Unlocking mechanisms implicated in drug-induced bizarre idiosyncratic behaviours - learning from people and molecules

Abstract

Zolpidem, an imidazopyridine hypnotic, which acts on GABA‐A receptors has been associated with the development of a number of disturbing neuropsychiatric adverse drug reactions (ADRs) including parasomnias, amnesia and hallucinations. Although other non-hypnotic medications are also implicated in the induction of such adverse events; the mechanism behind these ADRs remains elusive and have been postulated to arise from off-target receptor or pathway activation resulting in the disruption and dysregulation of keyneurotransmitters including GABA, acetylcholine, noradrenaline and dopamine. Using a novel multidisciplinary approach, we aim to investigate relationships between these rare idiosyncratic ADRs (parasomnia, movement-based parasomnia, non-movement based parasomnia, amnesia and hallucination) by identifying similarities in the chemical structure amongst drugs that share these reactions. These shared structural features or motifs may enable diverse drugs to participate in a pharmacological reaction with a mutual target receptor or pathway. By combining human population pharmacovigilance data with in silico computational techniques, insights into mechanisms underlying idiosyncratic reactions or toxicities can be elucidated.