Genetic variants in major depressive disorder: From pathophysiology to therapy

Abstract

In spite of promising preclinical results there is a decreasing number of new registered medications in major depression. The main reason behind this fact is the lack of confirmation in clinical studies for the assumed, and in animals confirmed, therapeutic results. This suggests low predictive value of animal studies for central nervous system disorders. One solution for identifying new possible targets is the application of genetics and genomics, which may pinpoint new targets based on the effect of genetic variants in humans. The present review summarizes such research focusing on depression and its therapy. The inconsistency between most genetic studies in depression suggests, first of all, a significant role of environmental stress. Furthermore, effect of individual genes and polymorphisms is weak, therefore gene x gene interactions or complete biochemical pathways should be analyzed. Even genes encoding target proteins of currently used antidepressants remain nonsignificant in genome-wide case control investigations suggesting no main effect in depression, but rather an interaction with stress. The few significant genes in GWASs are related to neurogenesis, neuronal synapse, cell contact and DNA transcription and as being nonspecific for depression are difficult to harvest pharmacologically. Most candidate genes in replicable GxE interactions, on the other hand, are connected to the regulation of stress and the HPA axis and thus could serve as drug targets for a depression subgroups characterized by stress-sensitivity and anxiety while other risk polymorphisms such as those related to prominent cognitive symptoms in depression may help to identify additional subgroups and their distinct treatment. Until these new targets find their way in the therapy, the optimization of current medications can be approached by pharmacogenomics, where metabolizing enzyme polymorphisms remain prominent determinants of therapeutic success.

Biotypes of major depressive disorder: Neuroimaging evidence from resting-state default mode network patterns

“…Findings of subtypes with distinct profiles of brain abnormalities may reveal the potential neurobiological substrates of key sources of heterogeneity in depression ( Price et al, 2017a , Williams, 2016 ). Additionally, inflammation and oxidative stress could also be implicated in differentiating the distinct subtypes of depression ( Gonda et al, 2019 ). Moreover, subgroups of individuals with MDD characterized by differing brain abnormalities may reflect qualitatively distinct genetic factors influence in the illness trajectory.…”

Nature and Nurture: Effects of Affective Temperaments on Depressive Symptoms Are Markedly Modified by Stress Exposure

“…Our results add to the long debate and ever-expanding research focusing on the relative role of nature or nurture, that is, biological or environmental contributors in the development and severity of depression ( 26 ). Although genetic approaches including both candidate gene and GWAS studies generally fail to provide replicable and conclusive results ( 14 , 27 ), temperaments, which develop on a strong genetic and biological basis ( 28 ), influence neuroendocrine and autonomic processes ( 29 ) and determine emotional and behavioral reactivity with an early manifestation and strong temporal stability, have been repeatedly shown to be associated with depression ( 30 – 32 ). While most temperamental models were developed on theoretical bases to describe the biological core of the healthy personality, specifically the model of affective temperaments was derived, besides drawing form theoretical underpinnings from Hippocrates, Kraepelin, and Kretschmer, from the observation of affective disorder patients and their healthy first-degree relatives ( 10 , 24 ), The pathoplastic role of affective temperaments in affective disorders were subsequently confirmed by a large number of independent studies ( 11 ).…”

“…There appears to be a continuum in case of different manifestations of depression depending on the relative contribution of environmental and genetic determinants from more “reactive” to more “endogenous” forms, however, although with differing weight, both biological/genetic and environmental contributors are necessary for the emergence of depression which develops in the interaction of these two major factors ( 12 – 14 ). That is, environmental events trigger depression in those who carry a biological/genetic predisposition such as in the form of innate affective temperaments, or this biological/genetic predisposition increases sensitivity towards environmental events and leads to the manifestation of depression only in case of exposure to stress.…”

“…Temperaments describe emotional reactivity and also determine reaction to environmental influences, which plays a significant etiological role in depression. As gene x environment studies have shown, the effects of genetic determinants of depression in several cases are not manifested without exposure to environmental events, as the majority of depressogenic genes do not directly contribute to depression, but increase vulnerability to stress, and similarly, the effects of environmental stressors of depression may not lead to the emergence of depression without the presence of vulnerability genes ( 12 – 14 ). Therefore it seems possible that the effects of affective temperaments, considered to be strongly and closely determined by genetic and biological factors, on depression could be understood in its complexity only by investigating the interaction effects between affective temperament and stress on depression.…”

Targeted exome sequencing identifies five novel loci at genome-wide significance for modulating antidepressant response in patients with major depressive disorder

“…Pharmacogenetic studies have indicated that genomic variations are one of the critical biological factors that prominently affect the individual differences of antidepressant response, in which common single nucleotide polymorphisms (SNPs) are estimated to explain 50% or more of the variation of the antidepressant response 9 . Nevertheless, previous findings from candidate gene approaches have been poorly replicated, with insufficient predictive power to be useful in clinical practice and analytical problems of uncontrolling population stratification or genetic heterogeneity 10,11 . In addition, so far a total of eight genome-wide association studies (GWAS) of antidepressant effectiveness have been carried out mainly in Caucasian ancestry populations (eight clinical studies, ten published articles); none of these studies have found a genetic variant that achieved genome-wide significance [12][13][14][15][16][17][18][19][20][21] .…”