Recurrent Serotonin Syndrome After Ketamine-assisted Electroconvulsive Therapy: A Case Report and Review of the Literature.

Serotonin (5-HT) syndrome (SS) consists of changes in mental status as well as autonomic and neuromuscular changes. Though not well understood, serotonergic pathways have been implicated in the mechanism of action of electroconvulsive therapy (ECT). Ketamine has been used as an induction agent in ECT and as therapy for treatment-resistant depression. Utilizing a case report and literature review, we explored the underlying serotonergic mechanisms of ECT and ketamine by which a syndrome of serotonin toxicity may be precipitated. We describe the case of a 72-year-old woman who developed recurrent SS on 2 occasions in similar circumstances involving the administration of ketamine for ECT. In our literature review, we found 5 cases in which SS was associated with ECT and 1 case linking ketamine to SS. There is emerging evidence that the mechanism of ECT involves 5-HT1A and 5-HT2A receptors, the same receptors that are involved in SS. ECT can transiently increase the permeability of the blood-brain barrier, leading to increased levels of antidepressants in the brain. ECT can, therefore, enhance 5-HT transmission and the likelihood of SS in the presence of serotonergic agents. The effect of ketamine on 5-HT transmission is mediated by the glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor. Ketamine increases α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid activity in the medial prefrontal cortex, which leads to downstream 5-HT release through glutamate. Through this mechanism, ketamine can increase 5-HT transmission, leading to SS. To our knowledge, this is the only case report of recurrent SS with concurrent use of ECT and ketamine. As ketamine is frequently used in ECT and many patients undergoing ECT are on serotonergic medications, it is important to recognize ketamine as a potential risk factor for SS. There is no evidence for added efficacy when combining ECT and ketamine. Thus, one should proceed with caution when combining these treatments. The burgeoning use of ketamine in ambulatory settings makes it necessary to elucidate the risks, which we discuss further. More research is needed into the mechanisms of ketamine and ECT, specifically how the combination of these treatments influence 5-HT levels.

Serotonin syndrome presenting as acute dizziness with supine hypertension and orthostatic hypotension.

Serotonin syndrome (SS) is a drug-induced clinical syndrome characterised by a combination of cognitive, neuromuscular and autonomic dysfunctions. The symptoms may include mild non-specific symptoms such as tremors and diarrhoea to coma and sudden death. Herein, we describe a case of SS in which acute dizziness was associated with supine hypertension and orthostatic hypotension. A man in his mid-30s had a 10-month history of anxiety, depression and chronic tension-type headache. He had been on amitriptyline (25 mg daily) and sertraline (50 mg daily). Increment of sertraline (75 mg daily) and amitriptyline (75 mg daily) and the addition of tramadol led to the development of acute severe dizziness. Physical examinations demonstrate supine hypertension and orthostatic hypotension. He also met the diagnostic criteria of SS. The administration of cyproheptadine provided a complete response to dizziness, supine hypertension, orthostatic hypotension and other clinical features of SS.

Black Cohosh Interactions with Prescription Medications Associated with Serotonin Toxicity and Rhabdomyolysis: A Case Report.

BACKGROUND: Serotonin toxicity is a well-described phenomenon that is commonly attributed to a variety of drug-drug combinations. Some unregulated herbal supplements have been implicated in the onset of serotonin toxicity, however, there is currently minimal literature available on the potential for black cohosh to contribute to rhabdomyolysis and serotonin toxicity, in spite of its known serotonergic properties. CASE REPORT: A middle-aged woman presented to the emergency department with serotonin toxicity and rhabdomyolysis shortly after taking black cohosh supplements in the setting of long-term dual antidepressant use. The serotonin toxicity and rhabdomyolysis resolved with IV fluids, benzodiazepines, and discontinuation of the offending drugs. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Patients are sometimes not aware of how over-the-counter supplements might interact with their prescription medications. Female patients taking black cohosh to manage hot flashes and menopausal symptoms could be at risk for developing rhabdomyolysis and serotonin toxicity if they are also taking other serotonergic agents.

Medication-overuse headache overlapping with serotonin syndrome.

Serotonin syndrome (SS) is an iatrogenic, drug-induced clinical syndrome caused by an increase in the intrasynaptic concentration of serotonin. Serotonin plays a significant role in the pathophysiology of migraines. Upregulation of 5-HT2A receptors is found in medication-overuse headache (MOH). Several migraine medications, both preventative and abortive drugs, act on serotonin receptors. We report two patients with chronic migraine who developed MOH. Besides headache, patients had frequent attacks of dizziness, restlessness, irritability, insomnia, excessive sweating, abdominal discomforts and tremors. These symptoms were suggestive of withdrawal headache. However, on physical examinations, we elicited hyperreflexia, hypertonia, clonus, tachycardia, hypertension, mydriasis and hyperactive bowel sound. Both patients also met the criteria for SS. Cyproheptadine was started. All features, including headaches, got better after cyproheptadine administration within 24 hours. In 7 days, there was practically total improvement. Both patients continued to take cyproheptadine as a preventative medicine, and migraine frequency was under control.

Cough elixir overdose causing toxic leuco-encephalopathy and serotonin syndrome.

Acute toxic leukoencephalopathy and serotonin syndrome are rare neurological complications associated with various drugs and toxins, some of which overlap. However, the co-occurrence of these conditions is poorly documented. We present the case of a 14-year-old boy who suddenly developed altered consciousness and autonomic dysfunction after consuming excessive quantities of cough remedies containing dextromethorphan, chlorphenamine, dichlorobenzyl alcohol, and amylmetacreson. Magnetic resonance imaging of the brain revealed distinct white matter lesions. With supportive care, the patient rapidly improved, and the magnetic resonance imaging abnormalities disappeared. The swift resolution, typical magnetic resonance imaging findings, and a history of exposure to drugs affecting the central nervous system's serotonergic system suggested concurrent acute toxic leukoencephalopathy and serotonin syndrome. The components of cough medications can be hazardous in overdose due to their potential to enhance serotonin toxicity and cause direct or indirect central nervous system white matter damage. Early recognition and appropriate treatment are essential for recovery.

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.

Serotonin syndrome: A pharmacovigilance comparative study of drugs affecting serotonin levels.

BACKGROUND: Serotonin syndrome is a rare and potentially fatal adverse drug reaction caused by serotonergic drugs and is due to an increase in serotonin concentration or activation of the 5-HT receptor in the central nervous system. We analysed adverse events in the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) data set to investigate the main drug classes related to reports of serotonin syndrome and the reporting risk in relation to age and sex. METHODS: We analysed data from the FAERS database to evaluate the main drug classes related to reports of the serotonin syndrome, and the reporting risk in relation to age and sex. RESULTS: We found 8,997 cases of serotonin syndrome; selective serotonin reuptake inhibitors (SSRIs) was the class of drugs with most reports, followed by opioids and other antidepressants. The highest Reporting Odds Ratios (ROR) for drug classes was for monoamine oxidase (MAO) inhibitors (45.99, 95% confidence interval (CI): 41.21-51.33) and SSRIs (32.66, 95% CI: 31.33-34.04), while the ten active substances with the highest ROR were moclobemide, isocarboxazid, oxitriptane, tranylcypromine, melitracen, phenelzine, linezolid, amoxapine, reboxetine and tryptophan; with values of ROR ranging from 44.19 (95% CI: 25.38-76.94) of tryptophan to 388.36 (95% CI: 314.58-479.46) of moclobemide. The ROR for the most commonly involved drugs was higher in the group of older adults (65 > years old), and higher in males. CONCLUSION: Prescribers need to be vigilant about drugs that can raise serotonin concentration or influence serotonergic neurotransmission, also when using drugs with less well-known risk for serotonin syndrome, like linezolid and triptans.

Fentanyl-Induced Serotonin Syndrome 5 Days After Cessation of Serotonergic Agents: A Case Report.

A 21-year-old patient with intellectual disability was admitted for gastroenteritis due to serotonergic medication overdose, and subsequently developed serotonin syndrome. Her symptoms initially improved after the cessation of serotonergic medications, but worsened 5 days later after fentanyl administration during general anesthesia. On emergence, she had convulsions and was nonresponsive. Subsequent imaging and electroencephalography did not demonstrate intracranial pathology or seizure activity. We suspect she had an exacerbation of her serotonin syndrome. She recovered successfully after supportive care. This case demonstrates that common medications used during anesthesia such as fentanyl can provoke serotonin syndrome, even several days after serotonergic drug discontinuation.

A clinical review of antidepressants, their sexual side-effects, post-SSRI sexual dysfunction, and serotonin syndrome.

Depression and anxiety are common, with one in six people experiencing symptoms in any given week. Of these people, 8.32 million are prescribed antidepressants. People living with HIV are likely to experience psychiatric disorder, with one in three experiencing depression and anxiety, and being at greater risk of developing post-traumatic stress disorder. Sexual side-effects of psychotropic medication are very common, cause distress, and can persist even after the medication has been withdrawn. Antidepressants are powerful drugs and can have severe interactions with many other substances. This article seeks to raise awareness of sexual side-effects of psychotropic medications and draw attention to ethical issues related to post selective serotonin reuptake inhibitor sexual dysfunction (PSSD). Additional risk factors and interactions between psychotropic medications and recreational drugs are identified. Recommendations are made to improve care and clinical outcomes through the development of therapeutic alliances.

The Neuropsychiatric Safety Profile of Lasmiditan: A Comparative Disproportionality Analysis with Triptans.

Migraine constitutes the world's second-leading cause of disability. Triptans, as serotonin 5-HT1B/1D receptor agonists, remain the first-line treatment, despite discouraged use in individuals at high cardiovascular risk. Lasmiditan, a selective lipophilic 5-HT1F agonist without vasoconstrictive effects, is an emerging option. We aimed to investigate the safety profile of lasmiditan in the WHO pharmacovigilance database (VigiBase®) using a comparative disproportionality analysis with triptans. VigiBase® was queried for all reports involving lasmiditan and triptans. Disproportionality analyses relied on the calculation of the information component (IC), for which 95% confidence interval (CI) lower bound positivity was required for signal detection. We obtained 826 reports involving lasmiditan. Overall, 10 adverse drug reaction classes were disproportionately reported with triptans, while only neurological (IC 1.6; 95% CI 1.5-1.7) and psychiatric (IC 1.5; 95% CI 1.3-1.7) disorders were disproportionately reported with lasmiditan. Sedation, serotonin syndrome, euphoric mood, and autoscopy had the strongest signals. When compared with triptans, 19 out of 22 neuropsychiatric signals persisted. The results of our analysis provide a more precise semiology of the neuropsychiatric effects of lasmiditan, with symptoms such as autoscopy and panic attacks. The cardiovascular adverse drug reaction risk with triptans was confirmed. In contrast, caution is warranted with lasmiditan use in patients with neurological or psychiatric comorbidities or serotonin syndrome risk. Our study was hindered by pharmacovigilance flaws, and further studies should help in validating these results. Our findings suggest that lasmiditan is a safe alternative for migraine treatment, especially when the neuropsychiatric risk is outweighed by the cardiovascular burden.

Serotonin syndrome from combination hydrocodone and cyclobenzaprine in a patient with cerebral palsy.

Aim: Serotonin syndrome (SS) is a life-threatening syndrome that occurs with the use of serotonergic drugs, most commonly due to two or more agents. Cerebral palsy is associated with mood disorders, and more commonly pain, with a prevalence of up to 50-80%. Case presentation: A 58-year-old female with cerebral palsy, metastatic malignancy and mood disorder who presented to the emergency department with acute-on-chronic pain, and signs of SS. She was initiated on iv. dilaudid, titrated off oral medications and scheduled for a left-sided sacroiliac joint injection. Results: It was suspected that due to additional doses of hydrocodone and cyclobenzaprine, she developed moderate-SS. Conclusion: Physicians need to be cognizant of comorbidities and uncommon pain medications that can predispose patients to SS.

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.

Real-world evaluation of linezolid-associated serotonin toxicity with and without concurrent serotonergic agents.

BACKGROUND: The risk of linezolid-associated serotonin toxicity remains unclear. This study sought to evaluate the incidence of serotonin toxicity among hospitalized patients who received linezolid with or without concurrent serotonergic agents (SAs). Secondary outcomes were to assess the dose, agent selection and number of SAs. METHODS: A single-centre, retrospective cohort study of hospitalized patients aged ≥18 years who received at least one dose of linezolid with or without SAs between 1 January 2014 and 30 June 2021 was performed. Patients were excluded if they were aged <18 years, had linezolid ordered but not administered, were pregnant or were incarcerated. Up to five concurrent SAs were assessed, and dose category was classed as low, moderate or high (dose <33%, 33-66% or >66% of maximum daily dose, respectively). Serotonin toxicity was identified by searching patients' electronic medical records. If identified, the Sternbach criteria and Hunter criteria were applied. RESULTS: Of 2022 patients screened, 1743 were included in this study. Mean age, weight and linezolid duration were 58.5 years, 90.7 kg and 3.8 days, respectively. Approximately 67% (1168/1743) of patients received linezolid with at least one SA, and several patients received multiple SAs. Most patients (53.8%; 616/1144) received moderate- and/or high-dose SAs. Only two patients (0.11%) were identified as possible cases of serotonin toxicity based on the electronic medical record search. However, the incidence of serotonin toxicity was 0.06% (1/1743) based on the Sternbach criteria and 0% (0/1743) based on the Hunter criteria. CONCLUSIONS: Serotonin toxicity among hospitalized patients who received linezolid with or without SAs was exceedingly rare, even among those who received multiple and high-dose SAs.

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.

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.