Clinically actionable pharmacogenomic landscape of antidepressants and antipsychotics in Qatar: a population-based cohort study

Abstract

Consortia like the Clinical Pharmacogenetic Implementation Consortium (CPIC) and the Dutch Pharmacogenetic Working Group (DPWG) provide clinical guidelines but pharmacogenomics implementation depends on population prevalence of actionable genetic variants and response phenotypes. We analyzed the distribution of actionable genetic variants and clinical recommendations in 14,354 adult Qataris, focusing only genes with guidelines (CYP2C19, CYP2D6, CYP2B6 and CYP3A4). Haplotypes and diplotypes were generated from 490 alleles using whole genome data and metabolizer phenotypes were predicted based on current knowledge. Qatari population predicted to have actionable metabolizer phenotypes of CYP2C19, CYP2B6 and CYP2D6 impacting response to antidepressants were in the range of 1%-58% and for antipsychotics 0.1%-33% based on CYP3A4 and CYP2D6. Fine-grained analysis based on clinical guidelines also revealed that while the Qataris may need prescription of an alternate antidepressant not metabolized by CYP2C19, patients from other populations may just need altering the dosage of tricyclic antidepressants like amitriptyline. Further studies incorporating other factors such as diet, environment and cultural habits alongwith population-specific variants will help in the pharmacogenomics implementation in the Qatari population.

Keywords: Clinical implementation; Pharmacogenomics; Precision medicine; Psychotropics; Whole genome sequencing.

Graphical abstract

Figure 1.

(A) Distribution of clinical implementation recommendations for sertraline based on the combined CYP2C19-CYP2B6 metabolizer status in the Qatari population and the 1,000 genomes. (B) Visualization of the computation of recommendations for the combined metabolizer status of CYP2C19 and CYP2B6. Various categories from A–G in the figure are as below. (A) Distribution of clinical implementation recommendations for sertraline based on the combined CYP2C19-CYP2B6 metabolizer status in the Qatari population and the 1,000 genomes. (B) Visualization of the computation of recommendations for the combined metabolizer status of CYP2C19 and CYP2B6. Various categories from A–G in the figure are as below. A Initiate therapy with recommended starting dose. If patient does not adequately respond to recommended maintenance dosing, consider titrating to a higher maintenance dose or switching to a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19 or CYP2B6 B Initiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose. C Initiate therapy with recommended starting dose. Consider a slower titration schedule and lower maintenance dose than normal metabolizers. D Consider a lower starting dose, slower titration schedule and 50% reduction of standard maintenance dose as compared to CYP2C19 normal metabolizers or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19. E Consider a lower starting dose, slower titration schedule and 25% reduction of standard maintenance dose as compared to CYP2B6 normal metabolizers or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2B6. F Consider a lower starting dose, slower titration schedule and 50% reduction of standard maintenance dose as compared to CYP2B6 normal metabolizers. G Select an alternative antidepressant not primarily metabolized by CYP2C19 or CYP2B6.

Figure 2.

Distribution of clinical implementation recommendations for tricyclic antidepressants such as amitriptyline based on the combined CYP2C19-CYP2D6 metabolizer status in the Qatari population and the 1,000 genomes. (B) Visualization of the computation of recommendations for the combined metabolizer status of CYP2C19 and CYP2D6. Various categories from A–E in the figure are as below. A Avoid amitriptyline use B Consider alternative drug not metabolized by CYP2C19. C Avoid amitriptyline use. If amitriptyline is warranted, consider titrating to a higher target dose (compared to normal metabolizers). D Avoid amitriptyline use. If amitriptyline is warranted, consider a 50% reduction of recommended starting dose. E Consider a 25% reduction of recommended starting dose.