Depression Affects Women's and Men's Genes in Opposite Ways

Marianne L. Seney, PhD

Women and men with major depressive disorder (MDD) display opposite alterations in the expression of the same genes, a new study has found.

The discovery indicates that males and females with MDD might require different depression treatments based on their sex, researchers from the University of Pittsburgh and the Centre for Addiction and Mental Health (CAMH), in Toronto, Canada, said.

“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,’’ lead author Marianne L. Seney, PhD, University of Pittsburgh Medical School, told MD Magazine.

“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,” Seney said.

Women are about twice as likely as men to be affected by MDD and they’re 3 times as likely to have atypical depression accompanied by excessive sleepiness and weight gain, the researchers wrote.

Seney and her colleagues set out to investigate whether the molecular mechanisms of the disorder may differ by sex. Their study, published in Biological Psychiatry, is the first to report the unique opposing pathology, the researchers said.

The team studied the brain tissue of 26 deceased men and 24 deceased women with MDD. They reviewed post-mortem brain tissue from the same number of unaffected individuals for comparison.

The researchers performed a meta-analysis of gene expression, which indicates how much protein a gene is producing, across 3 corticolimbic regions of the brain: the dorsolateral prefrontal cortex, the anterior cingulate cortex, and the amygdala.

The large-scale analysis included 8 published datasets. “In each individual study, gene expression was examined in one brain region in one sex,” Seney said.

The team particularly focused on gene expression changes that were consistent across several mood-related brain regions. The researchers used meta-regression to determine specifically whether the gene expression results were different in males and females.

“This ends up being similar to asking if there is an interaction of sex and MDD,” Seney said.

As compared to unaffected subjects, the researchers identified 706 genes that were expressed differently in men with MDD and 882 genes that were expressed differently in women with the disorder.

Of the few gene expression changes that were shared between the sexes, 21 genes were altered in the same direction while 52 were modified in opposite directions. The opposite changes were specific to the different brain regions, the team found.

“The brain transcriptional profile of MDD differs greatly by sex, with multiple transcriptional changes in opposite directions between men and women with MDD,” the researchers wrote.

For instance, women had increased expression of genes affecting synapse function, while men had decreased expression of the same genes. Women showed decreases in genes affecting immune function, while men had increased expression.

So far, it hasn’t been possible to identify overt behaviors or psychological differences between women and men with MDD that relate to the gene expression changes the authors identified, Seney said.

“All of our studies were performed on human postmortem brains,” she said. “Thus, it is unclear whether any gene expression changes correlate with specific depression symptoms dimensions in our subjects.”

While the study doesn’t pinpoint why MDD affects women more frequently — and more severely – than men, the findings do provide leads for further biological investigations on this question, she said.

As for next steps, Seney noted that the current research is more relevant to sex differences in depressed subjects rather than to sex differences that may indicate vulnerability to MDD.

“Further studies will investigate healthy subjects in more detail to determine underlying sex differences that might place females at higher risk for developing depression,” she said.