Serotonin toxicity involving MDMA (ecstasy) and moclobemide.

The use of MDMA (ecstasy) in Australia is a widespread and growing problem, promoting acute toxicity and disease which can lead to premature death in users. We report four cases of fatal serotonin toxicity caused by the combination of MDMA and moclobemide, a reversible MAO-A inhibitor with potent serotonergic activity. Despite the highly reported toxicity of this drug combination, there are very few reports of fatalities attributed to a MDMA and moclobemide interaction. Pathology and toxicology reports, initial police reports and coroners' findings were examined to determine the circumstances of the deaths. Symptoms of some of the four cases as reported by paramedics and medical staff included hyperthermia, hyperkalemia, profuse sweating, twitching and shaking. Two cases involved moclobemide concentrations consistent with common prescribed doses, while the other two cases involved much higher concentrations often associated with toxicity. Three of these cases presented with some form of heart disease.

Fatal serotonin toxicity caused by moclobemide and fluoxetine overdose.

Both moclobemide and fluoxetine are used in the treatment of depression, and have been shown to produce fewer side effects than conventional tricyclic antidepressants. A combination of moclobemide and fluoxetine has been used in refractory depression, however there is potential for severe serotonin toxicity. We describe a lethal case of serotonin toxicity in a 36 year-old woman after she ingested multiple drugs, including moclobemide 4500 mg, fluoxetine 200 mg, propranolol 300 mg and several benzodiazepines. The clinical features included coma, mydriasis, hyperthermia, tremor, hyperreflexia, rhabdomyolysis, renal failure and respiratory insufficiency. Eventually, the patient died of disseminated intravascular coagulation and circulatory collapse at 22.5 h postingestion. Toxicological analysis of the patient's blood confirmed high levels of moclobemide 150 µg/mL (therapeutic 1-3 µg/mL), fluoxetine 3750 ng/mL (therapeutic 47-469 ng/mL) and several benzodiazepines. In conclusion, a combination of moclobemide and fluoxetine should be avoided in depressed patients with high suicidal tendencies. Moreover, early recognition and aggressive intervention are the mainstays in the management of potentially life-threatening serotonin toxicity.

[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.

Death of a female cocaine user due to the serotonin syndrome following moclobemide-venlafaxine overdose.

To our knowledge, the majority of evidence supporting the relationship between the serotonin syndrome and medications that effect 5HT is based on case reports. The justification for taking up this subject has been a fatal outcome of a 21 year-old female following an administration of toxic doses of moclobemide (MAOI) and venlafaxine (SNRI). As a result of complex toxicological investigations including antemortem and postmortem material, antemortem clinical observations and postmortem examinations, the cause of death was identified as overdose with antidepressants--moclobemide and venlafaxine--in the mechanism of the clinically fully developed severe toxic serotonin syndrome. The analysis of a hair strand collected from the victim documented the use of the above-mentioned drugs simultaneously with cocaine in the period of at least 20 months preceding death. The fact is a matter of considerable interest in view of the employed pharmacotherapy, giving rise to suspicion that the woman had not developed the serotonin syndrome during the almost 2-year antemortem period until she took toxic doses of both medications.

[Seronin syndrome and cardiac arrest caused by high-dose moclobemide (case report)].

Serotonin syndrome is the syndrome resulting from brain tissue serotonin accumulation and accompanying by central nervous system dysfunction and circulatory collapse, which leads to a serious mortal danger to life. A female patient aged 31 years, diagnosed as having chronic psychosis in the history, was admitted to an intensive care unit in a critical state for having taking an increased moclobemide dose. The patient developed cardiac arrest and cardiopulmonary resuscitation (CPR) was initiated. A 15-minute CPR recovered sinus rhythm and pulse on the peripheral arteries of the limbs. When consciousness and respiration improved, the patient was weaned from resuscitation and extubated on the second day. On day 4, the patient was transferred from the intensive care unit to the department of psychiatry. The authors consider that patients with overdosage of antipsychotic agents at a risk for such serious complications, such as cardiac arrest, should be necessarily monitored in the intensive care unit.

Urinary serotonin level is associated with serotonin syndrome after moclobemide, sertraline, and citalopram overdose.

INTRODUCTION: Altered mental status, autonomic dysfunction, and neuromuscular abnormalities are a characteristic triad of serotonin syndrome. No laboratory tests confirm the diagnosis of serotonin syndrome. CASE REPORT: A 35-year-old woman took moclobemide, sertraline, and citalopram in a suicide attempt. She was conscious with mild tachycardia, hypertension, and tachypnea one hour after ingestion. In the second hour after ingestion diaphoresis, mydriasis, horizontal nystagmus, trismus, hyperreflexia, clonus, and tremor appeared. She became agitated and unresponsive. In the third hour after ingestion she became comatose and hyperthermic. She was anesthetized, paralyzed, intubated, and ventilated for 24 hours. Serum moclobemide, sertraline, and citalopram levels were above therapeutic levels. The serum serotonin level was within normal limits and the urinary 5-hydroxyindoleacetic acid:creatinine ratio was below the average daily value. The urinary serotonin:creatinine ratio was increased on arrival (1 mg/g). DISCUSSION AND CONCLUSION: The urinary serotonin level is increased in serotonin syndrome due to a monoamine oxidase inhibitor and selective serotonin-reuptake inhibitors overdose. It is possible that urinary serotonin concentration could be used as a biochemical marker of serotonin syndrome.

QTc abnormalities in deliberate self-poisoning with moclobemide.

BACKGROUND: Several medications have been found to prolong the QT interval in overdose. This can predispose to torsade de pointes-type ventricular tachycardia. AIMS: To analyse the effects of moclobemide deliberate self-poisoning on the length of both QT and corrected QT (QTc) intervals. METHODS: Electrocardiograms (ECG) of all patients presenting to a regional toxicology service with moclobemide ingestion were reviewed. Cases where a cardiotoxic agent was coingested were excluded. QT and QTc parameters were compared with a comparison group of patients ingesting paracetamol or benzodiazepines. RESULTS: Of 75 patients where ECG were available, the median ingested dose was 4.5 g (interquartile range (IQR): 2.4-7.5; range: 0.6-18 g) and the median age was 34 years (IQR: 26-44). The mean QT interval was 415 ms (standard deviation (SD): 51 ms) with a mean QTc of 459 ms (SD: 44 ms), and were prolonged compared with the comparison group. Twelve female patients had a QTc > 500 ms and in seven of these causality was established based on a pre- or post-ECG with a QTc < 500 ms. Only 10% of the moclobemide cases had a heart rate (HR) > 100 beats per minute, making overcorrection of HR by Bazett's formula an unlikely cause of the findings. No cardiac arrythmias were observed other than one case of first-degree heart block. CONCLUSIONS: Moclobemide prolongs the QT and QTc intervals in overdose and a 12-lead ECG should be done on all moclobemide deliberate self-poisonings. Continuous cardiac monitoring for what is otherwise a relatively benign overdose would appear to be an inappropriate use of resources but can be considered in patients with a QTc > 500 ms or with known risks for QT prolongation.

Death following acute poisoning by moclobemide.

A fatality due to ingestion of a reversible inhibitor of monoamine-oxidase A (MAO-A) is reported. Moclobemide is generally considered as a safe drug far less toxic than tricyclic anti-depressants. However, severe intoxications may result from interactions with other drugs and food such as selective serotonin reuptake inhibitors (SSRIs), anti-Parkinsonians of the MAOI-type (e.g. selegiline) or tyramine from ripe cheese or other sources. In the present case, high levels of moclobemide were measured in peripheral blood exceeding toxic values reported so far in the scientific literature. The body fluid concentrations of moclobemide were of 498 mg/l in peripheral whole blood, 96.3 mg/l in urine while an amount of approximately 33 g could be recovered from gastric contents. The other xenobiotics were considered of little toxicological relevance. The victim (male, 48-year-old) had a past history of depression and committed one suicide attempt 2 years before death. Autopsy revealed no evidence of significant natural disease or injury. It was concluded that the manner of death was suicide and that the unique cause of death was massive ingestion of moclobemide.

Moclobemide poisoning: toxicokinetics and occurrence of serotonin toxicity.

AIMS: To investigate the spectrum of toxicity of moclobemide overdose, the occurrence of serotonin toxicity, and to estimate toxicokinetic parameters. METHODS: All moclobemide overdoses presenting over a 10-year period to the Hunter Area Toxicology Service were reviewed. Clinical features, complications, length of stay (LOS) and intensive care (ICU) admission rate were extracted from a standardized, prospectively collected database. Comparisons were made between moclobemide alone and moclobemide with a serotonergic coingestant poisoning. Serotonin toxicity was defined by a combination of Sternbach's criteria and a clinical toxicologist's diagnosis. In five patients serial moclobemide concentrations were measured. Time to maximal plasma concentration (Tmax), peak plasma concentration (Cmax) and terminal elimination half-lives were estimated. RESULTS: Of 106 included patients, 33 ingested moclobemide alone, 21 ingested moclobemide with another serotonergic agent (in some cases in therapeutic doses) and 52 ingested moclobemide with a nonserotonergic agent. Eleven (55%) of 21 patients coingesting a serotonergic drug developed serotonin toxicity, which was significantly more than one (3%) of 33 moclobemide-alone overdoses (odds ratio 35, 95% confidence interval 4, 307; P < 0.0001). In six of these 21 cases severe serotonin toxicity developed with temperature >38.5 degrees C and muscle rigidity requiring intubation and paralysis. The 21 patients had a significantly increased LOS (34 h) compared with moclobemide alone overdoses (12 h) (P < 0.0001) and a significantly increased ICU admission rate of 57% vs. 3% (P < 0.0001). Time to peak plasma concentration was delayed in two patients where prepeak samples were obtained. Cmax increased slightly with dose, but all three patients ingesting > or = 6 g vomited or had charcoal. The mean elimination half-life of moclobemide in the five patients in whom serial moclobemide concentrations were measured was 6.3 h and elimination was first order in all cases. There was no evidence of a dose-dependent increase in half-life. CONCLUSIONS: The effects of moclobemide alone in overdose are minor, even with massive ingestions. However, moclobemide overdose in combination with a serotonergic agent (even in normal therapeutic doses) can cause severe serotonin toxicity. The elimination half-life is prolonged by two to four times in overdose, compared with that found in healthy volunteers given therapeutic doses. This may be a result of wide interindividual variation in overall elimination, also seen with therapeutic doses, but appears not to be due to saturation of normal elimination pathways.

Fatal combination of moclobemide overdose and whisky.

The antidepressant moclobemide (Aurorix) is a reversible inhibitor of monoamine oxidase-A. Pure moclobemide overdose is considered to be relatively safe. Mixed drug overdoses including moclobemide are potentially lethal, especially when serotonergical drugs are involved. So far, only one fatality due to moclobemide mono-overdose has been reported. We report here on a fatality following the ingestion of a moclobemide overdose in combination with half a bottle of whisky. Although dietary restrictions during moclobemide therapy are not considered necessary, the combination of large quantities of moclobemide and tyramine-containing products seems to be lethal, probably because monoamine oxidase-A selectivity is overwhelmed after massive overdoses. Since there is no specific antidote and treatment is only symptomatic, the severity of an overdose with moclobemide must not be underestimated.

Death following ingestion of MDMA (ecstasy) and moclobemide.

Four deaths following the ingestion of moclobemide and MDMA ('ecstasy') are described. The probable cause of death in each case was serotonin syndrome as a result of an interaction between the two drugs. As none of the victims had been prescribed moclobemide it seems that each had taken the drug to enhance the effects of MDMA, with fatal consequences. Warnings are needed against misinformed attempts to potentiate the pharmacological effects of illicit drugs.

[Serotonin syndrome. Several cases of this often overlooked diagnosis]. / Serotoninergt syndrom. Flera allvarliga fall med denna ofta förbisedda diagnos.

During the recent decade an increasing number of inquiries concerning cases of overdoses exhibiting typical signs of the serotonin syndrome have been recorded at the Swedish Poisons Information Centre. Four of these cases are presented together with a review of the literature. All patients had overdosed moclobemide and in one case this was the only drug taken. The other patients had ingested moclobemide together with citalopram (2 cases) and clomipramine (1 case). Moreover, other serotoninergic pharmaceuticals as sertraline and sumatriptan were simultaneously ingested in one case and buspirone in another. Three of the cases had hyperthermia, > 40 degrees C and the same number showed pronounced muscle rigidity, coma and mydriasis. Other severe signs and symptoms upon admission included positive Babinski and trismus in two cases each and seizures in one. All patients received mechanical ventilation. Two were treated with dantrolene sodium and one of them was given cyproheptadine as well. One patient received cyproheptadine treatment alone and another prolonged muscle relaxation. Three patients had a typical short clinical course, whereas one patient developed rhabdomyolysis, DIC and arrhythmias. All patients fully recovered.

[Serotonin syndrome--several cases of this often overlooked diagnosis]. / Serotoninergt syndrom--flera allvarliga fall med denna ofta förbisedda diagnos.

During the recent decade an increasing number of inquiries concerning cases of overdoses exhibiting typical signs of the serotonin syndrome have been recorded at the Swedish Poisons Information Centre. Four of these cases are presented together with a review of the literature. All patients had overdosed moclobemide and in one case this was the only drug taken. The other patients had ingested moclobemide together with citalopram (2 cases) and clomipramine (1 case). Moreover, other serotoninergic pharmaceuticals as sertraline and sumatriptan were simultaneously ingested in one case and buspirone in another. Three of the cases had hyperthermia, > 40 degrees C and the same number showed pronounced muscle rigidity, coma and mydriasis. Other severe signs and symptoms upon admission included positive Babinski and trismus in two cases each and seizures in one. All patients received mechanical ventilation. Two were treated with dantrolene sodium and one of them was given cyproheptadine as well. One patient received cyproheptadine treatment alone and another prolonged muscle relaxation. Three patients had a typical short clinical course, whereas one patient developed rhabdomyolysis, DIC and arrhythmias. All patients fully recovered.

A fatal case of serotonin syndrome after combined moclobemide-citalopram intoxication.

We present a case involving a fatality due to the combined ingestion of two different types of antidepressants. A 41-year-old Caucasian male, with a history of depression and suicide attempts, was found deceased at home. Multiple containers of medication, the MAO-inhibitor moclobemide (Aurorix), the SSRI citalopram (Cipramil), and the benzodiazepine lormetazepam (Noctamid) as active substance, as well as a bottle of whiskey were present at the scene. The autopsy findings were unremarkable, but systematic toxicological analysis (EMIT, radioimmunoassay, high-performance liquid chromatography-diode-array detection [HPLC-DAD], gas chromatography-nitrogen-phosphorus detection, and gas chromatography-mass spectrometry) revealed the following: ethanol (0.23 g/L blood, 0.67 g/L urine), lormetazepam (1.65 microg/mL urine), cotinine (0.63 microg/mL blood, 5.08 microg/mL urine), caffeine (1.20 microg/mL urine), moclobemide (and metabolites), and citalopram (and metabolite). There upon, we developed a new liquid chromatographic separation with optimized DAD, preceded by an automated solid-phase extraction, for the quantitation of the previously mentioned antidepressive drugs. The results obtained for blood and urine, respectively, were as follows: Ro 12-5637 (moclobemide N'-oxide) not detected and 424 microg/mL; Ro 12-8095 (3-keto-moclobemide) 2.26 microg/mL and 49.7 microg/mL; moclobemide 5.62 microg/mL and 204 microg/mL; desmethylcitalopram 0.42 microg/mL and 1.22 microg/mL; and citalopram 4.47 microg/mL and 19.7 microg/mL. The cause of death was attributed to the synergistic toxicity of moclobemide and citalopram, both antidepressants, which, by intentional or accidental combined ingestion, can produce a potentially lethal hyperserotoninergic state. Based on the history of the case and pharmacology of the drugs involved, the forensic pathologists ruled that the cause of death was multiple drug intoxication, resulting in a fatal "serotonin syndrome," and that the manner of death was suicide.