arrhythmias, Multi-Organ Failure. |
🔹 Hyperreflexia & clonus are key distinguishing features of serotonin syndrome.
Referral Criteria (NICE Guidelines)
Urgent Referral (Medical Emergency – Requires Immediate Hospital Admission)
- Severe Hyperthermia (>38.5°C).
- Severe Neuromuscular Excitation (Generalised Clonus, Myoclonus, Rhabdomyolysis).
- Severe Hypertension or Arrhythmias.
- Coma or Seizures.
- Multi-Organ Failure (Renal Failure, Metabolic Acidosis).
Routine Referral (If Symptoms Persist or Affect Functioning)
- Mild Serotonin Toxicity With No Systemic Instability.
- Patients Needing Medication Review to Prevent Recurrence.
🔹 Severe serotonin syndrome is a medical emergency requiring ICU care.
Diagnosis & Investigations
Clinical Diagnosis (Hunter Serotonin Toxicity Criteria – Most Sensitive & Specific)
- Serotonin Syndrome is Diagnosed If:
- Spontaneous Clonus
- Inducible or Ocular Clonus + Agitation or Diaphoresis
- Tremor + Hyperreflexia
- Hypertonia + Hyperthermia (>38.5°C) + Ocular or Inducible Clonus
🔹 Clonus & Hyperreflexia are the hallmark features distinguishing SS from other conditions.
Investigations to Rule Out Other Causes & Assess Severity
|
Investigation |
Purpose |
Findings in Serotonin Syndrome |
|
ABG/VBG |
Assess Metabolic Status |
Lactic Acidosis (Severe Cases). |
|
ECG |
Identify Arrhythmias, Prolonged QT. |
Sinus Tachycardia, Occasionally QT Prolongation. |
|
Creatine Kinase (CK) |
Assess Rhabdomyolysis Risk. |
Elevated If Severe Muscle Rigidity. |
|
Renal Function (U&E, Creatinine) |
Assess AKI From Rhabdomyolysis. |
Elevated Creatinine If Kidney Damage. |
|
LFTs |
Rule Out Hepatic Dysfunction. |
May Be Elevated in Severe Cases. |
Differential Diagnosis
|
Condition |
Key Differences |
|
Neuroleptic Malignant Syndrome (NMS) |
Bradyreflexia, Lead-Pipe Rigidity, Days to Develop. |
|
Malignant Hyperthermia |
Triggered by Anesthetics, No Clonus. |
|
Anticholinergic Toxicity |
Dilated Pupils, Dry Skin, Urinary Retention. |
|
Sepsis & Meningitis |
Fever With Infection Markers, No Clonus. |
🔹 Serotonin syndrome develops rapidly (within hours) and features hyperreflexia and clonus, unlike NMS.
Management (NICE Guidelines)
Immediate Discontinuation of Serotonergic Drugs
- Stop all serotonergic medications immediately.
Monitor for worsening symptoms (may progress rapidly).
Supportive Care (First-Line Treatment)
|
Scenario |
First-Line Treatment |
|
Mild-Moderate Cases |
IV Fluids, Benzodiazepines (Lorazepam, Diazepam). |
|
Severe Hypertension or Tachycardia |
Short-Acting Beta-Blockers (Esmolol) or Nitroprusside. |
|
Severe Hyperthermia (>39°C) |
Aggressive Cooling Measures, Ice Packs, IV Fluids. |
|
Severe Agitation or Neuromuscular Excitation |
Benzodiazepines (Midazolam, Diazepam). |
|
Severe Cases (Rhabdomyolysis, AKI, Seizures, Coma) |
ICU Admission, Sedation, Intubation. |
🔹 Benzodiazepines are the first-line symptomatic treatment for serotonin syndrome.
Serotonin Antagonist Therapy (For Severe Cases)
- Cyproheptadine (5-HT2A Antagonist) – Only Used in Severe Cases.
- Chlorpromazine – Occasionally Used for Severe Hyperthermia.
🔹 Cyproheptadine is rarely needed but may help in severe cases.
Avoid These Medications
- Antipyretics (Paracetamol, NSAIDs) – Ineffective for SS Fever.
Long-Acting Beta-Blockers – Risk of Unopposed Alpha-Stimulation & Hypertension.
Prognosis & Complications
Prognosis
|
Condition |
Outcome |
|
Mild Cases (With Early Treatment) |
Full Recovery Within 24-48h. |
|
Severe Cases (Delayed Treatment) |
High Mortality Due to Multi-Organ Failure. |
Complications of Serotonin Syndrome
|
Complication |
Features |
|
Rhabdomyolysis |
Severe Muscle Rigidity, CK Elevation, AKI. |
|
DIC (Disseminated Intravascular Coagulation) |
Severe Hyperthermia-Related. |
|
Acute Kidney Injury (AKI) |
Secondary to Rhabdomyolysis. |
|
Seizures & Coma |
Severe Neurotoxicity. |
🔹 Early recognition & treatment prevent complications.
UKMLA Key Points
- Best first-line treatment for serotonin syndrome: Benzodiazepines + Supportive Care.
- Best distinguishing feature: Hyperreflexia & Clonus.
- When to refer urgently: Severe hyperthermia, seizures, metabolic acidosis.
- Best long-term prevention: Avoid Serotonergic Polypharmacy.
Neuroleptic Malignant Syndrome
Definition
- Neuroleptic Malignant Syndrome (NMS) is a life-threatening neurological emergency caused by a dopamine blockade due to antipsychotic medications or abrupt dopamine withdrawal.
- Characterised by a classic tetrad: hyperthermia, autonomic dysfunction, altered mental status, and “lead-pipe” rigidity.
Medical emergency requiring immediate discontinuation of antipsychotics, supportive care, and potentially dopamine agonists.
Causes & Risk Factors
Pathophysiology
- Dopamine D2 Receptor Blockade (Due to Antipsychotics or Dopamine Withdrawal) → Impaired Dopaminergic Transmission in the Hypothalamus & Basal Ganglia.
- Leads to Excess Sympathetic Activation → Autonomic Dysfunction & Hyperthermia.
Muscle Rigidity Causes Rhabdomyolysis → Acute Kidney Injury (AKI) & Multi-Organ Failure.
Common Causes of Neuroleptic Malignant Syndrome
|
Category |
Examples |
|
Typical Antipsychotics (High Potency D2 Blockade) |
Haloperidol, Fluphenazine, Chlorpromazine. |
|
Atypical Antipsychotics (Lower Risk But Still Possible) |
Risperidone, Olanzapine, Clozapine, Aripiprazole. |
|
Dopamine-Depleting Agents |
Metoclopramide, Domperidone, Tetrabenazine. |
|
Abrupt Withdrawal of Dopamine Agonists |
Levodopa in Parkinson’s Disease. |
|
Polypharmacy |
Combination of Antipsychotics or Use With Lithium. |
🔹 NMS occurs in <1% of patients on antipsychotics but has a high mortality rate if untreated.
Clinical Features
Classic Tetrad of Neuroleptic Malignant Syndrome
|
Category |
Common Symptoms |
|
Hyperthermia |
Fever >38.5°C, Profuse Sweating. |
|
Autonomic Dysfunction |
Hypertension, Tachycardia, Diaphoresis, Labile Blood Pressure. |
|
Altered Mental Status |
Confusion, Delirium, Agitation, Stupor, Coma. |
|
“Lead-Pipe” Rigidity & Bradyreflexia |
Generalised Muscle Stiffness, No Clonus, Tremors. |
Additional Symptoms Based on Severity
|
Severity |
Symptoms |
|
Mild |
Tachycardia, Tremor, Low-Grade Fever. |
|
Moderate |
Severe Hypertension, Sweating, Mental Confusion, Stiffness. |
|
Severe (Life-Threatening) |
Hyperthermia >40°C, Seizures, AKI From Rhabdomyolysis, Respiratory Failure. |
🔹 NMS develops gradually over 24-72 hours (unlike serotonin syndrome, which develops in hours).
Referral Criteria (NICE Guidelines)
Urgent Referral (Medical Emergency – Requires Immediate Hospital Admission)
- Severe Hyperthermia (>39°C).
- Severe Muscle Rigidity With Rhabdomyolysis (Elevated CK, Myoglobinuria).
- Severe Autonomic Dysfunction (Arrhythmias, Hypotension, Shock).
- Altered Consciousness (Coma, Seizures, Respiratory Failure).
Routine Referral (If Symptoms Persist or Affect Functioning)
- Patients Needing Antipsychotic Review to Prevent Recurrence.
- Mild Cases That Respond to Early Treatment.
🔹 NMS is a medical emergency requiring ICU-level care in severe cases.
Diagnosis & Investigations
Clinical Diagnosis (Based on History & Examination)
|
Criterion |
Description |
|
Recent Antipsychotic Use or Dopamine Withdrawal |
Medication History Is Crucial. |
|
Classic Tetrad (Fever, Rigidity, Autonomic Instability, Confusion) |
Key Features of NMS. |
|
Absence of Hyperreflexia or Clonus |
Unlike Serotonin Syndrome. |
Investigations to Confirm Diagnosis & Assess Severity
|
Investigation |
Purpose |
Findings in NMS |
|
Creatine Kinase (CK) |
Assess Rhabdomyolysis |
Markedly Elevated (>1000 IU/L). |
|
ABG/VBG |
Assess Metabolic Status |
Lactic Acidosis in Severe Cases. |
|
ECG |
Identify Arrhythmias, QT Prolongation. |
Sinus Tachycardia, Possible QT Prolongation. |
|
Renal Function (U&E, Creatinine) |
Assess AKI From Rhabdomyolysis. |
Elevated Creatinine If Kidney Damage. |
|
LFTs |
Rule Out Hepatic Dysfunction. |
May Be Elevated in Severe Cases. |
Differential Diagnosis
|
Condition |
Key Differences |
|
Serotonin Syndrome (SS) |
Hyperreflexia, Clonus, Faster Onset (Within Hours). |
|
Malignant Hyperthermia |
Triggered by Anesthesia, Muscle Rigidity, Genetic Predisposition. |
|
Catatonia |
Waxing & Waning Consciousness, No Hyperthermia. |
|
Sepsis & Meningitis |
Fever With Infection Markers, No Muscle Rigidity. |
🔹 NMS features bradyreflexia and lead-pipe rigidity, unlike serotonin syndrome.
Management (NICE Guidelines)
Immediate Discontinuation of Dopamine Antagonists
- Stop all antipsychotics and dopamine-depleting drugs immediately.
Monitor for worsening symptoms (may progress rapidly).
Supportive Care (First-Line Treatment)
|
Scenario |
First-Line Treatment |
|
Mild-Moderate Cases |
IV Fluids, Cooling Measures, Benzodiazepines (Lorazepam, Diazepam). |
|
Severe Hypertension or Tachycardia |
Short-Acting Beta-Blockers (Esmolol) or Nitroprusside. |
|
Severe Hyperthermia (>39°C) |
Aggressive Cooling, Ice Packs, IV Fluids. |
|
Severe Agitation or Muscle Rigidity |
Benzodiazepines (Midazolam, Diazepam). |
|
Severe Cases (Rhabdomyolysis, AKI, Coma) |
ICU Admission, Sedation, Ventilation If Needed. |
🔹 Benzodiazepines help with agitation and muscle rigidity.
Dopamine Agonist Therapy (For Severe Cases)
- Bromocriptine (Dopamine Agonist) – Used in Severe NMS.
- Dantrolene (Muscle Relaxant) – Used for Severe Hyperthermia.
🔹 Dantrolene is more effective in malignant hyperthermia but may help in NMS.
Avoid These Medications
- Antipyretics (Paracetamol, NSAIDs) – Ineffective for NMS Fever.
Long-Acting Beta-Blockers – Risk of Unopposed Alpha-Stimulation & Hypertension.
Prognosis & Complications
Prognosis
|
Condition |
Outcome |
|
Mild Cases (With Early Treatment) |
Full Recovery in 1-2 Weeks. |
|
Severe Cases (Delayed Treatment) |
High Mortality Due to Multi-Organ Failure. |
Complications of NMS
|
Complication |
Features |
|
Rhabdomyolysis |
Severe Muscle Rigidity, AKI. |
|
DIC (Disseminated Intravascular Coagulation) |
Due to Hyperthermia. |
|
Seizures & Coma |
Severe Neurotoxicity. |
UKMLA Key Points
- Best first-line treatment for NMS: Benzodiazepines + Supportive Care.
- Best distinguishing feature: Lead-pipe rigidity & Bradyreflexia.
- When to refer urgently: Severe hyperthermia, seizures, metabolic acidosis.
- Best long-term prevention: Avoid rapid dose increases of antipsychotics.