Distribution of venlafaxine and O-desmethylvenlafaxine in a fatal case.

Venlafaxine is an extensively used antidepressant drug; it is considered to be quite safe and only a few pure cases of fatal poisoning have been reported. Here we describe a fatal case of venlafaxine self-poisoning including detailed tissue distribution of the drug and its metabolite O-desmethylvenlafaxine and the exact time sequence of events, as reported in the patient's clinical record. Qualitative analyses were performed by GC-MS while quantitative analyses were carried out by LC-MS/MS. We then compared our results with those of previously published cases. Fatal venlafaxine poisoning often occurs after the intake of an extremely elevated number of tablets, corresponding to tens of grams of the drug, or it can be due to interaction between the drug and other substances. In the present case, no other drugs or ethanol were found and death occurred 12h after ingesting only 3g of venlafaxine, despite timely medical treatment.

Pendular nystagmus associated with venlafaxine overdose: a forme fruste of the serotonin syndrome?

We describe a case of pendular nystagmus as a previously unreported side effect of venlafaxine, and speculate to its importance in the recognition of the serotonin syndrome. In particular, we discuss the importance of identifying incomplete forms of the syndrome, such as those presenting with predominantly ocular manifestations, as is in our case.

ABCB1 gene polymorphisms are associated with fatal intoxications involving venlafaxine but not citalopram.

P-glycoprotein (P-gp), encoded by the ABCB1/MDR1 gene, is a drug transporter at the blood-brain barrier. Several polymorphisms in the ABCB1 gene are known to affect the activity and/or expression of P-gp, thereby influencing the treatment response and toxicity of P-gp substrates like citalopram and venlafaxine. In this study, we aimed to investigate the frequency of ABCB1 genotypes in forensic autopsy cases involving these two antidepressants. Further, the distribution of ABCB1 genotypes in deaths related to intoxication was compared to cases not associated to drug intoxication. The study included 228 forensic autopsy cases with different causes and manners of deaths. The ABCB1 single nucleotide polymorphisms (SNPs) G1199A, C1236T, C3435T and G2677T/A for these individuals were determined. The SNPs C1236T and C3435T in venlafaxine-positive cases were significantly different between the intoxication cases and non-intoxications. This was not seen for cases involving citalopram, indicating that the effect of genetic variants might be substrate specific. This novel finding should, however, be confirmed in future studies with larger number of cases.

A poor metabolizer of both CYP2C19 and CYP2D6 identified by mechanistic pharmacokinetic simulation in a fatal drug poisoning case involving venlafaxine.

We present a fatal drug poisoning case involving venlafaxine (VEN). The deceased took his medication regularly (including 150 mg VEN twice daily), and nothing in the case or autopsy findings pointed towards suicide. The toxicological assessment concluded that the cause of death was most likely due to a poisoning with a combination of VEN, oxycodone and ethanol, and the manner of death was considered to be an accident. The blood concentration of VEN was high (4.5mg/kg), and the ratio of the VEN metabolite O-desmethylvenlafaxine (ODV) to VEN was exceptionally low (0.006). Mechanistic pharmacokinetic simulations suggested that the low metabolite ratio was the result of combined poor metabolizer (PM) status of cytochrome P450 (CYP) 2C19 and CYP2D6. This hypothesis was confirmed by genetic analysis. Simulations revealed that it was likely that the combined missing CYP2D6 and CYP2C19 activity would cause higher concentrations of VEN, but the simulations also suggested that there could be additional reasons to explain the high VEN concentration found in this case. Thus, it seems likely that the potentially toxic VEN concentration was caused by reduced metabolic capacity. The simulations combined with genotyping were considered very useful in this fatal drug poisoning case.

The spectrum of acute heart failure after venlafaxine overdose.

OBJECTIVE: Venlafaxine is a bicyclic antidepressant that may be associated with severe cardiotoxicity following large overdose. The purpose of this short case series is to present different patterns of venlafaxine-related cardiotoxicity and to discuss the potential mechanisms. CASE SERIES: Between January 2010 and July 2011, four patients were admitted to an ICU with acute left ventricular failure following large venlafaxine overdoses. The age of the four female patients ranged from 35 to 65 years. None of them had no history of cardiovascular disease. The amount of venlafaxine ingested by history ranged from 3150 to 13500 mg (extended-release preparation in two cases). The peak serum venlafaxine concentration was between 2153.3 and 9950 ng/ml. Three patients died and one recovered rapidly. The initial ECG revealed only mild abnormalities in two cases. In two patients, at least one ECG recording demonstrated a widening of QRS interval. In three patients, echocardiography disclosed a left ejection fraction of 15%-18%. Two patients presented a severe serotonin syndrome, with major rhabdomyolysis. Seizures were noted in two cases, including one patient with status epilepticus. Three patients were mechanically ventilated. The causes of death were refractory hypoxemia, malignant arrhythmias, and cardiogenic shock, respectively. DISCUSSION: Severe and diffuse left ventricular dysfunction may be observed after large venlafaxine overdoses and this is not always associated with severe cardiac conduction function abnormalities. The mechanisms underlying venlafaxine-related cardiac failure with preserved normal cardiac conduction are discussed. A possible explanation may be a catecholamine-induced myocardial damage in relationship with the inhibition of norepinephrine (and dopamine) reuptake.

Simultaneous detection of multiple designer drugs in serum, urine, and CSF in a patient with prolonged psychosis.

UNLABELLED: This case report is considered exempt from University of California-San Diego Investigational Review Board. INTRODUCTION: There is a limited published experience detailing detection and toxicity of multiple novel psychoactive substances. We report a case of a patient with prolonged psychosis who had JWH-072, cannabicyclohexanol, 3',4'-methylenedioxy-α-pyrrolidinopropiophenone (MDPPP) and methylenedioxyamphetamine (MDA) identified in multiple biological samples. CASE DETAILS: An 18-year-old man presented to the emergency department (ED) with acute onset psychosis after allegedly smoking "spice." Due to agitation and psychosis refractory to multiple medications, a lumbar puncture was performed and he was admitted. All blood, urine, and CSF (cerebral spinal fluid) testing was normal. He remained psychotic for almost 1 week. MDPPP, JWH-072 and MDA were detected in initial blood, urine, and CSF samples. Cannabicyclohexanol was detected only in his serum. DISCUSSION AND CONCLUSION: JWH-072 is a cannabinoid-2 receptor (CB-2) agonist which has not been reported previously in the literature. Its clinical effects are unknown. Cannabicyclohexanol is a known component of "spice" products and has been associated with agitation and psychosis. MDPPP and MDA are designer phenylethylamines likely to cause agitation and sympathomimetic symptoms. Simultaneous detection of novel psychoactive substances in multiple biological fluids has not been previously reported. This case suggests that the interaction of these particular substances may be associated with prolonged psychosis.

Determination of venlafaxine in post-mortem whole blood by HS-SPME and GC-NPD.

Venlafaxine is a phenethylamine derivative widely prescribed for the treatment of depression which inhibits both serotonin and norepinephrine reuptake (SNRI). In treatment with antidepressants of patient with depression and other psychiatric disorders there is also increased risk of suicidal thought and behaviour. Several lethal intoxications involving venlafaxine usually among psychotic patients have been reported in the literature. Sample preparation is of the greatest significance for a successful toxicological analysis. The development of simple, effective and rapid extraction procedures of drugs from post-mortem biological samples is a challenge. Headspace-solid phase microextraction (HS-SPME) offers significant advantages such as simplicity, low cost, compatibility with analytical systems, automation and solvent-free extraction. The aim of our work was the optimization of a HS-SPME procedure for the determination of venlafaxine in post-mortem biological samples by gas chromatography (GC) with nitrogen-phosphorous detection (NPD). Venlafaxine was extracted on 100 µm Polydimethylsiloxone Coating-Red (PDMS) SPME fiber and determined by GC-NPD. Salt addition, extraction temperature, preheating and extraction time were optimized to enhance the recovery of the extraction from aqueous solution spiked with venlafaxine. Finally the developed procedure was applied to post-mortem biological samples of a fatally poisoned woman by venlafaxine. The drug was quantified in post-mortem blood gastric and oesophagus contents of the deceased woman. A simple and rapid procedure using HS-SPME was developed for sample preparation of venlafaxine in post-mortem biological samples prior to GC-NPD determination. Validation data was satisfactory, thus enabling application in the toxicological analysis of forensic samples.

[Serotonin syndrome in the course of drug-poisoning--case presentation]. / Zespól serotoninergiczny w przebiegu zatrucia lekami--opis przypadku.

UNLABELLED: Serotonin syndrome is caused by excess serotonin in the central nervous system. It usually occurs as adverse drug-therapy (neuroleptic agents, monoamine oxidase inhibitors, serotonin reuptake inhibitors and others). CASE PRESENTATION: a 50-year-old woman with a history of depression, was admitted to our hospital, due to suicidal drug poisoning (moclobemide- 4500 mg, venlafaxine 1050 mg, mianserin 300 mg and cytisine 30mg). She was also drunk. The patient was unconscious and sweaty, on the ECG tachycardia (120/min) was observed. In addition, several hours after admission, the patient developed acute respiratory failure, we observed myoclonus, lockjaw, body temperature increased to 37.3 degrees Celsius, and blood pressure was 170/80 mmHg. During the neurological examination there was a tendency to bilaterall Babinski sign and the nystagmus was present. The patient was intubated, and we started an intravenous infusion of Relanium. In laboratory studies: ethanol: 2.52 g/l, tests for benzodiazepines and tricyclic antidepressants were negative, WBC 13.1 tys/microl, CPK was elevated to 372 U/L, other parameters (electrolytes, transaminases, serum total protein, glucose, CRP, creatinine) were normal. The patient required intensive care and treatment during the next two days. The diagnosis of serotonin syndrome was based on the Hunter's criteria, which are more sensitive and more specific than Sternbach's criteria. The patient was discharged from hospital in good condition.

The effect of decontamination procedures on the pharmacodynamics of venlafaxine in overdose.

AIMS: To investigate the relationship between decontamination procedures and seizure events caused by venlafaxine overdose and to estimate the time at which 90% of patients would have had their first seizure in the presence and absence of decontamination. METHODS: Data were collected from 319 patients who took an overdose of venlafaxine on 436 occasions. Seizures occurred on 24 of 436 occasions (5%). Patients received one of single dose activated charcoal (SDAC), whole bowel irrigation (WBI), a combination of either (SDAC/WBI) or no decontamination. Logistic regression and time to event analysis were used to investigate the influence of dose and decontamination on the probability of seizures and time to 90% (t(90) ) of seizure, respectively. RESULTS: A linear logistic regression model described the data. Simulation from the model showed that the probability of seizure was 0.05 (0.03-0.08), 0.19 (0.09-0.35) and 0.75 (0.30-0.96) at 1000, 5000 and 10 000 mg, respectively (median and 95% credible interval). At the mean dose of 2100 mg the odds ratios (OR) in the presence of SDAC, WBI and SDAC/WBI were 0.48 (0.25-0.89), 0.71 (0.35-1.22) and 0.25 (0.08-0.62), respectively. A modified Gompertz model described the time to seizure events. Simulations from the Gompertz model showed that the t(90) values for first seizure was 26 h and was not affected by dose or decontamination procedure. CONCLUSION: SDAC/WBI provided greater benefits than the sum of the independent effects of SDAC and WBI. Patients should be observed for at least 24 h for seizures based on the dose and risk of seizure occurring.

Lipid therapy for serotonin syndrome after intoxication with venlafaxine, lamotrigine and diazepam.

A 44-year-old woman developed coma and seizure activity after intentional ingestion of 200 mg diazepam, 20 g lamotrigine and 4.5 g venlafaxine. In our intensive care unit a distinct rigidity and hyperreflexia was observed. This status was not influenced by haemodialysis which was initiated directly after admission. Plasma concentrations of the ingested drugs were determined before hemodialysis was started (560 µg/L diazepam, 42.4 mg/L lamotrigine and 1254 µg/L venlafaxine). Eight hours after the start of haemodialysis a 150 mL (2.5 mL/kg) intravenous bolus of 20% lipid emulsion was given. Soon after administration of the lipid infusion the distinct rigidity and hyperreflexia disappeared. The further course was uneventful.

Fatal venlafaxine poisonings are associated with a high prevalence of drug interactions.

Venlafaxine (VEN) is an antidepressant found to possess a higher fatal toxicity index (FTI, i.e., deaths in proportion to consumption) than other newer antidepressants and selective serotonin reuptake inhibitors (SSRIs). The aim of this study was to elucidate using post-mortem cases whether the apparent high toxicity of VEN is associated with adverse drug interactions, pharmacogenetic factors and/or the manner of death. Within a 2-year period, a comprehensive post-mortem database and death certificates were searched for cases with laboratory findings of VEN, findings of other drugs, associated background information and the cause and manner of death. In 123 cases, the concentrations of VEN and its two metabolites, O-desmethylvenlafaxine (O-VEN) and N-desmethylvenlafaxine (N-VEN), and the CYP2D6 genotype were determined in post-mortem blood. The median concentrations of VEN, O-VEN and N-VEN were 560, 420 and 49 µg/l, respectively. A prominent feature of the VEN-positive cases was the high abundance of interacting drugs (46%), being more common with higher VEN concentrations. Compared to other common antidepressants, VEN-positive cases showed the highest suicide frequency, but also the proportion of suicidal VEN poisonings of all suicides was substantially higher than that of mirtazapine or SSRIs. Relative CYP2D6 activity did not predispose to high VEN concentrations, and the frequency of the extreme phenotypes followed the general population. In conclusion, the high suicide potential of VEN in combination with the high prevalence of drugs causing adverse interactions could be the reason for the observed high FTI.

Cognitive deterioration after venlafaxine overdose.

BACKGROUND: Venlafaxine is an antidepressant whose adverse event profile is similar to that of the SSRIs (selective serotonin reuptake inhibitors). Serious complications due to venlafaxine overdose have been described. These generally have been resolved with supportive measures alone. However, although patients usually recover even after massive intake of the drug, death may occur in rare cases. OBJECTIVE: This article reports a case of dementia after an overdose of venlafaxine. CASE REPORT: We present a case of severe cognitive deterioration in a 48-year-old woman after venlafaxine overdose in a suicide attempt. She became comatose after the overdose. On recovery from the coma, she suffered irreversible motor and cognitive alterations and seizures. Several factors could justify the possible association of these side effects with venlafaxine overdose: time relationship, severe focal deficit and other neurological signs, symptomatic fluctuation, relationship of serotonin networks with the cognitive functions and deficits related to the network damage, and the potential capacity of venlafaxine to damage the central nervous system. However, other alternatives, especially factors that could implicate a hypoxic encephalopathy as the origin of the dementia, cannot be entirely ruled out. CONCLUSION: Venlafaxine seems to have special toxicity vis-à-vis the SSRIs, and this case adds to the literature supporting this. Cognitive function should be monitored after an overdose with venlafaxine.

Evaluation of a QT nomogram for risk assessment after antidepressant overdose.

AIMS: A QT-heart rate nomogram has recently been proposed as a means of identifying patients at risk of torsades de pointes after antidepressant overdose, based on published cases of drug-induced torsades de pointes. The present study sought to examine the performance of the nomogram in patients who ingest an antidepressant overdose but do not develop arrhythmia. METHODS: A retrospective case control study of patients presenting to hospital after overdose of citalopram, mirtazapine and venlafaxine was carried out. The primary outcome variable was QT higher than the nomogram, and was compared with occurrence of QT(c) (QT corrected by Bazett's formula) greater than ≥440 ms and QT(c) ≥500 ms, with comparison between drugs. Data are expressed as proportions in each group with 95% confidence intervals. RESULTS: There were 858 electrocardiograms from 541 patients. QT was higher than the nomogram in 2.4% (1.4, 4.1%), whereas QT(c) was ≥440 ms in 23.1% (95% CI 19.8, 26.8%), and QT(c) was ≥500 ms in 1.1% (0.5, 2.5%). Citalopram overdose was more likely to be associated with QT higher than the nomogram compared with the other agents (difference 7.0%, 95% CI 2.9, 11.9%, P = 0.001) and more likely to be associated with QT(c) ≥440 ms (difference = 11.0%, 95% CI 2.6, 19.0%, P = 0.013). CONCLUSIONS: The QT nomogram was associated with a lower false positive rate than widely accepted QT(c) criteria, and allowed detection of different effects of individual drugs. The nomogram offers potential advantages over QT(c) criteria and merits further investigation in a clinical setting.

Convulsiones tardías tras intoxicación por topiramato, venlafaxina y quetiapina / Delayed seizures afte topiramate, venlafaxine and quetiapine overdose

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Broken heart syndrome: Tako Tsubo cardiomyopathy associated with an overdose of the serotonin-norepinephrine reuptake inhibitor Venlafaxine.

OBJECTIVE: To describe a case of Tako Tsubo cardiomyopathy [TTC] in a patient after an overdose of the serotonin-norepinephrine reuptake inhibitor [SNRI] Venlafaxine. METHODS: We present a case study including clinical and laboratory data. Current relevant literature is reviewed and summarized in regard to Tako Tsubo syndrome and SNRI. RESULTS: A 43year-old woman was admitted with acute angina pectoris after accidentally taking an overdose on Venlafaxine in order to treat major depression. Because of the ECG-T-wave-inversions in the precordial leads, the slightly increased Troponin/Creatine kinase levels and the apical systolic dysfunction of the left ventricle in echocardiogram a cardiac catheterization was performed. Coronary artery disease could be excluded by coronary angiography. The followed laevocardiography and cardiac MRI scan showed apical akinesis and basal hypercontractibility typical for apical ballooning (Tako Tsubo cardiomyopathy). Urine analysis revealed elevated normetanephrine level potentially caused by Venlafaxine. Six weeks after the first admission the echocardiogram showed a complete recovery to normal left ventricular function. CONCLUSIONS: To our knowledge this is the first reported case of an overdose of Venlafaxine (SNRI) associated Tako Tsubo cardiomyopathy.