Postmortem Forensic Toxicology of Selective Serotonin Reuptake Inhibitors: A Review of Pharmacology and Report of 168 Cases

Abstract

This paper reviews the complex pharmacology of the new class of antidepressant 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 through contributing to serotonergic excess resulting in serotonin syndrome, inhibiting the metabolism of other centrally acting drugs, leading to accumulation of toxic concentrations, and exerting complex vasoactive effects on the vascular smooth muscle. This latter feature is of particular concern in patients with preexisting heart disease. An analytical method involving isolation of the drugs by liquid/liquid extraction at alkaline pH into n-butyl chloride, and analysis by gas chromatography/mass spectrometry (GC/MS) is described, together with some of its limitations. Toxicologic and cause and manner of death data were examined in 60 deaths involving fluoxetine, 5 involving fluvoxamine, 75 involving sertraline, and 28 involving paroxetine. Deaths involving drug toxicity were generally 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 potential for drug interactions between members of this class of drugs is discussed as well as their metabolites and a variety of other therapeutic and abused 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 paroxetine, and 1.5 mg/L for sertraline. We had insufficient data to make even this crude assessment for fluvoxamine. Drug-induced elevation of serotonin concentrations may be a significant risk factor for patients with atherosclerotic cardiovascular disease (ASCVD). Other factors including preexisting disease and the presence of other drugs and their pharmacology need to be carefully considered before determining the appropriate cause and manner of death in these cases.

Inhibition of G Protein-Activated Inwardly Rectifying K+ Channels by the Antidepressant Paroxetine

“…High dosages of paroxetine are associated with convulsions in animals (51). The blood levels in postmortem cases involving toxicity from paroxetine overdoses are approximately 4 to 40 times higher than the upper limit of the therapeutic levels (52,53), thereby leading to the high brain concentrations (40). Therefore, inhibition of neuronal GIRK channels by paroxetine after overdose might contribute to an increased susceptibility to seizures by causing an increase in neuronal excitability.…”

Determination of antidepressants in human postmortem blood, brain tissue, and hair using gas chromatography–mass spectrometry

“…These highly prescribed drugs are, however, frequently used together with other legal or illegal drugs and can result in synergy of symptoms and intoxications [1][2][3][4][5][6][7][8][9][10][11][12]. Furthermore, severe life-threatening interactions such as the serotonin syndrome have been described [13][14][15][16].…”

The influence of putrefaction and sample storage on post-mortem toxicology results

“…Due to this problem more selective techniques are required and are increasingly being incorporated-generally either gas or liquid chromatography coupled with mass spectrometry (GC-MS or LC-MS). While the combination of these techniques is very useful, there can be issues such as thermal degradation of analytes in the injection port when using gas chromatography [36], or matrix effects with LC-MS [37]. The combination of all these issues may result in specimens that are very difficult to analyse without selective detection methods.…”