Serotonin syndrome

Serotonin syndrome can be a life-threatening neurological disorder due to increased serotonergic activity in the central nervous system.

Serotonin syndrome (SS) is a potentially life-threatening disorder that is characterised by altered mental status (i.e. confusion), autonomic hyperactivity, and neuromuscular abnormalities (e.g. rigidity, clonus, hyperreflexia). It is due to increased serotonergic activity in the central nervous system (CNS) that can be induced by a range of medications that increase serotonergic transmission by altering the neurotransmitter serotonin.

There is a wide clinical spectrum and the prognosis is generally favourable although severe cases may require treatment in intensive care.

The incidence of SS has been increasing due to the widespread use of serotonergic agents.

SS has been observed in all ages. A significant number of cases occur in young adults. The actual incidence of SS may be underreported because symptoms may be attributed to another cause or mild symptoms go unnoticed.

SS is important to consider in any patient who has taken an overdose of selective serotonin reuptake inhibitors (SSRIs). SSRIs are a common type of antidepressant and anxiolytic.

In SS, SSRIs are the most commonly implicated medications.

Any drug that increases serotonergic transmission is at risk of precipitating SS. Classically, this is seen with SSRIs that block the reuptake of serotonin from the synaptic cleft into the presynaptic neuron (e.g. citalopram, fluoxetine).

Serotonin physiology

Serotonin is a monoamine neurotransmitter that is derived from the amino acid tryptophan. It has important functions in the CNS and peripheral nervous system (PNS):

• CNS: modulates thermoregulation, behaviour, and attention
• PNS: regulates GI motility, vasoconstriction, bronchoconstriction, and uterine contraction
• Other: promotes platelet aggregation (thus, combined use with anti-platelets can increase bleeding risk)

Causative agents

A range of agents can induce SS by a variety of mechanisms that ultimately increase serotonergic transmission in the CNS:

• Increased release of serotonin: Amphetamines, MDMA (ecstasy), cocaine
• Impaired serotonin reuptake: SSRIs, SNRIs, MDMA, tricycle antidepressants, serotonin modulators
• Inhibit serotonin metabolism: Monoamine oxidase inhibitors
• Serotonin receptor agonists: Buspirone, Triptans
• Increased sensitivity of serotonin receptor: Lithium

NOTE: SS secondary to the use of monoamine oxidase inhibitors is usually more severe and can be fatal.

SS may occur due to exposure to a single agent that affects serotonergic transmission or a combination of drugs that collectively cause a net increase in serotonergic transmission.

Selective serotonin reuptake inhibitors are used in a range of clinical conditions including anxiety and depression.

SSRIs are a class of antidepressant and anxiolytic medications that are widely used in clinical practice. SSRIs are most commonly prescribed to treat depression, but can also be prescribed in a range of other conditions including anxiety and functional gastrointestinal disorders.

SSRIs work by inhibiting the reuptake of serotonin from the synaptic cleft into the presynaptic neuron. They achieve this by antagonising the serotonin transporter (SERT) on the presynaptic membrane. Collectively, this means more serotonin is available to induce neurotransmission by binding to serotonergic (5-HT) receptors on the post-synaptic membrane.

Commonly used SSRIs include:

• Fluoxetine
• Sertraline
• Paroxetine
• Citalopram

SSRIs are widely used due to their relatively little effect on other neurotransmitters including dopamine, noradrenaline, histamine, and acetylcholine. This limits the side-effect profile and improves concordance. Common side-effects with SSRIs include sexual dysfunction, sleep disturbance, weight change, anxiety, and gastrointestinal distress.

Importantly, SSRIs may increase the risk of suicidal ideation and self-harm, particularly during the initiation of therapy. Patients should be warned about this and reviewed within a week of starting therapy.

SS is characterised by altered mental status, autonomic hyperactivity, and neuromuscular abnormalities (e.g. hyperreflexia).

There is a wide clinical spectrum in SS with the intensity of symptoms thought to reflect the degree of serotonergic activity. Autonomic hyperactivity refers to features of hypertension, hyperthermia, and tachycardia. Neuromuscular abnormalities are common, particularly clonus and hyperreflexia.

Symptoms

• Altered mental status: may present as anxiety, restlessness, disorientation, or agitation
• Sweating
• Fever
• Vomiting
• Diarrhoea

Signs

The typical neuromuscular findings in SS are usually more pronounced in the lower limbs.

• Dilated pupils
• Flushed skin, diaphoresis
• Tachycardia, hypertension
• Hyperthermia (>38.0º)
• Hyperreflexia
• Clonus: repeated, rhythmic contractions
• Myoclonus: sudden jerky or spastic contraction
• Rigidity
• Bilateral upgoing plantars (Babinski sign)

The diagnosis of SS is based on typical clinical findings in patients taking serotonergic medications.

Various diagnostic criteria have been developed for SS, which is principally based on clinical features. The most accurate criteria is known as ‘Hunter criteria’. Additional investigations are important to exclude an alternative diagnosis and to investigate for complications (e.g. rhabdomyolysis).

Hunter criteria

SS can be diagnosed in a patient taking a serotonergic agent (e.g. SSRI) and presents with one of the following features:

• Spontaneous clonus
• Inducible/ocular clonus and agitation or diaphoresis
• Tremor and hyperreflexia
• Hyperthermia, hypertonia, and ocular/inducible clonus

Investigations

Investigations are useful to determine the severity of SS and to exclude alternative causes.

• Bedside: ECG, cardiac monitoring (particularly if profound autonomic symptoms), blood glucose, urine dip
• Bloods: full blood count, urea & electrolytes, LFTs, coagulation, blood cultures (if febrile), creatine kinase, and blood gas. Patients may have features of neutrophilia, acute kidney injury, or elevated CK levels. Severe cases of SS can lead to rhabdomyolysis (i.e. skeletal muscle necrosis).
• Imaging: cerebral imaging (i.e. CT/MRI) may be needed in patients with new-onset altered mental status to exclude an alternative cause. A chest x-ray is usually needed as part of a septic screen if patients are febrile.
• Special: a lumbar puncture may be needed to exclude an intracerebral infection or investigate for an alternative cause of confusion (e.g. autoimmune encephalopathy).

Differential diagnosis

Alternative diagnoses should be considered in any young patient presenting with new-onset confusion (e.g. encephalitis, drug intoxication, phaeochromocytoma). This list is very broad.

SS is one of several ‘acute dysautonomias’ that should be considered in patients with characteristic clinical features (e.g. hyperthermia, neuromuscular abnormalities):

• Neuroleptic malignant syndrome: similar presentation to SS that occurs in association with antipsychotic medications due to their anti-dopaminergic action. Characterised by altered mental status, fever, rigidity, and dysautonomia (i.e. autonomic instability).
• Malignant hyperthermia: a rare genetic disorder characterised by hyperthermia, muscle rigidity, and dysautonomia in the setting of exposure to certain anaesthetic agents (e.g. succinylcholine) or vigorous exercise.
• Recreational drug use: both use of MDMA (i.e. ecstasy) and cocaine can induce SS

Management of SS is largely supportive by managing complications, providing organ support, and stopping serotonergic agents.

The management of SS largely depends on the severity of symptoms. In mild cases, patients may be observed for 4-6 hours and then discharged. In severe cases, patients may need organ support in intensive care. Serotonin antagonists can be given in severe cases although evidence for their use is incomplete.

Supportive care

The serotonergic agent should be stopped and patients should be monitored in the appropriate setting. Cardiac monitoring is usually required due to dysautonomia. Patients should be monitored and specific complications treated (e.g. electrolyte imbalance, acute kidney injury, rhabdomyolysis). In severe cases, patients may require organ support (e.g. intubation & ventilation, haemofiltration) and admission to intensive care.

Specific interventions that are helpful include intravenous fluids to maintain euvolaemic state, antipyretics and cooling blankets for hyperthermia, specific antihypertensive agents for profound hypertension, and benzodiazepines as necessary for agitation. These are collectively used to restore normal vital signs.

In severe hyperthermia (>41º), antipyretics are unlikely to work as the increased body temperature is due to muscular activity not altered hypothalamic regulation. Therefore, sedation, paralysis, and tracheal intubation are usually required.

Medical therapy

If supportive measures including the use of benzodiazepines fail to improve vital signs or agitation, patients can be considered for serotonin antagonists (e.g. Cyproheptadine). Cyproheptadine is a histamine receptor antagonist with action against serotonin receptors.

Follow-up

SS usually resolves within 24 hours of stopping the serotonergic medication. Patients will mild symptoms who recover quickly may only need observation for 4-6 hours. Advice should always be sought from ‘Toxbase’ or a toxicologist if in doubt. This is particularly important in patients where an overdose has been taken. It is important to avoid co-prescription of multiple serotonergic agents to prevent the development of SS.

NOTE: Toxbase is a clinical toxicology database that provides information on the diagnosis, treatment, and management of patients exposed to a wide range of medications, chemicals, plants, and animals.

SS has a favourable prognosis and the majority of patients recover, but severe cases may occur particularly within the first 24 hours.

SS can be life-threatening and a number of severe complications can develop:

• Cardiac arrest
• Cardiac arrhythmias
• Acute kidney injury
• Rhabdomyolysis
• Disseminated intravascular coagulation
• Seizures
• Respiratory failure
• Venous thromboembolism