Fatal doxepin intoxication – Suicide or slow gradual intoxication?☆
Introduction
Doxepin is one of the most frequently prescribed antidepressants in Germany. The stereoisomers of doxepin, E-doxepin and Z-doxepin, are contained in all conventional preparations at a ratio of 85–15 (5.7). Both stereoisomers show different elimination kinetics. Doxepin has low bioavailability due to high first pass effect. As in most tricyclic antidepressants, the cytochrome P450 isoenzymes CYP2C9, CYP2C19 and CYP2D6 are involved in doxepin metabolism [1]. For these enzymes, genetic polymorphisms are known [2], so that there is an increased risk of adverse side effects under doxepin treatment [3].
Fatality cases with doxepin and other CNS drugs need careful investigation, as the drug metabolism can be further impaired by interactions with other prescribed medications and smoking. The presented case of fatal doxepin intoxication could be attributed both to acute and slow accumulative poisoning. The influence of dosage, drug interactions and genetic polymorphism of metabolizing enzymes on the concentration course of doxepin during doxepin treatment is discussed.
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Case history
The 52-year-old female patient of a psychiatric hospital was found dead in her bed at 2:50 a.m. Some months before, she had made several suicide attempts. However, according to family members and the nursing staff no suicidal tendencies had been observed any more lately. She was a heavy smoker and had been addicted to codeine for several years. Some weeks before her death, the patient had been transferred from the psychiatric hospital to a general hospital, as she had developed symptoms of
Effects on the biotransformation of doxepin
The tricyclic antidepressant doxepin is partly metabolized to nordoxepin in the body. Both substances are pharmacologically active. Demethylation is effected i.a. by the isoenzymes CYP1A2, CYP2C9 and CYP2C19. The formation of the inactive hydroxy metabolites of doxepin and nordoxepin is catalyzed by CYP2D6 (Fig. 1) [1]. For the enzymes CYP2D6, CYP2C9 and CYP2C19, enzyme mutations affecting the metabolic rate of doxepin are known:
Individuals belonging to the group of CYP2D6 “extensive
Conclusion
Especially in cases where high-doses or a lot of different medications are prescribed, regularly conducted comprehensive therapeutic drug monitoring would be recommended to early detect a possible slow gradual intoxication.
In intoxication cases involving CNS drug combinations, not only the interactions like enhancement of side effects but also a possible mutual influence on the drug metabolism and habits like smoking should be considered. In cases of unclear deaths due to doxepin it can be
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This paper is part of the special issue entitled “The 50th Annual Meeting of the International Association of Forensic Toxicologists (TIAFT)”. June 3–8, 2012, Hamamatsu, Japan. Guest edited by Adjunct Professor Einosuke Tanaka and Associate Professor Masaru Terada.