Fatal toxicity of serotoninergic and other antidepressant drugs: analysis of United Kingdom mortality data

Abstract

Several studies over the past 15 years have compared the number of fatal poisonings due to antidepressant drugs in the United Kingdom with drug use statistics to derive a fatal toxicity index: deaths per million prescriptions.1 2 Greater than 10-fold differences in the index have been shown between tricyclic antidepressants and even larger differences between some tricyclics and newer antidepressants. Explanations have focused on preference for noradrenaline or serotonin reuptake blockade, although only weak correlations have been observed 2 and the explanation is toxicologically implausible. 1 In the late 1990s the use of newer serotoninergic antidepressants increased dramatically. Some data show that venlafaxine in particular may not be as safe in overdose as other serotoninergic drugs, with reports of deaths, arrhythmias, and seizures. 3 We aimed to establish the relative frequency with which venlafaxine and other new antidepressants result in fatal poisoning. Methods and resultsWe obtained the number of deaths in Scotland, England, and Wales due to acute poisoning by a single drug, with or without co-ingestion of alcohol, from the General Register Office for Scotland and the Office for National Statistics for the years 1993-9. We used the number of prescription items for England, Wales, and Scotland supplied by the respective departments of health for these years as a measure of relative drug use. Use in hospital is not included, but prescribing of antidepressants overwhelmingly occurs in general practice. For each drug we calculated a fatal toxicity index expressed as deaths per million prescriptions. We calculated the lower and upper 95% confidence limits for the index by using exact confidence intervals for the deaths. The table lists the drugs in descending order of fatal toxicity index within British National Formulary drug classes. The serotoninergic drug class overall had a much lower index than the tricyclic antidepressants and monoamine oxidase inhibitors, but venlafaxine had a higher index than the individual and combined results of other serotoninergic drugs. CommentThe most striking new observation is that the fatal toxicity index for venlafaxine is higher than those for other serotoninergic antidepressants and similar to those for some less toxic tricyclic antidepressants. This raises the question of whether venlafaxine should continue to be a first line drug in patients with suicidal ideation. Our results also confirm previously reported large differences in fatal toxicity index between other antidepressant drugs.

Influence of CYP2D6 genotype on the disposition of the enantiomers of venlafaxine and its major metabolites in postmortem femoral blood

“…According to several studies VEN has a relatively higher fatal toxicity compared to SSRIs and other newer antidepressants [10,13,16,17,[48][49][50]. Different explanations to this finding have been suggested.…”

“…VEN has also been shown to have a relatively higher toxicity compared to the SSRIs [10,13,[16][17][18].…”

Morbidity and Mortality Associated With Medications Used in the Treatment of Depression: An Analysis of Cases Reported to U.S. Poison Control Centers, 2000–2014

“…Both indices were significantly greater than that for citalopram, which in turn had a significantly higher mortality index than sertraline. Prior reports, based on comparisons with prescriptions written, have suggested there is greater mortality associated with venlafaxine overdose than with SSRIs (35)(36)(37). Alternatively, Rubino and colleagues (38) found that venlafaxine was more likely to be used in patients who exhibited factors suggesting greater suicidal risk and that adjusting for those factors reduced mortality risk.…”

A Comparison of Venlafaxine and SSRIs in Deliberate Self-poisoning

“…More recently, a number of large epidemiological reviews in the UK and Finland have suggested that venlafaxine is associated with more deaths per written prescriptions than other SSRIs suggesting a greater inherent toxicity [3][4][5][6]. It is difficult to determine from these large studies whether this is a true toxic effect or one related to the possibility that venlafaxine is prescribed to patients at higher suicidal risk than those prescribed SSRIs [7].…”