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Most cases of serotonin toxicity are provoked by therapeutic doses of a combination of two or more serotonergic drugs, defined as drugs affecting the serotonin neurotransmitter system. Common serotonergic drugs include many antidepressants, antipsychotics, and opioid analgesics, particularly fentanyl, tramadol, meperidine (pethidine), and methadone, but rarely morphine and other related phenanthrenes. Symptoms of serotonin toxicity are attributable to an effect on monoaminergic transmission caused by an increased synaptic concentration of serotonin. The serotonin transporter (SERT) maintains low serotonin concentrations and is important for the reuptake of the neurotransmitter into the presynaptic nerve terminals. Some opioids inhibit the reuptake of serotonin by inhibiting SERT, thus increasing the plasma and synaptic cleft serotonin concentrations that activate the serotonin receptors. Opioids that are good inhibitors of SERT (tramadol, dextromethorphan, methadone, and meperidine) are most frequently associated with serotonin toxicity. Tramadol also has a direct serotonin-releasing action. Fentanyl produces an efflux of serotonin, and binds to 5-hydroxytryptamine (5-HT) 1A and 5-HT 2A receptors, whilst methadone, meperidine, and more weakly tapentadol, bind to 5-HT 2A but not 5-HT 1A receptors. The perioperative period is a time where opioids and other serotonergic drugs are frequently administered in rapid succession, sometimes to patients with other serotonergic drugs in their system. This makes the perioperative period a relatively risky time for serotonin toxicity to occur. The intraoperative recognition of serotonin toxicity is challenging as it can mimic other serious syndromes, such as malignant hyperthermia, sepsis, thyroid storm, and neuroleptic malignant syndrome. Anaesthetists must maintain a heightened awareness of its possible occurrence and a readiness to engage in early treatment to avoid poor outcomes., (Copyright © 2019 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

The serotonin syndrome is a potentially deadly complication resulting from drug adverse effect, drug-drug interaction or overdose involving one or more serotonergic molecules, e.g., antidepressants, psychostimulants and sometimes an "ignored" serotonergic compound. The serotonin syndrome typically consists of a clinical triad including cognitive/behavioral, neurovegetative and neuromuscular features. However, this syndrome is characterized by major clinical heterogeneity, making the diagnosis difficult in practice. Moreover, many practitioners are quite unaware of this syndrome. Available scores and classifications can help physicians in their diagnosis approach. Knowing the responsible molecules, their potential interactions and mechanisms of action can help preventing this complication allowing therapeutic education among patients. This updated article reviews the clinical presentation, prevention, management, and pathophysiology of the serotonin syndrome, and addresses the most recent advances in pharmacogenetics regarding this syndrome., (Copyright © 2018 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

The clinical manifestation of drug-induced abnormalities in thermoregulation occurs across a variety of drug mechanisms. The aim of this chapter is to review two of the most common drug-induced hyperthermic states, serotonin syndrome and neuroleptic malignant syndrome. Clinical features, pathophysiology, and treatment strategies will be discussed, in addition to differentiating between these two syndromes and differentiating them from other hyperthermic or febrile syndromes. Our goal is to both review the current literature and to provide a practical guide to identification and treatment of these potentially life-threatening illnesses. The diagnostic and treatment recommendations made by us, and by other authors, are likely to change with a better understanding of the pathophysiology of these syndromes., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Serotonin syndrome is gaining attention in perioperative and chronic pain settings due to the growing prevalence of multimodal therapies that increase serotonin levels and thereby heighten patient risk. A patient's genetic make-up may further increase the risk of serotonin syndrome. A case of serotonin syndrome on emergence after general anesthesia is presented. A subsequent cytochrome P4502D6 genetic test result suggested a potential alteration in metabolism. For this patient, who was taking combination antidepressant medications and receiving common perioperative medicines, additive pharmacodynamic effects converged with a pharmacogenetic predisposition, resulting in serotonin syndrome., (© 2013 Elsevier Inc. All rights reserved.)

A patient who manifested signs of serotonin syndrome during an intravenous anesthetic with remifentanil and propofol is presented. The patient displayed lower extremity clonus, nystagmus, and diaphoresis. At the time of surgery, the patient was being treated with fluoxetine (a selective serotonin reuptake inhibitor). A presumptive diagnosis of serotonin syndrome was made intraoperatively and all opioids were discontinued. His symptoms resolved in the Postanesthesia Care Unit without incident., (Copyright © 2013 Elsevier Inc. All rights reserved.)

There is a potential risk that 5-HT(1A) receptor blockade combined with blockade of the 5-HT transporter by an SSRI may cause a toxic increase in 5-HT within the synapse, sparking concern for 'serotonin syndrome', a rare but potentially life threatening condition. We evaluated the safety and pharmacodynamics of the combination of the 5-HT(1A) antagonist lecozotan and the SSRI citalopram in a well-controlled Clinical Pharmacology Unit setting using the Hunter Serotonin Toxicity Criteria (HSTC), a set of validated decision rules featuring neurological and body temperature measurements, to detect any clinically relevant serotonin toxicity. Forty-three young healthy male subjects were randomized, to 2 parallel double-blind treatment groups following a 10-day citalopram 40 mg run-in period: citalopram 40 mg/lecozotan 10mg or citalopram 40 mg/placebo for 9 days. Overall, the combined administration of active drugs was well tolerated, however, one subject experienced moderate hyperreflexia, tremor of the hands, and sweating of hands and feet after 3 days of combined treatment. The event prompted treatment withdrawal and was regarded as mild serotonin toxicity, as per the HSTC. The onset of the event was around the time of peak plasma concentrations (t(max)) of both lecozotan and citalopram, and its time course corresponds to the well-defined PK profile of lecozotan. No evidence of a PK interaction was detected trough lecozotan and citalopram plasma concentrations analysis. The utility of the HSTC in detecting the non-discrete group of symptoms commonly referred to as "serotonin toxicity" was demonstrated in this clinical pharmacology study combining two 5-HT agents in a clinically controlled setting., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: A recent series of case reports has demonstrated a significant, previously unrecognized drug interaction between serotonin reuptake inhibitors (SRIs) and methylene blue (MB)., Objective: The authors review the case reports and clinical audits relevant to this interaction and consider the diagnosis of serotonin syndrome in these cases., Method: Articles were obtained from a systematic search of MEDLINE and PsychInfo databases, and from the bibliographies of relevant articles. Studies were considered relevant if the patient received MB and developed an acute confusional state, neuropsychiatric complications, or autonomic instability., Results: The review identified nine case reports and two retrospective reviews; 26 patients developed an acute confusional state after MB infusion; 24 of these patients were taking an SRI, and 1 was taking clomipramine. Serotonin syndrome was a possible diagnosis in all 25 of these patients., Conclusion: SRIs can interact with MB, causing a serious adverse reaction consistent with serotonin syndrome.

Intrauterine exposure to SSRIs in late pregnancy can cause various serotonergic symptoms in the newborns. We associated the severity of these symptoms to neurotransmitter concentrations and genetic polymorphisms in the cytochrome P450, MAO-A and COMT enzymes. Altogether 20 children with prenatal exposure to citalopram or fluoxetine were genotyped. Infants with two high-activity alleles of the MAO-A gene had significantly higher serotonergic symptom scores than infants with at least one low-activity allele (mean 8.8 vs. 2.4, p=0.024). These infants had also higher cord blood DHPG concentrations (p=0.0054). Carriers of the high-activity COMT alleles had higher cord blood prolactin concentrations (p=0.044). According to our results, the higher serotonergic symptom score and cord blood DHPG concentration in rapid MAO-A metabolizers suggest that norepinephrine may modify the severity of perinatal serotonergic symptoms. The COMT 1947G>A polymorphism may affect the occurrence of respiratory distress symptoms in infants with prenatal SSRI-exposure via a mechanism involving prolactin.