SEROTONIN SYNDROME

Background:

- Serotonin is a neurotransmitter released from neurons in raphe nuclei of brainstem

- important roles in arousal, hunger, thermoregulation and emotion / mood

- implicated in depression, anxiety disorders and obesity

- many drugs targeting serotonin receptors in use

- Syndrome likely related to excessive stimulation of serotonergic receptors after overdose or combination of serotonergic drugs

- potentially fatal

Pathophysiology:

- Overstimulation of 5-HT-1A receptors (and possibly 5-HT-2 receptors)

- Related to excess precursors of serotonin (eg. trytophan), its agonists, or higher release, lower recapture / metabolic breakdown

- Often associated with drug combinations or overdosage of drugs

Drugs Implicated:

1) Monoamine oxidase inhibitors (MAOIs) in combination with most of below

2) L-Trytophan

3) Selective serotonin reuptake inhibitors (SSRI's) & nefazodone / trazodone / venlafaxine

4) Tricyclic antidepressants (TCAs) esp. clomipramine

5) Meperedine (demerol)

6) Dextromethorpan (DM)

7) MDMA (Ecstasy), also LSD

8) Lithium

9) St. John's wort (Hypericum perforatum)

Clinical Features:

Trid of mental, autonomic and neurological dysfunction

- 4 major symptoms or 3 major and 2 minor ones

- in conjunction with use of serotonergic agent and exclusion of other conditions

MENTAL:

Confusion, elevated mood, stupor or coma (major)

Agitation / delirium, insomnia, nervousness (minor)

AUTONOMIC:

Fever, hyperhidrosis (major)

Tachycardia, tachypnea & dyspnea, diarrhea, labile or low / high blood pressure (minor)

NEUROLOGIC:

Myoclonus, tremors, chills, rigidity, hyperreflexia (major)

Impaired coordination, mydriasis, akathisia (minor)

Investigations:

- usually elevated CK, leukocyte count and transaminases

- follow closely (every 12 hours) with CK, platelets, urea / creatinine

- EEG

Complications:

- Seizures

- DIC

- Renal failure (rhabdomyolysis, myoglobinuria)

- Metabolic acidosis

- Acute respiratory distress

- Hypotension

- Ventricular dysrhythmias

Differential Diagnosis:

1) Neuroleptic malignant syndrome

- main differentiating factors are mumbling incoherently (vs mute in NMS), agitated and restless (vs immobile in NMS), myoclonus and seizures more often in serotonin syndrome, greater risk of DIC / thrombocytopenia, hypotension greater than hypertension in NMS and greater risk of diarrhea (vs ileus in NMS)

- more sudden onset in serotonin syndrome vs subacute in NMS

- less often fatal and more uncommon than NMS

2) Malignant hyperthermia

3) Infection (esp CNS infection such as meningitis / encephalitis)

4) Drug toxicity (lithium, anticholinergic, MAOI, sympathomimetics)

5) Uremia (or other metabolic encephalopathies incl. hepatic failure)

6) Worsening of underlying psychiatric condition

7) Heat stroke

8) Delirium tremens

Management:

1) ABC's

- check blood pressure, respiration / ventilation

- consider intubation or other support if unstable or comatose

** Discontinue any serotonergic agents **

2) Look for seizures (EEG) and treat appropriately

3) Cooling blankets / antipyretics

4) Hydration & electrolyte replacement (monitor renal function and manage)

5) IV Benzodiazepines

- avoid neuroleptics

6) Other possible (investigational) agents include:

- cyproheptadine (histamine-1 receptor antagonist with anticholinergic and antiserotonergic properties)

- propranolol (blocks 5HT-1A receptors)

- chlorpromazine or new neuroleptics with 5-HT blocking properties (eg. ziprasidone)

Prognosis:

- usually recover completely within 1-2 days of admission with supportive care

- duration may be related to half-life of drug and dosage taken

References:

Birmes P, Coppin D, et al. Serotonin syndrome: a brief review. CMAJ 2003; 168: 1439-42.

Last update: August 31, 2003

Reviewed by: pending review

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