Men and women suffering from Major Depressive Disorder (MDD) experience opposite changes in gene expression of the same loci, according to a new study. The work, published in Biological Psychiatry, was carried out by researchers at the University of Pittsburg and the Centre for Addiction and Mental Health in Toronto, Canada, and involved examining the brains of deceased patients. The findings not only provide a clearer picture of disease pathology, but could also indicate that male and female MDD patients should be receiving different treatments.

MDD is known to affect men and women differently; females are twice as likely to be diagnosed and typically experience the condition more severely. The exact symptoms of the condition have also been seen to vary according to gender. Despite these differences, the majority of previous research into MDD has focused on male patients and, as a result, any pathological differences arising from gender have gone unrecorded.

To change this, the research team investigated gene expression data from eight separate datasets, four male and four female. Their study involved investigating post-mortem brain tissue from 26 male and 24 female MDD patients, with 50 unaffected samples as controls.

Their analysis found that the majority of the genes that were expressed abnormally in men were not the same genes that were being expressed abnormally in women. Out of 706 abnormally expressed genes in men and 882 abnormally expressed genes in women, only 73 genes were identified in both genders. Of those 73, only 21 of the gene expression changes were identified as being in ‘the same direction’ (i.e. both males and females overexpressed or underexpressed the gene). The remaining 52 overlapping genes were found to have changed in opposite directions (i.e. if male patients overexpressed the gene, females underexpressed it and vice versa).

When considering gene function, the team found that women typically were experiencing increased expression of genes that affect synapse function and decreased expression of those affecting immunological activities. In contrast, male patients were demonstrating lower expression of genes influencing synaptic activity and increased expression of immunological genes.

The study involved analysing three regions of the brain that are implicated in mood regulation and MDD: the anterior cingulate cortex, dorsolateral prefrontal cortex, and the amygdala. The team found that the opposing changes in gene expression were also linked to which brain region they occurred in. For example, a male patient experiencing overexpression of a gene in the amygdala but underexpression of that same gene in the anterior cingulate cortex could be matched to a female patient experiencing underexpression of the gene in the amygdala and overexpression in the anterior cingulate cortex.

“To conclude, our study reveals divergent corticolimbic molecular changes in men and women with MDD,” the authors wrote. “Thus, it follows that potential novel treatments should target sex-specific pathology. For instance, 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. Alternatively, future treatments may aim to target the limited shared pathology present in both men and women with MDD. The implications of MDD cell-specific changes between men and women remain to be further investigated.”