Abstract
Background: Zopiclone and zolpidem are widely prescribed hypnotic medications for insomnia, sharing similar efficacy but differing in side-effect profiles, particularly concerning taste disturbances. Identifying genetic predictors of intolerance to these medications could inform personalized treatment strategies.
Methods: We conducted a genome-wide association study to identify genetic variants associated with switching between zopiclone and zolpidem in 57,669 Icelanders, using electronic prescription data from Iceland (2003-2020), and 6590 British individuals from the UK Biobank (1990-2017). We included individuals who had received at least 3 prescriptions of either drug. We also investigated data on bitter taste perception using quinine taste test data from 2238 Icelandic individuals.
Results: A common sequence variant, rs6488335-G, within the TAS2R ∗ bitter taste receptor gene locus on chromosome 12, was associated with an increased likelihood of switching from zopiclone to zolpidem (Iceland: odds ratio [OR], 1.29; 95% CI, 1.24 to 1.35; United Kingdom: OR, 1.34; 95% CI, 1.12 to 1.59) and a decreased likelihood of switching in the reverse direction. The effect was more pronounced in women (ORfemales, 1.36; 95% CI, 1.29 to 1.44) than in men (ORmales, 1.19; 95% CI, 1.11 to 1.27). While the variant is associated with bitter taste perception of quinine, conditional analyses suggest that the pharmacogenetic association with drug switching is independent of taste perception.
Conclusions: Our findings indicate that carriers of the rs6488335-G variant, particularly homozygous women, were more likely to switch from zopiclone to zolpidem, potentially due to heightened sensitivity to taste-related side effects. Preemptive genetic testing could guide clinicians in prescribing zolpidem over zopiclone for individuals at risk, thereby reducing health care visits and improving treatment adherence.