Serotonin (5-hydroxytryptamine, or 5-HT) is a chemical messenger, or neurotransmitter, that is primarily found in the gastrointestinal tract, platelets, and the central nervous system (CNS) of animals and humans. In the CNS, its functions include the regulation of mood, sleep, appetite, and perception of pain.

Depression is often associated with low levels, or an imbalance between serotonin and other neurotransmitters, such as noradrenaline. Antidepressants work by correcting this imbalance and increasing the levels of serotonin and noradrenaline. There are many other medicines that also increase the amount of serotonin in the body, either through:

  • Increased serotonin synthesis or release,
  • Reduced serotonin uptake or metabolism, or
  • Direct serotonin receptor activation.

Both medicines and illicit drugs that increase serotonin levels in the CNS can induce a toxic drug effect called serotonin syndrome. This syndrome is a dose related toxic effect that can occur either from an overdose of a drug, when the dose of a drug is increased or most commonly when two or more serotonergic drugs are combined at therapeutic doses. The likelihood and severity of serotonin syndrome is more pronounced when drugs that increase the level of serotonin by different mechanisms are combined. They commonly include selective serotonin reuptake inhibitors (SSRIs) or monoamine oxidase inhibitors (MAOIs).

Table 1. Drugs Implicated in Serotonin Syndrome

Effect on Serotonin

Drug Examples

Release Increasers Dexamphetamine, lithium, phentermine
Reuptake Inhibitors Dextromethorphan, fentanyl, pethidine, sibutramine, SNRIs (selective noradrenaline reuptake inhibitors), SSRIs, St John’s wort, tramadol, tricyclic antidepressants
Metabolism Inhibitors Linezolid, MAOIs
Receptor Activators Buspirone, eletriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan

 

Signs and Symptoms

Diagnosis of serotonin syndrome is generally based on the presence of clinical features that are widely variable. Common signs and symptoms include agitation, confusion, increased heart rate (tachycardia), increased blood pressure (BP), pupil dilation, diarrhoea, headache, shivering, sweating (diaphoresis), loss of muscle coordination, and muscle rigidity. Unfortunately, most of these signs and symptoms are not specific to serotonin syndrome. The most important features in diagnosing serotonin syndrome are hyperreflexia and clonus (involuntary muscular contraction and relaxation), especially of the lower limbs. The symptoms usually develop rapidly and can happen within minutes of serotonin overload.

The severity of serotonin syndrome can be classified as mild, moderate or severe. The symptoms associated with mild cases could also be interpreted as the side effects of the drug, and which the patient may or may not be concerned by. These symptoms include increased heart rate, shivering, and dilated pupils. Moderate serotonin syndrome may result from the overdose of a drug or from within the adverse effect profile of the particular serotonergic drug. The additional symptoms include high blood pressure, temperatures as high as 40°C, and overactive reflexes in the lower limb. These symptoms are a significant concern to the patient and may require treatment, however are not life threatening. Severe cases of serotonin syndrome always involve the interaction between serotonergic drugs with different mechanisms of actions and usually involve either a SSRI or a MAOI. The symptoms develop rapidly and include severe increase in heart rate and blood pressure, muscle rigidity, hyperthermia above 41°C, and may lead to multiple organ failure if not treated within hours. Severe cases of serotonin syndrome can be fatal.

Table 2. Clinical Features of Serotonin Syndrome

Neuromuscular Effects

Autonomic Effects

Mental State Changes

Clonus

Hyperreflexia

Hypertonia/rigidity

Myoclonus

Shivering

Tremor

Diaphoresis

Flushing

Hyperthermia

  • Mild <38.5°C
  • Moderate 40°C
  • Severe ≥41°C

Mydriasis

Tachycardia

Agitation

Anxiety

Confusion

Hypomania

 

Treatment

The initial treatment of serotonin syndrome involves cessation of the serotonergic drug(s) and supportive care. Mild to moderate cases usually resolve within 24 to 72 hours. Severe cases require intensive care unit admission, where temperature, pulse, blood pressure, and urine output are monitored and managed. Passive and active cooling of the patient (e.g. ventilation, cool water sprays, and ice packs) may be required for hyperthermia.

Benzodiazepines have been used to provide symptomatic relief from muscle hyperactivity and seizures. Serotonin antagonists, such as cyproheptadine and chlorpromazine, have been used in moderate to severe cases. However, definitive evidence is lacking on their efficacy.

Conclusion

Although reports of severe cases of serotonin syndrome are limited, precautions should be taken to avoid this toxic effect, where possible, by monitoring the use of combinations of serotonergic drugs, and ensuring there are adequate washout periods for long-acting antidepressants before introducing an alternative. Severe cases of serotonin syndrome can potentially be life threatening and therefore health professionals need to consider the possibility of serotonin syndrome.

References:

  1. Ables AZ, Nagubilli R. Prevention, diagnosis and management of serotonin syndrome. Am Fam Physician. 2010;81(9): 1139-42.
  2. Hall M, Buckley N. Serotonin syndrome. Aust Prescr 2003;26: 62-3.
  3. Iqbal MM, Basil MJ, Kaplan J, Iqbal MD. Overview of serotonin syndrome. Ann Clin Psychiatry 2012;24(4): 310-18.
  4. Isbister GK, Buckley NA, Whyte IM. Serotonin toxicity: a practical approach to diagnosis and treatment. Med J Aust 2007;187(6):3 61-5.
  5. National Prescribing Service Ltd. NPS Medicinewise. Surry Hills, Australia.
  6. Rossi S (ed). Australian Medicines Handbook. Adelaide: Australian Medicines Handbook Pty Ltd; 2013.

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