Serotonin Syndrome Research Articles

Accidental Flibanserin Ingestion in Children Causing Acute Respiratory and Central Nervous System Depression: What Health Care Professionals Need to Know.

This commentary serves to raise awareness for health care professionals about the potential risks of accidental ingestion of flibanserin tablets by children. Flibanserin was approved by the U.S. Food and Drug Administration (FDA) for the treatment of acquired generalized hypoactive sexual desire disorder in premenopausal women. Since its approval in 2015, the FDA has identified five reports of serious accidental ingestion by toddlers. All five children, boys with ages ranging from 18 months to 2 years, presented with central nervous system and respiratory depression, and two of them required intubation. A combination of hypertension, hyperthermia, and seizure-like activity was also seen in four of the five children. The clinical manifestation resembles serotonin syndrome (eg, tachycardia, hypertension, and muscle stiffness). As flibanserin use increases, greater awareness by health care professionals regarding the risk of accidental pediatric ingestion is needed to facilitate preventative counseling for patients with young children.

Management of Medication-Induced Psychiatric Disorders.

Management of Medication-Induced Psychiatric Disorders.

A Clinical Review on Paroxetine and Emerging Therapies for the Treatment of Vasomotor Symptoms.

Most women experience vasomotor symptoms (VMS) during their menopausal transition. Menopausal hormone therapy (HT) is the most effective treatment for VMS, but some women choose not to use HT or have contraindications to using HT. Non-hormonal treatment options should be offered to these symptomatic menopausal women. Multiple large randomized controlled trials have demonstrated statistically significant reductions in hot flash severity and/or frequency with the use of selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs). To date, paroxetine mesylate remains the only non-hormonal treatment that has been approved by the United States Food and Drug Administration (FDA) for the management of moderate to severe postmenopausal vasomotor symptoms. Lower doses are needed to reduce VMS than those used to treat anxiety or depression, which is beneficial since side effects are typically dose dependent. The recommended dosage is 7.5 mg once daily at bedtime. Dose dependent side effects include nausea, fatigue, and dizziness. Knowing potential medication interactions is critical such as with medications that can lead to serotonin syndrome, concomitant use with monoamine oxidase inhibitors and being aware of p450 drug metabolism is essential for patients taking drugs that utilize the CYP2D6 enzyme for metabolism including tamoxifen. This review discusses in detail the available data supporting the use of paroxetine for the treatment of VMS, including side effects and considerations regarding prescribing. A discussion of other emerging treatments is included as well, including estetrol, oxybutynin and neurokinin 3 (NK3) receptor antagonists.

Phenazopyridine-Induced Methaemoglobinaemia The Aftermath of Dysuria Treatment.

IntroductionPhenazopyridine is an over-the-counter urinary analgesic commonly used to alleviate the burning and urgency associated with lower urinary tract infections. Methaemoglobinaemia is an uncommon adverse effect of phenazopyridine use. We report a case of methaemoglobinaemia in a patient prescribed daily phenazopyridine to treat urethral and bladder irritation caused by a chronic indwelling Foley catheter.Case descriptionA 55-year-old female resident of a long-term acute care facility with a chronic Foley, tracheostomy and ventilator-dependent respiratory failure was observed to have generalized dusky skin and hypoxia. Pulse oximetry was reading in the high 80s despite administration of 100% FiO2. ABG revealed paO2 of 451, oxyhaemoglobin level 75% and methaemoglobin level 22%. Medication review indicated that the patient was prescribed phenazopyridine 400 mg TID for the previous 2 months. This medication was discontinued. Considering she was chronically taking mirtazapine, she can increase risk of serotonin syndrome should she be administered first-line treatment with methylene blue. Vitamin C was thus instead administered as a second-line agent. Serial ABGs showed a rapid decline in methaemoglobin levels and an increase in oxyhaemoglobin within 2 days.DiscussionAcquired methaemoglobinaemia is a rare adverse effect of treatment with phenazopyridine. This risk increases when drug dosage and duration exceed manufacturer specifications. Treatment typically includes cessation of the offending drug and administration of methylene blue in severe cases. A thorough medication reconciliation should be performed prior to methylene blue initiation, as patients taking serotonergic medications (for example, MAOIs, SSRIs, SNRIs, TCAs) are at increased risk of serotonin toxicity with co-administration of methylene blue. In these instances, ascorbic acid/vitamin C can be chosen as an alternative treatment agent.ConclusionWork-up of refractory hypoxia should involve a thorough review of medications as even some over-the-counter drugs can cause the fatal side effect of methaemoglobinaemia. Treatment with vitamin C should be considered over methylene blue if serotonergic medications have been recently prescribed in order to avoid risk of serotonin syndrome.LEARNING POINTSMethaemoglobinaemia is an uncommon, life-threatening adverse effect of phenazopyridine use. Presentation depends on the severity of the disorder, ranging from headache, weakness, lightheadedness and dyspnoea, to arrhythmias, confusion, seizures and multiorgan failure.Workup of refractory hypoxia should involve a comprehensive medication review as even some over-the-counter drugs can cause methaemoglobinaemia.Management of methaemoglobinaemia involves cessation of the offending drug, administration of supplemental oxygen and treatment with methylene blue (1–2 mg/kg) if MetHb >30%, or for symptomatic patients with MetHb >20%. Vitamin C can be used as an alternative agent if there is a contraindication to methylene blue (for example, with patients simultaneously receiving serotonergic medications and/or those with G6PD deficiency).

POTENTIAL DRUG-DRUG INTERACTIONS IN PSYCHIATRIC PATIENTS DURING HOSPITALIZATION AND AT HOSPITAL DISCHARGE

Purpose: The present study aimed to evaluate the frequency of pDDIs in male patients admitted to a university-based intensive psychiatric unit over a twelve-month period and to assess patients' exposure to pDDIs as inpatients and potential outpatients. Material/Methods: Charts of 425 consecutive hospitalized patients with psychiatric disorders were reviewed. Potential DDIs were assessed and categorized using Lexicomp® drug interaction software. Statistical analyses were performed with IBM SPSS Statistics for Windows, Version 20.0. Results: A total of 1404 pDDIs (3.3 per patient) were identified for the hospitalization period. Categorized in risk rating categories X and D, considered most relevant for the safety of the patients were 346 (24.64%) of them. Among the pharmacodynamic pDDIs, most frequent were pDDIs associated with central nervous system depression, followed by QT‐interval prolongation. Hospital discharge prescriptions included 631 pDDIs (1.48 per patient). Out of them, 144 (22.82%) were identified in risk rating categories X and D. Among the pharmacodynamic pDDIs first in frequency were pDDIs related to QT-interval prolongation, followed by pDDIs associated with central nervous system depression. Potential DDIs that could lead to serotonin syndrome or extrapyramidal side effects were relatively infrequent during hospitalization and at discharge. No pharmacokinetic pDDIs were categorized in groups X and D. Conclusions: The study showed a higher frequency of pDDIs during the hospitalization period compared to hospital discharge with no change of the nature of the potential risks for the safety of the patients. Caution is warranted to limit the exposure of the patients to pDDIs.

Reported Cases of Serotonin Syndrome in MDMA Users in FAERS Database

3,4-Methylenedioxymethamphetamine (MDMA), is investigated as a treatment for post-traumatic stress disorder and other anxiety-related conditions in multiple placebo-controlled and open label studies. MDMA-assisted therapy is projected for approval by the United States Food and Drug Administration (FDA) and other regulatory agencies worldwide within the next few years. MDMA is a monoamine releaser and uptake inhibitor affecting serotonin, potentially increasing the risk of serotonin syndrome (SS). No instances of SS have occurred in clinical trials. The relatively small number of patients in controlled trials warranted a survey of FDA Adverse Event Reporting System data for the occurrence of SS in a larger database. We found 20 SS cases in people exposed to MDMA, all of which had also taken one or more substances with serotonergic properties in addition to MDMA, including amphetamines, stimulants, and opioids. There were no cases of SS associated with MDMA where MDMA was the sole reported compound taken.

Serotonin syndrome precipitated by diclofenac

Serotonin syndrome is a life threatening drug induced condition, associated with increased serotonergic activity in both central and peripheral nervous system. Serotonin syndrome can be due to overdose of serotonergic agent or concomitant use of multiple antidepressants, leading to exaggerated serotonin effects in the central nervous system. It can also result from overdosage of one serotonergic drug or by addition of any precipitating drug. This is a case of 45 year female diagnosed with serotonin syndrome, which was manifested even by minimum effective dose of serotonergic agent, especially by any precipating over the counter or illicit drugs.

Psychiatric management of Patients in intensive care units.

Psychiatric management of Patients in intensive care units.

Clinical considerations with use of psychotropic medications in COVID-19 patients

Clinical considerations with use of psychotropic medications in COVID-19 patients

Emergencies in Parkinsonism

Patients with Parkinsonism may present acutely to the ED with serious and even life-threatening conditions. Although falls are a common presentation in advanced Parkinsonism, early presentations with falls should alert the clinician that the patient might have a Parkinson syndrome other than Parkinson’s disease itself, including autonomic neuropathy causing orthostatic hypotension. Patients may present with neuroleptic malignant syndrome, acute psychosis, marked hypokinesis, freezing gait, aspiration pneumonia, dysphagia, serotonin syndrome, dopamine dysregulation syndrome and intestinal pseudo-obstruction. An inpatient admission is necessary for investigation and observation of these patients. We present a case of a patient who presented with an uncommon side effect of a common medication used for Parkinsonism.

RYR1-Related Rhabdomyolysis: A Spectrum of Hypermetabolic States Due to Ryanodine Receptor Dysfunction.

Variants in the ryanodine receptor-1 gene (RYR1) have been associated with a wide range of neuromuscular conditions, including various congenital myopathies and malignant hyperthermia (MH). More recently, a number of RYR1 variants, mostly MH-associated, have been demonstrated to contribute to rhabdomyolysis events not directly related to anesthesia in otherwise healthy individuals. This review focuses on RYR1-related rhabdomyolysis in the context of several clinical presentations (i.e., exertional rhabdomyolysis, exertional heat illnesses and MH), and conditions involving a similar hypermetabolic state, in which RYR1 variants may be present (i.e., neuroleptic malignant syndrome and serotonin syndrome). The variety of triggers that can evoke rhabdomyolysis, on their own or in combination, as well as the number of potentially associated complications, illustrates that this is a condition relevant to several medical disciplines. External triggers include but are not limited to strenuous physical exercise, especially if unaccustomed or performed under challenging environmental conditions (e.g., high ambient temperature or humidity), alcohol/illicit drugs, prescription medication (in particular statins, other anti-lipid agents, antipsychotics and antidepressants) infection, or heat. Amongst all patients presenting with rhabdomyolysis, genetic susceptibility is present in a proportion, with RYR1 being one of the most common genetic causes. Clinical clues for a genetic susceptibility include recurrent rhabdomyolysis, creatine kinase (CK) levels above 50 times the upper limit of normal, hyperCKemia lasting for 8 weeks or longer, drug/medication doses insufficient to explain the rhabdomyolysis event, and positive family history. For the treatment or prevention of RYR1-related rhabdomyolysis, the RYR1 antagonist dantrolene can be administered, both in the acute phase or prophylactically in patients with a history of muscle cramps and/or recurrent rhabdomyolysis events. Aside from dantrolene, several other drugs are being investigated for their potential therapeutic use in RYR1-related disorders. These findings offer further therapeutic perspectives for humans, suggesting an important area for future research.

Patient concerns regarding antidepressant drug–drug interactions: a retrospective analysis using data from a medicines call centre.

Introduction Antidepressant use has increased over the last two decades, with Australia and New Zealand among the highest antidepressant users in Organisation for Economic Co-operation and Development (OECD) countries. Comorbidity and polypharmacy are common in antidepressant users, increasing the likelihood of interaction-related adverse drug events, which are frequently preventable. Aim We aimed to identify, profile, and analyse potential antidepressant drug-drug interactions in information-seeking antidepressant users. Methods We retrospectively analysed antidepressant-related drug-drug interaction enquiries from patients or carers who contacted a pharmacist-led Australian national medicines call centre over an 8-year period to determine patient characteristics, concomitant drugs involved, prevalence and type of antidepressant-related drug-drug interaction across life stages, and associated risks. Results Of 3899 antidepressant drug-drug interaction calls, the most frequent concomitant drugs were antipsychotics, opioids, benzodiazepines, and complementary medicines. Narrative analyses of 2011 calls identified 81.0% of patients with potential drug-drug interactions and 10.4% categorised with worrying symptoms. The most frequent drug-drug interaction risks were excessive sedation, increased anticholinergic effects, serotonin syndrome, and suicidal thoughts. Carers of children aged Discussion Antidepressant users often have information gaps and safety concerns regarding drug-drug interactions that motivate help-seeking behaviour. Symptoms and drug-drug interaction consequences may be underestimated in these patients. Primary care health professionals have a role in proactively addressing the risk of drug-drug interactions to support benefit-risk assessment and shared decision-making.

Current research in pathophysiology of opioid-induced respiratory depression, neonatal opioid withdrawal syndrome, and neonatal antidepressant exposure syndrome

Respiratory depression (RD) is the primary cause of death due to opioids. Opioids bind to mu (µ)-opioid receptors (MORs) encoded by the MOR gene Oprm1, widely expressed in the central and peripheral nervous systems including centers that modulate breathing. Respiratory centers are located throughout the brainstem. Experiments with Oprm1-deleted knockout (KO) mice undertaken to determine which sites are necessary for the induction of opioid-induced respiratory depression (OIRD) showed that the pre-Bötzinger complex (preBötC) and the pontine Kölliker-Fuse nucleus (KF) contribute equally to OIRD but RD was not totally eliminated. Morphine showed a differential influence on preBötC and KF neurons – low doses attenuated RD following deletion of MORs from preBötC neurons and an increase in apneas after high doses whereas deletion of MORs from KF neurons but not the preBötC attenuated RD at both high and low doses. In other KO mice studies, morphine administration after deletion of Oprm1 from both the preBötC and the KF/PBN neurons, led to the conclusion that both respiratory centres contribute to OIRD but the preBötC predominates. MOR-mediated post-synaptic activation of GIRK potassium channels has been implicated as a cause of OIRD. A complementary mechanism in the preBötC involving KCNQ potassium channels independent of MOR signaling has been described. Recent experiments in rats showing that morphine depresses normal, but not gasping breathing, cast doubt on the belief that eupnea, sighs, and gasps, are under the control of preBötC neurons. Methadone, administered to alleviate symptoms of neonatal opioid withdrawal syndrome (NOWS), desensitized rats to OIRD. Protection lost between postnatal days 1 and 2 coincides with the preBötC becoming the dominant generator of respiratory rhythm. Neonatal antidepressant exposure syndrome (NADES) and serotonin toxicity (ST) show similarities including RD. Enzyme CYP2D6 involved in opioid detoxification is polymorphic. Individuals of different CYP2D6 genotype may show increased, decreased, or no enzyme activity, contributing to the variability of patient responses to different opioids and OIRD.

Serotonin – therapeutic aspects and lifestyle. How do we stimulate serotonin production?

According to medical research, we can say that serotonin is one of the most influential neurotransmitters our body needs to have a truly remarkable state of health. Serotonin is also called the “hormone of happiness“ because it is in­­volved in the most important neuropsychoendocrine pro­ces­ses of the body, such as nutrition, memory, exercise, im­mu­nity, emo­tion management, recovery of organs affected by oxi­da­tive stress, rest, to give us a state of well, mentally, phy­si­­cally and emotionally. This article contains references to therapeutic aspects related to the functions of serotonin, car­ci­noid syndrome, serotonergic syndrome and obsessive-com­pul­sive disorder (OCD). The recommendations for a healthy lifestyle are highlighted by the pro-serotonin diet and the Serotonin Program to maintain vitality. Serotonin is for the human body what the Silk Road represented for the economies of the countries where it passed through, be­cause it brought prosperity, recovery and innovation. Se­ro­to­nin does the same for us, it brings us regeneration, pro­tec­tion and a good mood, if we know how to respect its principles of optimal functioning. Let’s not forget to give serotonin a chance every day, to give us a life full of happiness, if we know how to feed it properly!

Serotonin Syndrome Masquerading as Status Epilepticus following Ingestion of Tranylcypromine and Clomipramine and L-Tryptophan: A Case Report.

Serotonin Syndrome Masquerading as Status Epilepticus following Ingestion of Tranylcypromine and Clomipramine and L-Tryptophan: A Case Report.

Management of Psychiatric Disorders in Patients with Hepatic and Gastrointestinal Diseases.

Management of Psychiatric Disorders in Patients with Hepatic and Gastrointestinal Diseases.

Onset of Transient Sadness Following the Concomitant Use of a Triptan and Selective Serotonin Reuptake Inhibitor/Serotonin Norepinephrine Reuptake Inhibitors Therapy: A Case Report

Background: Migraine and depression have a bi-directional, positive association. The likelihood of these conditions being comorbidities is high, thus, the possibility of concomitant use of an antidepressant and a triptan is also increased. Case Presentation: We present a case of a 39-year-old female with a history of migraine with aura and depression who had brief episodes of exacerbated depressive symptoms following oral administration of sumatriptan 100 mg daily as needed while taking various selective serotonin reuptake inhibitor (SSRI) and serotonin and norepinephrine reuptake inhibitor (SNRI) medications on different occasions. The patient experienced 30-minute episodes of sweating and subjective increase in temperature approximately 2–3 hours after administration of sumatriptan 100 mg. This was followed by a transient exacerbation of sadness described by the patient as unhappiness, hopelessness, and tearfulness, which lasted 1 to 2 hours. To date, there are no other published case reports that have described this particular presentation. Several studies have reported possible serotonin syndrome as a result of the combination. Current evidence and known pharmacological actions of SSRIs/SNRIs and triptans are not well-defined enough to explain how one can experience episodic worsening depression. Conclusion: This case illustrates that clinicians should consider other potential adverse effects of the combined use of triptans and SSRIs/SNRIs beyond serotonin syndrome.

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.

Opioid Overdose and Serotonin Syndrome due to Gastric Bezoar in a Woman with Autism and Pica Behaviour

We are presenting the case of a 38-year-old woman with nonverbal autism and intellectual disability, hospitalized in a neurobehavioural unit because of a pica behaviour for 3 years. During the hospitalization, the patient presented an episode of pain, agitation, restlessness, rhabdomyolysis, coma, tachycardia, hyperthermia, shivering, and diarrhoea. The main hypothesis raised was tramadol overdose because of the immediate antidote response to the injection of naloxone 0,4 mg/mL. Even if we did not exceed the recommended prescription dosage of tramadol, the presence of gastric bezoar slowed the absorption of the drug, and the consequence was an opioid overdose and serotonin syndrome.

A case of a mixed overdose involving kratom (Mitragyna speciosa) leading to serotonin syndrome

Objective: Drug overdose deaths have risen precipitously over the past two years in the United States. Polysubstance overdose with opiates and amphetamines have been of particular concern. Kratom (Mitragyna speciosa) is an unregulated widely available herb with both stimulant and opiate μ-receptor activity. Studies suggest that its use is quickly increasing. Case: We describe a patient who presented to a psychiatric hospital with a mixed toxic syndrome due to chronic kratom and prescribed SSRI use compounded by acute intake of methamphetamine. The patient displayed psychosis, tremulousness, myoclonus, and extreme anxiety. Her clinical picture was consistent with both serotonin syndrome and opiate withdrawal. Conclusion: We call attention to this case because polysubstance overdoses are common, and kratom is widely available. Complex toxic presentations that involve kratom are likely to be increasingly encountered.