Fatal venlafaxine poisonings are associated with a high prevalence of drug interactions.

Venlafaxine (VEN) is an antidepressant found to possess a higher fatal toxicity index (FTI, i.e., deaths in proportion to consumption) than other newer antidepressants and selective serotonin reuptake inhibitors (SSRIs). The aim of this study was to elucidate using post-mortem cases whether the apparent high toxicity of VEN is associated with adverse drug interactions, pharmacogenetic factors and/or the manner of death. Within a 2-year period, a comprehensive post-mortem database and death certificates were searched for cases with laboratory findings of VEN, findings of other drugs, associated background information and the cause and manner of death. In 123 cases, the concentrations of VEN and its two metabolites, O-desmethylvenlafaxine (O-VEN) and N-desmethylvenlafaxine (N-VEN), and the CYP2D6 genotype were determined in post-mortem blood. The median concentrations of VEN, O-VEN and N-VEN were 560, 420 and 49 µg/l, respectively. A prominent feature of the VEN-positive cases was the high abundance of interacting drugs (46%), being more common with higher VEN concentrations. Compared to other common antidepressants, VEN-positive cases showed the highest suicide frequency, but also the proportion of suicidal VEN poisonings of all suicides was substantially higher than that of mirtazapine or SSRIs. Relative CYP2D6 activity did not predispose to high VEN concentrations, and the frequency of the extreme phenotypes followed the general population. In conclusion, the high suicide potential of VEN in combination with the high prevalence of drugs causing adverse interactions could be the reason for the observed high FTI.