"Pharmacogenetic Variations and Clinical Implications of Actionable CYP2D6/CYP2C19 Variants in Central Indian Patients with Common Mental Disorders"

SANTENNA CHENCHULA^1*Atal Shubham²Rozatkar Abhijit²Tamonud Modak²Kohat Komal²Ratinder Jhaj²Singh Jitendra²Satyaprakash V²Sadasivam Balakrishnan²

• ¹All India Institute of Medical Sciences, Bhopal, Bhopal, India
• ²All India Institute of Medical Sciences Bhopal, Bhopal, India

Pharmacogenetic variation in CYP2D6 and CYP2C19, two highly polymorphic drug-metabolising enzymes, contributes to interindividual variability in antidepressant response and tolerability. Data from Central India, a genetically distinct and underrepresented region in pharmacogenomics research, remains limited. This study evaluated the prevalence and clinical relevance of actionable CYP2D6 and CYP2C19 variants in 509 patients with common mental disorders. Genotyping of the Tier 1 alleles, including copy number variations, was performed using KASP and TaqMan-based qPCR assays. Among CYP2D6 alleles, decreased-function variants *10 (21.6%) and *41 (17.3%) and non-functional alleles *3 (5.7%), *4 (10.4%), and *6 (1.9%) were observed. Gene deletions(*5) and duplications(xN) were detected in 4.2% and 4.1% of participants, respectively. For CYP2C19, the non-functional *2(37.3%) and *3 (2.3%) alleles and the increased-function *17(16.1%) allele were prevalent. Predicted non-normal metabolizer phenotypes were identified in 46.2% of participants for CYP2D6 and 74.2% for CYP2C19. Based on CPIC classifications, 86% of participants carried at least one actionable PGx variant with prescribing implications. To assess the clinical impact, predicted phenotypes were aligned with antidepressant prescribing data, showing high use of CYP2C19 substrates, including sertraline (34.1%), escitalopram (28.2%), and paroxetine (21.2%). Overall, 7.5% of patients carried CYP2D6 variants and 20.6% carried CYP2C19 variants for which CPIC guidelines recommend alternative drug selection or dose modification. These findings highlight the high prevalence of actionable CYP2D6 and CYP2C19 variants in this Central Indian cohort and strongly support the implementation of pharmacogenetic-guided prescribing to optimize antidepressant therapy.