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.

[Hyponatremia associated with SSRI/NRSI: Descriptive and comparative epidemiological study of the incidence rates of the notified cases from the data of the French National Pharmacovigilance Database and the French National Health Insurance]. / Les hyponatrémies sous ISRS/IRSNA : étude épidémiologique descriptive et comparative des taux d'incidence de cas notifiés à partir des données de la Banque nationale de pharmacovigilance et de l'Assurance maladie.

INTRODUCTION: Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) are frequently prescribed. These antidepressants can potentially induce serious hyponatremia through the SIADH syndrome. That seems to concern all molecules of these classes but the individual risk of each molecule is not well known. The aims of the study were to compare the incidence rate of each molecule in order to identify the existence of molecules more at risk of inducing hyponatremia and to characterize a profile of patients at risk for hyponatremia during a treatment with a SSRI or a SNRI. METHOD: The cases of hyponatremia under SSRI/SNRI were extracted from the French pharmacovigilance database (BPNV). The exposition to the different SSRIs/SNRIs in the French population was estimated from the French National Health Insurance database (SNIIRAM) using a sampled database (Echantillon Généralistes des Bénéficiaires). The study ran from 01/01/2011 to 31/12/2013. The primary study endpoint was the incidence rate of notifications of the hyponatremia cases in patients treated by SSRI/SNRI and recorded into the BNPV database, related to the average annual number of corresponding treatments initiated during the same period. RESULTS: The number of cases of hyponatremia included in the study was 169 for 3 749 800 adult patients initiating treatment. The incidence rate of cases was 1.64 for 100 000 persons per year (PY). The standardized incidence rates between the different molecules showed no difference except for duloxetine (2.79/100 000 PY p > 0.03). Identified risk factors were age, with a large increase of incidence rate from 75 years old (incidence 12.5 higher) and female gender. CONCLUSIONS: Comparison of the incidence rates from spontaneous reports indicates a greater risk of hyponatremia for duloxetine for 2011-2013. This result needs to be confirmed by other studies. The advanced age and female sex are risk factors, irrespective of the molecule.

Serotonergic medications, herbal supplements, and perioperative serotonin syndrome.

PURPOSE: Perioperative use of serotonergic agents increases the risk of serotonin syndrome. We describe the occurrence of serotonin syndrome after fentanyl use in two patients taking multiple serotonergic agents. CLINICAL FEATURES: Two patients who had been taking multiple serotonergic medications or herbal supplements (one patient taking fluoxetine, turmeric supplement, and acyclovir; the other taking fluoxetine and trazodone) developed serotonin syndrome perioperatively when undergoing outpatient procedures. Both experienced acute loss of consciousness and generalized myoclonus after receiving fentanyl. In one patient, the serotonin syndrome promptly resolved after naloxone administration. In the other patient, the onset of serotonin syndrome was delayed and manifested after discharge, most likely attributed to the intraoperative use of midazolam for sedation. CONCLUSION: Even small doses of fentanyl administered to patients taking multiple serotonergic medications and herbal supplements may trigger serotonin syndrome. Prompt reversal of serotonin toxicity in one patient by naloxone illustrates the likely opioid-mediated pathogenesis of serotonin syndrome in this case. It also highlights that taking serotonergic agents concomitantly can produce the compounding effect that causes serotonin syndrome. The delayed presentation of serotonin syndrome in the patient who received a large dose of midazolam suggests that outpatients taking multiple serotonergic drugs who receive benzodiazepines may require longer postprocedural monitoring.

Serotonin Syndrome from 5-Hydroxytryptophan Supplement Ingestion in a 9-Month-Old Labrador Retriever.

INTRODUCTION: 5-Hydroxytryptophan (5-HTP) supplements are available over the counter and labeled as sleeping aids and anxiolytics for human use. 5-HTP is a serotonin precursor and overdose can lead to serotonin syndrome. CASE REPORT: A 9-month-old female Labrador retriever was evaluated after ingestion of a 5-HTP supplement. Signs of agitation developed within 1 h of ingestion, and emesis was attempted by the owner with  3% hydrogen peroxide (H2O2) orally. On presentation, the dog was obtunded, bilaterally mydriatic and salivating. Physical exam revealed tachypnea, tachycardia, hyperthermia, and hypertension. Eighteen hours post presentation, the dog developed melena, hematemesis, and pigmenturia. A hemogram revealed mild anemia with evidence of oxidative erythrocyte damage (eccentrocytes, Heinz bodies, and siderocytes). A chemistry panel revealed markedly elevated creatine kinase and hyperbilirubinemia, supporting hemolytic anemia. A urinalysis revealed pigmenturia. Hemolytic anemia was presumed to be caused by oxidative damage secondary to gastrointestinal ulceration and circulatory embolism of H2O2. Treatment included fluid therapy, a mannitol constant rate infusion, antiemetics, gastroprotectants, and cyproheptadine as a serotonin antagonist. The patient responded well to treatment and was discharged within 48 h of presentation. DISCUSSION: Serotonin syndrome is an increasingly common toxic syndrome in veterinary medicine with the availability of over-the-counter medications that alter serotonin metabolism. The importance of appropriate client education regarding emesis with H2O2 is highlighted.

Serotonin syndrome: a reported case.

We describe a patient treated with SSRI and Ldopa, who developed agitation, rigidity, hyperreflexia, restlessness, autonomic instability, fever and finally death. CSF examination, MRI of the brain, laboratory investigations, except for serum CK, glycemia and WBC, were normal. His condition was thought to result from an central serotonin activity. The serotonin syndrome occurs following the use of serotomimetic agents (serotonin reuptake inhibitors, tricyclic and tetracyclic antidepressants, tryptophan alone or in combination with monoamine oxidase inhibitors).