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.

Black Seed Oil and Perioperative Serotonin Syndrome: A Case Report.

Perioperative serotonin syndrome has been associated with a number of medications and herbal supplements. We report a patient who developed serotonin syndrome immediately after an endoscopic procedure in which the preoperative use of black seed oil appears to have played a role in stimulating the syndrome. Black seed oil has not been previously reported in association with perioperative serotonin syndrome. Anesthesia professionals should be aware that patients taking black seed oil supplements may develop serotonin syndrome postoperatively.

Dietary Supplement-Drug Interaction-Induced Serotonin Syndrome Progressing to Acute Compartment Syndrome.

BACKGROUND Dietary supplements have been associated with an increase in emergency intervention as a result of unexpected adverse events. Limited resources and information on significant drug-drug interactions with dietary supplements and prescription medications have contributed to associated complications and unexpected events. We present the case of a patient who consumed multiple prescription medications and dietary supplements which resulted in significant complications. CASE REPORT A 28-year-old man presented to the Emergency Department complaining of severe calf pain after exercising. In addition to his prescription medications, which included sertraline, he also consumed dietary supplements prior to his workout. He developed serotonin syndrome with rhabdomyolysis, which rapidly progressed to acute compartment syndrome. An emergency bilateral four-compartment double-incision lower extremity and forearm fasciotomy was performed, with complete recovery. CONCLUSIONS Drug-drug interactions involving dietary supplements are frequently overlooked in most healthcare settings, especially in the Emergency Department. Health care providers should be cognizant of the potential drug- drug interactions resulting in serotonin syndrome to prevent the progression to acute compartment syndrome and associated complications. Pharmacists play a key role in recognizing drug-dietary supplement interactions and adverse effects.

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.

Síndrome serotoninérgico por interacción entre linezolid y 5-hidroxitriptófano / Serotoninergic syndrome due to interaction between linezolid and 5-hydroxytryptophan

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[The interaction of Rhodiola rosea and antidepressants. A case report]. / Das Zusammenwirken von Rhodiola rosea (Eisenwurz) und Antidepressiva.

OBJECTIVE: Rhodiola rosea (Russian Rhodiola/Golden Root) is a high mountain plant from the arctic regions of Europe and Asia which has the active substance phenylpropanoide. It has sedative, anti-depressive, drive-enhancing and stress-modulated properties stimulating the distribution of dopamine and serotonin; in combination with other drugs, an increase of side effects and risk profile has to be expected. METHODS: A case report is presented in order to illustrate the interaction between Rhodiola rosea and antidepressants. RESULTS: We report the case of a 68-year-old female patient with recurrent moderate depressive disorder with somatic syndrome (ICD-10 F33.11) who developed vegetative syndrome, restlessness feeling and trembling since she began to ingest Rhodiola rosea in addition to paroxetine. CONCLUSIONS: Prescribing Rhodiola rosea with paroxetine, pharmacokinetic and -dynamic interactions have to be assumed. The symptoms of the patient can be interpreted as a serotonergic syndrome. Because of its different effects, the plant is widely used. An increase of clinical relevant risks should be considered in the add-on treatments.

Use of serotonergic antidepressants and St John's wort in older Australians: a population-based cohort study.

OBJECTIVE: The study investigated the use of serotonergic antidepressants (SSRIs: selective serotonin reuptake inhibitors; SNRIs: serotonin-norepinephrine reuptake inhibitors) and St John's wort in a large NSW-based community sample, and sought to identify a potentially dangerous concomitant use of these medications. METHODS: Cross-sectional data from 266,848 participants from the '45 and Up' study were used. The questionnaire captures self-reported treatment for depression or anxiety and antidepressant medications in the last four weeks. RESULTS: 5.8% of participants received treatment for depression or anxiety, with 4.7% taking an SSRI and 1.3% an SNRI. St John's wort was taken by 0.3% of the participants. Use of SSRIs and SNRIs was reported more frequently by females than males (respectively, 64.1% vs 35.9%, 66.9% vs 33.1%). The gender difference was even more pronounced for St John's wort (75.6% vs. 24.4%). Use of antidepressants decreased after the age of 65 years. One hundred and forty people reported concurrent use of an SSRI and an SNRI, and 11 people of an SSRI with St John's wort. CONCLUSIONS: Around 7% of the study population aged 45-65 years reported the use of SSRIs or SNRIs, decreasing to 5% above 70 years of age. It is of concern that some individuals used an SSRI concurrently with St John's wort.

Extracellular serotonin, dopamine and glutamate levels are elevated in the hypothalamus in a serotonin syndrome animal model induced by tranylcypromine and fluoxetine.

Serotonin (5-HT) syndrome is a potentially fatal condition associated with various combinations of serotonergic drugs. The present study was undertaken to demonstrate that nervous systems other than the 5-HT system also participate in the pathophysiology of 5-HT syndrome. Concentrations of 5-HT, dopamine (DA) and glutamate in the hypothalamus were measured in two different 5-HT syndrome animal models using a microdialysis technique. The first model was induced by tranylcypromine, a nonselective monoamine oxidase (MAO) inhibitor (3.5 mg/kg) and fluoxetine, a selective serotonin reuptake inhibitor (SSRI) (10 mg/kg). The second model was induced by clorgyline, an MAO-A inhibitor (1.2 mg/kg) and 5-hydroxy-L-tryptophan, a precursor of 5-HT (5-HTP) (80 mg/kg). In the first model, the levels of 5-HT and DA increased by 40-fold and 44-fold, respectively, compared with the preadministration levels. In the second model, the concentrations of 5-HT increased by up to 140-fold, whereas DA levels increased by only 10-fold, of the preadministration levels. Although the level of glutamate in the second model barely changed, a delayed increase in the glutamate level was observed in the first model. These findings suggest that not only hyperactivity of the 5-HT system, but also hyperactivity of the DA system, are present in 5-HT syndrome, and that the glutamatergic system is influenced in some 5-HT syndrome cases in which the DA concentration markedly increases.

Memantine, an NMDA antagonist, prevents the development of hyperthermia in an animal model for serotonin syndrome.

BACKGROUND: Serotonin (5-HT) syndrome is the most serious side effect of antidepressants. Although several drugs have been used for the treatment of 5-HT syndrome, a universal pharmacotherapy has not been established. NMDA receptor antagonists have been reported to have neuroprotective effects. In the present study, the efficacy of NMDA antagonists, including memantine and MK-801, and potent 5-HT (2A) antagonists, including risperidone and ketanserin, was evaluated in a 5-HT syndrome animal model. METHODS: 5-Hydroxy-l-tryptophan (100 mg/kg) and clorgyline (2 mg/kg) were administered intraperitoneally in rats to induce 5-HT syndrome. The rectal temperature of the rats was measured, and the noradrenaline (NA) and 5-HT levels in the anterior hypothalamus were measured using a microdialysis technique. RESULTS: In the group pretreated with saline, the rectal temperature increased to more than 40 degrees C, and all of the animals died within 90 min of the drug's administration. The NA and 5-HT levels in the anterior hypothalamus increased to about 15- and 1100-fold of the pre-administration levels, respectively. Pretreatment with risperidone (0.5 mg/kg) and ketanserin (5 mg/kg) prevented the development of hyperthermia and the increase in the NA level. Memantine (10 mg/kg) and MK-801 (0.5 mg/kg) also prevented the development of hyperthermia and the increase in the NA level. These results suggest that NMDA antagonists, as well as potent 5-HT (2A) antagonists, may be effective drugs for the treatment of 5-HT syndrome. CONCLUSIONS: Since memantine is clinically well tolerated, this drug is a particularly promising therapeutic drug for 5-HT syndrome treatment.

Serotonin syndrome and the use of SSRIs.

Nurses need to become more aware of serotonin syndrome to avoid its development and to ensure a therapeutic response when early symptoms emerge. While polypharmacy tends to put individuals at greatest risk for the syndrome, use of a single serotonergic agent may also provoke an adverse response. Because the onset and progression of serotonin syndrome are rapid, prompt action may be needed to avoid potentially life-threatening consequences.

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).