Pharmacogenetics and Imaging–Pharmacogenetics of Antidepressant Response: Towards Translational Strategies

Abstract

Genetic variation underlies both the response to antidepressant treatment and the occurrence of side effects. Over the past two decades, a number of pharmacogenetic variants, among these the SCL6A4, BDNF, FKBP5, GNB3, GRIK4, and ABCB1 genes, have come to the forefront in this regard. However, small effects sizes, mixed results in independent samples, and conflicting meta-analyses results led to inherent difficulties in the field of pharmacogenetics translating these findings into clinical practice. Nearly all antidepressant pharmacogenetic variants have potentially pleiotropic effects in which they are associated with major depressive disorder, intermediate phenotypes involved in emotional processes, and brain areas affected by antidepressant treatment. The purpose of this article is to provide a comprehensive review of the advances made in the field of pharmacogenetics of antidepressant efficacy and side effects, imaging findings of antidepressant response, and the latest results in the expanding field of imaging-pharmacogenetics studies. We suggest there is mounting evidence that genetic factors exert their impact on treatment response by influencing brain structural and functional changes during antidepressant treatment, and combining neuroimaging and genetic methods may be a more powerful way to detect biological mechanisms of response than either method alone. The most promising imaging-pharmacogenetics findings exist for the SCL6A4 gene, with converging associations with antidepressant response, frontolimbic predictors of affective symptoms, and normalization of frontolimbic activity following antidepressant treatment. More research is required before imaging-pharmacogenetics informed personalized medicine can be applied to antidepressant treatment; nevertheless, inroads have been made towards assessing genetic and neuroanatomical liability and potential clinical application.

The serotonin transporter and the activity regulated cytoskeleton‐associated protein genes in antidepressant response and resistance: 5‐HTTLPR and other variants

“…A large amount of data supports the role of genetics in both the development of MDD and in AD response (Chirita, Gheorman, Bondari, & Rogoveanu, 2015;Lett, Walter, & Brandl, 2016). Several neurobiological theories were postulated, one of the most supported hypothesized deficits of the monoaminergic system (serotonin (5-HT), dopamine, and norepinephrine; Quesseveur, Gardier, & Guiard, 2013;Won & Ham, 2016).…”

Exploratory genome-wide association analysis of response to ketamine and a polygenic analysis of response to scopolamine in depression

“…In this context, elucidating the genetic variants that predict treatment response can potentially provide important biological information about the heterogeneity of depression (treatment-resistant and non-treatment-resistant), which may ultimately be relevant for clinical translation 28 . However, translation of these findings into clinical practice is limited by the small sample sizes and inconsistent findings 29 . More recently, two reports demonstrated the potential of pharmacogenetics in mood disorders.…”

From Pharmacogenetics to Imaging Pharmacogenetics: Elucidating Mechanisms of Antidepressant Response

“…A number of other candidate genes for antidepressant response have yielded interesting, however mixed, findings, among these genes encoding guanine nucleotide binding protein beta polypeptide 3, tryptophan hydroxylase, ionotropic glutamate kainate 4 receptor KA1 and several inflammatory genes [7].…”

“…Pharmacogenetics & imaging pharmacogenetics: elucidating mechanisms of antidepressant response Editorial nonremission to antidepressant treatment in carriers of the G-allele of the rs1049353 polymorphism in the cannabinoid receptor 1 gene [17], as well as an influence of variants in BDNF, IL1B and in NPY [7]. More recently, changes in levels of microRNAs, which are involved in regulation of gene expression, have been associated with changes in brain connectivity and activity in response to antidepressant treatment [18].…”