Serotonin syndrome-A focused review.

BACKGROUND: Serotonin syndrome is a potentially life-threatening syndrome with manifestations spanning from mild adverse effects to life-threatening toxicity. The syndrome is caused by overstimulation of serotonin receptors by serotonergic drugs. Since the use of serotonergic drugs is increasing, primarily due to the widespread use of selective serotonin reuptake inhibitors, cases of serotonin syndrome have likely seen a parallel increase. The true incidence of serotonin syndrome remains unknown due to its diffuse clinical presentation. OBJECTIVES: This review aims to provide a clinically focused overview of serotonin syndrome, covering its pathophysiology, epidemiology, clinical manifestations, diagnostic criteria, differential diagnosis and treatment, as well as classifying serotonergic drugs and their mechanism of action. The pharmacological context is emphasized, as it is crucial for the detection and management of serotonin syndrome. METHODS: Focused review based on a literature search using the PubMed database. FINDINGS AND CONCLUSION: Serotonin syndrome can occur through therapeutic use or overdose of a single serotonergic drug or as a drug interaction between two or more serotonergic drugs. Central clinical features consist of neuromuscular excitation, autonomic dysfunction and altered mental status, occurring in a patient undergoing new or altered serotonergic therapy. Early clinical recognition and treatment are crucial to prevent significant morbidity.

Hypothermia as a Possible Symptom of Serotonin Toxicity: A Case Report.

Background There are three commonly used sets of criteria to diagnose serotonin syndrome and all three diagnostic tools have all been shown to have shortcomings that do not fully encompass the possible symptoms of serotonin toxicity. Objective To describe a case of an atypical presentation of possible drug-induced serotonin syndrome, characterized by hypothermia, night sweats, muscle tremors, and confusion. Setting A rural and medically underserved area in eastern Washington State. Practice Description This patient case was identified as a part of a project to identify and intervene with complex and high-risk patients from local rural and underserved populations. The pharmacist identified the symptoms of possible drug-induced serotonin syndrome during a comprehensive medication review with the patient. Results The pharmacist identified a possible case of drug-induced serotonin syndrome and made a recommendation to the patient's physician that led to discontinuation of both fluoxetine and trazodone. At the follow-up visit, the patient reported that his symptoms had resolved completely. Discussion The three sets of diagnostic criteria for serotonin syndrome all include fever as a symptom, but do not list hypothermia. Effects at various 5-HT receptors and receptor subtypes have been linked to symptoms often seen in serotonin syndrome, but there are gaps in the currently used diagnostic criteria. Conclusion Pharmacists' comprehensive review of medications can allow identification of symptoms, such as hypothermia to identify possible serotonin syndrome.

High risk and low prevalence diseases: Serotonin syndrome.

INTRODUCTION: Serotonin syndrome is a rare, frequently misdiagnosed, serious condition with high morbidity. OBJECTIVE: This review highlights the pearls and pitfalls of serotonin syndrome, including diagnosis, initial resuscitation, and management in the emergency department (ED) based on current evidence. DISCUSSION: Serotonin syndrome is a potentially deadly toxidrome marked by excess serotonin receptor activity or neurotransmission. Features of serotonin syndrome include 1) neuromuscular excitation such as tremor, hyperreflexia, and clonus; 2) autonomic dysfunction such as tachycardia, hypertension/hypotension, and hyperthermia; and 3) altered mental status such as agitation, delirium, and coma. Although serotonin syndrome may be more obvious in patients who have overdosed on serotonergic agents such as serotonin reuptake inhibitors (SSRIs), multiple other medications may also cause serotonin syndrome. Alternative diagnoses such as sepsis, neuroleptic malignant syndrome, and decompensated hyperthyroidism should be considered. The primary components of therapy include stopping the offending agent and supportive care, which focuses on agitation control, monitoring for and treating hyperthermia, and managing autonomic instability. CONCLUSIONS: An understanding of serotonin syndrome can assist emergency clinicians in diagnosing and managing this disease.

Serotonin Syndrome After Treatment of Nausea and Vomiting in Pregnancy.

BACKGROUND: Nausea and vomiting in pregnancy often require pharmacotherapy for symptom management. Serotonin syndrome is a rare clinical entity that can be precipitated by the medications used to treat nausea and vomiting in pregnancy. CASE: A 35-year-old pregnant individual with a history of hyperemesis gravidarum in an earlier pregnancy requiring prolonged hospitalization presented with nausea and vomiting at 7 weeks of gestation. She was incidentally found to have severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection when she was universally screened at the time of admission. She required pharmacotherapy, including prochlorperazine and ondansetron for treatment of nausea as well as sumatriptan for migraine. She developed acute spasticity, autonomic dysfunction, and temperature rise, precipitated by antiemetic therapy, consistent with serotonin syndrome. The syndrome resolved with supportive care and benzodiazepines. CONCLUSION: Serotonin syndrome is a serious clinical entity that can be provoked by the pharmacotherapy given to treat nausea and vomiting in pregnancy. This medical emergency requires early recognition and prompt management.

Serotonin syndrome.

The serotonin syndrome is a life-threatening adverse drug reaction resulting from excess serotonergic agonism due to interactions between multiple drugs, poisoning, or less commonly due to therapeutic action of a single drug. The central triad of features in serotonin syndrome are altered mental state, autonomic hyperactivity, and neuromuscular abnormalities in the context of a patient with new/altered serotonergic therapy, although not all these features are consistently present in all patients. The severity of serotonin syndrome can be assessed clinically based on the number and severity of features. Severe serotonin syndrome warrants more careful management on a high-dependency unit. In case of temperature exceeding 38.5°C, urgent cooling measures and sedation should be employed, progressing to rapid sequence intubation and paralysis if cooling measures are ineffective.

Previously undiagnosed serotonin toxicity: From pre-anaesthetic assessment to postoperative management - a case report.

Serotonin syndrome (SS), also known as serotonin toxicity, is a life-threatening condition induced by certain drugs that affect serotonin metabolism. We report a case of SS, induced by a combination of three drugs encountered in a patient with a previously suspected allergy to metoclopramide and pitofenone discovered as an "anaesthetic incident". In the immediate postoperative period, following the administration of antiemetic and analgesic treatment, the patient presented generalized myoclonus and intense abdominal pain. The diagnosis of SS was established using the Hunter Criteria. After the discontinuation of potentially triggering medication and anticonvulsant therapy, the patient was discharged from the ICU with complete resolution within six days. Given the increased use in clinical practice of drugs that may interfere with serotonin metabolism, the rising prevalence of mental health disorders and the increasing use of illicit drugs, it is essential for anaesthetists to be aware of the potential for SS occurrence.

[Fatal serotonin syndrome induced by ecstasy consumption]. / Le cas clinique du mois. Un cas fatal de syndrome sérotoninergique induit par la consommation d'ecstasy.

The use of amphetamines and amphetamine derivatives such as ecstasy can cause serotonin toxic syndrome, an uncommon but potentially serious adverse effect. Although most of the reported cases evolve spontaneously and favourably, in rare cases, serious complications can occur leading to the death of the patient. We report the case of a 27-year-old man admitted to our emergency department for altered consciousness with hyperthermia at 42°C after illicit drug use. The patient developed severe multivisceral failure and disseminated intravascular coagulopathy despite maximalist management focused on cooling and multiorgan supportive therapy. The patient died within hours of admission. The diagnosis is essentially based on the patient history and clinical examination. The first treatment is to stop the toxic and then, to treat the symptoms and support possible organ failures.

La consommation d'amphétamines et de ses dérivés tels que l'ecstasy peut être responsable d'un syndrome toxique sérotoninergique, effet indésirable peu fréquent mais potentiellement redoutable. Bien que la plupart des cas rapportés évoluent spontanément favorablement, dans de rares cas, de graves complications peuvent survenir pouvant mener jusqu'au décès du patient. Nous rapportons le cas d'un homme de 27 ans, admis dans notre service des urgences pour altération de l'état de conscience avec hyperthermie à 42°C après consommation de drogues illicites. Le patient a développé une défaillance multiviscérale sévère ainsi qu'une coagulopathie intravasculaire disséminée malgré une prise en charge maximaliste centrée sur le refroidissement et le traitement supportif multi-organique. Le patient est décédé quelques heures après son admission. Le diagnostic du syndrome sérotoninergique est essentiellement basé sur l'anamnèse et l'examen clinique. La prise en charge comprend l'arrêt du toxique, le traitement des symptômes et le support des potentielles défaillances organiques.

Too much of a good thing? Diagnosis and management of patients with serotonin syndrome.

Serotonin syndrome is a rare but potentially life-threatening condition caused by excess serotonin in the central and peripheral nervous systems. Patients with serotonin syndrome present with a range of mild to severe autonomic, neuromuscular and mental state signs and symptoms. A variety of drugs affect the serotonin pathways by modifying serotonin release and reuptake mechanisms, or reducing metabolism. There are also several genetic polymorphisms and clinical risk factors that affect the development and course of serotonin syndrome. This article describes the pathophysiology of serotonin syndrome and discusses diagnosis and treatment with reference to a case study of a patient who attended an emergency department (ED) with signs and symptoms of the condition following an increase in antidepressant medicines. The article aims to increase clinicians' awareness of serotonin syndrome to improve identification and treatment of patients who present to EDs with the condition.

Pediatric Emergency Medicine Didactics and Simulation (PEMDAS): Serotonin Syndrome.

Introduction: Serotonin syndrome is caused by an accumulation of serotonin in the body from drug interactions or overdose of serotonergic medications, including commonly used antidepressants. Symptoms can be life-threatening and encompass both neurologic and cardiovascular toxicity, including agitation, seizure, tachycardia, rhabdomyolysis, and hyperthermia. Methods: This simulation case was developed for pediatric emergency medicine fellows and emergency medicine residents in the pediatric emergency department and can be altered to accommodate other learners. The case involved a 16-year-old male, represented by a low- or high-fidelity manikin, who presented with altered mental status/agitation after an overdose of antidepressant medication. The team of learners was required to perform a primary and a secondary assessment; manage airway, breathing, and circulation; and recognize and initiate treatment for serotonin syndrome. The patient had a seizure resulting in airway compromise requiring advanced airway support, as well as developed rhabdomyolysis requiring aggressive fluid hydration. We created a debriefing guide and a participant evaluation form. Results: Fifty-seven participants across five institutions completed this simulation, which included residents, fellows, faculty, and students. The scenario was rated by participants using a 5-point Likert scale and was generally well received. Participants rated the simulation case as effective in learning how to both recognize (M = 4.9) and manage (M = 4.8) serotonin syndrome. Discussion: This pediatric emergency simulation scenario can be tailored for a range of learner backgrounds and simulation environments. We used the participant evaluation form to improve future iterations of the simulation.

Slow on the Uptake, Progression to Heartbreak.

The prevalence of serotonin syndrome increases over the past several years as more serotonergic medications are being used in clinical practice. It is a potentially lethal condition caused by excessive serotonergic activity. Common causes of serotonin syndrome are the use of prescription medications, illicit drugs, or a combination of substances, leading to an increase in the activity of serotonin in the central and peripheral nervous system. The clinical symptoms range from mild to severe. We report a case of a 25-year-old woman with polysubstance abuse, including cocaine, who presented with confusion, rigidity, high-grade fever, and reduced biventricular function on echocardiogram. Based on the combination of substance used history, clinical presentation, and echocardiogram findings, she was diagnosed with serotonin syndrome complicated by takotsubo cardiomyopathy. She improved after being treated in the intensive care unit and was discharged from the hospital. This patient demonstrates the importance of recognizing and promptly initiating management of serotonin syndrome in order to improve morbidity and mortality.

Deep brain stimulation as a possible treatment of hyperthermia in patients with serotonin syndrome.

Maintaining a body temperature within a narrow range is vital for the survival of all mammals, including humans. With the help of optogenetics, a better understanding of the thermoregulatory organs and pathways is achieved. Optogenetic activation of the GABAergic neurons in the ventral part of the lateral preoptic nucleus (VLPO) leads to decrease in the body temperature. On the other hand, number of drugs could alter the thermoregulatory balance, leading to a hyperthermic state, such as serotonin syndrome (SS). SS is a potentially life-threatening clinical condition that occurs as a result of a drug-induced increase in the intrasynaptic serotonin (5-hydroxytryptamine, 5-HT) levels due to overdose of a single drug or due to interaction between two or more drugs with serotonergic mechanism of action. In this hypothesis, we propose a novel method for the treatment of hyperthermia, a core clinical sign of serotonin syndrome, through deep brain stimulation (DBS). An electrode is stereotactically placed in the VLPO, which may lead to reduction of the core body temperature. If proven effective, this technique should be left as a salvage method for reduction of hyperthermia, where the drug treatment is insufficient or ineffective. This technique could be used for the treatment of other syndromes, where hyperthermia takes a central place, including malignant hyperthermia, neuroleptic malignant syndrome, etc. DBS, on the other hand, could be used alone to induce hyperthermia in patients with malignant diseases. Hyperthermia improves the immune response, improves the drug penetration and stop the repair of already damaged tumor cells after chemotherapy or radiotherapy.

The anaesthetist, opioid analgesic drugs, and serotonin toxicity: a mechanistic and clinical review.

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-HT2A receptors, whilst methadone, meperidine, and more weakly tapentadol, bind to 5-HT2A but not 5-HT1A 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.

The Serotonin Syndrome: From Molecular Mechanisms to Clinical Practice.

The serotonin syndrome is a medication-induced condition resulting from serotonergic hyperactivity, usually involving antidepressant medications. As the number of patients experiencing medically-treated major depressive disorder increases, so does the population at risk for experiencing serotonin syndrome. Excessive synaptic stimulation of 5-HT2A receptors results in autonomic and neuromuscular aberrations with potentially life-threatening consequences. In this review, we will outline the molecular basis of the disease and describe how pharmacologic agents that are in common clinical use can interfere with normal serotonergic pathways to result in a potentially fatal outcome. Given that serotonin syndrome can imitate other clinical conditions, an understanding of the molecular context of this condition is essential for its detection and in order to prevent rapid clinical deterioration.

An atypical case of serotonin syndrome with normal dose of selective serotonin inhibitors: A case report.

RATIONALE: As increasing frequency of serotonergic drug use, SS (serotonin syndrome) occurred more than ever. But clinicians have not enough knowledge and experience about SS as a potentially life-threatening condition. SS is usually caused by the increased serotonin activity in the central nervous system which may due to a serotonergic agent overdose or the concomitant use of 2 or more serotonergic antidepressants. We report a case of SS due to a normal dose of selective serotonin inhibitors (SSRIs) thus to remind clinicians to pay attention to such patients and make an early diagnosis and initiation of therapy in the clinical practice. PATIENT CONCERNS: We report here a 49-year-old man presented with lethargic, less communicative, and insomnia for 20 days while a diagnosis of depression was considered and he was treated with SSRIs. DIAGNOSIS: The patient in our case fulfilled the 3 criteria existed now for diagnosing SS, including the Sternbach criteria, Radomski revised diagnostic criteria, and the Hunter serotonin toxicity criteria. INTERVENTIONS: All the antidepressants were stopped and cyproheptadine with an initial dose of 12 mg a day was started along with supportive care. The patient was also admitted to emergency intensive care unit for further treatment. He was sedated and paralyzed by intravenous Midazolam and Clonazepam along with physical cooling and supportive care. OUTCOMES: All of the patient's symptoms abated gradually and he soon could get off the bed and be communicative. Finally, the patient made a full recovery and he was discharged from the hospital. LESSONS: Our case suggests an atypical clinical course while the medicine the patient takes was not in so much dose. We assumed that there may have been some variation in metabolism of these agents, resulting in increased possibility that led to the subsequent syndrome. Thus, it is essential for clinicians to keep in mind when patients taking serotonergic agents who demonstrate acute change in their mental status. Besides, clinicians should be aware of such patients who seem to be sensitive to SSRIs, who may require a genetic testing before the initiation of SSRI therapy.

[The serotonin syndrome: An updated literature review]. / Le syndrome sérotoninergique : une revue actualisée de la littérature.

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.

Neuroleptic malignant syndrome and serotonin syndrome.

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.

Common toxidromes in movement disorder neurology.

BACKGROUND: Physicians can come across patients who are exposed to certain prescription drugs or toxins that can result in adverse effects and complications which have high rates of morbidity and mortality. OBJECTIVE: To summarise the key clinical features and management of the common movement disorder toxidromes relevant to physicians (with an interest in neurology). METHODS: We searched PUBMED from 1946 to 2016 for papers relating to movement toxidromes and their treatment. The findings from those studies were then summarised and are presented here. RESULTS: The key features of 6 of the common movement disorder toxidromes and their treatment are tabulated and highlighted. The management of toxidromes with the highest mortality like neuroleptic malignant syndrome and serotonin syndrome are discussed in detail. CONCLUSION: There are several toxidromes that have the potential to become a serious life-threatening emergency if there is a delay in recognition of key clinical features and instituting the appropriate treatment at the earliest is crucial.

Drug-Induced Serotonin Syndrome.

Serotonin syndrome is a potentially fatal condition caused by drugs that affect serotonin metabolism or act as serotonin receptor agonists. Monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors are the medications most commonly associated with serotonin syndrome. Serotonin syndrome can be mild and of short duration, but a prolonged course, life-threatening complications, and death are possible. Detection of serotonin syndrome is not difficult if the diagnostic criteria are understood and properly used, but the syndrome has no confirmatory tests and other drug-induced syndromes can, to a degree, mimic serotonin syndrome. The treatment is symptomatic and supportive. Antidotal therapies are available, but the evidence for their effectiveness is limited. If serotonin syndrome is promptly identified and aggressively treated, the patient should fully recover.

Serotonin Syndrome from 5-Hydroxytryptophan Supplement Ingestion in a 9-Month-Old Labrador Retriever.

INTRODUCTION: 5-Hydroxytryptophan (5-HTP) supplements are available over the counter and labeled as sleeping aids and anxiolytics for human use. 5-HTP is a serotonin precursor and overdose can lead to serotonin syndrome. CASE REPORT: A 9-month-old female Labrador retriever was evaluated after ingestion of a 5-HTP supplement. Signs of agitation developed within 1 h of ingestion, and emesis was attempted by the owner with  3% hydrogen peroxide (H2O2) orally. On presentation, the dog was obtunded, bilaterally mydriatic and salivating. Physical exam revealed tachypnea, tachycardia, hyperthermia, and hypertension. Eighteen hours post presentation, the dog developed melena, hematemesis, and pigmenturia. A hemogram revealed mild anemia with evidence of oxidative erythrocyte damage (eccentrocytes, Heinz bodies, and siderocytes). A chemistry panel revealed markedly elevated creatine kinase and hyperbilirubinemia, supporting hemolytic anemia. A urinalysis revealed pigmenturia. Hemolytic anemia was presumed to be caused by oxidative damage secondary to gastrointestinal ulceration and circulatory embolism of H2O2. Treatment included fluid therapy, a mannitol constant rate infusion, antiemetics, gastroprotectants, and cyproheptadine as a serotonin antagonist. The patient responded well to treatment and was discharged within 48 h of presentation. DISCUSSION: Serotonin syndrome is an increasingly common toxic syndrome in veterinary medicine with the availability of over-the-counter medications that alter serotonin metabolism. The importance of appropriate client education regarding emesis with H2O2 is highlighted.