Abstract
Genetic polymorphism contributes to variation in response to drug treatment of depression. We conducted three independent 6-week treatment studies in outpatients with major depressive disorder (MDD) to develop a pharmacogenomic model predicting response and nonresponse. We screened candidate genomic markers for association with response to selective serotonin reuptake inhibitors (SSRIs). No patients had received any antidepressant drug treatment in the current episode of depression. Outcome evaluation was blinded to drug and genotype data. The prediction model derived from a development sample of 239 completer cases treated with SSRIs comprised haplotypes and polymorphisms related to serotonin synthesis, serotonin transport, glutamate receptors, and GABA synthesis. The model was evaluated prospectively for prediction of outcome in a validation sample of 176 new SSRI-treated completer cases. The model gave a prediction in 60% of these cases. Predictive values were 85% for predicted responders and 86% for predicted nonresponders, compared to prior probabilities of 66% for observed response and 34% for observed nonresponse in those cases (both P<0.001). Convergent cross-validation was obtained through failure of the model to predict outcomes in a third independent sample of 189 completer cases who received non-SSRI antidepressants. We suggest proof of principle for genetic guidance to use or avoid SSRIs in a majority of Korean depressed patients.
Highlights
Response rates in drug treatment of major depression are variable and often less than 50% in ‘‘real world’’ studies [1], and there are no biomarkers to direct choice of antidepressant drug class
Text S2 provides additional descriptions of secondary analyses (Supplementary Results), which describes (1) comparisons of the three cohorts in respect of genotypes, clinical characteristics, and plasma drug levels in relation to response status; (2) single nucleotide polymorphism (SNP) associations with the secondary outcome of remission; (3) a test of the top 10 SNPs in the response prediction model for possible associations with the diagnosis of major depression – with no significant association being found; (4) details of the polymorphism prediction model that was replaced by the HAP-SNP model; (5) secondary conditional probability analyses in the cross-validation cohort, demonstrating a double dissociation of observed versus expected outcomes: cases predicted by the HAP-SNP model to do poorly with selective serotonin reuptake inhibitor (SSRI) treatment had significantly better observed outcomes with non-SSRI treatment, while cases
The markers associated with response to SSRI drugs comprised ten SNPs from the TPH2, SLC6A4, GRIK2, and GAD1 genes and six haplotypes from the TPH2, SLC6A4, and GRIK2 genes (Table 2 and Figure 2)
Summary
Response rates in drug treatment of major depression are variable and often less than 50% in ‘‘real world’’ studies [1], and there are no biomarkers to direct choice of antidepressant drug class. Many studies have focused on a few genes related to the primary actions of the drugs. Genetic polymorphism in the serotonin transporter (5-hydroxytryptamine transporter, 5-HTT), has been linked to antidepressant response to selective serotonin reuptake inhibitors (SSRIs) [5,6,7], not in all studies [8]. Among the factors affecting functional response to antidepressant drugs are multiple secondary neurobiological mechanisms, environmental factors, ethnicity, and drug class. Candidate genes were selected for the primary targets and secondary mechanisms affected by antidepressant drugs. We used a candidate gene strategy rather than an exploratory genome wide association study (GWAS) which requires much larger sample sizes [10]
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