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Molecular mechanisms of major depression differ by sex
Men and women with major depression have opposite molecular signatures in three corticolimbic brain regions, with multiple transcriptional changes in opposite directions, according to data published in Biological Psychiatry.
“Depression is a devastating psychiatric disorder that affects both men and women, but with sex differences in both incidence and symptoms,” Marianne L. Seney, PhD, of the department of psychiatry and the translational neuroscience program, University of Pittsburgh Medical School, told Healio Psychiatry. “Therefore, it’s important to study the brain pathology of depression in both sexes.”
To determine whether molecular mechanisms of major depression differ by sex, researchers conducted a gene expression meta-analysis across corticolimbic brain regions — the dorsolateral prefrontal cortex, subgenual anterior cingulate cortex and basolateral amygdala — then used a threshold-free approach, Gene Ontology and cell type–specific analyses to further examine the results. They included 26 men and 24 women with major depression as well as 50 sex-matched controls. For independent validation, the investigators used a separate data set of additional participants with major depression and controls.
Only 21 genes had altered expression in the same direction in both sexes out of 706 genes differentially expressed in men and 882 differentially expressed in women with major depression. However, 52 genes that were altered in both men and women were changed in opposite directions. When the researchers used a threshold-free approach, the results were the same, demonstrating that the transcriptional profile of major depression was opposite in men and women.
“Our findings suggest that the pathology is not only distinct in men and women, but many molecular changes occur in opposite directions in depressed men and women,” Seney told Healio Psychiatry. “This study underscores the notion that some psychiatric disorders might manifest differently in men and women, and that future novel treatments might need to be developed separately for men and women.”
Women with major depression showed increased expression of genes altering synapse function while men with MDD showed decreased expression in synapse-related genes, according to the results from the Gene Ontology analysis. Using cell type–specific analysis demonstrated that women with depression exhibited decreases in markers of oligodendrocyte- and microglia-related genes, which affect immune function, while men with depression had increases in these genes.
“It follows that potential novel treatments should target sex-specific pathology,” Seney and colleagues wrote in the full study. “Our results suggest that treatments to suppress immune function may be more appropriate for men with MDD, while treatments that boost immune function may be more appropriate for women with MDD. The implications of MDD cell-specific changes between men and women remain to be further investigated.” – by Savannah Demko
Disclosures: Seney reports no relevant financial disclosures. Please see the full study for all other authors’ relevant financial disclosures.