Case Report: Possible Serotonin Syndrome in a Patient Taking Kratom and Multiple Serotonergic Agents.

INTRODUCTION: Kratom, an unregulated herbal supplement, has emerged as self-treatment for anxiety/depression. Kratom exhibits inhibition at multiple cytochrome P450 isozymes involved in metabolism of prescription medications, including serotonergic agents. We report a case of possible serotonin syndrome induced by kratom use in combination with prescription psychotropic medications. CASE: A 63-year-old male presented with diaphoresis, flushing, aphasia, confusion, dysarthria, right facial droop, and oral temperature of 39.6oC (103.2oF), lactate 2.7 mmol/L, and creatine phosphokinase of 1507 IU/L. Initial differential diagnoses included acute ischemic stroke and bacterial meningitis. Despite partial treatment with alteplase and broad-spectrum antibiotics, symptoms persisted, and subsequent physical exam noted hyperreflexia, clonus, tremors, and temperature of 41.1oC (106oF). Home medications included a chronic regimen for anxiety/depression with bupropion, buspirone, desvenlafaxine, trazodone, and ziprasidone, in addition to kratom. Clinical suspicion for serotonin syndrome led to initiation of cyproheptadine, lorazepam, and cooling blankets. Aphasia, facial droop, and confusion improved after administration of cyproheptadine. Bupropion was restarted during hospitalization; remaining medications restarted at the discretion of the primary care provider. DISCUSSION: Risk of serotonin syndrome with multiple serotonergic agents is well-known. Kratom is metabolized by cytochrome P40 isozymes 3A4, 2C9, and 2D6, and exhibits inhibition at those enzymes, in addition to 1A2. Pharmacokinetic interactions of kratom with prescription serotonergic agents metabolized through these isozymes has the potential to increase systemic exposure of serotonin, potentially leading to serotonin syndrome. CONCLUSION: Because substances contained in kratom can inhibit metabolism of prescription serotonergic medications, clinicians must be aware of potential development of serotonin syndrome.

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.

Efficacy, tolerability, and safety of serotonergic psychedelics for the management of mood, anxiety, and substance-use disorders: a systematic review of systematic reviews.

INTRODUCTION: Mood, anxiety, and substance-use disorders are among the most prevalent psychiatric disorders in the population. Although several pharmacological treatments are available, they are not effective for a significant proportion of patients and are associated with several adverse reactions. Therefore, new treatments should be explored. Recent studies suggest that serotonergic hallucinogens/psychedelics including ayahuasca, psilocybin, and lysergic acid diethylamide (LSD) have anxiolytic, antidepressive, and antiaddictive effects. Areas Covered: A systematic review of systematic reviews assessing the efficacy, safety, and tolerability of serotonergic hallucinogens/psychedelic was performed using the PubMed data base until 11 April 2018. Systematic reviews with or without meta-analysis were analyzed, but only reviews that described at least one randomized controlled trial (RCT) were included. Expert Commentary: Psilocybin and LSD reduced anxiety and depression in cancer patients and symptoms of alcohol and tobacco dependence, and ayahuasca reduced depression symptoms in treatment-resistant depression. Although the results are promising, several studies were open label, and only few were RCTs, and most had small sample sizes and a short duration. Single or few doses of these drugs seem to be well tolerated, but long-term studies are lacking. New RCTs with bigger samples and longer duration are needed to replicate these findings.

Implications of Off-Target Serotoninergic Drug Activity: An Analysis of Serotonin Syndrome Reports Using a Systematic Bioinformatics Approach.

STUDY OBJECTIVE: Serotonergic adverse drug events (ADEs) are caused by enhanced intrasynaptic concentrations of 5-hydroxytryptamine (5-HT). No systematic process currently exists for evaluating cumulative 5-HT and off-target toxicity of serotonergic drugs. The primary study aim was to create a Serotonergic Expanded Bioactivity Matrix (SEBM) by using a molecular bioinformatics, polypharmacologic approach for assessment of the participation of individual 5-HT drugs in serotonin syndrome (SS) reports. DATA SOURCES: Publicly available databases including the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), ChEMBL, DrugBank, PubChem, and Kyoto Encyclopedia of Genes and Genomes (KEGG) were queried for computational and pharmacologic data. DESIGN: An in-house bioinformatics TargetSearch program ( http://dxulab.org/software) was used to characterize 71 serotonergic drugs interacting at 13 serotonin receptor subtypes and serotonin reuptake transporter protein (SERT). In addition, off-target interactions at norepinephrine transporter (NET), monoamine oxidase (MAO), and muscarinic receptors were included to define seven polypharmacological drug cohorts. Serotonin syndrome reports for each serotonergic drug were extracted from FAERS by using the Sternbach and Hunter criteria. MEASUREMENTS AND MAIN RESULTS: A proportional reporting adverse drug reaction (ADR) ratio (PRR) was calculated from each drug's total ADEs and SS case reports and aggregated by drug bioactivity cohorts. Triple-receptor interactions had a disproportionately higher number of SS cases using both the Hunter criteria (mean PRR 1.72, 95% CI 1.05-2.39) and Sternbach (mean PRR 1.54, 95% CI 1.29-1.79). 5-Hydroxytryptamine agonists were associated with a significantly lower proportion of SS cases using the Hunter and Sternbach criteria, respectively (mean PRR 0.49, 95% CI 0.17-0.81 and mean PRR 0.49, 95% CI 0.15-0.83). Drugs with disproportionately higher participation in SS vary considerably between the two diagnostic criteria. CONCLUSION: The SEBM model suggests a possible polypharmacological role in SS. Although further research is needed, off-target receptor activity may help explain differences in severity of toxicity and clinical presentation.

Delayed Serotonin Syndrome in the Setting of a Mixed Fluoxetine and Serotonin Antagonist Overdose.

BACKGROUND Serotonin syndrome is a condition characterized predominantly by neuromuscular symptoms and altered thermoregulation in response to serotonergic overtone. Treatment is focused on withdrawal of serotonergic agents, which leads to resolution in the majority of cases. In the setting of serotonergic overdose, the onset of serotonin syndrome is usually within 4 to 13 h. Here, we report a case of delayed-onset serotonin syndrome in a patient who ingested a mixture of longer-acting serotonin agonists with serotonin antagonists. CASE REPORT A 24-year-old male was transferred to our medical intensive care unit with hypotension and altered mental status after an overdose of fluoxetine, cyproheptadine, trazodone, olanzapine, risperidone, and bupropion. After approximately 72 h, the patient developed symptoms of fever, lower leg clonus, hyperreflexia, and agitation. He was diagnosed with delayed-onset serotonin syndrome, which responded well to re-administration of cyproheptadine, leading to resolution of symptoms by day 5 of his stay. CONCLUSIONS In this present case, our patient presented with the longest reported delay in the onset of serotonin syndrome after intentional ingestion. This was likely secondary to co-ingestion of long-acting serotonin agonists with protective shorter-acting serotonin antagonists (cyproheptadine and olanzapine). Clinicians should consider delayed-onset serotonin syndrome when patients ingest longer-acting serotonergic agents with serotonin antagonists.

Síndrome serotoninérgico / Serotonin syndrome

Introducción: el síndrome serotoninérgico es una rara afección, con reacción adversa a la administración de determinado grupo farmacológico. Objetivo: demostrar la evolución clínico-anestesiológica de un paciente con síndrome serotoninérgico. Caso clínico: paciente de 37 años con antecedentes de epilepsia, tratado con valproato de sodio. Ingresó al hospital por quemaduras de segundo y tercer grado en ambos miembros inferiores para debridamiento e implante de piel. Lleva tratamiento con tramadol 50 mg/6 h, ácido fólico 5 mg/d, fluoxetina 20 mg/d, tiamina 100 mg/d y vitamina C 500 mg/d. Se administró anestesia general con máscara laríngea. Inducción con fentanilo 100 µg, ketamina 20 mg, propofol 150 mg. Se colocó máscara laríngea 4. Respiración espontánea en modalidad PSVPro con O2 + aire + sevoflurane (CAM 0,6 por ciento). Cuando comenzó la asepsia quirúrgica se evidenció clonus en ambos miembros inferiores. No cambios hemodinámicos, ni de la temperatura (36,1 °C). Gasometría: alcalosis metabólica. Ionograma normal. Se administró 5 mg de midazolam. En el posoperatorio se retiró la máscara laríngea. TA: 106/60. Pulso: 95 lat/min. Temperatura: 35,8 °C, Sat Hb: 98 por ciento. Se constató clonus sostenido inducible al estímulo mínimo bilateral, clonus orbital e hiperreflexia. Se mantuvo en la sala de recuperación por dos horas. Se dio alta para la sala de cuidados especiales con indicaciones. Conclusiones: la evolución fue satisfactoria. Ante un paciente que llega de urgencia, se recomienda evaluar las enfermedades coexistentes y su tratamiento; no hacerlo puede traer consecuencias fatales(AU)

Introduction: The serotonin syndrome is a rare condition and includes an adverse reaction to the administration of a certain pharmacological group. Objective: To show the clinical-anesthesiological evolution of a patient with serotonin syndrome. Clinical case: A 37-year-old patient with a history of epilepsy, treated with sodium valproate. The patient was admitted to the hospital for second and third degree burns on both lower limbs for debridement and skin implant. The patient was treated with tramadol (50 mg every 6 hours), folic acid (5 mg every d), fluoxetine (20 mg every day), thiamin (100 mg every day), and vitamin C (500 mg every day). General anesthesia with laryngeal mask was administered. Induction with fentanyl (100 µg), ketamine (20 mg), propofol (150 mg). Laryngeal mask number 4 was placed. Spontaneous respiration in PSVPro modality with O2, air and sevoflurane (CAM 0.6 percent). When the surgical asepsis began, clonus was evident in both lower limbs. No hemodynamic or temperature changes (36.1 °C). Gasometry: metabolic alkalosis. Normal Ionogram. 5 mg of midazolam were administered. In the postoperative period, the laryngeal mask was removed. TA: 106/60. Pulse: 95 beats/min. Temperature: 35.8 °C, sat Hb: 98 percent. Sustained clonus inducible to minimal bilateral stimulus, orbital clonus and hyperreflexia was found. The patient remained in the recovery room for two hours and was released for the special care room with instructions. Conclusions: The evolution was satisfactory. When a patient arrives urgently, it is recommended to assess the coexisting diseases and their treatment; not doing so can bring fatal consequences(AU)

Ischemic Colitis as a Complication of Medication Use: An Analysis of the Federal Adverse Event Reporting System.

BACKGROUND: More than one decade ago, rising cases of ischemic colitis (IC) prompted the Federal Drug Administration to revoke alosetron's approval as treatment of irritable bowel syndrome (IBS). The aim of this study was to identify medical therapies associated with development of IC. METHODS: The Federal Adverse Event Reporting System was queried for the time between January 2004 and September 2015. We identified reports listing IC as treatment complication and extracted suspected causative and concomitantly administered drugs, indications for their use and outcomes. RESULTS: After eliminating duplicates, we found 2811 cases of IC (68.4 % women; 59.4 ± 0.4 years). Patients with IBS accounted for 3.9 % of the cases, mostly attributed to tegaserod or alosetron. Chemotherapeutic and immunosuppressive drugs, sex hormones, and anticoagulants were the most commonly suspected causes. Bisphosphonates, nonsteroidal anti-inflammatory drugs, antipsychotics, triptans, interferon therapy, and laxative use prior to colonoscopy were among the more commonly listed treatments. In 8 %, the adverse event contributed to the patient's death with male sex and older age predicting fatal outcomes. CONCLUSION: Beyond confirming known risks of IC, the results identified several potential culprits of ischemic colitis. This information may not only explain the development of this serious adverse event, but could also guide treatment decisions, cautioning healthcare providers when considering these agents in persons with known risk factors or other drugs that may increase their risk of IC.

Hyperthermia caused by drug interactions and adverse reactions.

Drug-induced hyperthermic syndromes are similar to heat illness. The purpose of this article is to discuss the drugs associated with the development of these syndromes and to review their pathophysiology, clinical manifestations, and management.

Catastrophic reversible cerebral vasoconstriction syndrome associated with serotonin syndrome.

OBJECTIVES: To report fulminant cases of reversible cerebral vasoconstriction syndrome (RCVS) in the setting of serotonin syndrome. BACKGROUND: RCVS is characterized by acute onset of severe headaches, with or without neurologic deficit, with evidence of reversible cerebral vasoconstriction. It is often benign, and prognosis is generally considered favorable. In the largest prospective study on RCVS, only 4% of patients were disabled from strokes and there were no fatalities. METHODS: We report a case series. RESULTS: We report 2 women with history of depression on selective serotonin re-uptake inhibitors who presented with thunderclap headache and dizziness, respectively. Through the course of hospitalization, both patients developed rigidity, diaphoresis, fever, tachycardia with labile blood pressures and clonus on examination. Since there was a recent addition/increase in a known serotonergic agent, they met criteria for serotonin syndrome. Cerebrovascular imaging in both patients revealed severe multi-focal vessel narrowing. The first patient developed large bi-hemispheric ischemic infarcts and increased intra-cranial pressure that was refractory to management, and she eventually expired. The second patient developed bilateral parieto-occipital strokes and decerebrate posturing. Her course slowly stabilized, and she was eventually discharged with residual left-sided hemiparesis. Repeat cerebrovascular imaging 1 month later showed normal vessels. In both patients, intra-arterial nicardipine infusion improved angiographic appearance of stenoses, consistent with RCVS. CONCLUSIONS: Both cases satisfied the Sternbach criteria for serotonin syndrome. Fatality in case 1 prevents demonstration of reversal of cerebral vasoconstriction, but improvement of arterial diameters with intra-arterial calcium channel blockers in both cases suggests that both had RCVS. Serotonergic agents are known triggers of RCVS, but the concurrent presence of serotonin syndrome likely precipitated the malignant course in our patients. Severe clinical and angiographic manifestations should be considered as part of the spectrum of RCVS.

Drug-induced valvular heart disease.

Drug-induced valvular heart disease (DIVHD) was first described in the 1960s. Initially, associations with ergot derivatives used for migraine prevention, or with anorectic drugs, were described. Drugs used for the treatment of Parkinson's disease and endocrine diseases, like hyperprolactinemia, may also induce VHD. More recently, the use of 3,4-methylendioxymetamphetamine (MDMA, 'Ecstasy') and benfluorexhave been found to be associated with DIVHD. Although some of these drugs were withdrawn from the market, several cases of patients requiring valve surgery even years after the cessation of therapy have been reported. DIVHD is not infrequent, may be severe, and has been described in association with several drugs. Even after drug cessation, long-term implications of this type of VHD may persist. The present review underlines the need for a careful evaluation of the associated clinical and echocardiographic risk factors to allow early recognition so as not to delay appropriate management.

Dietary restrictions and drug interactions with monoamine oxidase inhibitors: an update.

Monoamine oxidase inhibitors (MAOIs) are effective treatments for depression that has atypical features or that has failed to respond to other antidepressants. However, MAOIs are underused because clinicians are concerned about dietary and drug interactions with this class of medication. Hypertensive crisis and serotonin syndrome can occur in rare cases due to interactions between MAOIs and foods containing tyramine as well as interactions with serotonergic and sympathomimetic agents. A better understanding of the foods and drugs that can cause adverse reactions, as well as knowledge of newer MAOIs with mechanisms of action and delivery methods that reduce these risks, may help clinicians to consider the use of these medications, when appropriate, in their patients with depression.

Serotonin syndrome associated with polypharmacy in the elderly.

The increasing use of serotonergic agents, alone and in combination, across multiple disciplines, makes it likely that the prevalence of serotonin syndrome will rise. Caution should be used, especially in the elderly, to avoid unnecessary and potentially harmful polypharmacy. We describe a case of serotonin syndrome in a 79-year-old man taking mirtazapine, venlafaxine and quetiapine. As this case illustrates, serotonin syndrome can be caused by combinations of direct serotonin agonists (e.g., serotonergic antidepressants) and indirect serotonin agonists (e.g., atypical antipsychotics).

Deaths involving contraindicated and inappropriate combinations of serotonergic drugs.

In the Australian state of Victoria, all fatalities that were recorded from 2002 through to 2008 involving the use of certain serotonin active drugs (tramadol, venlafaxine, fluoxetine, sertraline, citalopram and paroxetine), were reviewed to assess the incidence of contraindicated or ill advised drug combinations. More than 1,000 were identified of which 326 cases formed the basis of this study. These cases involved contraindicated or inappropriate drug combinations that can lead to adverse drug reactions (ADRs) and subsequent fatal toxicity. Of these, 46% were drug-related, 35% were a result of natural disease and 13% were classified as external injury cases. The remaining cases were those where the cause of death (COD) was unascertained. Tramadol was the most common drug, usually detected alongside a serotonergic antidepressant (in 20% of cases). Twenty-five (8%) cases involved contraindicated drug combinations while the remainder (301 cases, 92%) involved drug combinations that are associated with adverse interactions ranging from minor to major severity. Of these 326 cases, the Coroner determined 166 cases (51%) to be acts of intentional self-harm or drug misuse, with the remainder unascertained or attributed to natural disease. Very few post-mortem reports and Coroners' findings made mention of possible ADRs when such combinations were actually present. The majority of cases comprising contraindicated drug combinations involved the combined use of five drugs (24%) at the time of death. A combination of three to five drugs was most common in cases involving inadvisable drug combinations. Combined drug toxicity was the most common COD, with heart disease the most common co-morbidity.

Síndrome serotonínico pediátrico: reporte de un caso / Serotonin syndrome pediatric: case report

El síndrome serotonínico es un cuadro neurológico agudo debido a hiperactividad serotoninérgica, por la interacción de drogas que refuerzan o mimetizan la acción del neurotrasmisor. La incidencia del síndrome de serotonina es ascendente por la disponibilidad creciente de fármacos serotoninérgicos como los antidepresivos. Por ello es importante que los médicos reconozcan y manejen adecuadamente el síndrome serotonínico. Este reporte de caso se refiere a una intoxicación accidental por el neuroléptico atípico olanzapina en un niño de 2 años, quien desarrolló manifestaciones clínicas como agitación, sudoración, mioclonías, clonus espontáneo e hipertermia, considerados como criterios diagnóstico del cuadro. La terapia consistió en descontaminación interna con lavado gástrico, carbón activado y sulfato de sodio, ciproheptadina, propranolol y furosemida. Su evolución fue satisfactoria. En nuestro país hay disponibilidad de la mayoría de los fármacos causales y tienen amplio uso, por lo que es probable el subregistro del síndrome. De allí la importancia de este reporte de caso

Serotonin syndrome is an acute neurologic picture due to serotonergic hyperactivity, due to the interaction of drugs that enhance or mimic the action of the serotonin. The incidence of serotonin syndrome is rising because of the growing availability of serotonergic drugs such as antidepressants. It is therefore important that clinicians recognize and manage appropriately this syndrome. This case report refers to an accidental poisoning by the atypical neuroleptic olanzapine in a 2 year old boy who developed clinical manifestations such as agitation, sweating, myoclonus, spontaneous clonus and hyperthermia, considered as diagnostic criteria for the syndrome. Therapy consisted of internal decontamination with gastric lavage, activated charcoal and sodium sulfate, cyproheptadine, propranolol and furosemide. The clinical outcome was satisfactory. In our country the majority of the causal drugs are easily available and widely employed, for which reason it is probable that this syndrome is under registered. Hence the importance of this case report

[Diagnosis and classification of pulmonary hypertension]. / Diagnostic et classification de l'hypertension pulmonaire.

Pulmonary hypertension (PH) has been defined as an increase in mean pulmonary arterial pressure (mPAP) > or = 25 mmHg at rest as assessed by right heart catheterisation (RHC). Precapillary pulmonary hypertension is defined by an increase in mPAP > or =25 mmHg and a pulmonary capillary wedge pressure (PCWP)< or =15 mmHg associated with a normal or reduced cardiac output. No definition for PH on exercise as assessed by RHC can be provided at the present time. In group 1 pulmonary arterial hypertension (PAH), the term "familial PAH" has been replaced by "heritable PAH". Heritable forms of PAH include clinically sporadic idiopathic PAH with germline mutations and clinical familial cases with or without identified germline mutations. Schistosomiasis and chronic haemolytic anaemia have been included among the group of associated PAH. Pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis have been individualized and designated as clinical group 1'.

Serotonergic thrombocytopathy and its effects on platelets during orthopaedic surgery.

The serotonergic effects on platelet dysfunction (thrombocytopathy) can cause deficient hemostasis during orthopaedic surgery. Peripheral serotonin located within the granules of platelets assists in initial platelet aggregation. Selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs) are drugs used to treat a myriad psychological-related, mental-related, and psychosocial-related disorders. A correlation exists between low levels of peripheral serotonin and a bleeding diathesis during orthopaedic surgery. The relationship of excessive bleeding during orthopaedic surgery secondary to thrombocytopathy and low levels of serotonin caused by drugs that inhibit the reuptake of serotonin is presented.

Neuroleptic malignant syndrome and serotonin syndrome.

This chapter is focused on drug-induced hyperthermia with special regard to use of antipsychotics and antidepressants for the treatment of schizophrenia and major depression, respectively. Neuroleptic malignant syndrome (NMS) develops during the use of neuroleptics, whereas serotonin syndrome is caused mainly by serotoninergic antidepressants. Although both syndromes show various symptoms, hyperthermia is the main clinical manifestation. In this review we describe the historical background, clinical manifestations, diagnosis, and differential diagnosis of these two syndromes based on our observations on the experimental and clinical data.