Higher Depression, Suicide Rate in Women Explained?

Nancy A. Melville

August 10, 2015

Women with major depressive disorder (MDD) and those who died as the result of suicide show significantly higher levels of glutamate receptor gene expression in the prefrontal cortex of the brain, suggesting a potentially greater response in those patients to glutamate-targeting therapies that have gained interest as potentially fast-acting antidepressants, new research shows.

"Our data could indicate that the dorsolateral prefrontal cortex differs between women and men with major depression," lead author Monsheel Sodhi, PhD, an assistant professor of pharmacy practice at the University of Illinois at Chicago, told Medscape Medical News.

"It could be speculated that drugs that modify glutamate activity will be more effective in depressed women."

The study was published online July 17 in Molecular Psychiatry.

Abnormal Function in Women

Although abnormalities in the glutamate system have been linked to conditions that include Alzheimer's disease, epilepsy, and autism, their role in depression has gained particular interest among researchers, who seek more effective, faster-acting alternatives to conventional antidepressants, which target the monoamine system and provide substantial improvement within several weeks to only about a third of patients, according to the study.

"The delay in treatment response...suggests that the primary pathophysiological mechanisms leading to MDD and suicide may lie outside the monoamine systems," the authors write.

In support of that argument is mounting evidence that low doses of ketamine (Ketalar, Par Sterile Products, LLC), an antagonist of the N-methyl-D-aspartate (NMDA) glutamate receptor, provide rapid and substantial antidepressant response in MDD and/or suicidal patients, within a matter of days, as opposed to weeks, as reported by Medscape Medical News.

In seeking to further explore the role of glutamatergic dysfunction in MDD, Dr Sodhi and her colleagues evaluated postmortem brain samples of 53 patients who had had MDD, including 26 men and 27 women, in comparison with 32 control persons, including 19 men and 13 women, who had been psychiatrically healthy.

Among the samples, 34 involved MDD with suicide, compared with 19 samples from patients with MDD who had not died as the result of suicide.

The researchers focused on the dorsolateral prefrontal cortex (DLPFC), which is linked to the regulation of mood and cognition and has been shown in previous studies to be altered in MDD.

They found that patients with MDD in both sexes had significantly higher expression of most of the 21 glutamatergic genes in the DLPFC that were tested (P = .006).

A post hoc analysis further showed that most of those with higher gene expression were women.

Specific genes showing higher expression levels in women with MDD included GRIN1, GRIN2A-D, GRIA2-4, GRIK1-2, GRM1, GRM4, GRM5, and GRM7. Only GRIN3A failed to meet the threshold of statistical significance.

Expression of GRM5 was lower in male MDD patients compared with male control persons.

Expression of GRIN2B was greater than all of those with MDD and suicide, compared with MDD without suicide, suggesting that higher expression of GRIN2B is a potential biological marker of suicide, the authors note.

"Indeed, genetic polymorphisms of GRIN2B have been reported [in previous studies] to predict treatment resistance in MDD, suicide attempts and reasoning ability," they write.

In a separate analysis of genes encoding monoamine transporters in the same cohort, which has not yet been published, the authors did not find similar patterns of gene expression.

"Our data could indicate that there is a general abnormality in the function of glutamatergic cells in the DLPFC of females with MDD," the investigators write.

Dr Sodhi noted that the study underscores the importance of looking at sex differences in researching the neuronal underpinnings of depression.

"The difference between our study and those of others is that we had a large number of women represented among our subjects," she said.

"If we had tested men alone, we would have only detected a reduced level of one glutamate receptor gene in the depressed men."

Women are known to have significantly higher levels of depression than men in general, and although they are two to three times more likely to attempt suicide, men are four times more likely to die as the result of suicide, the authors note.

Another Piece of the Puzzle

According to Alexis E Whitton, PhD, with the Center for Depression, Anxiety and Stress Research at McLean Hospital and Harvard Medical School, in Boston, Massachusetts, research into ketamine has supported the new study's findings, showing improved responses in women compared with men.

"What we do know of preliminary effects of ketamine in rats is there is a differential response to ketamine such that female rats actually show antidepressant response at a much lower dose of ketamine than male rats," she told Medscape Medical News.

"We don't know if this is reproduced in humans, but we do know glutamate is implicated in depression, and if depression is more common in females, then what we're seeing in this article makes sense."

Interestingly, one study of ketamine in rats showed that the difference in levels of response with regard to the sexes completely disappeared when female rats were ovariectomized, suggesting a key role of female hormones in the response.

"If the rats don't have ovaries and therefore aren't exposed to estrogen or progesterone, they don't show this same sensitivity to ketamine's antidepressant effects," Dr Whitton said.

Sensitivity has been shown to be reinstated by exposing the female rats to synthetic estrogen or progesterone.

"What seems clear is the likelihood that antidepressant benefits obtained through ketamine are dependent on the availability of female hormones," Dr Whitton said.

"So this also may have implications in terms of treatment of older postmenopausal women with lower levels of those hormones."

She noted that similar sex differences have been reported in numerous studies with selective serotonin reuptake inhibitors, with some showing the rate of response to be twice as high in women as men. Men appear to have greater response to tricyclic antidepressants.

Although ketamine has drawbacks of its own, including a short-lived response and disassociative effects during administration, its promising results have helped drive research in the development of additional glutamatergic agents for MDD, such as esketamine and rapastinel.

With the prospect of a much faster-acting, effective antidepressant suggested by some to possibly represent the "greatest discovery of the decade" in terms of depression treatment, the new findings add important insights, Dr Whitton said.

"There definitely is a push to really identify the mechanisms by which ketamine is producing an antidepressant effect, and I think this paper will add another piece of the puzzle."

The authors and Dr Whitton report no relevant financial relationships.

Mol Psychiatry. Published online July 14, 2015. Abstract

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