Prevalence and Correlates of Serotonin Syndrome in Real-World Inpatients.

BACKGROUND: Serotonin syndrome (SS) is a potentially life-threatening adverse drug reaction due to an increased central and peripheral serotonin activity, which usually presents as a triad of behavioral changes, neuromuscular excitability, and autonomic instability. Probably SS is often misdiagnosed, and its symptoms are mistaken for psychiatric symptoms or general medical issues: the true incidence of SS is not clear, and literature concerning potential risk factors is scarce. Our aims were to examine the prevalence of SS in a naturalistic sample of hospitalized patients and to evaluate potential factors related to the risk of developing the condition. METHODS: The sample included 133 patients being treated with serotonergic medications admitted to the psychiatric inpatient unit of the San Luigi Gonzaga Hospital. All patients received a medical examination (including a neurological examination) within 24 hours of admission. Serotonin syndrome was diagnosed according to Hunter Criteria. RESULTS: Sixteen patients (12%) were diagnosed with SS. In the subgroup of subjects with SS, we found a higher rate of male patients when compared with subjects with no SS (62.5% vs 33.3%, P = 0.023). CONCLUSIONS: SS probably is an underestimated condition, which should be carefully assessed in patients on serotonergic medications. Male gender was the only factor found to be significantly related to a higher risk of developing SS. Further studies on larger samples are needed, to gain more information on possible risk factors and to identify subjects more prone to developing SS, given the potential risk for patients' health.

Linezolid-associated serotonin toxicity: a systematic review.

PURPOSE: This systematic review aims to evaluate the existing evidence associating linezolid to serotonin toxicity when used as monotherapy or when co-administered with other serotonergic agents. METHODS: A systematic literature search using PubMed (till March 2023), IDWeek meetings (2003-2023), the European Congress of Clinical Microbiology and Infectious Disease Annual Meetings (2001-2023), and the American College of Clinical Pharmacy (1999-2023) identified studies and abstracts related to linezolid and serotonin toxicity. RESULTS: A total of 84 studies were included. The data collected in retrospective/observational studies compared the incidence of serotonin toxicity with linezolid monotherapy at 0.0050% and linezolid combination therapy at 0.0134%. All cases which discontinued linezolid and serotonergic agent/s at signs and symptoms of toxicity found symptom resolution; 75% of cases reported serotonin toxicity resolution within 24-48 h after discontinuation. CONCLUSION: Linezolid therapy when optimal should not be deferred due to the risk of serotonin syndrome. The data collected reveals a low prevalence of serotonin toxicity in both linezolid monotherapy and linezolid concurrent with other serotonergic agents.

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.

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.

Antidepressant-induced serotonin syndrome in older patients: a cross-sectional study.

BACKGROUND: Widespread prescription of antidepressants and their resulting role in serotonin syndrome (SS) are of great importance for clinical practice in the elderly. This study aims to investigate possible associations of antidepressant drug-induced SS with related variables in these patients. METHODS: A total of 238 older adults using antidepressants were included. Patients who fulfilled the Hunter Serotonin Toxicity Criteria (HSTC) for SS were considered as the clinical groups (mild, moderate, or severe), and those who did not as the control group. We recorded all patients' demographic and clinical characteristics, including age, gender, comorbidity index, number of medications, daily equivalent dose of the relevant antidepressant according to fluoxetine per day, electrocardiogram test results, laboratory results, and management. RESULTS: The mean age of all patients was 75.4 ± 7.6 years and 63.4% were female. Sixty patients had SS, while 178 patients did not. There was a significant difference between those with and without SS in terms of gender, frequency of combination antidepressant therapy, and daily equivalent antidepressant dose (P < 0.05). The most common diagnostic findings in SS patients were tremor and hyperreflexia and 31.7% was mild, and moderate in 68.3% with higher median age and number of medications (P < 0.041). Antidepressants were discontinued in all patients regardless of severity, of whom 71.7% were treated with benzodiazepines and 36.7% with cyproheptadine. After adjusting for age and sex, association with use of SSRI + SNRI, use of any combination therapy, and daily equivalent dose remained significant. CONCLUSIONS: The widespread single or combined use of antidepressants in older adults represents an increased clinical concern for SS and physicians should be aware of this drug-related complication in older patients.

Serotonin syndrome by drug interactions with linezolid: clues from pharmacovigilance-pharmacokinetic/pharmacodynamic analysis.

PURPOSE: To characterize the post-marketing reporting of serotonin syndrome (SS) due to drug-drug interactions (DDIs) with linezolid and investigate the relationship with pharmacokinetic/pharmacodynamic (PK/PD) properties of serotonergic agents. METHODS: We queried the worldwide FDA Adverse Event Reporting System to extract SS records due to DDIs where linezolid was reported as suspect. For each serotonergic agent concomitantly reported, proportion of SS reports and mean number of DDIs were calculated and three different "SS reporting zones" were created. Relevant PK (peak concentration, area under plasma concentration curve, volume of distribution (VD), and lipophilicity) and PD (values of binding affinity (Ki) and IC50 for serotonin reuptake transporter (SERT) and 5-HT2A) parameters were extracted for each serotonergic agent, and relevant PK/PD indexes were calculated to assess correlation with mean number of DDIs (PV index). RESULTS: Six hundred sixty-nine reports of SS mentioning linezolid were found, being linezolid-citalopram (N = 69; 10.3%) the most frequently DDI reported. Citalopram and methadone showed respectively the highest proportion of SS reports (0.28%) and the lowest mean number of DDIs (1.41). Citalopram, escitalopram, and methadone emerged as red (i.e., alert)-zone medications: they exhibited high lipophilicity and large VD (proxies of excellent central nervous system penetration) coupled with high potency. Among PK/PD indexes, a significant correlation with PV index was found for VD/Ki SERT ratio (p = 0.05). DISCUSSION: Our integrated approach suggests that linezolid is more likely to cause SS when co-administered with citalopram, escitalopram, and methadone, as inferred from their pharmacological properties. Proper management of SS should be tailored on a case-by-case basis.

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.

Serotonin syndrome from sertraline monotherapy.

Serotonin syndrome (SS) is a rare, potentially life-threatening adverse drug reaction. Selective serotonin reuptake inhibitors (SSRIs) are among a number of pharmaceuticals that all contribute to SS, but SS caused by SSRI monotherapy is rare. We present a case of probable sertraline-induced SS. A 36-year-old male presented to the emergency department four times in one week with a constellation of autonomic and neuromuscular symptoms. He had been taking sertraline at a therapeutic dose for less than three months. Moderate SS was diagnosed using the Hunter criteria during the fourth visit, when it was seen that he had hyperreflexia and inducible ankle clonus. The patient's symptoms resolved within 24 hours with lorazepam, intravenous fluids, and discontinuation of sertraline. In the emergency department it is important to have a high clinical suspicion for SS even if the patient is taking SSRI monotherapy at therapeutic doses.

Serotonin syndrome: a clinical review of current controversies.

Serotonin syndrome is a state of increased central and peripheral serotonin (5-hydroxytryptamine) activity. Unless recognized and treated early, serotonin syndrome can lead to seizures, shock and death. Both substances with direct and indirect serotonergic activity can precipitate the syndrome. Serotonin syndrome can occur not only in psychiatric but also in non-psychiatric settings. Yet, clinicians may not be familiar with the condition. We explore some of the current controversies regarding serotonin syndrome. Specifically, we tested the following assumptions: (i) Despite being rare, serotonin syndrome is still clinically relevant; (ii) The Hunter criteria are the gold standard for diagnosing serotonin syndrome; (iii) Hyperthermia is common in cases of serotonin syndrome; (iv) Serotonin syndrome usually develops fast; (v) Severe serotonin syndrome usually or almost exclusively involves monoamine oxidase inhibitors. We found that (i) despite being rare, serotonin syndrome was clinically relevant, (ii) the Hunter criteria could not be regarded as the gold standard for the diagnosis of serotonin syndrome since they missed more cases than the other two diagnostic criteria systems (Sternbach and Radomski criteria), (iii) Serotonin syndrome could occur in the absence of an elevated temperature, (iv) fast onset could not be regarded as a reliable clinical sign of serotonin syndrome, and (v) absence of monoamine oxidase inhibitors treatment did not exclude a diagnosis of serotonin syndrome. Clinicians should bear in mind that in the context of relevant drug history, serotonin syndrome may still be possible in these circumstances.

A Mixed Presentation of Serotonin Syndrome vs Neuroleptic Malignant Syndrome in a 12-Year-Old Boy.

BACKGROUND: Neuroleptic malignant syndrome (NMS) and serotonin syndrome (SS) are serious medical conditions associated with commonly prescribed psychiatric medications. Although the mechanisms differ, they can be clinically difficult to distinguish. We report a case of a pediatric patient with complicated psychiatric history that developed features of both syndromes in the setting of polypharmacy. CASE: A 12-year-old boy with a history of developmental delay, attention-deficit hyperactivity disorder, and posttraumatic stress disorder presented to the emergency department with behavior changes consisting of delayed reactions, gait instability, drooling, and slowed movements. Ten days before presentation, his outpatient psychiatrist had made multiple medication changes including discontinuation of cyproheptadine (an appetite stimulant) and initiation of aripiprazole. On arrival, the patient was noted to be tachycardia and hypertensive for age. He was disoriented, intermittently agitated, and tremulous with increased tonicity, clonus in the lower extremities, and mydriasis. He was supportively treated with lorazepam and intravenous fluids while discontinuing potential offending agents. His course was complicated by hypertension and agitation managed with dexmedetomidine infusion and benzodiazepines. His mental status, tremors, and laboratory values began to improve over the next 2 days, and eventually transitioned to the inpatient psychiatric unit on hospital day 7. DISCUSSION: Diagnosis of NMS or SS can be difficult when there is overlap between syndromes, particularly in the setting of multiple potential offending agents or underlying developmental delay. In addition, pediatric patients may present atypically as compared with adult patients with the same condition. CONCLUSION: The use of antipsychotic medications for young children with behavioral problems has risen dramatically in the last decade, increasing their risk for developing SS or NMS.

An 11-year retrospective review of cyproheptadine use in serotonin syndrome cases reported to the California Poison Control System.

WHAT IS KNOWN: Cyproheptadine is a serotonin and histamine antagonist that has been suggested as a treatment for serotonin syndrome in case reports. OBJECTIVE: We sought to examine the differences between outcomes and treatment recommendations in patients who received and did not receive cyproheptadine for a probable serotonin syndrome. METHODS: A retrospective review of cases reported to the California Poison Control System between 2006 and 2017 involving cyproheptadine administration or consideration for treatment of a probable serotonin syndrome. RESULTS AND DISCUSSION: A total of 1420 cases were identified and 288 cases met the inclusion criteria. Of these, 68 (23.1%) patients received cyproheptadine treatment and were significantly older (mean age 49.7 vs 33.5 years, P < 0.00001), intubated (n = 35, 51% vs n = 62, 28%, P < 0.05) and, although not statistically significant, were more frequently admitted to a critical care unit (n = 56, 82.3% vs n = 154, 70.0%, P = 0.09). There were no significant differences in serious outcomes (moderate or worse effects) or hospitalization rates (OR, 1.09, 95% CI, 0.49-2.64 and OR, 1.99, 95% CI, 0.86-4.58). There were eight fatalities, of which two patients received cyproheptadine. All fatalities were acute polypharmacy ingestions and had manifested severe symptoms (seizures, hypotension or hyperthermia) either prior to the administration or consideration of cyproheptadine therapy. Cyproheptadine was not administered in 138 (48%) cases primarily due to minimal clinical severity and patient improvement (43%), and not recommended in 82 (28%) cases for reasons from waiting for response to other supportive measures (30%), limited evidence of efficacy (28%) and undetermined diagnosis (14.6%). WHAT IS NEW AND CONCLUSION: The benefits of and indications for cyproheptadine are uncertain and questionable for the management of a serotonin syndrome. Future recommendations on its use should be based on diagnostic criteria, severity of symptoms and management in conjunction with other supportive measures.

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.

Serotonin Syndrome in a Pediatric Patient After Vilazodone Ingestion.

Serotonin syndrome (SS) is a serious toxicity that manifests with symptoms such as tremor, hyperthermia, agitation, and altered mental status that may lead to seizures, coma, or death. Selective serotonin reuptake inhibitors may precipitate SS, particularly in combination with other drugs that possess serotonergic activity. We present a case of SS in a 14-month-old after an ingestion of the selective serotonin reuptake inhibitor vilazodone.

Demystifying serotonin syndrome (or serotonin toxicity).

OBJECTIVE: To review the symptoms of serotonin toxicity (commonly referred to as serotonin syndrome) and the causative drugs and their mechanisms of action, and to equip primary care providers with practical strategies to prevent and identify serotonin toxicity. QUALITY OF EVIDENCE: PubMed and Google Scholar were searched for relevant articles on serotonin toxicity, the causes, and the differential diagnosis using search terms related to serotonin toxicity (serotonin syndrome, serotonin toxicity, serotonin overdose), causes (individual names of drug classes, individual drug names), and diagnosis (differential diagnosis, neuroleptic malignant syndrome, anticholinergic toxicity, discontinuation syndrome, malignant hyperthermia, serotonin symptoms). Experts in psychiatric medicine, psychiatric pharmacy, clinical pharmacology, and medical toxicology were consulted. Evidence is level II and III. MAIN MESSAGE: Serotonin toxicity is a drug-induced condition caused by too much serotonin in synapses in the brain. Cases requiring hospitalization are rare, and mild cases caused by serotonin-mediated side effects are unlikely to be fatal. Patients present with a combination of neuromuscular, autonomic, and mental status symptoms. Serotonin-elevating drugs include monoamine oxidase inhibitors, serotonin reuptake inhibitors, and serotonin releasers. Most cases involve 2 drugs that increase serotonin in different ways; the most concerning combination is a monoamine oxidase inhibitor with a selective serotonin reuptake inhibitor or a serotonin-norepinephrine reuptake inhibitor. CONCLUSION: Family physicians play a key role in identifying and preventing serotonin syndrome by teaching patients to recognize symptoms and monitoring patients throughout therapy.

[Age 89 years, depression, fall with pelvic fracture, severe confusion - serotonin syndrome : Differential diagnosis, importance of CYP450 and economic considerations]. / 89 Jahre, Depression, Sturz mit Beckenfraktur, schwerste Verwirrtheit ­ das serotonerge Syndrom : Differenzialdiagnose, Bedeutung von CYP450 und ökonomische Betrachtungen.

A case study of an 89-year-old patient is reported, who was admitted to hospital because of immobility due to pain. After the cause of the pain could initially be clarified and treated, the further clinical course in this very old woman showed an alarming symptom complex of agitation, confusion and cognitive deterioration, which took on grave forms. The work-up of this case showed a typical constellation of pain and depression in old age; however, the pharmaceutical treatment in this case is not atypical and could lead to a severe serotonin syndrome. The interaction, diagnostics, differential diagnosis, pharmacological, functional, codification and economic aspects of the course of the disease are discussed.

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.