2 fatal polyintoxication cases involving citalopram

Citalopram is a selective serotonin reuptake inhibitor (SSRI) class of antidepressants prescribed to treat severe depression and treat anxiety. Marketed in many countries, it is easily available to the French population, known to be one of the biggest consumers of antidepressants in Europe. Although citalopram overdose has long been known to cause cardiotoxicity especially QT prolongation and torsades de pointes, seizures and serotoninergic syndrome, only a few reports have analysed citalopram levels in post mortem blood. We report two fatal cases involving citalopram: a 47 year old woman and a 55 year old man. Both treated for severe depression, were discovered dead in what was believed to be a case of suicide. Toxicological screening was performed to assist in establishing the cause of death. Blood alcohol was determined using GC-FID (Thermo Scientific). When screening for organic xenobiotics, preparation consisted of liquid-liquid extraction of 1 mL of blood collected with sodium fluoride preservative at both acid and alkaline pH by ternary solvent (dichloromethane/hexane/ethyl acetate, 50/40/10, v/v/v). After evaporation, the dry residue was reconstituted in mobile phase at initial condition. The first half of the sample was directly analysed by LC-MS and DAD (Agilent 1100-MSD). Separation was performed on a Macherey-Nagel Nucleodur C18 Gravity column (150 mm x 2 mm, 3 µm) with a mobile phase gradient at 0.5 mL/min (methanol / water 5 mM ammonium formate with 0.2% formic acid). For the second part, after evaporation to dryness and acetylation, analysis was performed on full-scan mode with a GC-MS (Thermo Scientific) equipped with a Varian CP-Sil 8 CB Low Bleed/MS column (25 m × 0.25 mm × 0.25 µm). All substances found were subsequently quantified by LC-MS after addition of internal standard. In both cases, high blood concentration of citalopram was found (5.54 and 0.93 mg/L respectively) related to its main metabolite desmethylcitalopram (0.19 and 0.17 mg/L respectively). Citalopram was associated with various other psychoactive substances. In the first case, a toxic level of alimemazine (0.77 mg/L) was discovered as well as a therapeutic level of zolpidem (0.16 mg/L), nordazepam (0.53 mg/L) and cyamemazine (0.35 mg/L with 0.86 mg/L of norcyamemazine). In the second case, a high blood alcohol level was also found (3.53 ± 0.17 g/L) alongside various analgesics within therapeutic ranges (dextropropoxyphene, paracetamol and tramadol at 0.27, 3.7 and 0.6 mg/L respectively). Considering both cases, citalopram was identified within the toxic range (over 0.5 mg/L). Numerous CYP enzymes are involved in citalopram metabolism especially CYP2D6, CYP3A4 and CYP2C19. Use of citalopram with CYP2C19 inhibitors is not recommended by the FDA. Based on this recommendation, no significant pharmacokinetic drug interactions were found among citalopram and the other drugs reported. In those cases, the metabolizer status was not investigated. The overdose of citalopram appears to be responsible for the death, even though presence of other drugs may have potentiated its toxic effects