DEFINITION
The serotonin syndrome in a potentially life-threatening adverse drug reaction that results from therapeutic drug use, recreational use of certain drugs or inadvertent interaction between drugs. Serotonin syndrome is not an idiopathic drug reaction; it is a predictable consequence of excess serotonergic agonism of central nervous system (CNS) receptors and peripheral serotonin receptors. Some authors strongly prefer the terms serotonin toxicity or serotonin toxidrome because these more accurately reflect the fact that it is a form of poisoning. Excess serotonin produces a spectrum of clinical findings and clinical manifestation of the serotonin syndrome range from barely perceptible to lethal. The death of an 18-year-old patient named Libby Zion in New York City in 1984, which resulted from coadministration of meperidine and phenelzine, remains the most widely recognized and dramatic example of this preventable condition.
( Libby Zion's Lesson: Adverse Drug Reactions and Interactions )
EPIDEMIOLOGY
The incidence of the serotonin syndrome in thought to the mirror the increasing number of proserotoninergic agents being used in clinical practice. In 2002, the Toxic Exposure Surveillance System, which receives case description from office-based practices, inpatient settings, and emergency departments, reported 26,733 incidences of exposure to selective serotonin-reuptake inhibitors (SSRIs) that caused significant toxic effects in 7349 persons and resulted in 93 deaths. (Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose )
The sindrome occurs in approximately 14 to 16 percent of person who overdose on SSRIs.
Drug that have been associated with the serotonin syndrome:
A single therapeutic dose of an SSRI has caused the serotonin syndrome. ( Serotonin syndrome in a child after a single dose of fluvoxamine )
Moreover, the addition of drugs that inhibit cytochrome isoforms CYP2D6 and CYP3A4 to therapeutic SSRI regiments has been associated with the condition. ( Serotonin syndrome in a child associated with erythromycin and sertraline )
Administration of serotonergic agents within five weeks after the discontinuation of fluoxetine therapy has produce a drug interaction culminating in the serotonin syndrome, presumably the result of the demethylation of fluoxetine to norfluoxetine, a serotonergic metabolite with a longer serum half-life than its parent compound. ( Neonatal paroxetine withdrawal syndrome )
Serotonin syndrome following concomitant SSRI or SNRI (Selective Serotonin-Norepinephrine Reuptake Inhibitors) and triptan (5-Hydroxytryptamine Receptor Agonists) use is biologically plausible. SSRIs, SNRIs, and triptans independently increase serotonin levels. Therefore, it is expected that concomitant use of SSRIs or SNRIs and triptans would result in higher serotonin levels than the serotonin levels observed with the use of SSRIs, SNRIs, or triptans alone, potentially leading to serotonin syndrome.
MANIFESTATIONS
Spectrum of clinical findings. Manifestation of the serotonin syndrome range from mild to life-threatening. The vertical arrows suggest the approximate point at which clinical findings initially appear in the spectrum of disease, but all indings may not be consistently present in a single patient with the serotonin syndrome. Severe signs may mask other clinical findings. For example, muscular hypertonicity can overwhelm tremor and hyperreflexia.
The serotonin syndrome encompasses a range of clinical findings:
Mild: afebrile, tachycardia, autonomic findings such as shivering, diaphoresis, or mydriasis. The neurologic examination may reveal intermittent tremor or myoclonus, as well as hyperreflexia.
Moderate: vital-sign abnormalities such as tachycardia, hypertension, hyperthermia (a core temperature as high as 40°C is common in moderate intoxication). Common features of the physical examination are mydriasis, hyperactive bowel sounds, diaphoresis, and normal skin color. Patellar deep-tendon reflexes often demonstrate clonus for several seconds after a single tap of the tendon, whereas the brachioradialis reflex is only slightly increased. Change in mental status include mild agitation or hypervigilance, as well as slightly pressured speech. Patients may easily startle or adopt a preculiar head.turning behavior characterized by repetitive rotation of the head with the neck held in moderate extension.
Severe: severe hypertension and tachycardia that may abruptly deteriorate into frank shock. Agitated delirium as well as muscular rigidity and hypertonicity. The increase in muscle tone in considerably grater in the lower extremities. The muscle hyperactivity may produce a core temperature of more than 41.1°C in life-threatening cases. Laboratory abnormalities that occur in severe cases include metabolic acidosis, rhabdomyolysis, elevated levels of serum aminotransferase and creatinine, seizures, renal failure, and disseminated intravascular coagulopathy. The onset of symptoms is usually rapid, with clinical findings often occurring within minutes after a change in medication or self-poisoning. Approximately 60 percent of patients with the serotonin syndrome present within six hours after initial use of medication, an overdose, or a change in dosing. (Serotonin syndrome. Presentation of 2 cases and review of the literature )
PATHOPHYSIOLOGY ANDMOLECOLAR MECHANISMS
Serotonin is produced by the decarboxylation and hydroxylation of L-tryptophan. Its quantity and actions are tightly regulated by a combination of reutake mechanisms, feedback loops, and metabolizing enzymes.
Pathways by which serotonin acts within the central nervous system, including serotonin reuptake transport, and metabolism of serotonin by monoamine oxidase
Solid-line arrows = agonist action; broken-line arrows = antagonist or inhibitor action. MAOI = monoamine oxidase A inhibitor; LSD = lysergic acid diethylamide; TC = tricyclic; SSRI = selective serotonin reuptake inhibitor; 5-HT = 5-hydroxytryptamine.
Serotonin receptors are divided into seven 5-hydroxytryptamine (5-HT) families, several of which have multiple members. Serotonergic neurons in the CNS are found primarily in the midline raphe nuclei, located in the brain stem from the midbrain to the medulla. The rostral end of this system assists in the regulation of wakefulness, affective behavior, food intake, the thermoregulation, migraine, emesis, and sexual behavior. The neurons of the raphe in the lower pons and medulla participate in the regulation of nociceptin and motor tone. In the periphery, the serotonin system assist in the regulation of vascular tone and gastrointestinal motility. No single receptor appears to be responsible for the development of the serotonin syndrome, although several line of evidence converge to suggest that agonism of 5-HT 2A receptors contribute substantially to the condition.
DIAGNOSIS
A number of diagnostic criteria have been suggested for serotonin toxicity. The first and most commonly used are Sternbach’s criteria. ( Sternbach H. The serotonin syndrome ) Many of the 10 clinical features suggested as typical of serotonin toxicity by Sternbach are non-specific. These would also be commonly observed in many other conditions such as anticholinergic delirium, and alcohol and drug withdrawal states Sternbach’s clinical definition was based on case reports and small published case series. Sternbach recognised that the features were non-specific and specified that other possible causes of the features must be excluded. Unfortunately, this caveat on the original description is almost routinely ignored. Has been recently developed a new diagnostic criteria for serotonin toxicity — the Hunter Serotonin Toxicity Criteria (HSTC) — by studying large numbers of patients ingesting serotonergic agents in overdose. The HSTC can be used to determine whether a patient who has taken an overdose has significant serotonin toxicity.
As the HSTC were validated in the setting of a toxicology service where other drug-induced syndromes are frequent, the criteria are much more specific than Sternbach’s criteria for features that solely relate to serotonin toxicity. Because they are more specific, the HSTC can be used for adverse drug reactions, but have not been validated for this purpose.
MANAGEMENT
Treatment for all forms of serotonin toxicity is supportive care and cessation of any serotonergic medications. Severe serotonin toxicity or serotonin crisis is a medical emergency and initial management must focus on airway, breathing and circulation. Supportive care, including passive and active cooling of the patient, sedation, intubation and muscle paralysis, must take precedence over any specific pharmacological treatment. Hyperthermia and muscle rigidity appear to be the most important effects, and this supportive care can prevent secondary complications, such as rhabdomyolysis, renal failure and disseminated intravascular coagulation.
Serotonin toxicity may progressively increase over a number of hours after ingestion of implicated drugs. Patients who have moderate serotonin toxicity should be observed for a period of 6 hours; however, if a slow-release formulation has been ingested, such as venlafaxine, observation should be continued for 12 hours. It is appropriate to provide symptomatic treatment for these patients, including benzodiazepine sedatives, antiemetics and specific pharmacological therapy. Most patients will improve within 24 hours of ceasing the serotonergic medication.
There may be a role for specific serotonin antagonists in serotonin toxicity, and animal studies provide data that non-specific HT2-antagonists and more selective 5-HT2A-antagonists reverse the lethal effects of serotonin toxicity. ( Potent serotonin (5-HT)(2A) receptor antagonists completely prevent the development of hyperthermia in an animal model of the 5-HT syndrome )
There are numerous case reports of patients improving after being given serotonin antagonists.
( Treatment of the serotonin syndrome with cyproheptadine )
However, it is difficult to separate these “responses” from the natural resolution of toxicity. There are no controlled trials demonstrating their effectiveness and further study is required.
PREVENTION
The serotonin syndrome can be avoided by a combination of pharmacogenomic research, education of physicians, modifications in prescribing practices, and the use of technological advances. The application of pharmacogenomics principles can potentially protect patients at risk for the syndrome before administration of serotonerigc agents. Once toxicity occurs, consultation with a medical toxicologist, a clinical pharmacology service, or a poson-control center can identify proserotonergic agents and drug interaction, assist clinicians in anticipating adverse effects, and provide valuable clinical decision-making experience. The avoid of multidrug regimens is critical to the prevention of the serotonin syndrome. If multiple agents are required, however, computer-based ordering system and the use of personal digital assistants can detect drug interactions and decrease reliance on memory in drug ordering.
