Pharmacogenomics of selective serotonin reuptake inhibitor treatment for major depressive disorder: genome-wide associations and functional genomics.

A genome-wide association (GWA) study of treatment outcomes (response and remission) of selective serotonin reuptake inhibitors (SSRIs) was conducted using 529 subjects with major depressive disorder. While no SNP associations reached the genome-wide level of significance, 14 SNPs of interest were identified for functional analysis. The rs11144870 SNP in the riboflavin kinase (RFK) gene on chromosome 9 was associated with 8-week treatment response (odds ratio (OR)=0.42, P=1.04 × 10⁻6). The rs915120 SNP in the G protein-coupled receptor kinase 5 (GRK5) gene on chromosome 10 was associated with 8-week remission (OR=0.50, P=1.15 × 10⁻5). Both SNPs were shown to influence transcription by a reporter gene assay and to alter nuclear protein binding using an electrophoretic mobility shift assay. This report represents an example of joining functional genomics with traditional GWA study results derived from a GWA analysis of SSRI treatment outcomes. The goal of this analytical strategy is to provide insights into the potential relevance of biologically plausible observed associations.

SLC6A4 variation and citalopram response.

The influence of genetic variations in SLC6A4 (serotonin transporter gene) on citalopram treatment of depression using the Sequenced Treatment to Relieve Depression (STAR*D) sample was assessed. Of primary interest were three previously studied polymorphisms: 1) the VNTR variation of the second intron, 2) the indel promoter polymorphism (5HTTLPR or SERT), and 3) a single nucleotide polymorphism (SNP) rs25531. Additionally, SLC6A4 was resequenced to identify new SNPs for exploratory analyses. DNA from 1914 subjects in the STAR*D study were genotyped for the intron 2 VNTR region, the indel promoter polymorphism, and rs25531. Associations of these variants with remission of depressive symptoms were evaluated following citalopram treatment. In white non-Hispanic subjects, variations in the intron 2 VNTR (point-wise P = 0.041) and the indel promoter polymorphism (point-wise P = 0.039) were associated with remission following treatment with citalopram. The haplotype composed of the three candidate loci was also associated with remission, with a global p-value of 0.040 and a maximum statistic simulation p-value of 0.0031 for the S-a-12 haplotype, under a dominant model. One SNP identified through re-sequencing the SLC6A4 gene, Intron7-83-TC, showed point-wise evidence of association, which did not remain significant after correction for the number of SNPs evaluated in this exploratory analysis. No associations between these SLC6A4 variations and remission were found in the white Hispanic or black subjects. These findings suggest that multiple variations in the SLC6A4 gene are associated with remission in white non-Hispanic depressed adults treated with citalopram. The mechanism of action of these variants remains to be determined.

Using a pharmacogenomic algorithm to guide the treatment of depression.

The objective of this study was to evaluate the potential benefit of utilizing a pharmacogenomic testing report to guide the selection and dosing of psychotropic medications in an outpatient psychiatric practice. The non-randomized, open label, prospective cohort study was conducted from September 2009 to July 2010. In the first cohort, depressed patients were treated without the benefit of pharmacogenomic testing (the unguided group). A DNA sample was obtained from patients in the unguided group, but the results were not shared with either the physicians or patients until the end of the 8-week study period. In the second cohort (the guided group), testing results were provided at the beginning of the 8-week treatment period. Depression ratings were collected at baseline and after 2 weeks, 4 weeks and 8 weeks of treatment using the Quick Inventory of Depressive Symptomatology, Clinician Rated (QIDS-C16) and the 17-item Hamilton Rating Scale for Depression (HAM-D17). Clinician and patient satisfaction was also assessed. The reduction in depressive symptoms achieved within the guided treatment group was greater than the reduction of depressive symptoms in the unguided treatment group using either the QIDS-C16 (P=0.002) or HAM-D17 (P=0.04). We concluded that a rapidly available pharmacogenomic interpretive report provided clinical guidance that was associated with improved clinical outcomes for depressed patients treated in an outpatient psychiatric clinic setting.