Females often left out of neuroscience research around stress and depression

Although the global population is approximately 50% female, much of the research about how stress and depression affect the human brain does not ring true for women. A review article by Vancouver Coastal Health Research Institute scientist Dr. Liisa Galea highlights a significant gap in neuroscience research and knowledge: there are sex differences in how stress affects the brain and behaviour throughout a person’s lifespan. The male-focused models predominantly used for this research ignore these differences.

“We need to consider sex as a very important, separate variable to study because you can get the completely opposite effects or brain responses to stress and depression between males and females,” says Dr. Galea, researcher at the Djavad Mowafaghian Centre for Brain Health and professor at the UBC Department of Psychology at the University of British Columbia (UBC).

"We are different, so it’s not surprising that treatments for depression and stress might affect us differently. Not recognizing this is a potential reason for why we don’t have a lot of good translation from pre-clinical research to clinical practice.”

The article, published in Frontiers in Neuroscience, was co-authored by Dr. Galea and two of her PhD students, Aarthi Gobinath and Rand Mahmoud, both from the Graduate Program in Neuroscience, Faculty of Medicine, at UBC. Approximately 250 articles were reviewed to assess both preclinical and clinical research that investigates how sex influences depression endophenotypes at the behavioral, neuroendocrine, and neural levels across the lifespan.

The current state of neuroscience research trying to show how stress, sex, and depression are connected is extremely complicated and difficult to understand, according to Gobinath.

“Our goal was to shed light on how from the beginning of development, whether being male or female can play a pivotal role in how stress exposure influences risk for depression later in life, and hopefully add some clarity to this research,” she says.

“By not prioritizing how the female physiology, especially during pregnancy and postpartum, influence depression, we are missing crucial pieces in the puzzle as to how stress and depression are connected.”

“Because male and female brains respond differently to stress, this leads to different vulnerabilities to mental illnesses, including depression,” adds Mahmoud. 

“We believe that biological sex is fundamental to individualized medicine and central in the management of mental illnesses,” says Mahmoud. “Only when the scientific community fully recognizes this can we find therapies that are safe and effective for both men and women.”

New mandates in health research requiring sex differentiation is promising, but also raises concerns

Dr. Galea is hopeful that new mandates set out by the Canadians Institutes of Health Research (CIHR) and National Institutes of Health (NIH) to have sex be considered as a variable in research will make findings and knowledge more accurate for both sexes.

“I think it’s great that CIHR and NIH are making it part of the mandate that we should all be looking at this,” she says. “My worry though is that people still aren’t necessarily convinced that it’s an important variable to look at or that male and female variables will simply be added together rather than separated out as variables.”

“For example, if you look at the effects of stress on the adolescent brain, plasticity is reduced in the female’s hippocampus but it increases in the male,” explains Dr. Galea. “These are completely opposite responses, however, if you put them together without differentiating the sexes, you’ll get a net-zero effect suggesting that the stress didn’t affect the brain when it actually did.”

“This is the sort of thing we need to pay attention to,” she adds. “In our article we wanted to show that it does matter – there are differences.”