Why do Amitriptyline and Dothiepin Appear to be so Dangerous in Overdose?

Data from different analyses of reported deaths from overdose with antidepressants in the U.K. reveal that amitriptyline & dothiepin are the antidepressants most likely to be associated with death from overdose. All widely used tricylic antidepressants (TCAs) except clomipramine & lofepramine appear to be dangerous in overdose, whereas the newer antidepressants such as mianserin, trazodone, viloxazine & the TCA lofepramine appear to be relatively safe. The toxicity of amitriptyline & dothiepin appears to be greater than all antidepressants including other TCAs. A number of explanations for this are considered. (17 refs)