Serotonin syndrome

SS  syndrome is a potentially life-threatening syndrome that is precipitated by the use of serotonergic drugs and overactivation of both the peripheral and central postsynaptic 5HT-1A and, most notably, 5HT-2A receptors.


((Serotonin) is  (5-hydroxytryptamine [5-HT]).

Serotonin syndrome is caused by drugs that stimulate the 5-hydroxytryptamine family of serotonin receptors.

The incidence of this disorder is rising due to increased use of serotonergic drugs.

Avpotentially fatal condition characterized by abrupt onset muscle rigidity, hyperthermia, rhabdomyolysis, mental status changes (e.g. coma, hallucinations, agitation), etc.


It is formed from the decarboxylation and hydroxylation of tryptophan.


Serotonin is then stored in vesicles and released into the synaptic cleft when stimulated. 


Serotonin is metabolized by monoamine oxidase-A (MAO-A) into 5-hydroxyindoleacetic acid. 


Serotonin can bind to at least 7 families of 5-HT receptors.


5HT-2A receptors are the most important serotonin receptors involved in SS.


The SS consists of a combination of mental status changes, neuromuscular hyperactivity, and autonomic hyperactivity. 

SS presentation varies from mild symptoms to a life-threatening syndrome. 


Life-threatening SS findings  include:  hyperthermia (>38.5�C), peripheral hypertonicity, truncal rigidity because of the high risk of progression to respiratory failure.


SS symptoms usually begin within 24 hours of an increased dose of a serotonergic agent, the addition of another serotonergic agent to a drug regimen, or overdosing. 


Patients with mild symptoms may have a more subacute or chronic presentation


Mild cases of SS present with mild hypertension, tachycardia, mydriasis, diaphoresis, shivering, tremor, myoclonus, and hyperreflexia. 


Moderate SS  usually have the above symptoms plus fever (40�C), hyperactive bowel sounds, ocular clonus, mild agitation, hypervigilance, and pressured speech. 

Severe cases of SS have all of the above symptoms plus hyperthermia greater than 41.1�C, swings in pulse rate, blood pressure, delirium, and muscle rigidity. 

Severe cases may be associated with complications: seizures, rhabdomyolysis, myoglobinuria, metabolic acidosis, renal failure, acute respiratory distress syndrome, respiratory failure, diffuse intravascular clotting, coma, and death.

Mild cases of SS are usually without fever.


Symptoms include mental status changes such as agitation, hallucinations, autonomic instability with tachycardia, labile blood-pressure, and hyperthermia, neuromuscular changes with hyperreflexia, incoordination, and G.I. symptoms with nausea vomiting and diarrhea.

The neurological symptoms of hyperreflexia, rigidity, and clonus tend to be more prominent in the lower extremities.

The SS can occur from the therapeutic use of serotonergic drugs alone, an overdose of serotonergic drugs, or classically, as a result of a complex drug interaction between two serotonergic drugs that work by different mechanisms. 

Serotonin is produced by the decarboxylation of L-tryptophan.

Serotonin is a neurotransmitter that has a significant role in many physical and mental conditions.

Serotonin toxicity, the serotonin syndrome, refers to the clinical effects of excess serotonin on the CNS and peripheral nervous systems.

Serotonin levels are regulated by various mechanisms, including reuptake mechanisms and various enzymes.

There are 7 serotonin receptors with multiple members, but no single receptor appears to be involved in the serotonin syndrome.

Serotonin syndrome can be life-threatening.

SS symptoms are a product of the overactivation of both the central and peripheral serotonin receptors as a result of high levels of serotonin. 



A multitude of drug combinations can result in serotonin syndrome.



Many commonly used medications have proven to be associated with the SS.

It can result from therapeutic drug use, drug interactions, and intentional self poisoning excess.

Excess stimulation of seotonergic receptors produce multiple clinical manifestations which can range from mild to lethal.

Incidence increasing as the number of serotonergic agents are used in clinical practice.

The actual incidence of SS is unknown. but the number of actual cases is likely much greater than the actual reported cases. 



SS often misdiagnosed: mild symptoms attributed to being a general side effect of treatment, unawareness of the syndrome, varying diagnostic criteria, or misdiagnosis.


SS  has been documented in all age groups.

The syndrome occurs in 15% of patients who overdose on selective serotonin reuptake inhibitors.

Clinically patients manifest with neuromuscular excitation, clonus, hyperreflexia, Maye clonus, rigidity, I don’t gnomic stimulation with hypothermia, tachycardia, and diaphoresis, tremors, and altered mental status.

The severity of this syndrome is categorized as mild, moderate, but not life-threatening, and severe which can be life-threatening and is associated with hypertonicity and fever greater than 41�C.

Diagnosis includes a history of exposure to a serotonergic agent within the last five weeks, along with clonus, agitation, tremor, hyperreflexia, and diaphoresis.


SS is a diagnosis of exclusion.


Differential diagnosis: 

 neuroleptic malignant syndrome (NMS), 

malignant hyperthermia, 

anticholinergic toxicity, 

serotonergic discontinuation syndrome, 

sympathomimetic drug intoxication, 



heat stroke,

central hyperthermia.


The diagnosis of serotonin syndrome is entirely clinical and is based on the history and physical examination along with history of the patient’s use of a serotonergic drug. 


Several diagnostic criteria  include: the use of a serotonergic agent plus 1 of the 5 following criteria: spontaneous clonus, inducible clonus plus agitation or diaphoresis, ocular clonus plus agitation or diaphoresis, tremor and hyperreflexia, hypertonia and a temperature above 38�C plus ocular or inducible clonus.

Clonus and hyperreflexia are most important findings for the diagnosis.


Medications that can cause the syndrome include SSRIs, monoamine oxidase inhibitors, tricyclic antidepressants, opioids, cough suppressants, antibiotics, and antimigraine medications, lithium and herbal agents.


Enzyme inhibition results in the accumulation of serotonergic drugs such as venlafaxine, methadone, tramadol, oxycodone, risperidone, dextromethorphan, and phentermine: 

the SSRI inhibits the metabolism of a certain drug, which in turn increases serotonergic activity. 


The development of serotonin syndrome occurs with the concomitant use of an SSRI with tramadol.

Ciprofloxacin has been reported to cause serotonin syndrome via its CYP3A4 inhibition.

The  concomitant use of citalopram and fluconazole suggested that the inhibition of CYP2C19 by fluconazole resulted in the accumulation of its substrate citalopram.

CYP450 interactions are important in the development of serotonin syndrome. 

This syndrome can manifest independent of the dosage of the medication.

No laboratory tests can confirm the diagnosis.

Laboratory abnormalities may be seen in serotonin syndrome: leukocytosis, low bicarbonate level, elevated creatinine level, and elevated transaminases. 


Serum serotonin concentrations are not correlated with the severity of this syndrome.

A potentially life-threatening drug reaction that may occur following therapeutic drug use, interactions between drugs, overdose of particular drugs, or the recreational use of certain drugs.

Not an idiopathic drug reaction..

The SS is a consequence of excess serotonergic activity at central nervous system (CNS) and peripheral serotonin receptors.

Symptoms include: cognitive, autonomic, and somatic effects.

The symptoms may range from barely perceptible to fatal.

Reported to occur with numerous drugs and drug combinations.

The drugs that have been reported to cause serotonin syndrome and their mechanisms: 


inhibition of serotonin uptake, decreased serotonin metabolism, increased serotonin synthesis, increased serotonin release, and activation of serotonergic receptors, the inhibition of certain cytochrome P450 (CYP450) enzymes by the SSRIs themselves, including CYP2D6 and CYP3A4.

Diagnosis depends on observing the symptoms produced and the patient’s history.

The syndrome can be mistaken for other illnesses, particularly the neuroleptic malignant syndrome.

No laboratory tests presently confirm the diagnosis.

Treatment: discontinuing medications which may contribute and in moderate to severe cases administering a serotonin antagonist.

Symptom onset is usually rapid.

Can manifest within minutes of drug exposure.

SS manifests with a wide range of clinical findings.

Mild symptoms may only consist of tachycardia, shivering, sweating, dilated pupils, myoclonus, tremor as well as hyperreflexia.

A moderate syndrome includes additional abnormalities: such as hyperactive bowel sounds, hypertension and hyperthermia with temperature as high as 40 �C (104 �F).

Overactive reflexes and clonus may be more profound in the lower limbs than in the upper limbs.

CNS status changes include hypervigilance, agitation and seizures.

Severe symptoms include severe tachycardia, and hypotension that may lead to shock.

Fever above 41.1 �C (106.0 �F) may be life-threatening.

The symptoms are often described as a clinical triad of abnormalities of cognitive, autonomic, and somatic effects.

Cognitive effect alterations: headache, agitation, hypomania, mental confusion, hallucinations, and coma.

Autonomic effects include : shivering, sweating, hyperthermia, hypertension, tachycardia, nausea, and diarrhea.

Somatic effects include: myoclonus, hyperreflexia and tremor.

Patients with end-stage renal disease who are on selective serotonin reuptake inhibitors (SSRIs) and hemodialysis, are prone to developing serotonin toxicity.

Many medications either alone or in combination can produce serotonin syndrome.:

Antidepressants, monoamine oxidase inhibitors (MAOIs), TCAs, SSRIs, SNRIs, bupropion, trazodone, and mirtazapine.

The  combination is an SSRI with an MAOI can precipitate this syndrome and therefore should be used with great caution. 


The development of serotonin syndrome is concentration dependent. 



Opioids, tramadol, tapentadol, fentanyl, pentazocine, buprenorphine, oxycodone, hydrocodone

CNS stimulants, phentermine, diethylpropion, serotonin releasing agents like amphetamines, sibutramine, methylphenidate, methamphetamine, cocaine,

5-HT1 agonists triptans,

L-Dopa, valproate, buspirone, lithium, linezolid, dextromethorphan,5-hydroxytryptophan, chlorpheniramine, risperidone, olanzapine, ondansetron, granisetron, metoclopramide, ritonavir.

Many cases occur in patients who have ingested combinations of drugs that synergistically increase synaptic serotonin.

The combination of MAOIs, alcohol or other serotonin agonists or precursors pose a particularly severe risk of a life-threatening serotonin syndrome.

Reported to occur in patients of all ages, including the elderly, children, and even newborn infants due to in utero exposure.

Serotonergic toxicity of SSRIs increases with dose, but it is insufficient to cause fatalities from serotonin syndrome in healthy adults.

Serotonin is a neurotransmitter involved in aggression, pain, sleep, appetite, anxiety, depression, migraine, and vomiting.

Overstimulation of primarily the 5-HT2A receptors appears to contribute substantially to the condition.

Noradrenergic CNS hyperactivity may play a role as CNS norepinephrine concentrations are increased in serotonin syndrome and levels appear to correlate with the clinical outcome.

NMDA receptor antagonists and GABA have been suggested as affecting the development of the syndrome.

Serotonin toxicity is more pronounced following supra-therapeutic doses and overdoses.

No laboratory test for serotonin syndrome exists.

Diagnosis is by symptom observation and investigation of the patient’s history.

The most important symptoms for diagnosing serotonin syndrome are tremor, extreme aggressiveness, akathisia, or clonus, spontaneous, inducible and ocular.

Assessment of deep-tendon reflexes, muscle rigidity, the dryness of the oral mucosa, the size and reactivity of the pupils, the intensity of bowel sounds, skin color, and the presence or absence of sweating should be noted.

History of prescription and over-the-counter drugs, illicit substances, and dietary supplements have been implicated in the development of serotonin syndrome.

Hunter Criteria-a patient must have taken a serotonergic agent and meet one of the following conditions:

Spontaneous clonus, or Inducible clonus plus agitation or diaphoresis

Ocular clonus plus agitation or diaphoresis

Tremor plus hyperreflexia

Hypertonism plus temperature > 38C (100F) plus ocular clonus or inducible clonus

Serotonin toxicity presents with a characteristic picture, but in some situations it may go unrecognized because it may be mistaken for a viral illness, anxiety, neurological disorder, anticholinergic poisoning, sympathomimetic toxicity, or worsening psychiatric condition.

Most often confused with serotonin syndrome is neuroleptic malignant syndrome.

In both conditions, autonomic dysfunction and altered mental status develop, however, they have different underlying dysfunction: serotonin excess vs dopamine blockade.

Serotonin toxicity has a rapid onset after the administration of a serotonergic drug.

Fluoxetine and its metabolite norfluoxetine have longer half-lives 


than other selective serotonin reuptake inhibitors (SSRIs) and can therefore precipitate this syndrome even if discontinued for up to 6 weeks before the patients begin taking another serotonergic agent. 


Irreversible monoamine oxidase inhibitors (MAOIs), can cause symptoms to persist for days to weeks even with treatment.

Serotonin toxicity responds to serotonin blockade such as drugs like chlorpromazine and cyproheptadine.

Serotonin syndrome causes hyperkinesia and clonus and neuroleptic malignant syndrome is associated with bradykinesia and extrapyramidal rigidity,


stopping the use of the precipitating drugs,

Administration of serotonin antagonists such as cyproheptadine.

supportive care to control of agitation,

Control of autonomic instability

control of hyperthermia.

After ingesting a large dose of a serotonergic agent, administering activated charcoal within an hour of overdose may help in gastrointestinal decontamination.

Treatment intensity depends on the severity of symptoms.

For patients with mild symptoms discontinuation of the offending medication or medications, and providing benzodiazepines for myoclonus is sufficient.

Moderate cases benefit from serotonin antagonists, and have their fever and

cardiorespiratory abnormalities corrected.

The serotonin antagonist cyproheptadine is the recommended initial therapy.

For severe case administering atypical antipsychotic drugs with serotonin antagonist activity such as olanzapine may be beneficial.

Olanzapine and risperidone are atypical antipsychotics, that induce a serotonin syndrome and also treat this syndrome:5HT-2A and 5HT-3A receptor antagonism by these atypical antipsychotics, resulting in serotonin accumulation and cumulative  activation of 5HT-1A receptors. 

Critically ill patients should receive additional therapies including sedation or neuromuscular paralysis.

With autonomic instability, such as low blood pressure, treatment with sympathomimetics such as epinephrine, norepinephrine, or phenylephrine may be necessary.

Hypertension or tachycardia can be treated with short-acting antihypertensive drugs.

Treatments include the control of agitation due to the extreme possibility of injury, but physical restraints are not recommended.

The agitation can cause muscle breakdown and rhabdomyolysis.

Treatment includes reducing muscle over-activity via sedation with a benzodiazepine.

In severe cases muscular paralysis with vecuronium, intubation, and artificial ventilation may be required.

Succinylcholine is not recommended for muscular paralysis as it may increase the risk of cardiac arrhythmia from rhabdomyolysis induced hyperkalemia.

Antipyretic agents are not recommended as the increase in body temperature is due to muscular activity and not to a hypothalamic temperature set point abnormality.

Most cases resolve within 24 hours of stopping serotonergic drugs.

Bromocriptine, a dopamine agonist used to treat neuroleptic malignant syndrome, may exacerbate serotonin syndrome by increasing serotonin levels.


To prevent this syndrome: avoidance of multidrug regimens and to discontinue any serotonergic agent before starting another. 

Patients with mild cases are monitored for worsening of symptoms.

There must be a a high clinical suspicion for serotonin syndrome, as early recognition and treatment of serotonin syndrome can prevent significant morbidity and mortality.

Symptoms, such as delirium, may persist for a longer time frame in patients having a long elimination half-life, active metabolites, or a protracted duration of action.

Muscle pain and weakness persisting for months, can occur rarely.

Associated with a favorable prognosis.

The incidence may be increasing as a larger number of pro-serotonergic drugs that are now being used.

About 14 to 16 percent of patients who overdose on SSRIs are thought to develop serotonin syndrome.

Common lab abnormalities include metabolic acidosis, rhabdomyolysis, elevated liver functions, DIC, and kidney failure.

Treatment includes removal of the offending agent, intravenous fluids, control of agitation.

As hyperthermia and muscle rigidity are common, supportive treatment to prevent secondary complications is primary, including airway protection and neuromuscular paralysis control.

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