Postmortem forensic toxicology of selective serotonin reuptake inhibitors:A review of pharmacology and report of 168 cases

This paper reviews the complex pharmacology of the new class of antidepress ant medications exhibiting selective inhibition of serotonin reuptake. The four selective serotonin reuptake inhibitors (SSRIs) considered-fluoxetine, fluvoxamine, sertraline and paroxetine-can result in toxicity and death th rough contributing to serotonergic excess resulting in serotonin syndrome, inhibiting the metabolism of other centrally acting drugs, lending to accum ulation of toxic concentrations, and exerting complex vasoactive effects on the vascular smooth muscle. This latter feature is of particular concern i n patients with preexisting heart disease. An analytical method involving isolation of the drugs by liquid/liquid extr action at alkaline pH into n-butyl chloride, and analysis by gas chromatogr aphy/mass spectrometry (GC/MS) is described, together with some of its limi tations. Toxicologic and cause and manner of death data were examined in 60 deaths involving fluoxetine, 5 involving fluvoxamine, 75 involving sertral ine, and 28 involving paroxetine. Deaths involving drug toxicity were gener ally a result of ingestion of multiple drugs, and in only a small number of the cases was death attributed principally to the SSRI involved. The poten tial for drug interactions between members of this class of drugs is discus sed as well as their metabolites and a variety of other therapeutic and abu sed drugs which can contribute to their toxicity. In the absence of other risk factors, the lowest concentrations determined to have resulted in death were 0.63 mg/L for fluoxetine, 0.4 mg/L for parox etine, and 1.5 mg/L for sertraline. We had in sufficient data to make even this elude assessment for fluvoxamine. Drug-induced elevation of serotonin concentrations may be a significant risk factor for patients with atheroscl erotic cardiovascular disease (ASCVD). Other factors including preexisting disease and the presence of other drugs and their pharmacology need to be c arefully considered before determining the appropriate cause and manner of death in these cases.