Serotonin Syndrome with Severe Hyperthermia after Ingestion Of Tranylcypromine Combined with Serotonin Reuptake Inhibitors and Tyramine-Rich Food in a Case of Suicide

The monoamine oxidase inhibitor (MAO-I) tranylcypromine was introduced about 50 years ago. It has been used for a long time as a third-line antidepressant for treatment-resistant depression. The blood plasma half-life of tranylcypromine is relatively short (1.5–3 h), but its biological effects last considerably longer. The combination of MAO-I with drugs which enhance the activity of the serotonergic system can result in a severe serotonin syndrome [2] with malignant hyperthermia syndrome [1] [3].

The authors report a case with fatal outcome in a 53-year-old woman after tranylcypromine ingestion in combination with serotonin reuptake inhibitors (SSRIs). The patient was suffering from a recurrent depressive disorder and alcohol dependence (based on ICD-10 criteria). She received 10 mg fluoxetine per day as an antidepressant treatment. The patient worked as a psychiatric nurse, and had an exact knowledge about the pharmacological characteristics of tranylcypromine. Primarily she was admitted to an emergency unit because of severe alcohol intoxication (ethanol blood level: 2.17‰). She rejected an admission to a psychiatric hospital and discharged herself against medical advice. 2 h later she was re-admitted and declared that she had ingested tranylcypromine (70 mg Jatrosom^®) combined with SSRIs (150 mg sertraline and 30 mg fluoxetine) with suicidal intention. In addition, she reported consumption of very large amounts of tyramine-rich aliments (red wine and aged cheese). 90 min after this second admission to the hospital the patient became severely agitated, disoriented, developed hypersalivation, hyperhidrosis, tachycardia with a frequency of 130/min, low blood pressure values (RR 90/60 mm Hg), and a generalised increased muscle tone most prominent at the lower legs. Head CT scan, and laboratory tests, including CPK, INR, pH and lactate, were normal. Therapeutic management included supportive care, application of lorazepam (Tavor Expidet^®, dosage 2.5 mg), esmolol hydrochloride, a cardioselective beta 1 receptor blocker with rapid onset (Brevibioc^®, after one “loading dose”, a continuous intravenous infusion was started), and cyproheptadine (Peritol^®, total dosage 24 mg), which acts as a 5-HT₂ receptor antagonist. Body temperature increased rapidly during the first hour after admission from 37.9°C to 39.6°C, and up to 43.5°C 2 h later despite therapeutic activities. Furthermore, the patient developed respiratory failure, and received artificial ventilation. Later on, spontaneous hemorrhages occurred, which were caused by severe disseminated intravascular coagulation (DIC), as shown by lab chemistry. The situation was further complicated by a cardiac arrest. In spite of cardiopulmonary resuscitation, the patient died about 9 h after admission. After death, a toxicological investigation was carried out. Qualitative analysis of serum and urine were positive for tranylcypromine, sertraline, fluoxetine, tyramine and ethanol. The quantitative analysis showed a fluoxetine serum concentration of 844 nmol/L (reference range: 289–1 156 nmol/L), and a concentration of its active metabolite, norfluoxetine (N-desmethyl metabolite) of 573 nmol/L (reference range: 40–500 nmol/L). Tranylcypromine serum concentration was 13.5 μg/L (reference range: to 250 μg/L).

The patient might have taken the specific mode to commit suicide from a movie shown on television a few days earlier, in which it was planned to kill a man by application of tranylcypromine in combination with tyramine-rich food. The influence of mass media may be a relevant factor (“Werther effect”) in this case and should be perhaps considered.

This uncommon suicide with an ingestion of tranylcypromine and substances enhancing serotonergic activity shows the difficult diagnosis and the clinical management of this form of intoxication [7]. The case demonstrates the rapid and lethal course of a serotonin syndrome [2] with hyperthermia [1] [6] after combined tranylcypromine, serotonergic drugs and tyramine-rich food ingestion in spite of a relatively low serum concentration of tranylcypromine [4], which was caused by the high toxicity of MAOI effects in association with serotonin reuptake block. This toxicity might be fairly independent from MAOI serum level. The reports of severe adverse drug reactions of tranylcypromine in the literature [5] are rare and may be underreported. It is still important that such cases are documented within the framework of post-marketing surveillance (with respect to suicide risk). Although tranylcypromine is currently rarely prescribed as compared to the past, clinicians should also consider the risk of concomitant use of other drugs and interaction risks (for example, with ephedrine and pseudoephedrine, phenylpiperidine derivative opioids like pethidine or tramadol, triptans like sumatriptan, amphetamines).

References

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• 3 Christiansen LR, Collins KA. Pathologic findings in malignant hyperthermia: a case report and review of literature.  Am J Forensic Med Pathol. 2004;  25 3271-3233
• 4 Linden CH, Rumack BH, Strehlke C. Monoamine oxidase inhibitor overdose.  Ann Emerg Med. 1984;  13 1137-1144
• 5 Mirchandani H, Reich LE. Fatal malignant hyperthermia as a result of ingestion of tranylcypromine (Parnate) combined with white wine and cheese.  J Forensic Sci. 1985;  30 217-225
• 6 Nasir KK, Zafar AB, Mansoor F. et al . Malignant hyperthermia.  J Coll Physicians Surg Pak. 2004;  14 39-40
• 7 Pennings EJ, Verkes RJ, de Koning J. et al . Tranylcypromine intoxication with malignant hyperthermia, delirium, and thrombocytopenia.  J Clin Psychopharmacol. 1997;  17 430-432

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