Serotonin toxicity: a practical approach to diagnosis and treatment

Abstract

Excess serotonin in the central nervous system leads to a condition commonly referred to as the serotonin syndrome, but better described as a spectrum of toxicity — serotonin toxicity. Serotonin toxicity is characterised by neuromuscular excitation (clonus, hyperreflexia, myoclonus, rigidity), autonomic stimulation (hyperthermia, tachycardia, diaphoresis, tremor, flushing) and changed mental state (anxiety, agitation, confusion). Serotonin toxicity can be: mild (serotonergic features that may or may not concern the patient); moderate (toxicity which causes significant distress and deserves treatment, but is not life‐threatening); or severe (a medical emergency characterised by rapid onset of severe hyperthermia, muscle rigidity and multiple organ failure). Diagnosis of serotonin toxicity is often made on the basis of the presence of at least three of Sternbach's 10 clinical features. However, these features have very low specificity. The Hunter Serotonin Toxicity Criteria use a smaller, more specific set of clinical features for diagnosis, including clonus, which has been found to be more specific to serotonin toxicity. There are several drug mechanisms that cause excess serotonin, but severe serotonin toxicity only occurs with combinations of drugs acting at different sites, most commonly including a monoamine oxidase inhibitor and a serotonin reuptake inhibitor. Less severe toxicity occurs with other combinations, overdoses and even single‐drug therapy in susceptible individuals. Treatment should focus on cessation of the serotonergic medication and supportive care. Some antiserotonergic agents have been used in clinical practice, but the preferred agent, dose and indications are not well defined.

Serotonin syndrome caused by drug to drug interaction between escitalopram and dextromethorphan

“…Reportedly therapeutic doses of serotonergic medications alone rarely cause severe toxicity; overdoses often lead to mild to moderate toxicity 2. Drug interactions that alter serotonin metabolism are often the causes leading to severe toxicity 2. Once recognised, the main treatment is removal of the offending medications 1 2.…”

Challenges in a large mixed drug overdose patient

“…It is unlikely that any single medication caused severe serotonin toxicity in our patient;7 we hypothesise that his rapid, severe and prolonged symptoms were due to the additive effects from multiple drugs leading to an excess of serotonin and modulation of 5-HT receptors. Several of the medications to which the patient had access have complementary serotonergic activity (table 1).…”

“…Several of the medications to which the patient had access have complementary serotonergic activity (table 1). Although not well understood, some individuals may also be more susceptible to serotonin excess and toxicity due to individual pharmacokinetic or pharmacodynamic effects 7. In addition, our patient's concomitant alcohol withdrawal made his diagnosis and treatment difficult and may have contributed to his prolonged hospital admission.…”

“…The patient did not develop significant rhabdomyolysis, renal failure or coagulation abnormalities, all serious complications of serotonin syndrome 7. Despite receiving cyproheptadine on admission to the ICU, there was no clinical effect on his serotonergic symptoms.…”

“…Serotonin syndrome is a clinical diagnosis with specific neurological signs, the most important being generalised hyper-reflexia which occurs in moderate-to-severe cases and is seen rarely in any other condition 7. Commonly, there is sustained clonus at the ankle and ocular clonus, and lower limbs have a greater degree of hyper-reflexia than the upper limbs.…”