Thakur Tanu MBBS, Aguilar-Henríquez Andrés MD, Leontieva Luba MD, PhD, Megna James MD, PhD.
Background: Idiosyncratic drug reactions are unpredictable events known to produce serious morbidity and mortality. There is little understanding of the pathophysiology underlying these adverse effects, specifically with psychotropic medications.
Material and Methods: A literature search were conducted in Pubmed and Cochrane by using the following terms in varying combinations: idiosyncratic reactions, fluphenazine, chlorpromazine, escitalopram, clozapine, risperidone, quetiapine, olanzapine, sertraline, duloxetine, amitriptyline, nortriptyline, valproic acid, carbamazepine, drug induced liver injury, agranulocytosis, genome site, and polymorphism. Case reports were excluded in order to have a review with articles reflective of a strong sample size. The Food and Drug Administration was contacted for updates on pre-existing knowledge on idiosyncratic reactions. Our intention was to analyze and to integrate the proposed mechanisms from the existing scientific literature.
Results: Reported frequencies of idiosyncratic drug reactions range from an upper limit of 5% to as low as 1 in 10,000 to 100,000 individuals. However, these data are mostly based upon reports describing non-psychotropic medications. Postulated mechanisms of idiosyncratic drug reactions include immune mediated and non-immune mediated types. Suggested mechanisms are explored with emphasis on drug induced liver injury and agranulocytosis
reactions with chlorpromazine and clozapine, respectively.
Conclusion: Idiosyncratic drug reactions are rarely, if ever, detected during randomized controlled trials, usually emerging during post marketing surveillance. More mechanistic studies are needed so that a better understanding of the underlying pathophysiologic processes can be obtained, and improved surveillance can be implemented. Recently developed techniques (including homology modeling, docking simulations, and quantitative systems
pharmacology) will be instrumental in the aforementioned process.