CAN THE FATAL TOXICITY OF ANTIDEPRESSANT DRUGS BE PREDICTED WITH PHARMACOLOGICAL AND TOXICOLOGICAL DATA

Antidepressant drugs are among the most common drugs involved in fatal poisoning and large variations between antidepressant drugs have been noted. Despite the fact that a large number of studies have calculate d a fatal toxicity index (FTI) for antidepressants, no serious attempt s have been made to compare the differences in fatal toxicity against known pharmacological and toxicological differences in receptor affini ty. It is potentially from such data that screening of drugs during th eir pre-clinical development can be facilitated. We examined correlati ons between the FTI and noradrenaline (norepinephrine)/serotonin (5-hy droxytryptamine; 5-MT) reuptake inhibition selectivity, the dose that is lethal to 50% of animals (LD50), lipid solubility, and antagonist a ctivity at cholinergic, histaminergic, alpha-adrenergic and gamma-amin obutyric acid (GABA)A receptors or sodium and potassium channel blocki ng effects. We obtained data on the number of fatal poisonings between 1983 and 1992 in England and Wales caused by a single antidepressant drug from the Department of Health in the UK. This number was divided by the number of prescriptions in England for these drugs over this ti me to derive a FTI of deaths per million prescriptions. The highest FT Is were for amoxapine, viloxazine, desipramine and dothiepin. Lofepram ine, paroxetine and fluoxetine had very low FTIs. Using Poisson regres sion, there was a significant positive relationship between the FTI of antidepressant drugs and their lethal toxicity in animals, and measur es of their cardiac effects. The relative noradrenaline/serotonin reup take inhibition, lipid solubility and their potency at histamine H-1, muscarinic and alpha(1)-adrenergic receptors had no substantial associ ation with the FTI. Limited data suggest that some cardiac effects and potency as a GABA(A) antagonist may be important predictors of signif icant toxicity. Further data using standardised bioassays are needed t o compare the direct cardiac effects of antidepressants. Thus, the bes t current pre-clinical indicator of fatal toxicity in humans is the LD 50 in animal studies. Clearly, there are humane and practical reasons for developing a better pre-clinical indicator of toxicity in overdose for this rapidly expanding group of drugs.