Large-scale analysis demonstrates the influence of CYP2C19 genotype on specific SSRI side effects.

CYP2C19 genotype defines a continuum of metabolic capacity, from ultrarapid to poor metabolizer, graded here from 0 to 4 and regressed against SSRI response outcomes.

The authors assessed the effect of CYP2C19 genotype on SSRI response in 114,627 research participants, grading metabolizer status from 0 for ultrarapid to 4 for poor metabolizers and regressing drug response outcomes on this grade. Among participants taking escitalopram or citalopram, slower metabolizers reported side effects significantly more often (OR 1.04 per grade, 95% CI 1.02-1.06 and OR 1.05 per grade, 95% CI 1.02-1.07) and were more likely to discontinue treatment because of them (OR 1.05, 95% CI 1.03-1.08, i.e. 29.7% of poor versus 21.6% of ultrarapid metabolizers; OR 1.07, 95% CI 1.04-1.11, i.e. 25.7% versus 20.2%). On escitalopram, slower metabolizers reported more sleep and sexual problems; on sertraline, they reported tremor more often. The authors conclude that these substantial genotype-related differences in side effect risk support pharmacogenetically guided treatment selection.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The odds ratio per grade, around 1.05, is trivial taken alone, but the gap between the two ends of the metabolic spectrum, 29.7% versus 21.6% discontinuation for side effects, is perfectly legible in clinic: that is the figure to remember. The limitation lies in ascertainment, with side effects self-reported by participants, no severity scale and no verification of prescribed dose, in a volunteer research cohort poorly representative of psychiatric practice. The genotype-side effect association is solid here; it says nothing about the benefit of testing before prescribing, a question the randomised trial published the same week answers in the negative.

Analysis by Dr Thibaut Benquey