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MRI-guided dmPFC-rTMS as a Treatment for Treatment-resistant Major Depressive Disorder
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Systems Approach to Identify Common Genes and Pathways Associated with Response to Selective Serotonin Reuptake

Ankit Srivastava1,2, Priyanka Singh3,4, Hitesh Gupta5

  • 1Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Delhi 110007, India. ankit.srivastava@igib.in.

International Journal of Molecular Sciences
|April 26, 2019
PubMed

Insights

Identifying genes and pathways linked to major depressive disorder (MDD) and antidepressant response is crucial. This study highlights key molecular pathways, offering potential targets for novel, etiology-based antidepressant therapies.

Area of Science:

  • Genetics and Molecular Biology
  • Neuroscience
  • Pharmacology

Background:

  • Major depressive disorder (MDD) susceptibility and treatment response lack clear molecular understanding, hindering etiology-based drug development.
  • Current antidepressant therapies exhibit a high failure rate (~30%), necessitating novel therapeutic strategies.
  • Existing research on MDD and antidepressant response has not fully elucidated the underlying genetic and molecular mechanisms.

Purpose of the Study:

  • To identify probable genes and molecular pathways associated with both MDD susceptibility and antidepressant response.
  • To explore potential targets for developing more effective, etiology-based antidepressant medications.
  • To integrate findings from candidate gene studies and genome-wide association studies (GWAS) for a comprehensive analysis.

Main Methods:

  • Conducted a systematic review to identify genes and pathways linked to antidepressant response and MDD.
  • Utilized an integrative genetics approach, analyzing single nucleotide polymorphisms (SNPs) and genes from candidate studies and GWAS.
  • Performed gene set enrichment analysis on identified gene sets (Set A: 245 genes for antidepressant response; Set B: 800 genes for MDD).

Main Results:

  • Identified 245 significantly associated genes for antidepressant response (Set A) and 800 for MDD (Set B).
  • Gene set enrichment analysis revealed five key co-occurring molecular pathways: Cushing syndrome, Axon guidance, cAMP signaling pathway, Insulin secretion, and Glutamatergic synapse.
  • These pathways demonstrate a strong association with synaptic plasticity, suggesting its role in MDD and treatment response.

Conclusions:

  • Integrative analysis of GWAS and candidate gene data provides insights into molecular mechanisms of MDD and antidepressant response.
  • Identified pathways, particularly those related to synaptic plasticity, represent promising targets for novel antidepressant drug development.
  • This research paves the way for developing disease etiology-based antidepressants, potentially overcoming limitations of current symptomatic treatments.
Keywords:
GWASMDDSSRIantidepressantaxon guidancecAMP signaling pathwaycushing syndromeglutamatergic synapse

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