Depression comes in a range of symptoms, including feelings of hopelessness, persistent sadness, loss of interest and appetite, as well as insomnia. While the overarching hallmark symptoms of depression are generic, research suggests that biological sex is a contributing factor to the specific manifestations and risk of individual symptoms.

Do women and men experience severe depression differently?

Statistics show that women are more likely to experience severe symptoms of depression, with experts theorising that the differential risk primarily stems from inbuilt biological sex differences.

Women are two to three times more likely to develop major depressive disorder (MDD) and more commonly exhibit more complex and severe symptoms, as well as responding less effectively to antidepressant treatment. These variations in risk and symptoms are evident from the onset of puberty until the later hormonal changes of menopause and ‘late-onset hypogonadism’, also known colloquially as ‘male menopause’.

What is the hypothetical underlying sex-based neurovascular cause of depressive symptoms?

Attempting to uncover the mystery behind depression and how it relates to sex-based biology, scientists at the Canadian Université Laval, through post-mortem examinations of people with severe depression, have discovered neurovascular alterations located in different parts of the brain relevant to each sex.

A previous study conducted by the research team at Université Laval demonstrated that prolonged stress in male mice weakens the blood-brain barrier separating the brain from peripheral blood circulation. Researchers in that study theorised that these changes were due to the loss of a protein called claudin-5 in the nucleus accumbens, a part of the brain associated with reward and the control of emotions. While in female mice, the blood-brain barrier alterations caused by the claudin-5 loss were found to be exclusively located in the prefrontal cortex, an area of the brain involved in mood regulation, anxiety, and self-perception.

These gendered differences and changes were also replicated and evidenced in the study examining the post-mortem brains of the men and women who suffered from depression.

Lead author Caroline Ménard, professor at the Faculty of Medicine at Université Laval, explained the findings of the two studies:

“Depression is very different between men and women… [Our] findings suggest that chronic stress alters the brain barrier differently according to gender. In women, the disease is twice as common, the symptoms are different, and the response to antidepressants is not the same as in men. Our goal was to find out why.”

Promisingly for the development of a future diagnostic depression biomarker test, the Université Laval research team also identified a blood marker linked to the brain barrier health. The marker, soluble E-selectin, is an inflammatory molecule found at higher concentrations in the blood of stressed female mice, while also similarly being found present in blood samples of women with depression, but not in men.

Prof Ménard added: “Today, depression is still diagnosed through questionnaires… Our group is the first to show the importance of neurovascular health in depression and to suggest soluble E-selectin as a depression biomarker. It could potentially be used to screen for and diagnose depression. It could also be used to measure the efficacy of existing treatments or treatments in development. But first, large-cohort clinical studies will need to be conducted to confirm the biomarker’s reliability.”