SEROTONIN SYNDROME DEFINITION The clinical syndrome resulting from excessive stimulation of central and peripheral serotonergic receptors. It is characterized by changes in mental status, and motor and autonomic function. TOXIC CAUSES The serotonin syndrome is most commonly the result of a drug interaction where two or more agents which enhance serotonergic neurotransmission by different mechanisms are administered in combination or taken in overdose. It may rarely occur following overdose of a single agent. Secondary to increased serotonin production Tryptophan Secondary to increased release of stored serotonin Amphetamines (including "ecstasy") Bromocriptine Cocaine L-dopa Secondary to impaired reputake of serotonin into presynaptic nerve Dextromethorphan Nefazadone Pethidine (meperidine) Selective serotonin reuptake inhibitors (SSRIs) Citalopram Fluoxetine Fluvoxamine Paroxetine Sertraline Selective serotonin and norepinephrine reuptake inhibitors Venlafaxine Tricyclic antidepressants Secondary to inhibition of serotonin metabolism Monoamine oxidase (MAO) inhibitors Moclobemide Non-selective MAO inhibitors Secondary to post-synaptic serotonin receptor stimulation Lysergic acid diethylamide (LSD) Secondary to enhanced post-synaptic response to serotonin stimulation Lithium NON-TOXIC CAUSES None CLINICAL FEATURES Onset of clinical features may be from hours to days after exposure to the causative agent(s). The classic triad of clinical features includes mental status, motor and autonomic changes. The combination of features observed is extremely variable between individual cases. Mental status changes reported include anxiety, agitation, confusion, restlessness, hypomania, hallucinations and coma. Motor changes include tremor, myoclonus, hypertonia, hyperreflexia and incoordination. Increased muscle tone is often most prominent in the lower limbs. Autonomic and other clinical features include fever, sweating, nausea, vomiting, diarrhoea and hypertension. Life-threatening acute complications include coma, seizures, rhabdomyolysis and disseminated intravascular coagulation (DIC). DIFFERENTIAL DIAGNOSIS Neuroleptic malignant syndrome This is the most important differential diagnosis and is the more likely diagnosis where a neuroleptic agent has been started or increased in dose prior to the onset of signs and symptoms. Anticholinergic syndrome Carbamazepine toxicity Central nervous system infections Ethanol withdrawal Heat stroke Hypnotic/sedative withdrawal Lithium toxicity Opioid withdrawal Sympathomimetic overdose RELEVANT INVESTIGATIONS There are no specific investigations to confirm the diagnosis of serotonin syndrome. In particular, measurement of serum concentrations of implicated agents is unhelpful. Investigations may be important in excluding alternative diagnoses and in the diagnosis and management of complications such as disseminated intravascular coagulation and rhabdomyolysis. TREATMENT The principles of treatment consist of discontinuation of implicated agent(s) and provision of symptomatic and supportive care until the clinical features of the syndrome resolve. Specific pharmacological therapy based on theoretical or empirical grounds has been advocated and used in moderate-to-severe cases but is of unproven efficacy. Important components of supportive care may include administration of intravenous fluids, control of delirium with titrated doses of benzodiazepines, control of the airway, and cooling measures for hyperthermia. In severe cases with marked muscle rigidity and hyperthermia, intubation and ventilation and paralysis with neuromuscular blockers provides control of the airway, ensures oxygenation, controls muscle rigidity and hyperthermia and prevents continued rhabdomyolysis. Specific pharmacological agents that have been advocated include: Cyproheptadine: 4 to 8 mg orally followed by 4 mg every 8 hours for 24 hours. Chlorpromazine: 12.5 mg IM or IV and repeat as needed to a maximum of 1 mg/kg. CLINICAL COURSE AND MONITORING The clinical syndrome is of variable severity and duration. Most usually it is mild and self-limiting once the precipitating agents are withdrawn: most signs and symptoms usually abate within 24 hours although the delirium may persist a little longer. Even in more severe cases, the clinical features of excess serotonergic activity resolve within 24 to 48 hours although complications such as hyperthermia, rhabdomyolysis, and DIC may prolong the clinical course. These complications are potentially lethal. Early diagnosis and treatment of severe cases before the development of complications results in a more benign clinical course and an improved outcome. Very mild cases may be discharged once the causative agents are withdrawn. All other patients should be admitted and carefully monitored until the syndrome resolves. The level of monitoring depends on the clinical severity. LONG TERM COMPLICATIONS None specific AUTHOR(S)/REVIEWERS Author: Lindsay Murray, Senior Lecturer in Emergency Medicine, Queen Elizabeth II Medical Centre, Nedlands, WA 6009, Australia (March 1999). Reviewers: Birmingham 3/99: T. Meredith, L. Murray, A. Nantel, J. Szajewski.