Opposite Molecular Signatures of Depression in Men and Women
Open accessAbstract
Background Major depressive disorder (MDD) affects women approximately twice as often as men. Women are three times as likely to have atypical depression, with hypersomnia and weight gain. This suggests that the molecular mechanisms of MDD may differ by sex. Methods To test this hypothesis, we performed a large-scale gene expression meta-analysis across three corticolimbic brain regions: the dorsolateral prefrontal cortex, subgenual anterior cingulate cortex, and basolateral amygdala (26 men, 24 women with MDD and sex-matched control subjects). Results were further analyzed using a threshold-free approach, Gene Ontology, and cell type-specific analyses. A separate dataset was used for independent validation (13 MDD subjects/sex and 22 control subjects [13 men, 9 women]). Results Of the 706 genes differentially expressed in men with MDD and 882 genes differentially expressed in women with MDD, only 21 were changed in the same direction in both sexes. Notably, 52 genes displayed expression changes in opposite directions between men and women with MDD. Similar results were obtained using a threshold-free approach, in which the overall transcriptional profile of MDD was opposite in men and women. Gene Ontology indicated that men with MDD had decreases in synapse-related genes, whereas women with MDD exhibited transcriptional increases in this pathway. Cell type-specific analysis indicated that men with MDD exhibited increases in oligodendrocyte- and microglia-related genes, while women with MDD had decreases in markers of these cell types. Conclusions The brain transcriptional profile of MDD differs greatly by sex, with multiple transcriptional changes in opposite directions between men and women with MDD.
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Cortical GABAergic disinhibition in depressive disorders co-occurs with increases in glutamatergic gene expression in the default mode network (DMN).
“Specifically, cortical GABAergic disinhibition in depressive disorders co-occurs with increases in glutamatergic gene expression in the DMN [24,26,27,28,29,30,31,32].”
From Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression (2023) · cites this paper as [30]
From the transcriptomic perspective, there were sex-specific transcriptional profiles in cortical regions and limbic systems among patients with major depressive symptoms.
“From the transcriptomic perspective, there were sex-specific transcriptional profiles in cortical regions and limbic systems among patients with major depressive symptoms [ 93 ].”
From Anxiety and Depression Symptoms among Youth Survivors of Childhood Sexual Abuse: A Network Analysis (2023) · cites this paper as [93]
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Self-citation
- Authors
- Seney, M. L., Huo, Z., Cahill, K., French, L., Puralewski, R., Zhang, J., Logan, R. W., Tseng, G., Lewis, D. A., & Sibille, E.
- Affiliations
- University of Pittsburgh (US)
- Centre for Addiction and Mental Health (CA)
- Corresponding author
- Seney, Marianne L.
- Sibille, Etienne
- ORCID
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2018-07
- Volume
- 84
- Issue
- 1
- Pages
- 18-27
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC6014892
- OpenAlex
- W2793970618
- Cited by
- 272
- References
- 55
- Citations by year
- 2026: 24 · 2025: 33 · 2024: 28 · 2023: 37 · 2022: 34 · 2021: 46 · 2020: 32 · 2019: 28 · 2018: 10
- FWCI
- 3.38
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (ES, MH084060, MH085111, MH103473)
- Brain and Behavior Research Foundation
- Pfizer
- National Alliance for Research on Schizophrenia and Depression
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- major depressive disorder, sex differences, gene expression, transcriptome, atypical depression, dorsolateral prefrontal cortex, subgenual anterior cingulate cortex, basolateral amygdala, synapse-related genes, oligodendrocytes, microglia, cell type-specific gene expression
- MeSH terms
- Brain, Major Depressive Disorder, Depressive Disorder, Major, Female, Humans, Male, Neuroglia, Neurons, Sex Characteristics, Gene Expression, Case-Control Studies, Statistics, Nonparametric, Microarray Analysis, Transcriptome, Gene Ontology
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