Serotonin syndrome (SS) is a potentially life-threatening condition caused by excessive serotonin activity in the brain and body.
Key facts:
- SS is characterized by a triad of mental status changes, neuromuscular abnormalities, and autonomic instability.
- It is usually caused by certain combinations of serotonergic medications, especially MAOIs mixed with SSRIs or SNRIs.
- Diagnosis is clinical – based on history, exam findings, and ruling out other causes.
- Treatment involves stopping causative medications, supportive care, sedation, cooling, and sometimes serotonin antagonists.
- Most cases resolve within 24 hours of stopping medications, but severe cases can lead to death if not recognized and treated promptly.
Serotonin Syndrome Cause: Excessive 5-HT in Synapses
Serotonin, also known as 5-hydroxytryptamine (5-HT), is a neurotransmitter with diverse functions in the brain and body.
It is synthesized from the amino acid tryptophan via the enzyme tryptophan hydroxylase (TPH).
There are two TPH isoforms – TPH1 in the periphery and TPH2 in the brain.
Once synthesized, serotonin is stored in presynaptic vesicles and released into the synaptic cleft when the neuron fires.
It binds to various 5-HT receptor subtypes, causing downstream effects based on the subtype activated.
Its actions are terminated by reuptake via the serotonin transporter (SERT).
SS occurs when excess serotonin accumulates in the synapses, directly or indirectly activating 5-HT receptors – especially 5-HT1A and 5-HT2A subtypes.
This causes neuromuscular, mental status, and autonomic effects.
Severe SS is often caused by MAOIs preventing serotonin breakdown combined with SSRIs/SNRIs increasing serotonin levels further by blocking reuptake.
However, many other serotonergic drug combinations can also precipitate SS.
Serotonin Syndrome Symptoms & Signs
SS causes a characteristic triad of findings:
- Neuromuscular abnormalities – Hyperreflexia, clonus (inducible, spontaneous or ocular), rigidity, tremor, myoclonus. Severe cases cause severe hypertonicity and muscle rigidity.
- Mental status changes – Agitation, confusion, hypomania, anxiety, delirium. Altered mental status ranges from mild agitation to delirium and coma.
- Autonomic instability – Hyperthermia, diaphoresis, tachycardia, tachypnea, hypertension, vomiting, diarrhea. Hyperthermia is a cardinal sign, often >40°C in moderate/severe cases.
Other findings may include hyperactive bowel sounds, mydriasis, metabolic acidosis, and renal failure.
Symptom onset is usually within 24 hours of starting or increasing serotonergic medications.
Rapid symptom progression with high fevers, muscle rigidity, and mental status changes indicates severe SS.
Diagnosis of Serotonin Syndrome
There is no single diagnostic test for SS – it is a clinical diagnosis made based on history, exam, and exclusion of other causes.
Key steps include:
- Detailed history of medication/drug use, onset and progression of symptoms
- Physical exam focusing on vital signs, neuromuscular tone, reflexes, clonus
- Review for recent additions/increases of serotonergic medications
- Ruling out infections, seizures, anticholinergic toxicity, NMS, sypathomimetic toxicity
- Checking creatine kinase, liver enzymes, renal function to assess for complications
- Toxicology screen and electrolytes in overdose situations
Three diagnostic criteria systems exist.
The Hunter Criteria focusing on clonus, agitation, diaphoresis, tremor and hyperreflexia are most commonly used.
Diagnosis requires a high index of suspicion in the right clinical context.
Conditions Similar to Serotonin Syndrome in Presentation
It is important to differentiate SS from related toxicities including:
- Neuroleptic malignant syndrome (NMS) – Caused by dopamine antagonists, presents with lead pipe rigidity, bradykinesia, little reflex/clonus
- Anticholinergic toxicity – Dry skin, mydriasis, hypoactive bowel sounds, normal reflexes
- Sympathomimetic toxicity – Agitation, hypertension, tachycardia, hyperthermia, seizures
- Malignant hyperthermia – Triggered by anesthesia, causes sudden hyperthermia, rigidity, and acidosis
Serotonin Syndrome Treatments
Treatment centers on removing causative medications, providing support, controlling symptoms, and monitoring for complications:
- Stop serotonergic agents. Long half-life drugs like fluoxetine may require extended monitoring.
- Supportive care – IV fluids, oxygen, cardiac monitoring, control fever
- Sedate agitation with benzodiazepines
- Treat hypertension cautiously. Avoid long-acting agents.
- Aggressively control severe hyperthermia (>41°C) with cooling methods. Paralytic agents may be required.
- Consider serotonin antagonists (cyproheptadine) if symptoms persist despite above measures.
- Monitor for complications – rhabdomyolysis, DIC, renal failure, ARDS.
- Admit moderate/severe cases to ICU. Observe mild cases closely.
Most cases resolve within 24 hours of stopping causative medications.
However, symptoms may persist longer if long-acting serotonergic agents are involved.
Overall prognosis is good with prompt recognition and treatment.
Preventing Serotonin Syndrome: How to Avoid It
SS prevention requires education around dangerous serotonergic drug interactions, cautious prescribing, and ongoing research:
- Inform providers and patients about potentially deadly combinations like MAOIs with SSRIs/SNRIs
- Use electronic prescribing systems to flag dangerous interactions
- Avoid vague warnings about minor interactions lacking strong evidence
- Start serotonergic drugs at low doses and uptitrate slowly when combining agents
- Monitor for early symptoms suggesting toxicity
- Research pharmacogenomics underlying variable patient susceptibility
The Future – Can We Target Serotonin Production?
An interesting avenue of research for treating serotonin excess in SS focuses on tryptophan hydroxylase (TPH) inhibitors to reduce serotonin synthesis.
TPH inhibitor drugs like telotristat, developed to treat carcinoid syndrome, can lower peripheral serotonin without crossing into the brain.
Specific TPH2 inhibitors may have a future role in targeting central serotonin production to manage severe SS, but these drugs remain to be developed.
Conclusion: Serotonin Syndrome Usually Treatable
In summary, SS is a potentially deadly but treatable condition caused by excessive serotonergic activity in the brain and body.
A high index of suspicion and prompt treatment of moderate/severe cases is crucial.
Clinician and patient education around dangerous medication interactions can help prevent serious morbidity and mortality.
Ongoing research focused on the serotonin pathway may uncover future targeted treatment options for this toxic triad.
References
- Study: Serotonin syndrome: pathophysiology, clinical features, management, and potential future directions
- Authors: William J Scotton et al. (2019)
