Serotonin Syndrome

Serotonin syndrome (SS) is a complication resulting from excessive effects of serotonin on the central nervous system, and it usually results from taking medications, such as the antidepressant agents known as selective serotonin reuptake inhibitors (SSRIs), that elevate levels of serotonin either therapeutically or with intentional overdoses. Many reported cases are the result of unintended drug interactions that elevate the effects of the serotonergic medication.1,2 Because prompt recognition and appropriate treatment are necessary for patient recovery, all critical care practitioners should be aware of this syndrome. However, a study reported that more than 85% of physicians are unaware of SS as a clinical diagnosis.3 The purpose of this column is to review the pathophysiology, epidemiology, signs and symptoms, and appropriate treatment of SS.Serotonin is produced by decarboxylation and hydroxylation of l-tryptophan. Several serotonin receptors are divided into seven 5-hydroxytryptophan (5-HT) families, and several of these receptors have subtypes.1 Agonism of 5-HT2A receptors contributes most substantially to SS. Serotonin is involved in regulating wakefulness, affective behavior, thermoregulation, emesis, and sexual behavior as well as regulation of vascular tone and gastrointestinal motility.The first cases of SS were reported in the 1950s with monoamine oxidase inhibitors (MAOIs). Reports have increased as the use of SSRIs has increased. A 2002 report from the Toxic Exposure Surveillance System identified 26 733 exposures to SSRIs, resulting in 7349 major or moderate adverse effects and 93 deaths.4 A 2004 report from the Toxic Exposure Surveillance System identified 48 204 exposures to SSRIs that resulted in moderate or major adverse outcomes in 8187 patients and death in 103 patients, with most fatalities associated with coingestions of other substances.5The signs and symptoms of SS can run the spectrum from mild to life-threatening and are summarized in Table 1. As reviewed by McAllen and Rhoney,6 3 sets of criteria have been developed to diagnose SS: the Sternbach criteria, the Hunter Serotonin Toxicity criteria, and the Radomski criteria.7–9Table 2 summarizes the criteria for each of these sets. The Sternbach criteria rely heavily on mental status changes, and patients with delirium due to anticholinergics may be diagnosed as positive for SS by the Sternbach criteria.9 The Radomski criteria differentiate mild and severe SS. The Hunter criteria may be the most accurate criteria, with 84% sensitivity and 97% specificity when compared to diagnosis by a medical toxicologist.8Serotonin syndrome is most commonly caused by SSRIs. Other drugs that can lead to the development of SS include tricyclic antidepressants (TCAs), opiate analgesic agents, antibiotics, antiemetics, antimigraine agents, illicit drugs, and over-the-counter drugs (eg, St. John’s wort, dextromethorphan). Table 3 lists serotonergic agents that can cause SS either alone or in combination with other agents. Serotonin syndrome can be precipitated when MAOIs are given in combination with serotonin agonists, especially SSRIs. Taking multiple causative agents, self-poisoning with serotonergic agents, and drug interactions among SSRIs can lead to SS. People who are on a chronic regimen of SSRIs have a higher risk of SS, but it also has been documented in patients taking therapeutic doses of SSRIs.16Monoamine oxidase inhibitors are used to treat depression and anxiety, but they are used rarely because of the risk of toxicity and food and drug interactions. Examples of MAOIs include phenelzine and isocarboxazid. Selective serotonin reuptake inhibitors and MAOIs can interact, overstimulating the serotonin receptors in the brain. The serotonin transporter on presynaptic terminals of neurons mediates the reuptake of serotonin into the presynaptic terminal. Treatment with an SSRI blocks reuptake and results in enhanced and prolonged serotonergic neurotransmission. Normally, serotonin in a neuron is removed from the synapse by active transport back into the presynaptic neuron. In the presynaptic neuron, serotonin is either “repackaged” for release into the synapse or broken down by monoamine oxidase.10 Monoamine oxidase is an intracellular enzyme that is bound to the mitochondrial membrane, and its function is to inactivate norepinephrine, dopamine, and serotonin via oxidation. When monoamine oxidase is inhibited, neurotransmitters accumulate in the presynaptic nerve.17When an MAOI is taken concomitantly with an SSRI, the serotonin reuptake mechanism as well as serotonin breakdown is blocked by the MAOI. As a result, no serotonin is released into the synapse. To avoid potential interaction between medications causing SS, clinicians should wait an adequate length of time between discontinuation of one medication and initiation of another; this waiting time is known as a “washout period.” For example, the SSRI fluoxetine has a long half-life as a result of its metabolite, so a 5-week washout period between discontinuing fluoxetine and adding an MAOI is required to decrease the risk of SS.18 Other SSRIs should have a washout period of 2 weeks.10Venlafaxine is a serotonin-norepinephrine reuptake inhibitor (SNRI) that binds both serotonin and norepinephrine inhibitors. A 14-day washout period is required after ending MAOI therapy and before starting venlafaxine treatment.19 Only a 7-day washout is required after discontinuing venlafaxine and beginning an MAOI. Duloxetine, another SNRI, requires only a 5-day washout period after discontinuing duloxetine and before beginning MAOI treatment.19Trazodone and nefazodone are weak inhibitors of serotonin uptake. Serotonin syndrome can occur if MAOIs are administered with these drugs. Of note, trazodone has serotonin reuptake inhibition at antidepressant doses of 150 mg or higher.20Tricyclic antidepressants (TCAs) have actions similar to those of the SNRIs but have more adverse effects than SNRIs. Each TCA has different selectivity toward serotonin and norepinephrine. For example, clomipramine is a potent serotonin reuptake inhibitor. The other TCAs can be used with caution for patients who are severely resistant to treatment.20 Tricyclic antidepressants should not be used concurrently with MAOIs or within 14 days of discontinuing MAOI therapy. Cyclobenzaprine, carbamazepine, and oxcarbazepine are structurally related to the TCAs; however, these drugs do not block serotonin or norepinephrine uptake, so they can be used with caution.20Opiates such as dextromethorphan, fentanyl, meperidine, methadone, and tramadol have serotonin reuptake inhibition. The level of risk with serotonergic opiates is most likely low based on the level of evidence that exists, but opiates not known to be serotonergic reuptake inhibitors should be used with caution.18 Morphine, hydromorphone, aspirin, and acetaminophen are presumed safe analgesic alternatives.2Buspirone is a 5-HT1A partial agonist, and it could theoretically contribute to SS; therefore, it should be administered with caution.20 However, no good evidence has shown that buspirone causes SS when administered with SSRIs and MAOIs.21Linezolid is an oxazolidinone antibiotic drug that was originally found to have psychotropic effects through mild reversible nonselective inhibition of monoamine oxidase.12 This drug was also found to have activity against drug-resistant bacteria such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. When linezolid is taken with serotonin agonists, a small risk of SS exists. Quinn and Stern 12 and Lawrence et al14 concluded that decisions about discontinuing or not initiating SSRIs with linezolid need to be based on risks versus benefits of need for this antibiotic versus the risk of SS.5-Hydroxytryptamine receptor agonists (triptans) are antimigraine agents that activate the 5-HT1B and 5-HT1D receptors in the brain. When used in combination with an SSRI or SNRI, SS can occur. However, the evidence supporting this association is controversial. In July 2006, the US Food and Drug Administration (FDA) issued a warning that SS can occur when a triptan is taken with an SSRI or SNRI. Evans et al22 concluded that only class IV evidence (uncontrolled studies, case series, case reports, expert opinions) is provided in the literature and through the FDA registration of adverse events to support the July 2006 FDA statement. They also concluded that data were conflicting and that no evidence-based recommendations could be made. Sclar et al23 reviewed the number of patients who were prescribed triptan and an SSRI or SNRI after the FDA warning in 2006 (1.8% of patients). They concluded that not enough literature is available as to the number of cases of SS resulting from the concomitant use of triptan with SSRI or SNRI. Note that ergotamine and its analogs do not seem to cause SS as reported in the literature.21MDMA (Ecstasy) is a recreational drug that is an amphetamine derivative and directly releases serotonin from the nerve terminals, which can induce SS when used alone or facilitated by high temperatures and dehydration. Lysergic acid diethylamide does not seem to cause SS in either usual doses or overdoses.21Synthetic cathinones, also known as bath salts, have been associated with SS. Bath salts increase the synaptic concentration of serotonin and inhibit monoamine uptake transporters.24Hypericum perforatum, commonly known as St. John’s wort, is an herb available over the counter that is used to treat depression. St. John’s wort has been associated with SS when taken with 5-HT reuptake inhibitors.13Early recognition of SS is crucial. If a patient is taking multiple agents that can cause SS, clinicians should counsel him or her on the signs and symptoms of SS. The treatment of SS is summarized in Table 4. First-line treatment includes withdrawal of the serotonergic drugs. Benzodiazepines, such as diazepam, can be used to control agitation in mild, moderate, and severe cases. Mild cases are typically managed by supportive care, withdrawal of causative agents, and treatment with benzodiazepines.1Moderate cases include cardiorespiratory and thermal abnormalities, and these patients may benefit from an antidote such as cyproheptadine. Cyproheptadine is a 5-HT2A antagonist; however, evidence is inconclusive on its effectiveness in SS. Cyproheptadine is available only in oral form, but tablets may be crushed and administered via a nasogastric tube.1 Chlorpromazine or olanzapine can also be used, but they have adverse and toxic effects. Chlorpromazine can cause hypotension, lower the seizure threshold, and cause dystonic reactions.18,26 Olanzapine has a potential to lower the seizure threshold as well.Severe cases caused by hyperthermia may require intubation, neuromuscular paralysis, and sedative agents.25 Antipyretic agents do not help with hyperthermia in these cases, because hyperthermia in SS is caused by muscle hypermetabolism and not by central nervous system effects. Muscle relaxants can be used for muscle rigidity and hyperthermia caused by SS; however, the use is controversial, because no controlled trials support it.1,10,28 In severe cases, nondepolarizing agents, such as vecuronium, can be used in conjunction with intubation and ventilation. Note that succinylcholine should not be used in these patients for paralysis because of risk for arrhythmias.1Serotonin syndrome can be a life-threatening adverse reaction to SSRIs and other drugs and supplements that have serotonergic effects or that may interact with these agents. Prompt recognition, withdrawal of precipitating agents, and treatment may prevent complications from SS.