Systems Approach to Identify Common Genes and Pathways Associated with Response to Selective Serotonin Reuptake Inhibitors and Major Depression Risk.

Ankit Srivastava,Divya Vohora,Debleena Guin,Jyoti Yadav,Rakesh Kumar Chadda,Mamta Sood,Harpreet Kaur,Luciano Saso,Priyanka Singh,Hitesh Gupta,Neha Kanojia,Ritushree Kukreti

doi:10.3390/ijms20081993

Abstract

Despite numerous studies on major depressive disorder (MDD) susceptibility, the precise underlying molecular mechanism has not been elucidated which restricts the development of etiology-based disease-modifying drug. Major depressive disorder treatment is still symptomatic and is the leading cause of (~30%) failure of the current antidepressant therapy. Here we comprehended the probable genes and pathways commonly associated with antidepressant response and MDD. A systematic review was conducted, and candidate genes/pathways associated with antidepressant response and MDD were identified using an integrative genetics approach. Initially, single nucleotide polymorphisms (SNPs)/genes found to be significantly associated with antidepressant response were systematically reviewed and retrieved from the candidate studies and genome-wide association studies (GWAS). Also, significant variations concerning MDD susceptibility were extracted from GWAS only. We found 245 (Set A) and 800 (Set B) significantly associated genes with antidepressant response and MDD, respectively. Further, gene set enrichment analysis revealed the top five co-occurring molecular pathways (p ≤ 0.05) among the two sets of genes: Cushing syndrome, Axon guidance, cAMP signaling pathway, Insulin secretion, and Glutamatergic synapse, wherein all show a very close relation to synaptic plasticity. Integrative analyses of candidate gene and genome-wide association studies would enable us to investigate the putative targets for the development of disease etiology-based antidepressant that might be more promising than current ones.

Highlights

Major depressive disorder (MDD) is the third largest cause of burden of disease and it is responsible for almost 80% of psychiatric hospitalizations
Integrative analyses of candidate gene and genome-wide association studies would enable us to investigate the putative targets for the development of disease etiology-based antidepressant that might be more promising than current ones
A systematic review of candidate gene studies for selective serotonin reuptake inhibitors (SSRIs) response and systematic literature search of genome-wide association studies (GWAS) for SSRI response and major depressive disorder (MDD) both revealed 245 and 800 genes to be significantly associated with SSRI response and MDD pathophysiology, respectively

Summary

Introduction

Major depressive disorder (MDD) is the third largest cause of burden of disease and it is responsible for almost 80% of psychiatric hospitalizations. Over 800,000 lives are lost yearly due to suicide, which translates to 3000 suicide deaths every day [2] It is almost more than half a century since the first antidepressant drug was discovered, starting from non-specific monoamine oxidase inhibitors (MAO-I) and tricyclic antidepressants (TCA) to target specific selective serotonin reuptake inhibitors (SSRIs). SSRIs have proven to be the most effective drugs to date, yet approximately 30–40% of depressive patients do not or partially respond to the therapy whereas 60–75% fail to achieve complete remission [3]. This may be attributed to the poor understanding of MDD pathophysiology and lack of etiology-based drugs. Candidate gene-based studies and GWAS have shown that the clinical heterogeneity in therapeutic outcome is influenced by a variety of genetic (single nucleotide polymorphisms, SNP; copy number variations, CNV; insertions, I; deletions, D etc.), pathophysiological and environmental factors [4,5]

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