A review of vilazodone exposures with focus on serotonin syndrome effects

Background: Vilazodone is an antidepressant with selective serotonin reuptake inhibition and partial 5HT1A agonism. Serotonin syndrome is believed to be due to excessive stimulation of 5-HT2A and 5-HT1A receptors, resulting in the clinical triad of altered mentation, autonomic instability and neuromuscular abnormalities. The goal of this study is to define serotonergic effects after vilazodone exposure.

Methods: A retrospective review of two databases: the American Association of Poison Controls Centers’ National Poison Data System (NPDS) and the American College of Medical Toxicology’s Toxicology Investigators Consortium (ToxIC Registry). A case series of four patients from one medical toxicology service is also presented.

Results: During the 52-month study period, a total of 3192 vilazodone human exposures were reported to NPDS. Of these, 1734 (54%) were isolated vilazodone cases. The clinical effects of vilazodone toxicity included drowsiness (20%), vomiting (14%), tachycardia (11%) and agitation (10%). Most patients (71%) had symptoms for between 2 and 24?h, though some (14%) remained symptomatic for more than 24?h. The most common treatment was intravenous fluids (15%) and the most serious intubation (2%). From the ToxIC Registry, a total of 23 cases of vilazodone exposures were identified. Of these, 17 (74%) had vilazodone listed as the first (primary) agent and 10 (43%) involved vilazodone-only ingestions. Nine (39%) cases documented serotonin syndrome; and most (8/9; 89%) listed vilazodone as the primary agent. All (n?=?4) subjects in the case series with acute vilazodone toxicity had serotonin syndrome.

Conclusions: Vilazodone overdose, including vilazodone-only ingestions, are associated with serotonin syndrome. Serotonergic toxicity and appropriate treatments should be considered when caring for patients with vilazodone ingestions.     

Two Cases of Serotonin Syndrome After Bupropion Overdose Treated With Cyproheptadine

BackgroundBupropion is not known to have direct serotonin agonism or inhibit serotonin reuptake. In spite of this, it has been implicated as a causative agent of serotonin syndrome. We highlight two cases of single-agent bupropion overdose that subsequently met the diagnosis of serotonin syndrome by the Hunter criteria, despite the absence of direct serotonergic agents.Case 1A 14-year-old boy intentionally ingested an estimated 30 bupropion 75-mg immediate-release tablets. He presented in status epilepticus, was intubated, and was placed on midazolam and fentanyl infusions. He developed tremor, ankle clonus, and agitation. He was administered cyproheptadine for presumed serotonin syndrome with temporal improvement in his symptoms.Case 2A 19-year-old woman intentionally ingested an estimated 53 bupropion 150-mg extended-release tablets. She had a seizure and required sedation and intubation. During her course, she developed hyperthermia, inducible clonus, and hyperreflexia. She was treated with cyproheptadine without temporal improvement of symptoms but improved the following day.Why Should an Emergency Physician Be Aware of This?Although bupropion is not known to be directly serotonergic, it has been implicated as the single causative agent after overdose. This may be due to an indirect increase in activity of serotonergic cells. In these cases, bupropion overdose resulted in a clinical presentation consistent with serotonin syndrome, with the first having a temporal improvement after treatment with cyproheptadine. Physicians need to be aware of the potential serotonergic activity of bupropion for accurate assessment and treatment of this dangerous condition.     

Citalopram overdose and severe serotonin syndrome in an intermediate metabolizing patient

IntroductionCitalopram is a selective serotonin reuptake inhibitor used for treatment of depression. Metabolism is primarily through CYP3A4 and CYP2C19; activity of the latter can vary depending on genetics. Although rare after single agent exposure, large citalopram ingestions can lead to serotonin syndrome. We report a case of citalopram overdose in an intermediate CYP2C19 metabolizer complicated by severe serotonin syndrome.Case detailsA 25-year-old female presented after intentional citalopram overdose with seizures, tachycardia, persistent neuromuscular findings, and severe hyperthermia requiring aggressive sedation and cooling. Protracted symptoms required critical care services throughout a 14 day hospital stay despite traditional treatment of serotonin syndrome. Pharmacogenomic studies revealed intermediate CYP2C19 metabolism which reduces citalopram inactivation and may cause increased levels and toxicity.DiscussionIn the majority of serotonin syndrome cases, symptoms resolve rapidly after treatment initiation and discontinuation of the offending agents. Severe cases are typically associated with ingestion of multiple serotonergic agents. Our patient had severe toxicity after single agent ingestion. Pharmacogenetic testing identified abnormal CYP2C19 activity and previous cases have associated enzyme dysfunction and citalopram toxicity.ConclusionCitalopram overdose may be associated with severe serotonin syndrome and further investigation is warranted to understand the impact of enzyme genotype on toxicity.     

Serotonin syndrome: early management with cyproheptadine

OBJECTIVE: To report a psychiatric patient who developed serotonin syndrome after a medication overdose and whose marked mydriasis was quickly reversed by administration of cyproheptadine. This phenomenon was confirmed when other cases of serotonin syndrome were studied. METHOD: In the index patient as well as in three subsequent cases of serotonin syndrome, pupil diameter, muscle tone, mental status, and vital signs were monitored before and after a test dose of cyproheptadine as medications were discontinued and antiserotonergic therapy begun. RESULTS: In each patient, cyproheptadine produced rapid reversal of mydriasis within one hour of the initial dose. Other signs of serotonin syndrome remitted more slowly. As the signs and symptoms of serotonin syndrome remitted and pupils returned to normal size and reactiveness, cyproheptadine therapy seemed to produce mydriasis after each dose. Cessation of therapy after this point did not result in recurrence of symptoms. One patient developed serotonin syndrome twice. Two patients developed serotonin syndrome during treatment with medications that are partial serotonin antagonists (mirtazapine and nefazodone). CONCLUSIONS: Rapid reversal of mydriasis in serotonin syndrome by cyproheptadine may serve as a specific suppressive test for the condition, and possibly may add to our understanding of the syndrome. Treatment with cyproheptadine is not thought to abbreviate the illness, but provides symptomatic relief while symptoms persist.     

Acute quetiapine poisoning

Quetiapine (Seroquel®) is a member of a new class of antipsychotic agents used in the treatment of schizophrenia. Its pharmacologic effect is primarily mediated via antagonistic binding to serotonergic (5HT2) and dopaminergic (D2) receptors. Presented is a case of acute quetiapine overdose in a patient with associated tachycardia, hypotension, prolonged QTc, and rapid progression to coma. Management included activated charcoal, i.v. saline, and intubation for airway protection. The patient’s mental status rapidly improved within several hours of the ingestion, and the prolonged QTc and tachycardia resolved by the second and third days of hospitalization, respectively, without further intervention. This case illustrates the potential for hemodynamic instability and sudden deterioration in level of consciousness, warranting close monitoring and early intubation for airway protection. All patients with acute quetiapine overdose requiring hospitalization should be admitted to an intensive care unit setting.     

Serotonin syndrome with elevated paroxetine concentrations

OBJECTIVE: To describe a case of serotonin syndrome due to paroxetine and ethanol. CASE SUMMARY: A 57-year-old white man was brought to the emergency department one day after ingesting paroxetine 3600 mg and a pint of hard liquor. He denied the use of any other drug or herbal products and regular use of alcohol. Upon arrival to the hospital, vital signs were blood pressure 188/103 mm Hg, heart rate 114 beats/min, respiratory rate 28 breaths/min, temperature 36.8 degrees C, and O2 saturation 96% on room air. Findings on physical examination included dilated pupils, facial flushing, diaphoresis, shivering, myoclonic jerks, tremors, and hyperreflexia. A tentative diagnosis of serotonin syndrome was made. Initially, cyproheptadine 8 mg was administered orally with no observable effect. An additional 12 mg was given in 3 doses over 24 hours. Symptoms abated slowly over the next 6 days, during which a thorough evaluation failed to reveal any other potential causes for the patient's condition. Serum paroxetine concentrations at 27.5 and 40 hours after ingestion were 1800 and 1600 ng/mL, respectively (normal 20-200 ng/mL). DISCUSSION: Serotonin syndrome is rarely reported in patients taking only one serotonergic medication. Although serum paroxetine concentrations have not been shown to correlate with efficacy or toxicity, our patient's serum paroxetine concentration was 9 times the upper end of the therapeutic range. Cyproheptadine, which has been suggested as a therapy, did not appear beneficial in this patient. Use of the Naranjo probability scale indicated a probable relationship between the serotonin syndrome and the overdose of paroxetine taken by this patient. CONCLUSIONS: More studies are needed to better assess the role of cyproheptadine and other serotonin antagonists in the management of the serotonin syndrome. Regardless of the use of cyproheptadine or other agents, attention should be paid to fluid status, decontamination, and management of hyperthermia, agitation, and seizures.     

Dexmedetomidine for Acute Management of Intrathecal Baclofen Withdrawal

BackgroundIntrathecal baclofen (ITB) is a mainstay of treatment for patients with chronic spasticity. Up to 40% of all patients receiving ITB experience overdose or withdrawal symptoms, which in the most severe cases can lead to multisystem organ failure and death. There is currently no well-established treatment for ITB withdrawal. One previous case report details an intubated pediatric patient who underwent baclofen pump removal in which dexmedetomidine was used in combination with other medications to prevent baclofen withdrawal.Case ReportWe report a case of baclofen withdrawal where the decision was made to initiate a dexmedetomidine infusion, with subsequent improvement of the patient's hypertension and tachycardia. At no point during her stay did the patient require intubation for airway protection, and the patient was ultimately discharged to her previous nursing facility on hospital day 9 with no new neurologic deficits.Why Should an Emergency Physician Be Aware of This?Emergency physicians should be aware of dexmedetomidine as a promising option for the treatment of ITB withdrawal in the acute setting. Although little evidence is currently present, dexmedetomidine was used successfully in this case, and should be considered as a temporizing treatment for ITB withdrawal. Dexmedetomidine holds promise in the management of ITB withdrawal compared to other previously described treatments, including oral baclofen, cyproheptadine, and dantrolene. In addition, dexmedetomidine has a superior safety profile compared to propofol or large doses of benzodiazepines. Further research will be useful in supporting the use of dexmedetomidine for this purpose.     

Serotonin syndrome due to an overdose of moclobemide?

Serotonin syndrome, a triad of autonomic instability, altered mental status and neuromuscular abnormalities, is usually attributed to serotonergic overdoses. Moclobemide is a new selective monoamine oxidase inhibitor (MAOI) that generally causes mild, self-limited gastrointestinal and central nervous system effects after ingestion. We present a case of serotonin syndrome that occurred after moclobemide overdose, and discuss the recognition and treatment of this important condition. Serotonin syndrome may become increasingly common because of the liberal use of selective serotonin reuptake inhibitors, new MAOIs and other agents such as codeine and meperidine, which have the potential for harmful interaction.     

Flu-like symptoms associated with fluoxetine overdose: A case report

Abstract

The serotonin reuptake inhibitor zimelidine may cause flu-like symptoms and Guillain-Barre syndrome. Guillain-Barre syndrome has not been reported with the use of the structurally related serotonin reuptake inhibitor fluoxetine. Flu-like symptoms are described in the manufacturer's literature on fluoxetine but are absent from published studies. We describe a patient who developed flu-like symptoms, urticaria and angioedema 2 days after fluoxetine overdose. There were no neurologic sequelae. This case confirms that fluoxetine may be associated with flu-like symptoms and suggests that, because these symptoms occurred after overdose, they may be dose related. The additional findings in this patient suggestive of allergy, an unusual feature of drug overdose, are discussed.     

Influence of CYP3A4 Induction/Inhibition on the Pharmacokinetics of Vilazodone in Healthy Subjects

PurposeVilazodone is a serotonin reuptake inhibitor and 5-HT_1A partial agonist approved for the treatment of major depressive disorder in adults. Vilazodone seems to be metabolized primarily by the cytochrome P-450 (CYP) 3A4 isozyme and non-CYP–mediated pathways; concomitant use of drugs that affect CYP3A4 activity could potentially alter systemic exposure to vilazodone. The present studies evaluated whether CYP3A4 inhibition (study 1) or induction (study 2) affected the pharmacokinetics of vilazodone.MethodsParticipants were healthy adult volunteers. Study 1 was conducted in 2 parts and evaluated the pharmacokinetics of single-dose vilazodone administered with multiple-dose (200 mg once daily) ketoconazole, a CYP3A4 inhibitor. Part 1 was an open-label pharmacokinetic assessment of a single 5-mg vilazodone dose with or without ketoconazole. Part 2 was a randomized, double-blind, placebo-controlled, crossover study comparing vilazodone pharmacokinetics after a single 10-mg dose alone or co-administered with ketoconazole or placebo. Study 2 was an open-label, multiple-dose, single-sequence study evaluating the effect of steady-state carbamazepine, a CYP3A4 substrate and inducer, on the pharmacokinetics of steady-state vilazodone (40 mg once daily). Primary pharmacokinetic parameters for both studies were AUC and C_max for vilazodone. Lack of pharmacokinetic interaction was concluded if the 90% CIs of the ratio of vilazodone plus the CYP3A4 inhibitor/inducer relative to vilazodone alone (or plus placebo) for AUC and C_max were within the 80% to 125% range. Subject-reported and investigator-identified adverse events (AEs), laboratory values, vital signs, and 12-lead ECG parameters were recorded.FindingsIn study 1/parts 1 and 2 (n = 15 and 22 enrolled, respectively), mean vilazodone AUC increased 42% and 51%, respectively, in the presence of ketoconazole (expected to be at steady state) versus vilazodone alone (part 1) or with placebo (part 2). The upper limit of the 90% CIs for the vilazodone AUC and C_max geometric mean ratios exceeded 125%. In study 2 (n = 30 enrolled), co-administration of vilazodone and the carbamazepine extended-release formulation decreased mean steady-state vilazodone exposure ~45%, and the 90% CIs for the vilazodone AUC and C_max geometric mean ratios were not within the range of 80% to 125%. In both studies, most AEs were of mild intensity, and gastrointestinal AEs predominated.ImplicationsThese results suggest that up to a 50% decrease of vilazodone dosage should be considered when it is given in combination with strong CYP3A4 inhibitors; conversely, increasing the vilazodone dosage up to a maximum of 80 mg/d should be considered when it is given in combination with strong CYP3A4 inducers. (Study registration numbers: SB-659746/029; VLZ-PK-02.)     

Evaluation of dose and outcomes for pediatric vilazodone ingestions

Background: Selective serotonin reuptake inhibitor (SSRI) exposures among children younger than 6 years of age are generally well tolerated. Vilazodone is an SSRI with partial agonism at the 5-HT_1A receptor with demonstrated clinical efficacy for depression whose off-label usage is likely to increase. Recent evidence suggests that unintentional ingestion of vilazodone in children under 6 years old is associated with more severe clinical effects than other SSRIs. We chose to evaluate dose and outcomes for pediatric vilazodone ingestions.

Methods: A retrospective analysis of single-substance exposures associated with vilazodone among children younger than 6 years of age from 2011 through 2016 was conducted using data from the National Poison Data System.

Results: During 2011–2016, 753 vilazodone ingestions among children <6 years old were reported to US poison control centers. A near majority (49.0%, n?=?369) experienced one or more clinical effects. The dose ingested was reported for 596 children (79%).

The median dose associated with major effects was 50.0mg (Mean: 106.0) compared with 40.0mg (Mean 81.1) for moderate effects. Half (50.0%) of children with a major effect and 54.0% with a moderate effect ingested ≤40?mg of vilazodone. As the dose of vilazodone ingested increased, the proportions of exposures admitted to a healthcare facility (HCF) (p?p?Conclusions: Exposure to vilazodone poses a unique and potentially serious threat to children <6 years of age. Children in this age group who are exposed to vilazodone should be evaluated promptly in a clinical setting. Off-label use of vilazodone in children under 6 years should be discouraged until further research is conducted regarding its safety in this population.     

Clinical Experience in Acute Overdosage of Diphenidol

Abstract

Background: Diphenidol (Cephadol, Vontrol®), an antiemetic agent used in the treatment of vomiting and vertigo, has been reported to cause various adverse effects including drowsiness, hypotension, confusion, hallucination, restlessness, and other antimuscarinic effects. Serious toxic effects might be anticipated after intentional or accidental ingestion. Materials and methods: Retrospective analysis of all case records of the PCC-Taiwan defining diphenidol overdose during 1985–1996. Results: The data of 21 patients with diphenidol overdose were analyzed; 17 were < 3 years old and unintentionally poisoned, in contrast to the suicide attempts by four adults. The average amount of ingestion was 222.5 mg with a range of 25–800 mg. Most patients manifested only transient CNS, cardiovascular, or oculo-facial effects, but four children suffered from severe toxicity after an ingestion of 11.7–80 mg/kg diphenidol. Commonly reported toxicity in diphenidol overdose included facial flush (10), tachycardia, restlessness (6), seizures (4), dyspnea, drowsiness, mydriasis, coma, and fever (3). With supportive therapy, a good recovery was the rule except for one fatality of a 21/2-year-old boy who ingested 15 mg/kg diphenidol and presented with recurrent seizures, hypotension, respiratory failure, and coma. Conclusions: Although not previously reported, accidental diphenidol overdose may result in serious anticholinergic toxicity in children. Treatment is supportive and the therapeutic role of physostigmine in diphenidol poisoning is still unclear.     

Sympathetic overactivity from fenfluramine-phentermine overdose.

A 24-year-old male presented to the emergency department with hyperadrenergic manifestations of fenfluramine-phentermine overdose: tachycardia, mydriasis, fever, diaphoresis, hyperventilation, and combativeness. Sedatives, neuromuscular paralytics, adrenergic antagonists, and mechanical ventilation were required to care for the patient. In addition, the patient had self-inflicted 15% TBSA second-degree burns and developed adult respiratory distress syndrome which required continued intubation and mechanical ventilation for 12 days. The patient had split thickness skin grafts for his leg burns on day 11. He was discharged after a 26-day hospital stay. We are unaware of any previously reported cases of fenfluramine-phentermine overdose with such profound degree of sympathetic storm.     

Intrathecal Baclofen Overdose With Paradoxical Autonomic Features Mimicking Withdrawal

BackgroundIntrathecal Baclofen (ITB) has become an increasingly common treatment for severe muscle spasticity associated with conditions such as cerebral palsy and spinal cord injury. Classically, withdrawal symptoms mimic symptoms of serotonin syndrome with hypertension, increased spasticity, clonus, hyperthermia, tachycardia, and possibly acute psychosis. Hypotension, muscle flaccidity, and respiratory depression are generally considered symptoms of toxicity or overdose.Case ReportWe present the case of a male with recent ITB pump revision who presented with autonomic features suggestive of Baclofen withdrawal, while the remainder of his physical examination suggested appropriate medication dosing. Interrogation of the patient's ITB pump revealed normal function, and the patient had no clinical change with intravenous benzodiazepines, but his condition ultimately improved when his Baclofen dosing was decreased, indicating toxicity instead of withdrawal.Why Should an Emergency Physician Be Aware of This?As Baclofen pump use increases, the importance of recognizing these potentially life-threatening complications also increases. This case presents the emergency physician with an atypical presentation and emphasizes the importance of a thorough neurologic examination to diagnose patients accurately.     

Serotonin syndrome caused by overdose with paroxetine and moclobemide.

Well known clinical syndromes can be produced by overdose with more commonly ingested substances such as opiates or tricyclic antidepressants. A case of a much more unusual syndrome presenting to the accident and emergency department resulting from overdose with a combination of tablets is reported. The clinical presentation of serotonin syndrome and its management are described. This resulted from acute ingestion of paroxetine, a selective serotonin reuptake inhibitor, and moclobemide, a monoamine oxidase inhibitor.     

Serotonin syndrome caused by overdose with paroxetine and moclobemide.

Well known clinical syndromes can be produced by overdose with more commonly ingested substances such as opiates or tricyclic antidepressants. A case of a much more unusual syndrome presenting to the accident and emergency department resulting from overdose with a combination of tablets is reported. The clinical presentation of serotonin syndrome and its management are described. This resulted from acute ingestion of paroxetine, a selective serotonin reuptake inhibitor, and moclobemide, a monoamine oxidase inhibitor.     

Serotonin syndrome due to an overdose of moclobemide and clomipramine

The serotonin syndrome is frequently characterized by minor neurologic manifestations that regress rapidly (such as confusion, tremor, ...). Many medications including tricyclic antidepressants, serotonin reuptake inhibitors, tryptophan and the association of monoamine oxidase inhibitors together with a serotoninergic agent have been implicated in this syndrome. In certain cases, and for poorly understood reasons, clinical manifestations can include circulatory collapse, malignant hyperthermia, convulsions and rhabdomyolysis. These forms are often fatal. Treatment, other than the withdrawal of the offending drug, is symptomatic. Dialysis may be of value in withdrawing the drug from the circulatory system. We report a patient with the serotonin syndrome of favorable outcome due to an overdose of moclobemide and clomipramine. Received: 24 April 1996 Accepted: 4 October 1996     

Serotonin syndrome induced by low-dose venlafaxine

OBJECTIVE: To report the case of a patient with serotonin syndrome induced by low-dose venlafaxine. CASE SUMMARY: A 29-year-old Taiwanese woman with major depressive disorder abruptly developed serotonin syndrome during low-dose (37.5 mg/d) venlafaxine monotherapy, with symptoms of restlessness, tremor, shivering, diarrhea, vomiting, ataxia, tachycardia, and myoclonus. The patient recovered in 2 hours after receiving prochlorperazine and lorazepam in the emergency department. Venlafaxine was discontinued, and she was discharged home. Two weeks later, the patient started to receive fluoxetine 20 mg/d and reported no adverse adverse effects during follow-up clinic visits. DISCUSSION: The clinical manifestations of this case meet Sternbach's criteria of serotonin syndrome. Its possible etiologic factors include panic attack, adverse drug reaction, pharmacodynamic interaction, and congenital absence of CYP2D6 enzyme activity. The Naranjo probability scale suggested a probable causality of venlafaxine treatment and serotonin syndrome. CONCLUSIONS: Clinicians should be aware of the risk of serotonin syndrome when the patient receives not only a combination of 2 antidepressants, but also the single potent serotonergic agent venlafaxine.