Abstract
It has been suggested that outcomes of antidepressant treatment for major depressive disorder could be significantly improved if treatment choice is informed by genetic data. This study aims to test the hypothesis that common genetic variants can predict response to antidepressants in a clinically meaningful way. The NEWMEDS consortium, an academia-industry partnership, assembled a database of over 2,000 European-ancestry individuals with major depressive disorder, prospectively measured treatment outcomes with serotonin reuptake inhibiting or noradrenaline reuptake inhibiting antidepressants and available genetic samples from five studies (three randomized controlled trials, one part-randomized controlled trial, and one treatment cohort study). After quality control, a dataset of 1,790 individuals with high-quality genome-wide genotyping provided adequate power to test the hypotheses that antidepressant response or a clinically significant differential response to the two classes of antidepressants could be predicted from a single common genetic polymorphism. None of the more than half million genetic markers significantly predicted response to antidepressants overall, serotonin reuptake inhibitors, or noradrenaline reuptake inhibitors, or differential response to the two types of antidepressants (genome-wide significance p<5×10(-8)). No biological pathways were significantly overrepresented in the results. No significant associations (genome-wide significance p<5×10(-8)) were detected in a meta-analysis of NEWMEDS and another large sample (STAR*D), with 2,897 individuals in total. Polygenic scoring found no convergence among multiple associations in NEWMEDS and STAR*D. No single common genetic variant was associated with antidepressant response at a clinically relevant level in a European-ancestry cohort. Effects specific to particular antidepressant drugs could not be investigated in the current study. Please see later in the article for the Editors' Summary.
Highlights
Major depressive disorder (MDD) is a disabling illness, affecting a high proportion of individuals at some point in their life [1]
No single common genetic variant was associated with antidepressant response at a clinically relevant level in a European-ancestry cohort
The quantile–quantile plot showed a uniform distribution of p-values, with no inflation of the test statistic
Summary
Major depressive disorder (MDD) is a disabling illness, affecting a high proportion of individuals at some point in their life [1]. If a predictor of differential outcome with alternative treatments is identified, a clinician could use it to select the antidepressant that is most likely to alleviate depression in a given individual. For both applications, the clinical implications are predicated on the effect size of the prediction. A consensus criterion has been set for what size of difference in depressive symptoms is clinically meaningful: a panel of experts and service users has concluded that a difference in outcome equal or greater than three points on the Hamilton Rating Scale for Depression is noticeable to the patients and their relatives and can be considered as clinically significant [8,9]. Others think that because the action of most drugs is influenced by many different genes, a variant in one of those genes is unlikely to have measurable effect in most cases
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