Clinical manifestations

Presentation and course

Clinical manifestations of the syndrome are as follows:

The onset of serotonin syndrome ranges from minutes after receiving the second drug to weeks after a stable dosage. Most of the patients present with symptoms of serotonin syndrome within 24 hours of medication initiation, overdose, or change in dosage. Most cases involve only minor symptoms that resolve over 12 to 24 hours; other cases may proceed on to more serious sequelae, such as takotsubo syndrome (28). Severity of overall clinical presentation varies from mild state of serotonin-related symptoms to full-blown serotonin syndrome. A severe case of serotonin syndrome due to overdose of venlafaxine presented with ocular flutter in addition to agitation, myoclonus, fever, and tachycardia (53). Myoclonus and autonomic hyperactivity abated after injection of midazolam, but ocular flutter persisted, and the patient died a few days later.

There are some difficulties with the clinical diagnosis of serotonin toxicity, particularly using Sternbach's criteria (57). Retrospective analysis of prospectively collected data show that, of numerous clinical features associated with serotonin toxicity, only clonus (inducible, spontaneous, or ocular), agitation, diaphoresis, tremor, and hyperreflexia are needed for accurate prediction of serotonin toxicity as diagnosed by a clinical toxicologist. The Hunter Serotonin Toxicity Criteria were developed using these seven clinical features and were found to be simpler, more sensitive, and more specific than Sternbach’s criteria (10).

Prognosis and complications

Most patients recover from serotonin syndrome following drug withdrawal and minor supporting therapy, as this is a self-limiting condition. There are, however, reports of severe complications such as seizures, disseminated intravascular coagulation, respiratory failure, and severe hypothermia, with deaths in a few cases. A young man, following MDMA 3, 4-methylenedioxymethamphetamine (ecstasy) ingestion, presented with severe rhabdomyolysis, multiple organ failure, and severe serotonin syndrome with temperature 108.9 °F (42.7 °C), but he made a full recovery within three weeks following aggressive supportive care including ventilatory support (05).

A female patient with a preliminary diagnosis of serotonin syndrome, as she was on several SSRIs including venlafaxine, presented with altered level of consciousness, headaches, seizure, and visual changes, and her imaging findings were consistent with posterior reversible encephalopathy syndrome (31). She recovered following discontinuation of medications. In another instance of posterior reversible encephalopathy syndrome, a hypertensive young male with a history of chronic tension-type headache and depression had been receiving amitriptyline and paroxetine when increase in the dose of paroxetine led to the development of various new clinical features, fulfilling three Hunter criteria of serotonin syndrome (46). MRI brain revealed high-signal intensity lesions on T2 fluid-attenuated inversion recovery and T2-weighted imaging in the posterior regions of the occipital, parietal, temporal, and cerebellum lobes, suggestive of posterior reversible encephalopathy syndrome. The patient responded to cyproheptadine. Autonomic hyperactivity due to serotonin syndrome is the most likely explanation of this association.

Biological basis

Etiology and pathogenesis

Serotonin syndrome may result from overdose of serotonergic drugs as well some drugs of abuse with serotonergic effect. However, the most common cause is the interaction between serotonergic agents and MAO inhibitors. It may also result as an adverse effect of serotomimetic drugs. A study has devised a serotonergic expanded bioactivity matrix by using a molecular bioinformatics, polypharmacologic approach for assessment of the participation of individual 5-HT drugs in serotonin syndrome reports (04). The results of this study suggest a possible polypharmacologic role in serotonin syndrome and off-target receptor activity may help explain differences in severity of toxicity as well as clinical presentation.

Serotonin syndrome due to drugs of abuse. High doses of stimulants such as methamphetamine and cocaine with ecstasy increase the risk of serotonin syndrome. Serotonin precursors also influence the course of serotonin syndrome when used with ecstasy. Monoamine oxidase inhibitors are most likely to lead to serious increases in serotonin when used with ecstasy.

Serotonin syndrome as an adverse reaction of antidepressant monotherapy. Serotonin syndrome has been reported in patients treated with tricyclic antidepressants, such as clomipramine and moclobemide, which are known to increase synaptic serotonin level and serotonergic activity in the brain.

Serotonin syndrome due to monotherapy with reversible MAO inhibitors is extremely rare. Serotonin syndrome has been described as an adverse effect of rasagiline, an irreversible MAO-B inhibitor (14).

Serotonin syndrome may result from serotonin reuptake inhibitor monotherapy but is not common because of the wide therapeutic window of these drugs. Rapid titration of fluoxetine has been reported to contribute to serotonin syndrome under the stress of deployment (29). Mirtazapine monotherapy has been reported to induce serotonin syndrome. A possible mechanism is overstimulation of serotonin type 1A receptors in the brainstem and spinal cord in an individual with risk factors for hyperserotoninemia due to reduced acquired endogenous serotonin metabolism. Diagnosis of serotonin syndrome induced by mirtazapine and venlafaxine was confirmed in a patient by positive challenge, de-challenge, and re-challenge, with final resolution of symptoms 48 hours after discontinuation of both drugs (08). Escitalopram, the newest selective serotonin reuptake inhibitor, has also been associated with serotonin syndrome. Overdose of vilazodone, a SSRI with partial 5HT1A agonism, is associated with serotonin syndrome (20).

Serotonin syndrome has been reported with use of milnacipran, an antidepressant that inhibits the reuptake of serotonin and norepinephrine and is also used for the treatment of fibromyalgia (59).

HIV-positive patients receiving antiretroviral and antidepressant therapies may develop serotonin syndrome. In these cases, serum antidepressant levels rise due to inhibition of P450 enzymes by antiretroviral drugs such as protease inhibitors and nonnucleoside reverse transcriptase inhibitors; relief of symptoms occurs by reduction of antidepressant dosage.

Atypical antipsychotics. Serotonin syndrome has been reported as a rare adverse effect of ziprasidone monotherapy (30). It is an agonist of 5-HT1A receptor and potent antagonist of 5-HT1D, 5-HT2A, and 5-HT2C receptors as well as moderate inhibitor of serotonin reuptake.

Antimigraine drugs. Patients with migraine are reported to have developed symptoms suggestive of serotonin syndrome. Several drugs were used in these cases. Dihydroergotamine, an ergot derivative, is associated with serotonin syndrome. In each instance, the symptoms were transient, and there was full recovery. Sumatriptan has agonist action on the presynaptic and postsynaptic 5-HTID receptor, but none of the controlled studies of it reported serotonin syndrome. There are, however, case reports of serotonin syndrome associated with triptan monotherapy (54). In 2006, the FDA issued an alert that risk of serotonin syndrome increases due to interaction of triptans with other serotonergic drugs. A 14-year study that used electronic health record data from the Partners Research Data Registry concluded that the risk of serotonin syndrome associated with concomitant use of triptans and SSRIs or SNRIs was low, although coprescription of these drugs is common and did not decrease after the 2006 FDA advisory (43). These results question the validity of the FDA warning and suggest that it should be reconsidered.

Overdosage with antidepressants. Overdose of the following antidepressants has been reported to be associated with serotonin syndrome:

Combined overdose of MAO inhibitors and serotonergic drugs can result in serotonin syndrome with a fatal outcome. Symptoms and signs of the syndrome may not develop until 6 hours to 12 hours after the overdose.

Miscellaneous drugs. Serotonin syndrome has been reported to be induced by dextromethorphan administrated as an antitussive at the conventional dose (26). Serotonin syndrome has been reported following overdose of a centrally acting muscle relaxant, metaxalone, in patients on SSRI therapy (32). The mechanism of action of metaxalone is not known but is assumed to have serotonergic effects.

Serotonin syndrome was reported in a young female following treatment with the atypical antipsychotic paliperidone for new-onset psychosis when the dose was increased to 12  mg per day (60). Paliperidone (9-hydroxyrisperidone), a dopamine antagonist and 5-HT2A antagonist, is the primary active metabolite of risperidone and is assumed to act via similar pathways.

A patient with bipolar disorder II who was well controlled with lithium and quetiapine therapy developed serotonin syndrome on treatment with tramadol for fibromyalgic pain, but symptoms resolved after discontinuation of tramadol (52). Tramadol, a synthetic opioid that binds to μ-opioid receptors, is also a weak inhibitor of reuptake of norepinephrine and serotonin.

Several antiviral medications have been studied to help treat COVID during the recent pandemic. A case report was published describing a patient developing serotonin syndrome that was precipitated by Paxlovid, which is a combination medication consisting of nirmatrelvir and ritonavir (38).

Poisoning. Serotonin syndrome is rarely reported with herbal medicines. It may occur in some cases of poisoning with plants. Serotonin syndrome has been reported in three cases of psilocybin mushroom poisoning (58).

Drug interactions. Drug interactions are the most important and most frequent causes of serotonin syndrome. A classification of these interactions according to drug category is shown in Table 1.

Table 1. Drug Interactions Associated with Serotonin Syndrome

Interactions involving serotonin reuptake inhibitors

Interaction of two serotonin reuptake inhibitors. Serotonin syndrome can be induced by the synergistic effect of two drugs from this category, such as venlafaxine and fluoxetine or fluvoxamine and mirtazapine.

Serotonin reuptake inhibitors and MAO inhibitors. The use of fluoxetine and MAO inhibitors, either together or in close succession, has been reported to be accompanied by serotonin syndrome in several cases. Serotonin syndrome has also been reported to be induced by the interaction of moclobemide with the serotonin reuptake inhibitor, imipramine. Serotonin syndrome due to the interaction of fluoxetine with selegiline has been described. Serotonin syndrome has been described as an interaction of citalopram with the antibiotic linezolid, which is a weak monoamine oxidase inhibitor (35). An integrated approach suggests that linezolid is more likely to cause serotonin syndrome when coadministered with serotonergic agents such as citalopram as inferred from their pharmacological properties (15). Another case of serotonin syndrome was described as drug interaction when linezolid was added to a drug regimen of lithium, venlafaxine, and imipramine (37; 13).

Cases of serotonin syndrome have been described as an interaction between sertraline selective serotonin reuptake inhibitor and MAO inhibitors: isocarboxazid, phenelzine, and tranylcypromine. This syndrome can also occur if fluoxetine is started within two weeks after discontinuation of tranylcypromine, a MAO inhibitor.

Serotonin reuptake inhibitors and tryptophan. Fluoxetine, a specific inhibitor of serotonin reuptake into neurons, has been found to be effective in the treatment of obsessive-compulsive disorders. Fluoxetine, when combined with L-tryptophan, can lead to the development of a toxic reaction resembling serotonin syndrome. Such reactions have occurred in patients who had no adverse effects while on treatment previously with fluoxetine alone. A possible mechanism of this adverse reaction is that tryptophan increases the central nervous system levels of serotonin.

Serotonin reuptake inhibitors and dexfenfluramine. Concern has been expressed that a combination of these two medications could produce serotonin syndrome. However, no such cases have been reported yet.

Selective serotonin reuptake inhibitor and carbamazepine. Serotonin syndrome has been reported with combination of carbamazepine and fluoxetine therapy for affective disorders, but the symptoms usually resolve after discontinuation of fluoxetine. The pathomechanism of serotonin syndrome in such cases is not clear. A fatal case of serotonin syndrome has been reported with concomitant use of paroxetine and carbamazepine.

Serotonin reuptake inhibitors and lithium. Serotonin syndrome has been reported when fluvoxamine is added to long-standing lithium therapy. Recovery usually occurs after discontinuation of fluvoxamine and replacement by an antidepressant that is not a serotonin reuptake inhibitor.

Serotonin reuptake inhibitors and opioids. Serotonin syndrome has been reported as an interaction among fentanyl, an opioid, and citalopram. However, there is a case report of a child who developed serotonin syndrome from the use of fentanyl alone, without concomitant medications known to cause serotonin syndrome (50). Discontinuation of fentanyl in this case led to complete recovery.

Serotonin reuptake inhibitors and linezolid or methylene blue. Serotonin reuptake inhibitors and linezolid (an antibiotic) or methylene blue (a drug used to treat methemoglobinemia) can interact to trigger serotonin syndrome according to a warning issued by the FDA in 2011. Concomitant use of linezolid, an antibiotic, with methadone (a serotonin reuptake inhibitor) has been reported to be involved in serotonin syndrome (34).

Serotonin reuptake inhibitor (paroxetine) and cold remedy. Serotonin syndrome has been described as an interaction between paroxetine and an over-the-counter cold remedy containing ephedrine and dextromethorphan. Serotonin syndrome has also been reported as an interaction of SSRI escitalopram with dextromethorphan (11).

Serotonin reuptake inhibitor (sertraline) and anesthetics. Serotonin syndrome has been described after local anesthetic blocks on a patient who was on sertraline therapy. The likely explanation is that that the medications used for anesthesia (lidocaine, midazolam, and fentanyl) bind to plasma proteins and cause an increased free fraction of sertraline owing to displacement from plasma proteins.

Serotonin reuptake inhibitors and methylene blue. Methylene blue (a MAO inhibitor) is used for the treatment of ifosfamide-induced encephalopathy, and serotonin syndrome has been reported by their concomitant use (36).

Serotonin reuptake inhibitor (paroxetine) and clonazepam. There is a case report of serotonin syndrome following use of clonazepam in a patient who was on paroxetine therapy for anxiety. Her symptoms resolved after treatment with intravenous lorazepam. This interaction is of clinical importance because patients with anxiety disorders may take these two medications together and may develop serotonin syndrome.

Interactions involving tricyclic antidepressants

Tricyclic antidepressants and MAO inhibitors. This combination is generally considered to be without risk of an interaction. However, serious side effects, including fatalities, can occur with the combination of imipramine, a tricyclic antidepressant, and MAO inhibitors. Clomipramine, a tricyclic antidepressant, is involved in several interactions with MAO inhibitors.

Clomipramine, a tricyclic antidepressant, given together with moclobemide, a selective MAO inhibitor, has been reported to produce serotonin syndrome fulfilling the criteria of Sternbach. Fatal cases of serotonin syndrome due to simultaneous ingestion of an overdose of moclobemide and clomipramine have been reported.

Serotonin syndrome has also been reported as the result of an interaction between clomipramine and phenelzine, an MAO inhibitor.

Tricyclic antidepressants and antipsychotics. Serotonin syndrome occurred with simultaneous use of the olanzapine (an atypical antipsychotic) and a clomipramine tricyclic antidepressant but resolved after discontinuation of antidepressants and administration of biperiden and cyproheptadine.

Clomipramine and S-adenosylmethionine. S-adenosylmethionine stimulates serotonin and norepinephrine metabolism in the brain and is used in the treatment of depression. Serotonin syndrome has been reported in patients with combined clomipramine and S-adenosylmethionine therapy and is attributed to the synergic action of these two drugs.

Clomipramine and lithium. Serotonin syndrome has been reported after the addition of lithium to clomipramine therapy. Treatment with lithium alone, after discontinuation of clomipramine, does not lead to a recurrence of serotonin syndrome.

Interactions involving MAO inhibitors

MAO inhibitor and tricyclic antidepressants. Selegiline, a selective MAO inhibitor, is used in the treatment of Parkinson disease. Selegiline's package insert was revised to reflect the potential risk of adverse effects when it is used in combination with selective serotonin reuptake inhibitors and tricyclic antidepressants.

MAO inhibitors and serotonin reuptake inhibitors. MAO inhibitors are known to cause serotonin toxicity when administered with selective serotonin reuptake inhibitors. Intravenous methylene blue, used for identification of parathyroid gland during surgery, is a MAO inhibitor and has been reported to precipitate serotonin syndrome in patients using selective serotonin reuptake inhibitors. Venlafaxine, a selective serotonin reuptake inhibitor, has been reported to interact with MAO inhibitors to produce serotonin syndrome.

MAO inhibitors and tryptophan. The combination of MAO inhibitors and tryptophan can produce serotonin syndrome.

MAO inhibitors and lithium. Serotonin syndrome has been reported following treatment with this combination. It is possible that lithium may intensify the effect of serotonin, although it is not involved in the metabolism of serotonin.

MAO inhibitors and dextromethorphan. Serotonin syndrome can develop after taking an over-the-counter cold remedy containing dextromethorphan, which can block the neural uptake of serotonin.

MAO inhibitors and meperidine. Meperidine (pethidine) blocks the neuronal uptake of 5-hydroxytryptamine and its interaction with MAO inhibitors can lead to serotonin syndrome. The MAO inhibitor and meperidine interaction has two distinct forms: an excitatory and a depressive form. Meperidine should not be used in the presence of MAO inhibitors because of the risk of fatal excitatory interaction (serotonin syndrome). Cases have been reported of meperidine-induced serotonin syndrome. Morphine does not cause this excitatory reaction and is the drug of choice under these circumstances.

MAO inhibitors and ecstasy. Marked hypertension, diaphoresis, hypertonicity, and altered mental status can develop after ingesting ecstasy and phenelzine. Sympathomimetic-MAO inhibitor interaction can cause excessive release of endogenous bioactive amines leading to a reaction that resembles serotonin syndrome but does not fulfill the diagnostic criteria.

Miscellaneous interactions

L-Dopa and bromocriptine. L-dopa induced serotonin syndrome can follow the use of bromocriptine therapy in Parkinson disease. Acute administration of levodopa-carbidopa could have produced a sudden displacement of endogenous serotonin into the synaptic cleft and on to serotonin receptor sites, thus, increasing the availability of serotonin in the synapse. Because bromocriptine also enhances serotonin metabolism in the CNS, serotonin syndrome could have resulted from a synergistic effect of the two drugs. An atypical case of serotonin syndrome related to levodopa use in a patient with probable Lewy body dementia and an absence of history of a known serotonergic drug has been reported, indicating that levodopa can contribute to its occurrence (27).

Lithium and clozapine. Patients treated with a combination of lithium and clozapine can develop reversible neurologic symptoms such as myoclonus and agitation. Some of these neurologic symptoms appear to be early manifestations of serotonin syndrome, and the pathomechanism of these symptoms may be the interaction of the serotonergic effects of clozapine and lithium. Lithium has also been shown to facilitate the onset of serotonin syndrome with L-tryptophan and MAO inhibitor combination without rise of its serum levels.

Mirtazapine and metoclopramide. Mirtazapine, an antidepressant, acts as an antagonist of certain adrenergic and serotonin receptors. Metoclopramide, used for the treatment of gastroesophageal reflux disorder, interacts with receptors for acetylcholine and dopamine. A patient with bipolar disorder who was taking mirtazapine presented developed serotonin syndrome after taking metoclopramide, but the symptoms subsided after reduction of dose of mirtazapine and treatment with lorazepam (19).

Ritonavir and SSRIs. Ritonavir is used in combination with therapy for COVID-19 and can trigger serotonin syndrome in patients with concomitant treatment with SSRIs and SNRIs, mainly due to diminished elimination. In the first two reported cases, the respective administration of lopinavir/ritonavir with an SNRI (duloxetine) and lithium, and lopinavir/ritonavir with risperidone (a second-generation antipsychotic) and morphine, resulted in a combination that triggered typical serotonin syndrome with rapid improvement of the symptoms after their withdrawal (33). As risperidone is a CYP2D6 and CYP3A4 substrate, both of which are inhibited by ritonavir, an increase in its serum concentrations likely occurred.

Trazodone and buspirone. Buspirone, a partial 5-hydroxytryptamine 1 agonist, can contribute to the development of serotonin syndrome in patients who have been on trazodone therapy previously.

Trazodone with isocarboxazid and methylphenidate. Serotonin syndrome has been reported with simultaneous use of trazodone (a nontricyclic, nontetracyclic antidepressant) and methylphenidate. Trazodone has a weak 5-hydroxytryptamine reuptake inhibiting action and a metabolite, m-chlorophenylpiperazine, which has partial agonist activity at many 5-hydroxytryptamine subtypes.

St. John's Wort combined with antidepressants. Hypericin, the major active ingredient of St. John’s Wort, has many psychoactive properties and is used as a nonprescription herbal medicine for the treatment of several conditions, including depression, anxiety, insomnia, and inflammation. Several cases of serotonergic syndrome have been reported in patients who have combined prescription antidepressants with St. John's Wort.

L-tryptophan is a precursor of 5-hydroxytryptamine. Ingestion of excessive amounts of pure L-tryptophan by normal subjects can produce significant CNS signs and symptoms. The synthesis of serotonin begins when ingested tryptophan crosses the blood-brain barrier via a nonspecific amino acid transporter and enters neurons to be hydrolyzed, resulting in placement into storage vesicles ready for release into the synaptic cleft with depolarization of presynaptic neurons. The following manifestations have been recorded in well-designed experiments in human volunteers:

These effects were due to raised levels of 5-hydroxytryptamine induced by L-tryptophan ingestion. These symptoms may be present in serotonin syndrome, but pure L-tryptophan has not been shown to induce the full-blown serotonin syndrome. The enzyme MAO (MAO inhibitor) is involved in the degradation of 5-hydroxytryptamine, and concomitant use of MAO inhibitors may lead to accumulation of 5-hydroxytryptamine and its neurologic effects. The syndrome can be blocked by using various 5-hydroxytryptamine precursors in combination with medications that increase their bioavailability.

According to 5-hydroxytryptaminergic hypothesis of obsessive-compulsive disorders, there is hypersensitivity of 5-hydroxytryptamine receptors. This lends support to the use of 5-hydroxytryptamine uptake inhibitors in obsessive-compulsive disorders. Serotonin syndrome may be due to drug effects causing enhanced transmission at the 5-hydroxytryptamine 1A level or at the postsynaptic level.

The reports of serotonin syndrome due to drug interaction are mostly anecdotal, but the evidence that symptoms are due to 5-hydroxytryptamine is based on animal experiments. 5-hydroxytryptamine 1A activation of serotonin receptors in the brainstem and spinal cord with overall enhancement of neurotransmission is a possible mechanism.

The mechanism underlying serotonin syndrome following interaction between a MAO inhibitor and a serotonin reuptake inhibitor is that MAO can no longer perform its function of degrading serotonin. Restoration of enzymes that perform the degradation takes about two weeks following cessation of therapy, and serotonin syndrome can develop if a MAO inhibitor is switched over to a serotonin reuptake inhibitor within less than two weeks after discontinuation of the MAO inhibitor.

The recreational drug ecstasy stimulates the release and inhibits the reuptake of serotonin. Ecstasy can produce mild versions of the serotonin syndrome and can aggravate the symptoms by interacting with MAO inhibitors.

Serotonin syndrome bears a striking clinical resemblance to high pressure neurologic syndrome, which is a sequela of deep diving and is an additional support for the serotonin theory of high pressure neurologic syndrome.

Central 5-hydroxytryptamine 1A receptor is not the only receptor subtype that is involved in the etiology of serotonin syndrome. Another receptor that appears closely related to the syndrome is the 5-hydroxytryptamine 2A receptor. The appearance of the most severe serotonin syndrome symptoms may be related to the agonism of these receptors, as its stimulation can cause platelet aggregation, bronchoconstriction, vasoconstriction (and consequent hypertension), and behavioral cognitive changes characteristic of this syndrome (45). Other factors that may contribute are the endogenous as well as iatrogenic deficits in the peripheral 5-hydroxytryptamine metabolism, the activation of several 5-hydroxytryptamine subtypes, and a stimulus for the release of 5-hydroxytryptamine. A patient's genetic profile can amplify exposure risk, as many serotonergic drugs are metabolized by CYP450 enzymes and functions of these enzymes may be altered polymorphisms (44)

Predisposing factors for the development of serotonin syndrome are as follows:

Epidemiology

The incidence of serotonin syndrome in humans is difficult to determine as there are no universally accepted criteria for its diagnosis. The syndrome may be underreported due to the lack of awareness of this syndrome among medical professionals. The prevalence of this syndrome appears to be increasing, and the two likely explanations are increase in the use of drugs and combinations that lead to it as well as increasing recognition of this syndrome. Approximately 7300 diagnosed cases of serotonin syndrome occur each year worldwide and about 100 of these cases result in death. Considering the millions of patients who are exposed to a combination of drugs that can produce serotonin syndrome, the frequency of occurrence is rare.

There has never been a population-based prospective study on serotonin syndrome, but other studies give some insight into the relative incidence of this disease. Some studies have used a combination of MAO inhibitors and tryptophan in a prospective manner to measure clinical efficiency and adverse effects. The patients who showed improvement frequently experienced adverse symptoms such as the feeling of intoxication, ataxia, and drowsiness, which were not seen in the control group receiving MAO inhibitor and placebo. These symptoms did not completely fulfill the criteria of serotonin syndrome and were seldom the cause for withdrawal of therapy.

In a large pharmacovigilance database in France, 125 cases (84%) were associated with a serotonergic drug, of which SSRIs were the most frequent (42%) and serotonin-noradrenalin reuptake inhibitors were involved to a lesser extent (01). Most of the cases (59%) resulted from pharmacodynamic drug-drug interactions, most often involving serotonin reuptake inhibitors and opioids, but also occurred with a single serotonergic drug in 40% of cases. Finally, a major pharmacokinetic drug-drug interaction may have played a role in 20 of cases.

Prevention

Substances that deplete 5-hydroxytryptamine or block 5-hydroxytryptamine receptors have been shown to prevent serotonin syndrome in experimental animals. Blockade of 5-hydroxytryptamine 1 receptors rather than of 5-hydroxytryptamine 2 receptors is required. Cyproheptadine, a nonspecific 5-hydroxytryptamine receptor antagonist, can block serotonin syndrome in animal models. A patient on multiple serotonergic agents who was at high risk for development of serotonin syndrome received prophylactic treatment with cyproheptadine, which was effective and well tolerated (07). Beta-blockers have been reported to block 5-hydroxytryptamine receptors and prevent serotonin syndrome.

The combination of drugs known to produce serotonin syndrome should be avoided as a preventive measure. Caution should be exercised in prescribing serotomimetic agents after the discontinuation of an MAO inhibitor or when commencing an MAO inhibitor after discontinuation of a serotomimetic agent. Most of the MAO inhibitors are irreversible enzyme inhibitors, and following their cessation, enzyme replacement may take a few weeks. Serotonin syndrome has been reported in patients prescribed clomipramine up to four weeks after terminating clorgyline. Therefore, 4 to 6 weeks should elapse between the switch over of these two classes of medications. Long-term administration of high-dose fluoxetine may require a 3-month washout period.

Differential diagnosis

Confusing conditions

In the older literature on adverse effects of antidepressants and their interactions with other drugs, serotonin syndrome was not recognized. Conditions to be considered in differential diagnosis of serotonin syndrome include the following:

Carcinoid syndrome. This is due to tumors of enterochromaffin cells that originate mainly in the gastrointestinal tract and secrete a variety of hormones. Serotonin is the most common secretory product of carcinoid tumors and is synthesized by enzymatic modification of circulating tryptophan. Manifestations include the classic triad of flushing, diarrhea, and valvular heart disease. This occurs in 5% of all patients with carcinoid tumors. The diagnosis of this syndrome is established by the presence of a carcinoid tumor and it is differentiated from serotonin syndrome by absence of relationship to medications known to produce the serotonin syndrome. Carcinoid syndrome can be controlled with somatostatin analogues, and surgery is the mainstay of treatment.

Neuroleptic malignant syndrome. Some of the cases of serotonin syndrome are difficult to differentiate from neuroleptic malignant syndrome. A comparison of the clinical features of neuroleptic malignant syndrome and serotonin syndrome is shown in Table 2.

Table 2. Comparison of the Clinical Features of Neuroleptic Malignant Syndrome and Serotonin Syndrome

Adverse drug reactions related to neuroleptics and serotonergic agents could produce symptoms compatible with both conditions.

A feature common to both syndromes is hyperthermia. Serotonin and dopamine are both important neurotransmitters in temperature regulation, and it is likely that hyperthermic reactions result from drug-induced changes in the levels of these neurotransmitters. Toxic reactions to the designer drug ecstasy resemble both serotonin syndrome and neuroleptic malignant syndrome because it affects both serotonin- and dopamine-containing neurons. The predominant manifestations, however, are those of serotonin syndrome. The two syndromes can overlap as shown by the case of a child who presented with fever, hypertonia, tremors, and clonus 1 day after starting metoclopramide; the clinical course was suggestive of neuroleptic malignant syndrome (as well as serotonin syndrome, which can both be triggered by metoclopramide) (03).

Tyramine "cheese reaction" and overdose of MAO inhibitors. This is well known following ingestion of cheese by patients on MAO inhibitor. The distinguishing feature of this is hypertension, which is not a characteristic of serotonin syndrome.

Patients with an overdose of MAO inhibitors may show symptoms like those of serotonin syndrome. In severe cases death may result from hyperthermia, cardiopulmonary arrest, or disseminated intravascular coagulation with renal failure.

The diagnosis of serotonin syndrome may be overlooked in patients with Parkinson disease who are on serotonin reuptake inhibitors because of depression.

Diagnostic workup

Most commonly used diagnostic criteria of serotonin syndrome are those suggested by Sternbach (57):

The diagnosis is based on history and clinical features. Various EEG abnormalities that are noted in cases of serotonin syndrome are: delta range activity, slow waves, spikes and waves, and triphasic waves. This may be an important test in the setting of concomitant neurologic disorders.

Management

In clinical practice, serotonin syndrome is often transient and does not require discontinuation of the offending medication or any special treatment. If the clinical features are a cause for concern, the offending medication should be discontinued and supportive measures should be used.

There are no prospective studies of the evaluation of treatment of serotonin syndrome in man. Management strategies are based on studies in animal models and case reports on human patients. In most of the reported cases, symptoms resolved after discontinuation of the offending medications. After discontinuation of the contributing agents, milder cases can be sent home and followed up. Management of moderate to severe cases involves hospitalization with close monitoring and appropriate supporting measures. Apnea and coma may occur in serotonin syndrome and require intensive care. The following medications have been investigated for counteracting the serotonin syndrome.

The following drugs have been used for alleviating rigidity and tremor, but no clear cut benefit on serotonin syndrome has been established:

For practical management of the patient, the following medications may be tried in the order listed.

Serotonin syndrome can be treated successfully with sedative propofol and muscle relaxant rocuronium followed by intubation, artificial respiration, and cooling with a hypothermia blanket. Electroconvulsive therapy was used effectively for the treatment of severe serotonin syndrome in two patients (42). Aripiprazole, a drug with high affinity to 5HT1A as well as 5HT2A receptors, was reported to prevent severe symptoms of serotonin syndrome in spite of high serotonin levels as it protects both postsynaptic receptors from a surplus of serotonin (49).

Special considerations

Pregnancy

The low reported incidence of serotonin syndrome is mostly due to underrecognition, as the syndrome can mimic other more common obstetric diagnoses such as preeclampsia. A case of a pregnant patient with schizophrenia was admitted to an intensive care unit where she was managed conservatively by discontinuation of the offending drug, intravenous fluids, supplemental oxygen, telemetry, hourly neurologic assessments, and monitoring of fetal status (02). After stabilization, the patient was transferred to daily inpatient psychiatry for continued care.

Infants exposed to selective serotonin reuptake inhibitors during late pregnancy are at increased risk for serotonergic central nervous system adverse effects. There is a case report of an infant with suspected serotonin toxicity following in utero exposure to 20 mg escitalopram throughout pregnancy (09). Close monitoring for symptoms of serotonin toxicity and prolongation of QTc on electrocardiograph of infants exposed to escitalopram during pregnancy is recommended. The severity of these symptoms is significantly related to cord blood 5-hydroxyindoleacetic acid levels.

Anesthesia

Serotonin syndrome may complicate the administration of drugs frequently used in anesthetic practice, including pethidine and tramadol. Although most cases improve with symptomatic and supportive care, severe cases need intensive care and frequently require mechanical ventilation (25). A patient was being treated with fluoxetine (a selective serotonin reuptake inhibitor), developed serotonin syndrome during intravenous anesthesia with remifentanil (an opioid) and propofol, but recovered following discontinuation of remifentanil (06). Serotonin syndrome has been reported due to an interaction between selective serotonin reuptake inhibitors and fentanyl, a commonly used opioid in anesthesia practice (17).