Completed suicides of citalopram users—the role of CYP genotypes and adverse drug interactions

• Published in: International journal of legal medicine Vol. 133; no. 2; pp. 353 - 363
• Main Authors: Rahikainen, Anna-Liina, Vauhkonen, P., Pett, H., Palo, J. U., Haukka, J., Ojanperä, I., Niemi, M., Sajantila, Antti
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.03.2019; Springer Nature B.V
• Subjects: Adult; Aged; Aged, 80 and over; Antidepressants; Case-Control Studies; Citalopram - pharmacokinetics; Citalopram - poisoning; Cytochrome P-450 CYP2C19 - genetics; Cytochrome P-450 CYP2D6 - genetics; DNA Copy Number Variations; Drug Interactions - genetics; Fatalities; Female; Finland; Forensic Medicine; Forensic Toxicology; Gene Frequency; Genotype; Humans; Male; Medical Law; Medicine & Public Health; Mental depression; Middle Aged; Original Article; Pharmacogenomic Variants - genetics; Pharmacology; Poisoning; Polymorphism, Single Nucleotide; Population genetics; Risk analysis; Serotonin; Serotonin Uptake Inhibitors - pharmacokinetics; Serotonin Uptake Inhibitors - poisoning; Service life assessment; Suicide; Suicides & suicide attempts; Finland; Suicide; Drug interactions; Postmortem; Citalopram; CYP2C19; CYP2D6
• ISSN: 0937-9827; 1437-1596
• DOI: 10.1007/s00414-018-1927-0

Depression is known to be a risk factor for suicide. Currently, the most used antidepressants are selective serotonin reuptake inhibitors (SSRIs). Not all users, however, benefit from them. In such cases, treatment failure can be explained in part by genetic differences. In this study, we investigated the role of pharmacogenetic factors in citalopram-positive completed suicides ( n  = 349). Since citalopram is metabolized by CYP2C19 and CYP2D6 enzymes, the study population was genotyped for clinically relevant CYP2C19 and CYP2D6 polymorphisms and CYP2D6 copy number variation. To assess genetic differences between suicide cases and Finns in general, Finnish population samples ( n  = 855) were used as controls. Also, the role of drug interactions among suicide cases was evaluated. We found enrichment of a combined group of genetically predicted poor and ultrarapid metabolizer phenotypes (gMPs) of CYP2C19 among suicide victims compared to controls 0.356 [0.31–0.41] vs. 0.265 [0.24–0.30] ( p  = 0.0065). In CYP2D6 gMPs, there was no difference between cases and controls when the study population was analyzed as a whole. However, there were significantly more poor metabolizers among females who committed suicide by poisoning compared to female controls. In 8% of all drug poisoning deaths, lifetime drug-drug interaction was evaluated having a contribution to the fatal outcome. From clinical perspective, pharmacogenetic testing prior to initiation of SSRI drug could be beneficial. It may also be useful in medico-legal settings as it may elucidate obscure poisoning cases. Also, the possibility of unintentional drug interactions should be taken into account in drug poisoning deaths.