Brain Autopsy Shows Sex-Specific Differences in Depression

Pauline Anderson

March 26, 2018

Men and women with major depressive disorder (MDD) have opposite genetic mechanisms that contribute to the condition, a new brain autopsy study shows.

Dr Etienne Sibille

For instance, investigators found that expression of genes related to synapse function was decreased in men but increased in women, and expression of immune genes was increased in men and decreased in women.

"The beauty of these findings is that they should generate hypotheses for people to test," author Etienne Sibille, PhD, senior scientist and chair, Campbell Institute, Center for Addiction and Mental Health, and professor, Departments of Psychiatry and Pharmacology, University of Toronto, Canada, told Medscape Medical News.

The results reinforce the message that men and women with depression should be treated differently, with the eventual aim, perhaps, of suppressing the immune function in men but not in women, said Sibille.

The study was published online February 3 in Biological Psychiatry.

Women More Vulnerable

Research suggests that women are twice as likely as men to be diagnosed with a single MDD episode and are four times more likely to be diagnosed with recurrent MDD.

MDD is more severe in women than in men, and MDD symptomatology differs between the sexes. For instance, women are three times more likely to have atypical depression, characterized by hypersomnia and weight gain.

Women and men with MDD also tend to have different comorbidities. Women are more likely to have an anxiety disorder, whereas men are more likely to have a substance use disorder.

Researchers accessed brain samples obtained at autopsy. The study included samples from 50 patients who had been diagnosed with MDD (26 men and 24 women) and samples from 50 sex-matched unaffected individuals, which served as controls.

Investigators used molecular methods to examine the expression of genes in three brain regions implicated in MDD: the dorsolateral prefrontal cortex, the subgenual anterior cingulate cortex, and the basolateral amygdala.

The investigators combined eight microarray datasets from these brain regions and conducted a large-scale gene-expression analysis to probe for sex differences.

The analysis showed that in control individuals, expression of the examined genes was the same in men and women.

When comparing differential expression (DE) genes in the autopsy samples of men and women who had had MDD, 633 of 706 transcripts were found in those from men only, and 809 of 882 transcripts were found in those from women only.

Only 73 DE genes were found in both men and women who had had MDD; in 52 of these 73 genes, expression changed in opposite directions with respect to the sexes.

This means that only 21 DE genes were affected in the same way in men and women with MDD.

"We report almost no overlap in transcriptional changes across corticolimbic brain regions in men and women with MDD, but instead opposite transcriptional changes," the authors note.

Increased Inflammation Men

Of note is that immune-related reductions characterized MDD in women, and that in men, there was an increase in markers of inflammation.

The authors found it "quite interesting" that in both men and women, the neuronal- and microglial-related changes occurred in opposite directions.

Because the new study was performed using the human postmortem brain samples, it is unclear whether the synaptic differences observed in MDD — decreased in men, increased in women — are driven by microglia changes or vice versa, say the authors.

"Additionally, it is unclear whether the opposite molecular signatures of MDD in men and women may drive sex differences in MDD symptomatology," they write.

With respect to the sex-specific markers of immune function, Sibille suggested that researchers might reexamine data from studies of drugs that affect the immune system — for example, drugs taken by patients with rheumatoid arthritis — to look for effects on depression.

Sex-specific molecular changes in MDD are only now being reported. The authors noted that previous postmortem brain analyses in MDD were performed mostly in men and that those studies that did include both sexes often lacked sufficient statistical power to stratify by sex.

Postmortem brain samples come mostly from male persons, perhaps owing to cultural taboos, said Sibille, "so it's more difficult to create a cohort to study women's brains."

Also, methods to examine sex-specific gene expression on a large scale have only recently been developed, he said.

Sex differences in MDD may be driven by developmental processes, the authors note. Developmental exposure to testosterone around the time of birth and through puberty permanently masculinizes the structure of several brain regions, they write.

Adolescence is also a sensitive developmental period in which extensive neuroanatomic, functional, and chemical brain maturation occur, they add. Events during adolescence that affect these developmental processes can increase risk for adult psychopathology.

Role of Sex Hormones

Because the current study included only adults, the researchers were unable to determine whether the observed sex differences emerge during development or in adulthood.

In the study, the medications that had been taken by male and female individuals were largely similar. In animal models, there are no notable sex differences in molecular responses to psychiatric drugs, but in this postmortem study, "we don't have enough samples with different drugs to really make a full analysis," said Sibille.

It is unclear why the molecular signatures for men and women with MDD differ.

In addition to the roles that different sex hormones play — testosterone in men and estrogen in women — sex chromosomes may also be important, said Sibille.

Having an X and Y chromosome makes men more vulnerable to depression, but this vulnerability is compensated for by the action of testosterone, he said.

"It's not that women are more vulnerable to depression, it's actually that men are more protected," he said.

The study findings were validated using recently published data generated by specimens from a different brain bank.

The new findings, which are similar to those in a recent study published in Nature Medicine, highlight the importance of "personalized" medicine, said Sibille.

"If you don't know there's a difference, you would tend to treat everybody the same way. Once you know there's a difference, then you can start to treat accordingly," he said.

Psychiatrists and general practitioners likely already know this, but the new study "reinforces" the message and "gives a biological reason" for it, he said.

"Fascinating" Research

Commenting on the findings for Medscape Medical News, James Potash, MD, Henry Phipps Professor of Psychiatry and Behavioral Sciences, Department Director, psychiatrist-in-chief, Johns Hopkins Medicine, in Baltimore, Maryland, and a member of the American Psychiatric Association's Council on Research, said he found the study "fascinating."

The new article, said Potash, largely confirms results of the Nature Medicine study that also found distinctly different sex-specific signatures of depression.

"This is important because whenever there's a dramatic finding — and that Nature Medicine finding was pretty dramatic — it's important to know whether other people will see the same thing or not."

The new study highlights a finding that has received a lot of attention lately — that some genes associated with depression play a role in immune function, said Potash.

"The idea is that there is a sex-specific divergence in those genes, where there's decreased expression of immune genes in women and increased expression of immune genes in men," he said.

Potash agreed that this raises the possibility that treatments might aim to boost the immune function for women and suppress it in men.

The number of persons represented in the current study is "smallish" compared to some genetic studies, which have included tens of thousands of individuals, said Potash. But he recognized the difficulty of conducting studies of the human brain that can only be carried out after death.

"There just aren't that many people whose brains you can access," he said.

Also, when examining the brains of people who have died, invariably, it is difficult to control for such factors as the use of medications and the use of alcohol or street drugs. "Those things can change gene expression, and it's hard to account for that," said Potash.

The new study is "incredibly important," given that depression "by many measures is the most important psychiatric illness" and is probably the most common condition that psychiatrists treat, said Potash.

In addition to depression being much more common in women, there are many female-specific aspects of depression, noted Potash. These include the worsening of depression premenstrually and the occurrence of postpartum and perimenopausal depression.

The study was supported by the National Institute of Mental Health and the Brain and Behavior Research Foundation. The funding agencies had no role in the study design, data collection, and analysis. The content does not necessarily represent the official views of the National Institute of Mental Health. Dr Sibille and Dr Potash have disclosed no relevant financial relationships.

Biol Psychiatry. Published online February 3, 2018. Abstract

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