The toxicology of serotonergic drugs and pharmacogenetics in sudden death

Drug-associated death is relatively common in Victoria. Many cases involve elevated drug concentrations which may be related to genetic variation in metabolising capability. This is particularly important when using serotonin-active drugs, as metabolic variations and certain drug combinations can lead to potentially fatal serotonin toxicity. Moreover, despite product warnings, many contraindicated combinations involving these drugs are commonly detected. Using Australian Coronial databases in addition to comprehensive genotyping methods, an understanding of the outcomes and implications of the use of specific serotonin-active drugs, in addition to the involvement of genetic variation and inappropriate drug combinations in sudden death, is presented. The research indicated that the use of serotonergic drugs may carry significant risk, depending on co-administered drugs and inter-individual differences in metabolic capacity. The issues of inappropriate prescribing, awareness of serotonin toxicity in a clinical and forensic setting, and preventative measures to reduce the risk of unintentional drug toxicity, were explored. Contraindicated and inadvisable combinations of serotonergic drugs appeared to be a considerable issue, identified in a number of cases and often not mentioned in reports relating to the coronial process. The data demonstrated the need for collaboration between specialists in the coronial investigation to better facilitate the opportunity for death prevention. Genotyping of a selection of the cohort indicated that perhaps pharmacogenetics does not appear to play as large a role in sudden and unexpected death as originally anticipated and is only relevant in a small subset of cases.