Ginsenoside Re Protects against Serotonergic Behaviors Evoked by 2,5-Dimethoxy-4-iodo-amphetamine in Mice via Inhibition of PKCδ-Mediated Mitochondrial Dysfunction.

It has been recognized that serotonin 2A receptor (5-HT2A) agonist 2,5-dimethoxy-4-iodo-amphetamine (DOI) impairs serotonergic homeostasis. However, the mechanism of DOI-induced serotonergic behaviors remains to be explored. Moreover, little is known about therapeutic interventions against serotonin syndrome, although evidence suggests that ginseng might possess modulating effects on the serotonin system. As ginsenoside Re (GRe) is well-known as a novel antioxidant in the nervous system, we investigated whether GRe modulates 5-HT2A receptor agonist DOI-induced serotonin impairments. We proposed that protein kinase Cδ (PKCδ) mediates serotonergic impairments. Treatment with GRe or 5-HT2A receptor antagonist MDL11939 significantly attenuated DOI-induced serotonergic behaviors (i.e., overall serotonergic syndrome behaviors, head twitch response, hyperthermia) by inhibiting mitochondrial translocation of PKCδ, reducing mitochondrial glutathione peroxidase activity, mitochondrial dysfunction, and mitochondrial oxidative stress in wild-type mice. These attenuations were in line with those observed upon PKCδ inhibition (i.e., pharmacologic inhibitor rottlerin or PKCδ knockout mice). Furthermore, GRe was not further implicated in attenuation mediated by PKCδ knockout in mice. Our results suggest that PKCδ is a therapeutic target for GRe against serotonergic behaviors induced by DOI.

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

The serotonin syndrome is a potentially deadly complication resulting from drug adverse effect, drug-drug interaction or overdose involving one or more serotonergic molecules, e.g., antidepressants, psychostimulants and sometimes an "ignored" serotonergic compound. The serotonin syndrome typically consists of a clinical triad including cognitive/behavioral, neurovegetative and neuromuscular features. However, this syndrome is characterized by major clinical heterogeneity, making the diagnosis difficult in practice. Moreover, many practitioners are quite unaware of this syndrome. Available scores and classifications can help physicians in their diagnosis approach. Knowing the responsible molecules, their potential interactions and mechanisms of action can help preventing this complication allowing therapeutic education among patients. This updated article reviews the clinical presentation, prevention, management, and pathophysiology of the serotonin syndrome, and addresses the most recent advances in pharmacogenetics regarding this syndrome.

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.

Serotonin syndrome: Preventing, recognizing, and treating it.

As the use of serotonergic agents to treat depression has increased, so too has the incidence of serotonin syndrome. We identify the common agents implicated in serotonin syndrome and the clinical tools to diagnose, manage, and prevent serotonergic toxicity.

Serotonin Syndrome: Prophylactic Treatment With Cyproheptadine.

Despite the numerous advantages of linezolid therapy, one disadvantage continuing to hinder its use is the risk of serotonin syndrome when coadministered with other serotonergic agents. Developing a better understanding of serotonin syndrome is essential for the prevention and management of this potentially life-threatening condition. This report describes a patient with schizophrenia, depression, and severe, acute osteomyelitis. The patient was taking multiple serotonergic agents and required the use of linezolid without the possibility of a sufficient washout period. The severity of the patient's condition in conjunction with increased risk for serotonin syndrome warranted prophylactic treatment with cyproheptadine. The complex pathophysiology of prophylactic treatment of serotonin syndrome with cyproheptadine is worthy of discussion.

The impact of pharmacists' input to reduce serotonin syndrome drug interactions in an Australian hospital.

BACKGROUND: Drug interactions contribute significantly to adverse-related events and hospital admissions. Example of common drug interactions includes combinations of medications that induces serotonin syndrome. Pharmacists are well placed in the multidisciplinary team to alert prescribers of these drug interactions and offer an alternative management. OBJECTIVE: The objective is to evaluate the effectiveness of pharmacists' input in preventing patients being discharged on clinically relevant drug interactions that have the potential to cause serotonin syndrome in an Australian hospital. METHOD: A retrospective cross-sectional audit of patients' case notes who were prescribed a combination of drugs likely to induce serotonin syndrome on admission were examined over a 3-month period. A predefined list of serotonin syndrome-inducing drugs of severity 1 and 2 was used to search for patients on these drug combinations on admission. The severities of the drug combinations were classified as per the Monthly Index of Medical Specialties drug interactions guide. Subsequent pharmacists' interventions were recorded on discharge to observe any change in prescribing practice. Descriptive statistics were used to analyze the data. P values were obtained using the Student's t-test and Fisher's exact tests. RESULTS: A total of 144 patients over 3 months were identified to have been prescribed a combination of drugs with a potential to cause serotonin syndrome during admission. Of these patients, 79 and 21% were prescribed combination of serotonergic drugs that were classified as severity 1 and 2, respectively, according to Monthly Index of Medical Specialties. A total of 56% (n = 81) of the audited patients were discharged with no serotonin syndrome-inducing drug combinations and 44% (n = 63) were discharged on serotonin syndrome-inducing drug combinations of severity 1 or 2. Pharmacist input has led to a significant reduction (relative risk reduction 44%; P < 0.0001) in the total number of patients who were discharged on severity 1 and 2 serotonin syndrome-inducing drug combinations. There were 87 patients (60%) who had a pharmacist input during admission. In this subset of the cohort, 36% (n = 31) of patients were discharged on serotonin syndrome-inducing drug combinations (combined both severity 1 and 2) compared with 56% (n = 32) in those who did not get a pharmacist input, P = 0.017. In addition, 64% (n = 56) of patients in this group were discharged on no serotonin syndrome-inducing drug combinations compared with 44% (n =  25) in the nonpharmacist group, P = 0.017. CONCLUSION: The audit highlights the pharmacists' role in significantly reducing clinically relevant drug interaction in patients prescribed serotonin syndrome-inducing drug combination in a single-center Australian hospital on discharge.

[Analgesics in geriatric patients. Adverse side effects and interactions]. / Analgetika beim geriatrischen Patienten. Unerwünschte Arzneimittelwirkungen und Interaktionen.

Pain is a widespread symptom in clinical practice. Older adults and chronically ill patients are particularly affected. In multimorbid geriatric patients, pharmacological pain treatment is an extension of a previously existing multimedication. Besides the efficacy of pain treatment, drug side effects and drug-drug interactions have to be taken into account to minimize the health risk for these patients. Apart from the number of prescriptions, the age-related pharmacokinetic and pharmacodynamic changes significantly increase the risk among older adults. The use of non-steroidal anti-inflammatory drugs (NSAID) is widespread but NSAIDs have the highest risk of adverse drug reactions and drug interactions. In particular, the gastrointestinal, cardiovascular, renal and coagulation systems are affected. Apart from the known toxic effect on the liver (in high doses), paracetamol (acetaminophen) has similar risks although to a lesser degree. According to current data, metamizol is actually better than its reputation suggests. The risk of potential drug interactions seems to be low. Apart from the risk of sedation in combination with other drugs, tramadol and other opioids can induce the serotonin syndrome. Among older adults, especially in the case of polypharmacy, an individualized approach should be considered instead of sticking to the pain management recommended by the World Health Organization (WHO) in order to minimize drug-drug interactions and adverse drug reactions.

[Serotonin syndrome and pain medication : What is relevant for practice?]. / Serotoninsyndrom und medikamentöse Schmerztherapie : Was ist für die Praxis relevant?

Serotonin syndrome is a dangerous and rare complication of a pharmacotherapy and can lead to death. Caused by unwanted interactions of serotonergic drugs, it is characterised by a neuroexcitatory triad of mental changes, neuromuscular hyperactivity and autonomic instability. Opioids with serotonergic effects include the phenylpiperidine series opioids fentanyl, methadone, meperidine and tramadol and the morphine analogues oxycodone and codeine. In combination with certain serotonergic drugs, e.g. antidepressants, they can provoke serotonin syndrome. In patients with such combinations, special attention should be paid to clinical signs of serotonergic hyperactivity. Higher risk combinations (e.g. monoamine oxidase inhibitors with tramadol) must be avoided. Treatment with serotonergic agents must be stopped in moderate or severe serotonin syndrome. Patients with a severe serotonin syndrome require symptomatic intensive care and specifically a pharmacological antagonism with cyproheptadine or chlorpromazine.

[Dopaminergic treatment in Parkinson's disease: what has each therapeutic family got to offer?]. / Tratamiento dopaminérgico en la enfermedad de Parkinson: ¿qué puede ofrecer cada familia terapéutica?

Different families of dopaminergic agents have allowed to increase the availability of dopamine within the central nervous system by different mechanisms of action. Each drug family has specific efficacious properties, as well as a different profile of adverse events. The knowledge in detail of these specificities is mandatory to avoid severe systemic or neuropsychiatric complications. Despite these limitations, the development of new drugs within the past 20 years has prolonged survival in Parkinson's disease, increasing the time with preserved daily day functionality compared with the levodopa era, when this drug was the only dopaminergic drug available. The correct combination of dopaminergic drugs with different mechanisms of action allows the management of Parkinson's disease motor symptoms within safety dose ranges, and up to day, this appears as the best algorithm to maintain functionality for longer periods of time.

TITLE: Tratamiento dopaminergico en la enfermedad de Parkinson: que puede ofrecer cada familia terapeutica?Diferentes familias de farmacos dopaminergicos han permitido aumentar el suministro de dopamina en el estriado por diferentes mecanismos. Cada familia de farmacos posee un grado de eficacia determinado, asi como un perfil de efectos secundarios especifico que debe conocerse en detalle para evitar complicaciones sistemicas y neuropsiquiatricas graves. A pesar de estas limitaciones, la disponibilidad de multiples farmacos ha permitido aumentar la supervivencia media en la enfermedad de Parkinson, con un periodo de funcionalidad en el dia a dia significativamente mas largo al que se conseguia cuando la levodopa era practicamente el unico farmaco disponible. La correcta adicion de farmacos dopaminergicos con diferentes mecanismos de accion permite tratar la enfermedad de Parkinson sin tener que llegar a dosis excesivamente altas de ninguno de ellos, lo que parece, en el momento actual, el mejor algoritmo para el control de los sintomas motores durante un periodo lo mas duradero posible.

Serotonin syndrome: is it a reason to avoid the use of tramadol with antidepressants?

BACKGROUND: There is a warning associated with all serotonergic antidepressants and its concomitant use with tramadol due to the concern for a drug-drug interaction resulting in serotonin syndrome (SS). The prescribing of antidepressants with tramadol may be unnecessarily restricted due to fear of causing this syndrome. OBJECTIVES: There are 3 objectives of this review. To (1) review case reports of SS associated with the combination of tramadol and antidepressant drugs in recommended doses, (2) describe the mechanisms of the drug interaction, and (3) identify the potential risk factors for SS. METHODS: Case reports of SS associated with tramadol and antidepressants were identified via Cochrane Library, PubMed, and Ovid (through October 2012) using search terms SS, tramadol, antidepressants, fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, escitalopram, venlafaxine, desvenlafaxine, duloxetine, mirtazapine, milnacipran, trazodone, vilazodone, and bupropion. Cases involving monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants were excluded. RESULTS: Nine articles were identified describing 10 cases of suspected SS associated with therapeutic doses of tramadol combined with an antidepressant. Mechanisms of the drug-drug interactions involve pharmacodynamic, pharmacokinetic, and possible pharmacogenetic factors. CONCLUSIONS: Review of the available case reports of tramadol combined with antidepressant drugs in therapeutic doses indicates caution in regard to the potential for SS but does not constitute a contraindication to their use. Tramadol is only contraindicated in combination with MAOIs but not other antidepressants in common use today. These case reports do suggest several factors associated with a greater risk of SS, including increased age, higher dosages, and use of concomitant potent cytochrome P450 2D6 inhibitors. Tramadol can be safely combined with antidepressants; however, monitoring and counseling patients are prudent when starting a new serotonergic agent or when doses are increased.

Ecstasy use and serotonin syndrome: a neglected danger to adolescents and young adults prescribed selective serotonin reuptake inhibitors.

BACKGROUND: At present, there are scarce clinical and basic lab data concerning the risk of acute serotonin toxicity from selective serotonin reuptake inhibitors (SSRIs) and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) co-administration. The health care community can strongly benefit from efforts to address the high risks associated with serotonin syndrome from this specific drug combination. OBJECTIVE: The aim of this work is to review the risk of serotonin syndrome in adolescents and young adults prescribed with SSRIs and are concurrently using ecstasy. DATA SOURCES: An electronic search of the major behavioral science bibliographic databases (Pubmed, PsycINFO, Medline) was conducted to retrieve peer-reviewed articles, which detail the clinical characteristics, biological mechanisms and social implications of SSRIs, MDMA, and their potential synergism in causing serotonin syndrome in the pediatric and young adult population. Search terms included "serotonin syndrome", "ecstasy", "MDMA", "pediatric", and "SSRI". Additional references were incorporated from the bibliographies of these retrieved articles. RESULTS: MDMA, in combination with the widely-prescribed SSRI antidepressant class, can lead to rapid, synergistic rise of serotonin (5-HT) concentration in the central nervous system, leading to the acute medical emergency known as serotonin syndrome. This review addresses such complication through an exploration of the theoretical mechanisms and clinical manifestations of this life-threatening pharmacological interaction. CONCLUSION: The increasing incidences of recreational ecstasy use and SSRI pharmacotherapy among multiple psychiatric disorders in the adolescent population have made this an overlooked yet increasingly relevant danger, which poses a threat to public health. This can be curbed through further research, as well as greater health care provision and attention from a regulatory body owing.

Avoiding serotonin syndrome: the nature of the interaction between tramadol and selective serotonin reuptake inhibitors.

OBJECTIVE: To investigate the nature of the interaction between selective serotonin reuptake inhibitors (SSRIs) and tramadol to mitigate or avoid serotonin syndrome. DATA SOURCES: PubMed, Ovid MEDLINE, and International Pharmaceutical Abstracts from January 1990 to August 2012 were searched. Key words used were tramadol, antidepressive agents, antidepressants, drug interactions, selective serotonin uptake inhibitors, and serotonin syndrome. STUDY SELECTION AND DATA EXTRACTION: Only English-language studies were included. No randomized controlled trials were identified. Review articles, case reports, and 1 case series that identified the scope of interaction between tramadol and SSRIs were evaluated. Review articles evaluating the role of pharmacogenetics in the use of tramadol, SSRIs, and serotonin syndrome were also reviewed. DATA SYNTHESIS: Published documentation describing the interaction between tramadol and SSRIs and its relevance to serotonin syndrome is limited to a few case reports and 1 case series. While both tramadol and SSRIs increase the amount of serotonin in the brain, the interaction is much more complicated. Tramadol is metabolized through CYP2D6 enzymes and all SSRIs are inhibitors of these enzymes. Inhibitors of CYP2D6 can increase the concentration of tramadol in the blood and thus increase its effects on serotonin in the brain, contributing to the development of serotonin syndrome. CYP2D6 poor metabolizers are at a greater risk of serotonin syndrome and an inadequate analgesic effect. CONCLUSIONS: Coadministration of tramadol and SSRIs has caused serotonin syndrome. An attempt should be made to identify individuals who are poor metabolizers of CYP2D6 and avoid this combination in those patients. When SSRIs and tramadol must be used in combination, it is critical that patients be aware of the signs and symptoms of serotonin syndrome, should they occur.

Prevention, recognition, and management of serotonin syndrome.

Serotonin syndrome is a potentially life-threatening condition caused by excessive serotonergic activity in the nervous system. It is characterized by mental status changes, autonomic instability, and neuromuscular hyperactivity. Most reported cases of serotonin syndrome are in patients using multiple serotonergic drugs or who have had considerable exposure to a single serotonin-augmenting drug. Diagnosis is made using the Hunter Serotonin Toxicity Criteria, which require the presence of one of the following classical features or groups of features: spontaneous clonus; inducible clonus with agitation or diaphoresis; ocular clonus with agitation or diaphoresis; tremor and hyperreflexia; or hypertonia, temperature above 100.4 degrees F (38 degrees C), and ocular or inducible clonus. Most cases of serotonin syndrome are mild and may be treated by withdrawal of the offending agent and supportive care. Benzodiazepines may be used to treat agitation and tremor. Cyproheptadine may be used as an antidote. Patients with moderate or severe cases of serotonin syndrome require hospitalization. Critically ill patients may require neuromuscular paralysis, sedation, and intubation. If serotonin syndrome is recognized and complications are managed appropriately, the prognosis is favorable.