Serotonin Syndrome

An adverse drug reaction to serotonergic agents, ie 5-HT (5-hydroxytryptamine) agonists. It can occur as a consequence of normal therapeutic drug use, self-poisoning or drug interactions. The syndrome is not caused by an idiopathic reaction, rather it is a foreseeable consequence of excessive stimulation of CNS and peripheral serotonin receptors. There is a wide spectrum of illness ranging from barely noticeable minor symptoms such as tremor, through to life-threatening acute illness.¹ It is a clinical syndrome² characterised by the presence of a triad of:

• Mental-status changes
• Autonomic hyperactivity
• Neuromuscular abnormality

Not all of these features are present in all cases. The syndrome is not widely recognised amongst clinicians, and one survey found that 85% of UK general practitioners were unaware of the diagnosis.³ A failure to appreciate the syndrome means that mild cases may be overlooked; continuing or increasing the offending drug can cause progression to severe illness.¹ It is underdiagnosed due to the heterogeneity of its presentation, because there are evolving diagnostic criteria, a lack of awareness amongst prescribers and mistaking of the symptoms for features of a pre-existing psychiatric illness.

• Incidence is unclear due to the extent of under diagnosis.
• Post-marketing surveillance studies on nefazodone (no longer licensed but unlicensed preparations are still available) suggest an incidence of 0.4 cases per 1000 patient-months of treatment.¹
• It is estimated that 14 to 16 percent of those who take overdoses of SSRIs display features of the syndrome.⁴
• Deaths with SSRI overdose are associated with combinations of other medications or illicit substances.

Risk Factors

Use of serotonergic agents is the risk factor for the serotonin syndrome. This may be produced by a variety of agents which may cause excess serotonergic activity through a variety of mechanisms. The serotonin syndrome may be produced by large doses or by combinations of drugs. The risk may be from antidepressants, anti-emetics, anti-migraine drugs, over the counter cold remedies, recreational drugs, herbal remedies or involve interactions between such drugs. It is helpful to consider these agents according to the mechanism of increased serotonergic activity.These include:

• Direct 5HT receptor stimulation:
  • Lithium
  • Carbamazepine
  • Triptans (migraine)
  • Busipirone (BuSpar)
  • Recreational drugs such as LSD (lysergic acid diethylamide), mescaline
• Direct release of stored 5 HT:
  • Amphetamine, cocaine and ecstasy (MDMA)
  • MAOIs (for example phenelzine, moclobemide)
  • Levodopa
  • Codeine
  • Pentazocine
• Increased availability of 5HT precursors:
  • L-tryptophan
• Reduced 5HT reuptake:
  • SSRIs
  • Trazodone or nefazodone (latter no longer licensed but unlicensed preparations are still available)
  • Venlafaxine⁵
  • Cocaine
  • St John's wort (Hypericum plant species)
  • Amphetamines
  • Carbamazepine
  • Methadone
• Decreased 5HT degradation:
  • MAOIs
  • St Johns wort
• Drug interactions - there are many. It is worth checking with a reputable formulary or toxicologist whether there are any known interactions causing the syndrome, where it is suspected in an individual taking serotonergic agents. ⁶
• Other drugs:
  • Anti emetics such as ondansetron, metoclopramide
  • Over the counter drugs especially dextromethorphan in cough and cold remedies
  • Other recreational drugs for example LSD ('acid')
  • Natural remedy preparations, for example St John's Wort, ginseng, tryptophan

Symptoms usually occur within 6 hours of taking the provoking drug. Mild cases may go unrecognised. Tremor, akathisia and diarrhoea are early features. Agitation, hyper vigilance and pressured speech may occur. Acute delirium is a feature of severe cases.
Examination should seek signs of autonomic disturbance, namely:

• Hypertension
• Tachycardia
• Hyperthermia
• Hyperactive bowel sounds
• Mydriasis
• Excessive sweating
• Neuromuscular dysfunction, namely:
  • Tremor
  • Clonus
  • Ocular clonus
  • Hypertonicity
  • Hyperreflexia (this symptom can be masked if there is severe muscle rigidity)
• Progression from restlessness, diaphoresis, neuromuscular dysfunction to confusion, convulsions and death is described.²
• Skin appearance should be normal in serotonin syndrome, a fact that helps to differentiate it from two similar diagnoses (see below). The presence of muscular hyper tonicity, sustained clonus and hyperthermia (which may rise as high as 41°C), indicate severe disease.

A neonatal behavioural syndrome caused by mothers taking SSRIs in the last trimester of pregnancy has recently been postulated.⁷

• Anticholinergic poisoning (normal reflexes, dry mouth, hot and dry skin, absent bowel sounds)
• Malignant hyperthermia (caused by inhalational anaesthetics, mottled and patchily cyanotic skin, severe rigidity and hyporeflexia)
• Neuroleptic malignant syndrome (slow-onset idiopathic reaction to dopamine antagonists with bradykinesia and "lead-pipe" muscular rigidity)
• Other poisoning
• Catatonia
• Dystonia
• Recreational drug toxicity esp. amphetamines/cocaine (many features of their toxicity are due to serotonergic effects)
• Hyperthyroidism
• Tetanus
• Delirium tremens
• Encephalitis
• Rhabdomyolysis
• Meningitis
• Withdrawal syndromes
• Wernicke's encephalopathy

• There are no specific confirmatory investigations
• Check U&E's and creatine kinase to look for evidence of rhabdomyolysis and consequent renal impairment
• Toxicology screen particularly for agents likely to be responsible
• FBC and blood culture/microbiological samples can suggest alternative causes of fever
• Liver function tests
• CXR if respiratory complications
• CT scanning of head if trauma, seizures, hypertension or focal neurology
• Lumbar puncture if fever and altered mental state

• In all cases the most important step is to remove the offending agent or interacting drugs. If recently ingested/large overdose, then activated charcoal may help to prevent absorption. Supportive measures such as IV fluids and control of agitation with benzodiazepines are also used.
• Mild cases usually resolve within 24 hours of discontinuation and may need supportive measures only. Beware of drugs with long half-lives or active metabolic breakdown products (for example fluoxetine), where it may take longer.
• Moderately severe cases should have cardiovascular and thermal disturbances corrected and receive 5-HT2A antagonists such as cyproheptadine (as yet there is no definitive evidence for its efficacy).
• Severe cases need aggressive treatment and intensive care with early sedation, neuromuscular paralysis and ventilatory support.

• Hyperthermia can lead to metabolic acidosis, rhabdomyolysis, renal failure and disseminated intravascular coagulation. Thermal disturbance should be aggressively managed. Any patient with a temperature over 40.5 °C should be managed with:
  • Paralysis and ventilation
  • Ice bath immersion if not responsive (to prevent disseminated intravascular coagulation and organ failure)
  Antipyretic agents have no role as hyperthermia is due to muscular activity rather than hypothalamic mechanisms. Chlorpromazine may be used to treat agitation and hyperthermia.
• Seizures
• Aspiration pneumonia
• Respiratory failure

If patients recover from acute episode and avoid provoking agents then the outlook is good. Most deaths occur within the first 24 hours.

• Caution in the prescription of serotonergic agents. All patients starting SSRIs should be counseled about:
  • Potential interactions (including over the counter and 'herbal' medication)
  • The symptoms of serotonin toxicity and the serotonin syndrome
• Improved knowledge amongst medical community. Particular care should be taken when changing SSRIs or prescribing more than one antidepressant.
• Improved pharmacogenetic understanding to identify those at increased risk
• Adequate post-marketing surveillance of new serotonergic therapies