Mirtazapine fatal poisoning.

Mirtazapine is a noradrenergic and specific serotoninergic antidepressant agent that stimulates norepinephrine and serotonin release while also blocking serotonin receptors (5-HT2 and 5-HT3). Although the drug is used extensively, at present we do not know of any fatal cases due to mirtazapine alone. On the contrary, the published literature describes several fatal poisoning cases related to the intake of mirtazapine together with other drugs. Here we describe a fatal case of mirtazapine self-poisoning, since the other drug detected (lorazepam), was within the therapeutic range. Analyses were performed by LC-MS/MS on body fluids and a hair sample and mirtazapine concentration measured in blood was very high: 9.3mg/L. N-Desmethylmirtazapine was also quantitated. We then compared our results with those of previously published cases. In conclusion, even though mirtazapine can be considered a relatively safe drug, taking a large amount alone or in combination with other drugs, could lead to death.

Poisoning suicide with ingestion of the pyrethroids alpha-cypermethrin and deltamethrin and the antidepressant mirtazapine: A case report.

This case report describes a death attributed to the intake of the pyrethroid insecticides, alpha-cypermethrin and deltamethrin, and the antidepressant mirtazapine. The autopsy findings showed absence of external traumatic injuries and internal generalized visceral congestion, edema and cyanosis. The toxicological results revealed the presence of a toxic concentration of mirtazapine (12.5mg/L and 10.7mg/L in blood and urine, respectively) and high concentrations of pyrethroids (2.46mg/L alpha-cypermethrin and 2.40mg/L deltamethrin in blood, and 0.41mg/L alpha-cypermethrin and 0.46mg/L deltamethrin in urine, respectively). Blood ethanol concentration was 0.75g/L. All the evidence - from autopsy, police investigation and toxicology - was consistent with the intentional self-harm of the deceased. The current case was determined and recorded as a poisoning suicide. Cause of death of the deceased was reported as the synergistic toxicity of the ingested pyrethroids and mirtazapine. The presence of a significant blood ethanol concentration was considered a secondary contributory factor to the fatal outcome. The case presented herein is the first death attributed to poisoning from ingestion of pyrethroids in combination with mirtazapine, with the intention of the victim to cause self-harm, with corresponding toxicology results.

Effect of lipid emulsion during resuscitation of a patient with cardiac arrest after overdose of chlorpromazine and mirtazapine.

No specific treatment exists for poisoning with most fat-soluble drugs. Intravenous lipid emulsion (ILE) may be effective therapy against such drugs, but effects of ILE treatment are unclear. A 24-year-old woman with depression seen sleeping in the morning was found comatose in the evening, and an emerging lifesaving technologies service was called. After emerging lifesaving technologies departure to hospital, she stopped breathing, became pulseless, and cardiopulmonary life support was started immediately. Electrocardiographic monitoring showed asystole during resuscitation even after arrival at hospital. Empty packaging sheets of 60-tablet chlorpromazine (CPZ) (50 mg/tablet) and 66-tablet mirtazapine (MZP) (15 mg/tablet) found at the scene suggested drug-related cardiopulmonary arrest. Along with conventional administration of adrenaline (total dose, 5 mg), 20% Intralipid 100 mLwas given intravenously 8 minutes after hospital arrival and readministered 27 minutes after hospital arrival because of continued asystole. Return of spontaneous circulation occurred 29 minutes after arrival (70 minutes after cardiac arrest). The patient recovered without any major complications and was transferred to another hospital for psychiatric treatment 70 days after admission. Concentrations of CPZ and MZP were still high when return of spontaneous circulation was achieved with ILE. This case suggested the possible benefit of ILE in treating life threatening cardiotoxicity from CPZ and MZP overdose.

Toxic leukoencephalopathy in the intensive care unit.

In this article, we report two cases of acute toxic leukoencephalopathy to highlight this acute clinicoradiological syndrome as an important, although uncommon, consideration in the undifferentiated comatose patient who fails to wake following drug overdose or has unexplained neurology with a history of drug exposure. We then review the current literature and discuss potential differential diagnoses in this setting, along with proposed treatments for this condition. The cases presented demonstrate a more fulminant onset than previously well-defined acute toxic leukoencephalopathy subtypes and highlight the prognostic importance of magnetic resonance imaging in diagnosing a condition from which significant functional recovery seems possible.

Disopyramide and mianserin intoxication: a unique fatal case--review of the literature.

Lethal occurrence is exceptional after disopyramide or mianserin poisoning. A case of intentional lethal intoxication with these drugs was reported, as well as a review of the literature. Pre- and postmortem blood concentrations of disopyramide or mianserin were assessed in a woman who died from acute cardiac failure after ingestion. The premortem blood concentration of disopyramide alone was considered lethal, and a toxic premortem concentration of mianserin was observed that may have increased cardiovascular failure induced by disopyramide because the metabolism of both drugs is mediated via cytochrome P450. Moreover, it was shown that the postmortem redistribution of disopyramide was limited, as pre- and postmortem concentrations were 48 and 65 mg/L, respectively. As regards mianserin, redistribution was observed after death with pre- and portmortem concentrations at 0.23 and 0.79 mg/L, respectively. This case illustrates that if postmortem blood concentration of disopyramide is known, the premortem concentration can be deduced.

Mirtazapine overdose is unlikely to cause major toxicity.

OBJECTIVE: There is limited information on mirtazapine overdose, but cases of severe effects (seizures, serotonin toxicity and coma) have been reported. We aimed to investigate the clinical effects and complications of mirtazapine overdose. METHODS: This was an observational case series of mirtazapine overdoses (> 120 mg) identified from admissions to a toxicology unit between January 1987 and August 2013. Demographic information, details of ingestion, clinical effects, ECG parameters (HR, QT and QRS), and length of stay were extracted from a clinical database. RESULTS: From 267 mirtazapine overdoses, there were 89 single-agent mirtazapine ingestions and 178 cases where mirtazapine was taken with at least one other drug. The median age of the 89 single-agent mirtazapine ingestions was 36 years [interquartile range (IQR): 26-49 years; Range: 15-81 years]; 45 were female (51%). The median ingested dose was 420 mg (IQR: 270-750 mg; Range: 150-1350 mg) and 41 patients (46%) had a Glasgow coma score (GCS) < 15, but the minimum GCS was 10. There were no seizures, serotonin toxicity or delirium. Tachycardia occurred in 29 patients (33%) and hypertension in 32 patients (36%). The median QRS was 80 ms (Range: 80-120 ms) and there were no cases with QT prolongation. There were no arrhythmias and no deaths. The median length of stay was 14 h (IQR: 8.8-18.2 h; Range:2.2-75 h). No single-agent mirtazapine patient was admitted to intensive care. The 178 patients taking co-ingestants had more severe toxicity depending on the co-ingested drug. CONCLUSION: Mirtazapine appears to be relatively benign in overdose, associated with tachycardia, mild hypertension and mild CNS depression not requiring intervention.

Simultaneous determination of 5 psychotropic drugs of various types in an autopsy case of acute multiple drug poisoning.

We attempted the simultaneous determination of 5 drugs, mirtazapine, sertraline, chlorpromazine, amoxapine and zolpidem, detected in a gas chromatography-mass spectrometry screening test in an autopsy case. The solid-phase extraction of the analytes from biological samples was achieved using Oasis(®)HLB cartridges (Waters, Milford, MA, USA). Gas chromatography was performed on a HP-5MS fused silica capillary column (30 m × 0.25 mm i.d., 0.25 µm film thickness, Agilent Technologies). The mass spectrometer was operated with an electron energy of 70 eV in electron impact mode. The qualitative and quantitative analyses were performed in full-scan mode and the selected ion monitoring mode, respectively. The total ion chromatogram showed good separation of these drugs. Linear graphs were obtained with good correlation coefficients for these drugs from 0.001 to 2.0 µg/mL (r(2)=0.9909-0.9986) using imipramine-d6 as an internal standard. The recoveries of these drugs were found to be 62.8-88.0% in spiked whole blood. Mirtazapine, sertraline, chlorpromazine, amoxapine and zolpidem were found in post-mortem samples of the deceased at concentrations of 2.67, 0.07, 0.25, 0.32 and 0.68 µg/mL, respectively. The concentration of mirtazapine was within the lethal level and those of amoxapine and zolpidem were within the toxic level. We diagnosed that the cause of death was acute multiple drug poisoning. The simple and practical procedure used in this study is useful for the simultaneous determination of psychotropic drugs of various types in post-mortem biological 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.

A fatal case of simultaneous ingestion of mirtazapine, escitalopram, and valproic acid.

Mirtazapine, escitalopram, and valproic acid are newer antidepressant drugs than traditional tricyclic antidepressants and are supposed to be less toxic. Nevertheless, intoxication cases due to their overdosage have been repeatedly reported. In the case presently reported, a 64-year-old woman with a previous history of chronic depression was found dead in her apartment. Several packages of pharmaceutical drugs were found, including mirtazapine, escitalopram, and valproic acid. During the autopsy, no evidence of natural disease or trauma was found to account for this death. In order to determine whether massive drug assumption might have determined a lethal intoxication, heart blood, urine, and gastric content were collected and submitted to toxicological analysis. Specific liquid chromatography-tandem mass spectrometry protocols were purposely developed and validated. Blood concentrations of mirtazapine, escitalopram, and valproic acid were 20.3, 65.5, and 417 mg/L, respectively, whereas urine concentrations were 17.0, 94.5, and 423 mg/L, respectively. High concentrations of these drugs were also detected in the gastric content, confirming their ingestion shortly before death. The agreement between authoptic examination by forensic pathologists and toxicological findings are consistent with the suicidal hypothesis, where the death arose by drug intoxication due to simultaneous high-dosage ingestion of mirtazapine, escitalopram, and valproic acid.

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.

Bradycardia and hypotension in mianserin intoxication.

Cardiotoxicity is an important adverse effect of tricyclic antidepressants. But cardiac side effects after intoxication with the tetracyclic mianserin are rare. In this paper, we describe a case in which bradycardia and hypotension occured due to mianserin overdose. A 37-year-old woman was admitted to the medical intensive care unit for self-poisoning with 30 tablets of 10 mg mianserin 2 hours before her admission. The patient denied taking any other drugs. Four hours after her admission, bradycardia and hypotension occurred and she began to suffer from giddiness. Atropine and theophylline were given. On the second and third day, her heart rate and blood pressure were normal. Based on this case, we estimate the probability of bradycardia and hypotension in mianserin intoxication and the significance of closely monitoring the patient.

Outcomes after isolated mirtazapine (Remeron) supratherapeutic ingestions.

Mirtazapine (Remeron) is a newly approved medication for the treatment of depression. It is an alpha(2)-adrenergic antagonist that causes increased levels of neuronal norepinephrine and serotonin. It is also believed to be an antagonist at the serotonin receptors 5-HT(2) and 5-HT(3). Little is known about isolated mirtazapine ingestions. We conducted a retrospective chart review of mirtazapine ingestions reported to our Poison Center during 2004. A standardized data sheet was completed collecting information regarding standard demographic data along with co-ingestants, neurologic and cardiovascular symptoms, and disposition. Data collection was reviewed by a second investigator, and a kappa score was calculated. Of 71 patients identified with mirtazapine ingestions, there were 33 isolated exposures that were further reviewed. A kappa score for inter-reviewer reliability was calculated and at 0.61, 95% confidence interval 56-70. The average age of these patients was 27 years (range 6-82 years), with the mean ingestion of 343 mg (range 15-1500 mg). The most common neurologic symptom was drowsiness seen in 8/23 patients, 1 patient became agitated, and 14 patients had no abnormal neurologic findings. Cardiovascular effects were recorded in 4/23 patients, with 3 patients exhibiting tachycardia and 1 patient with bradycardia and hypotension. Seven of 23 patients required admission; there were no deaths. Mirtazapine overdoses are generally very well tolerated, with the most common symptoms being drowsiness and lethargy. This study is limited by being a retrospective chart review.

Therapeutic and toxic concentrations of mirtazapine.

Six cases involving the antidepressant mirtazapine were analyzed in detail at the San Diego County Medical Examiner's Office from 2004 to 2005. Mirtazapine was initially detected and confirmed in each of these cases by a liquid-liquid gas chromatography (GC)-MS basic drug screen. Following another liquid-liquid basic extraction, mirtazapine was quantitated by GC with nitrogen-phosphorus detection. For each case, mirtazapine concentrations in peripheral blood (pb), central blood (cb), vitreous (vit), and liver were determined against matrix specific calibration curves (limit of detection 0.01 mg/L; linear range 0.025-1.0 mg/L). In contrast with earlier studies of postmortem distribution of mirtazapine, we found concentrations in liver that were significantly higher. Mirtazapine was identified in the cause of death by the pathologist in three cases. In the drug-related deaths, mirtazapine concentrations (mean +/- S.D.) were 2.0 +/- 1.5 mg/L (pb), 1.6 +/- 1.0 mg/L (cb), 0.78 +/- 0.56 mg/L (vit), and 10 +/- 7.4 mg/kg (liver). Alternatively, concentrations considered therapeutic (three non-drug-related deaths) were (mean +/- S.D.) 0.18 +/- 0.22 mg/L (pb), 0.16 +/- 0.17 mg/L (cb), 0.12 +/- 0.16 mg/L (vit), and 0.73 +/- 0.68 mg/kg (liver). Although mirtazapine concentrations were elevated in blood and liver in three cases, it should be noted that other drugs were also found in toxic concentrations in each case. These data may further support the fact that mirtazapine is a relatively safe drug with respect to overdose.

Tissue distribution of mirtazapine and desmethylmirtazapine in a case of mirtazapine poisoning.

An ingestion of an unknown quantity of mirtazapine in a suicide attempt leading to death is described. Sertraline and amitriptyline have been co-ingested. Because mirtazapine is reported to be relatively safe in overdose, body fluids and tissues were investigated for both mirtazapine and desmethylmirtazapine by high-pressure liquid chromatography/tandem mass spectrometry following liquid-liquid extraction. The limit of detection was sufficiently low to also apply the assay in pharmacokinetic studies. The levels of amitriptyline and nortriptyline were very low (38 and 19 ng/mL femoral venous blood) and the amount of sertraline in blood taken from the femoral vein (880 ng/mL) was considerably lower than those seen in overdosage. Accumulation of mirtazapine and N-desmethylmirtazapine was evident in fluids and tissues involved in enterohepatic circulation and excretion. The concentration determined in a brain sample suggests a contribution of the metabolite to the drug's pharmacodynamic activity. Based on literature data, significant adverse or synergistic effects among the drugs detected as well as adverse reactions such as a serotonin reaction appeared less probable. Mirtazapine exhibits alpha(1)-antagonistic properties on the cardiac-vascular system and may cause hyponatraemia. In the face of the cardiac findings at autopsy and the lack of an apparent cause of death, these effects of mirtazapine may have initiated a process leading to death.

Comparative toxicity of citalopram and the newer antidepressants after overdose.

OBJECTIVE: To compare the toxicity of citalopram, venlafaxine, mirtazapine, and nefazadone after overdose. METHODS: Two-year retrospective review of consecutive patients admitted to the toxicology unit of Edinburgh Royal Infirmary. Outcome measure included physiological variables, ECG recordings, peak creatine kinase, development of arrhythmias, seizure, tremor or agitation, and the need for admission to a critical care facility. RESULTS: A total of 225 patients were studied. Venlafaxine was associated with a significantly higher pulse rate (p < 0.0001) and tremor (p = 0.007) than other antidepressants. Citalopram was associated with a significantly longer QT interval on ECG recording (p < 0.0001) but mean QTc durations were not significantly different between all drugs studied. No arrhythmias were recorded. Only venlafaxine and citalopram caused seizures and were associated with the need for admission to Intensive Care, but there was no significant difference between them. CONCLUSIONS: Mirtazapine and nefazadone appear safe in overdose and were associated with minimal features of neurological or cardiovascular toxicity. Citalopram is more likely to cause QT prolongation but other features of cardiovascular toxicity were uncommon. Both citalopram and venlafaxine are proconvulsants. Venlafaxine also causes more frequent features of the serotonin syndrome.

[Vasopressin analogue injection as ultimate measure for counteracting severe catecholamine-refractory poisoning by several vasodilators taken with suicidal intent]. / Vasopressinanaloga als Ultima ratio bei einer schweren Intoxikation mit Vasodilatanzien.

HISTORY AND CLINICAL FINDINGS: A 78-year-old woman was admitted to the intensive care unit 9 hours after ingestion of 2 g of isosorbitmononitrate, 430 mg of amlodipine, 250 mg of benazepril and 600 mg of mirtazapin in suicidal intent. INVESTIGATIONS: Clinical findings and invasive monitoring showed signs of a hyperdynamic hemodynamic cardiovascular failure caused by toxic vasodilatation. TREATMENT AND COURSE: Despite of primary detoxication, intravenous volume infusion with calcium gluconate, glucagon and naloxone and administration (norepinephrine up to 2 micro g/kg/min) no hemodynamic stabilization was achieved. Only when the vasopressin-analogue argipressin was given peripheral vasodilatation was overcome and hemodynamic stabilization resulted. 10 hours after discontinuing argipressin and norepinephrine the patient developed a mesenteric ischemia, and she finally died on the third day after admission. CONCLUSION: In circulatory shock due to toxic vasodilatation the use of vasopressin analogue argipressin can be helpful as an ultima therapeutic measure in catecholamine refractory shock caused by vasodilatation. Attention must be paid to overwhelming vasoconstrictor effects resulting in mesenteric ischemia.