Postmortem Forensic Toxicology of Trazodone

Abstract

Trazodone is a popular antidepressant medication that has been available for approximately 30 years. It has a reputation as a safe drug with relatively few reported fatalities attributed solely to it. We review the pharmacology and forensic toxicology of trazodone and report toxicology and cause and manner of death in a series of 37 deaths in which trazodone was detected. Although the normal upper therapeutic blood concentration for trazodone is about 2 mg/L, fatalities are rarely attributed solely to it at blood concentrations below 9 mg/L. Considering the pharmacology of the drug, potential interactions between other drugs with serotonin reuptake properties need to be considered, as does the increased susceptibility to the toxic effects in patients with pre-existing heart disease. In the cases reviewed, none were attributed solely to trazodone, although trazodone was frequently present together with other serotonergic drugs, such as the selective serotonin reuptake inhibitors like fluoxetine and sertraline. Ten cases had blood trazodone concentrations above 2 mg/L. Of these cases, trazodone played a primary role in the death of three subjects, with blood concentrations all greater than 9 mg/L. We confirm the conclusions of others that trazodone is a relatively safe drug except in massive overdose, although its toxicity may be influenced by the presence of other drugs and underlying pathophysiology.

Investigation of inclusion complex of trazodone hydrochloride with hydroxypropyl-β-cyclodextrin

“…The TRD metabolite 1-m-chlorophenyl-piperazine (m-CPP) is a potent post-synaptic serotonin agonist. It is sometimes referred to as a serotonin antagonist reuptake inhibitor (SARI) (Goeringer, Raymon, & Logan, 2000).…”

A fatal case due to combined toxicity of psychotropic drugs

“…Blood concentrations following therapeutic dose of trazodone and paroxetine ingestion range up to 2.3 mg/ml and 0.075 mg/ ml, while fatal levels are those over 9 mg/ml and 0.4 mg/ml, respectively [2][3][4][5]. In the present case, the postmortem concentrations of trazodone and paroxetine in the femoral venous blood were at toxic levels, but below the fatal ranges.…”

QT Prolongation and delayed atrioventricular conduction caused by acute ingestion of trazodone

“…Cardiovascular effects of trazodone ingestion are generally minor, and include mild hypotension. A small number of fatalities have been reported, and these have involved patients who ingested massive quantities of trazodone or co-ingested other drugs, particularly selective serotonin reuptake inhibitors (4,5). Both QT prolongation and torsades de pointes are recognized complications of trazodone overdose (6,7).…”

“…Toxic effects correlate poorly with serum concentrations after trazodone overdose (3,4). Serum concentrations of around 1.2 mg/L are sufficiently high to prolong the QT interval by 25 ms in healthy young people (11).…”