Serotonin Syndrome/Serotonin Toxicity

Moderate-to-severe ST symptoms require hospitalization, usually in the intensive care unit (ICU). At this stage, clonus progresses from the lower extremities to the upper body and becomes more generalized. Ocular clonus can be continuous, intermittent, or have a ping pong effect (short cycle, periodic, alternating lateral gaze).

Severe ST is life threatening and leads to multiorgan failure within hours if not treated. The patient is intubated to assist with breathing and sedated because excess agitation and muscular tremors can increase temperature, which is already elevated by the time the symptoms reach the severe state. Of note, hyperthermia is due to a noninfectious elevation of body temperature from hypertonicity, agitation, and muscle rigidity.A true core temperature > 105.8°F causes irreversible cell damage, cerebral injury, and death.^32,33 The patient can develop seizures and a coma. Multiorgan failure occurs, including rhabdomyolysis, myoglobinuria, renal failure, metabolic acidosis, acute respiratory distress, and disseminated intravascular coagulation.

Diagnosis

The diagnosis of ST is clinical and based on a history of ingesting serotonin-elevating medications and physical findings as per Hunter Serotonin Toxicity Criteria³⁴ (Table 4). An in-depth history needs to include previous and current prescriptions, indications of the prescriptions (eg, therapeutic, increase in dosage, suicide intent), OTC medications, and illicit drug use. Early recognition of symptoms, identification of serotonergic medications, and appropriate resuscitative measures lead to more successful outcomes. A serotonin drug level is ineffective and does not correlate with the dosage since serotonin does not cross the blood-brain barrier.

The type of drug determines the length and response of the episode. The drug(s) elimination half-lives need to be calculated along with the pharmacokinetic or pharmacodynamics; agonist, antagonist, reuptake inhibitor, etc. Many drugs have half-lives of < 24 hours; therefore, reducing or eliminating the offending drug(s) will result in a steady reduction of symptoms.Exceptions include medications with a longer activity, such as the irreversible MAOIs (eg, phenelzine, isocarboxazid) and drugs with a longer half-life, such as fluoxetine. These types of medications may have been stopped weeks earlier and may prolong reduction of symptoms.

When initiating or increasing SSRIs or SNRIs, there are common nontoxic AEs that are not consistent with ST, including anxiety, restlessness, and irritability that may last for 2 weeks. The difference in toxic vs nontoxic reactions are the timing and rapid progression of symptoms. The toxic symptoms will start within hours of ingesting the offending agents(s) and progress rapidly to severe symptoms within 24 hours. Therefore, it is imperative to review AEs with the patient and or caregiver, so they may act as their own advocate and seek immediate assistance.

Differentials

There are symptoms specific to ST that can be used to differentiate it from other conditions. These include hyperthermia, bilateral symmetric clonus (inducible, spontaneous, ocular), and hyperreflexia.These criteria form the basis for Hunter criteria.

Differential diagnoses to consider include neuroleptic malignant syndrome; antidepressant initiation AEs; antidepressant discontinuation syndrome; malignant hyperthermia; anticholinergic toxicity; meningitis/encephalitis; sepsis; drug overdose; alcohol/benzodiazepine withdrawal; and preeclampsia. Neuroleptic malignant syndrome (NMS) is the disorder most often misdiagnosed as ST.Key elements that distinguish ST from NMS include the timing of the clinical course (NMS develops over days to weeks); the medications ingested (NMS from dopaminergic drugs); and the symptoms of NMS (bradyreflexia, bradykinesia, bradyphrenia, and no clonus).According to Gillman, serotonin toxicity is a manifestation of toxicity that is predictable and common with specific drug combinations, while NMS is a “rare idiosyncratic reaction to essentially normal doses and very rarely occurs after overdoses.”³⁵ Preeclampsia is a pregnancy complication that can mimic ST with symptoms of hypertension, clonus, and hyperreflexia. It has been estimated to complicate 2% to 8% of pregnancies and remains a principle cause of maternal and fetal morbidity and mortality.^36,37