Pharmacogenetics of Antidepressants, A Review of Significant Genetic Variants in Different Populations

Abstract

Major depressive disorder is a highly prevalent disease that is challenging to treat, often requiring medication and dose adjustments. Genetic factors play an important role in psychotropic medication responses. However, the translation of pharmacogenetics findings to clinical recommendations with regards to antidepressant responses is still in its early stages. We reviewed recent primary research articles, meta-analyses, and reviews on the pharmacogenetics of antidepressant treatment for major depressive disorder in different populations. We identified eight genes with likely associations with treatment responses and summarized genetic variants most likely to influence treatment responses. We determined the frequency of these variants in Caucasian, Asian, Hispanic, and African American populations. The genes are related to functions in drug metabolism, transport, signalling, stress response, and neuroplasticity. Clinical recommendations already exist for CYP2D6 and CYP2C19 cytochrome P450 drug metabolism genes. The other genes are: ABCB1 with single nucleotide polymorphisms (SNPs) rs2032583 and rs2235015; FKBP5 with SNPs rs1360780, rs3800373, and rs4713916; GNB3 with SNP rs5443; BDNF with SNP rs6265; HTR2A with SNPs rs7997012 and rs6313; and SLC6A4 with polymorphisms 5-HTTLPR and STin2. There is significant variability of the frequencies of these polymorphisms in the different populations we reviewed. There is also variability in the antidepressant responses between populations carrying the same polymorphism in some cases, indicating a likely polygenic influence. Future studies in the pharmacogenetics of antidepressants would benefit from including more subjects from underrepresented ethnic groups and stratifying results.

Pharmacogenetic Variants Associated with Fluoxetine Pharmacokinetics from a Bioequivalence Study in Healthy Subjects

“…One subject with homozygote allele A/A for SNV rs1065852, associated with decreased CYP2D6 function, was found in our study sample, and we confirmed that the plasmatic t 1/2 increased about three times compared with A/G and G/G alleles. This SNV frequency in our study ( 1 / 24 = 4.2%) is consistent with reports in the literature, ranging from 2.8% and up to 4.3% in Caucasian, Hispanic, and Afro-American populations [ 37 ]. Together with CYP2D6 rs11358490, this SNV is part of the CYP2D6*10 haplotype [ 7 ], known to have decreased cytochrome function along with other gene variants [ 38 ].…”

Results and challenges of Cytochrome P450 2D6 (CYP2D6) testing in an ethnically diverse South Florida population

“…Thus, pharmacogenetic test results would be more useful and accurate if laboratories sequenced the entire CYP2D6 gene, rather than selected polymorphisms. As a whole, sequencing would also provide a better depiction of the allelic variation within underrepresented communities (Barron et al, ; Bernard, ; Claudio‐Campos, Orengo‐Mercado, et al, ; Ortega & Meyers, ). Importantly, minority groups are predicted to become the majority by 2044, with a quarter being Hispanic (Colby & Ortman, ).…”

A Review of Clinical Pharmacogenetics Studies in African Populations

“…Major depressive disorder is a mental health disorder characterized by persistently depressed mood or loss of interest in activities, causing significant impairment in daily life [ 122 ]. No pharmacogenomics studies in this context were extracted from Africa.…”

“…However, a recent review highlighted eight genes implicated in antidepressant treatment response in mixed populations (including African-Americans). These included CYP2D6, CYP2C19, SLC6A4, ABCB1 (rs2032583 and rs2235015), FKBP5 (rs1360780, rs3800373 and rs4713916); GNB3 (rs5443); BDNF (rs6265); and HTR2A (rs7997012 and rs6313) [ 122 ]. Another study used genome-wide single nucleotide polymorphism data to examine independent contributions of race and genetic ancestry to antidepressant response [ 123 ].…”