TORONTO, March 13, 2018 – Men and women with major depressive disorder have opposite changes in the same genes, according to a new study by researchers at the Centre for Addiction and Mental Health (CAMH) and the University of Pittsburgh. Published today in Biological Psychiatry, the findings reveal significant biological differences, and suggest that men and women may need different types of treatment for depression.
It’s the first time these opposing molecular changes in men and women have been identified. “These findings confirm the absolute necessity of doing parallel studies in men and women and of reassessing what we’ve taken for granted – depression is not just depression,” says Dr. Etienne Sibille, senior author of the study and Chair of the Campbell Family Mental Health Research Institute at CAMH.
“This important paper highlights the divergent molecular mechanisms contributing to depression in men and women. It challenges the assumption that a similar diagnosis across people has the same biology,” says Dr. John Krystal, Editor of Biological Psychiatry.
There are obvious differences in depression between men and women – women are twice as likely to be diagnosed with depression, and tend to report greater illness severity, more symptoms and different types of symptoms than men.
Yet, says lead author Dr. Marianne Seney, Assistant Professor of Psychiatry at the University of Pittsburgh, “While researchers have been examining the brains of depressed subjects for decades, many of these studies included only men.” As one example of how the illness is different, a less common form of depression that involves weight gain and sleep disturbances, called hypersomnia, is three times more likely in women than in men. Another example is among people with depression who experience a co-occurring mental illness. In women, depression typically occurs alongside anxiety disorders, while men are more likely to report co-occurring substance use problems.
In the new study, the researchers analyzed genes in the postmortem brain tissue of 26 men and 24 women with major depressive disorder, and in a comparison group of men and women without depression. Specifically, the team investigated gene expression levels, which indicate how much protein a gene is producing.
Most of the affected genes – more than 1,500 in total – showed changes either only in men, or only in women. However, the majority of genes that were altered in both men and women were changed in opposite directions. Women had increased expression of genes affecting synapse function, whereas men had decreased expression of the same genes. (Synapses are the connection sites where chemical signals pass from one nerve cell, or neuron, to another.) Women had reduced expression of genes affecting immune function, whereas men had increased expression of these genes. Additionally, the researchers then examined the same genes in another group of individuals, which confirmed the same findings.
The study focused on genes in three brain regions that regulate mood and are dysfunctional in depression: the anterior cingulate cortex, the dorsolateral prefrontal cortex and the amygdala. The opposite changes in gene expression were specific to the different brain regions. So if women had increased expression of a particular gene in one region and decreased in another, men showed just the opposite.
Because the study examined postmortem brain tissue, it’s unclear when these molecular changes occur. But the findings support that depression at the molecular level is different in men and women.
“These results have significant implications for the development of potential novel treatments and suggest that these treatments should be developed separately for men and women,” says Dr. Seney. For example, in the paper, the researchers suggest that new treatments might aim to suppress immune function in men, or boost its function in women.
The new findings build on earlier work by the collaborators showing sex-related differences in depression. Their research into hormones and brain development revealed that sex-specific genes present on the X and Y chromosomes make men more vulnerable to depression, but also that testosterone strongly protects against depression. While rates of depression tend to be significantly higher among women, “it’s not that women are more vulnerable to developing depression, but that men are more protected, because testosterone has an antidepressant effect,” says Dr. Sibille. “Our new findings provide a clearer picture of the full landscape of the differences in men and women with depression.”
The Centre for Addiction and Mental Health (CAMH) is Canada's largest mental health and addiction teaching hospital and a world leading research centre in this field. CAMH combines clinical care, research, education, policy development and health promotion to help transform the lives of people affected by mental illness and addiction. CAMH is fully affiliated with the University of Toronto, and is a Pan American Health Organization/World Health Organization Collaborating Centre. For more information, please visit camh.ca or follow @CAMHnews and @CAMHResearch on Twitter.
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