Abstracts
3427192
(#41) Assessment of Genetic Variants in Drug Metabolizing Enzymes Among Individuals with Treatment-Resistant Major Depressive Disorder
Abstract: Major Depressive Disorder (MDD) is a leading cause of disability in the United States and is associated with significant morbidity and mortality. Approximately 30% of MDD patients demonstrate an inadequate therapeutic response even after two or more anti-depressant trials and are classified with treatment-resistant MDD (TRD). TRD is associated with poorer outcomes in comparison to patients with MDD. Pharmacogenetics (PGx) has emerged as a promising clinical tool for therapeutic drug selection/dosage optimization. Several first-line agents for MDD are metabolized by the cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP2D6, and genetic alterations in these genes can lead to alternations in metabolism and diminished drug efficacy.
We evaluated the frequency and relevance of actionable pharmacogenomic variants amongst a cohort of individuals with clinically verified TRD who also had remnant blood samples available. Over a period of 7 months (Jul 2025-Feb 2026), 18 TRD individuals underwent PGx analysis for 11 actionable pharmacogenes, including CYP2D6, CYP2C19 and CYP2C9. Amongst this TRD cohort, the median number of anti-depressants attempted was 6 (IQR: 7.75-5). At least one clinically actionable pharmacogenomic variant was observed in 83% (15/18) of individuals; 40% had two phenotype alterations and 20% had three. While PGx results were not available for clinical management, based on observed variants, 44% (8/18) of individuals were discharged on a therapeutic regimen that may have decreased efficacy.
The prevalence of genomic alterations supports the incorporation of PGx testing in clinical management of TRD patients. PGx implementation may reduce the timeframe to achieving therapeutic efficacy and improve clinical outcomes.
Short Description: Among a cohort of 18 individuals with treatment-resistant major depressive disorder (TRD), we highlight the frequency of clinically relevant variants in the CYP2C9, CYP2C19, and CYP2D6 pharmacogenes. We further demonstrate the frequency of co-occurring variants among these genes and their potential impact on anti-depressant drug responses. We also looked at the associations of these genetic variants with regimen-specific failures. Our findings support the utility of pharmacogenomic testing to optimize clinical outcomes in this population.
Name of Sponsoring Organization(s): Dr. Sulaiman received partial support by the Physician Scientist Training Program, Microgrant (Johns Hopkins).
We evaluated the frequency and relevance of actionable pharmacogenomic variants amongst a cohort of individuals with clinically verified TRD who also had remnant blood samples available. Over a period of 7 months (Jul 2025-Feb 2026), 18 TRD individuals underwent PGx analysis for 11 actionable pharmacogenes, including CYP2D6, CYP2C19 and CYP2C9. Amongst this TRD cohort, the median number of anti-depressants attempted was 6 (IQR: 7.75-5). At least one clinically actionable pharmacogenomic variant was observed in 83% (15/18) of individuals; 40% had two phenotype alterations and 20% had three. While PGx results were not available for clinical management, based on observed variants, 44% (8/18) of individuals were discharged on a therapeutic regimen that may have decreased efficacy.
The prevalence of genomic alterations supports the incorporation of PGx testing in clinical management of TRD patients. PGx implementation may reduce the timeframe to achieving therapeutic efficacy and improve clinical outcomes.
Short Description: Among a cohort of 18 individuals with treatment-resistant major depressive disorder (TRD), we highlight the frequency of clinically relevant variants in the CYP2C9, CYP2C19, and CYP2D6 pharmacogenes. We further demonstrate the frequency of co-occurring variants among these genes and their potential impact on anti-depressant drug responses. We also looked at the associations of these genetic variants with regimen-specific failures. Our findings support the utility of pharmacogenomic testing to optimize clinical outcomes in this population.
Name of Sponsoring Organization(s): Dr. Sulaiman received partial support by the Physician Scientist Training Program, Microgrant (Johns Hopkins).
