Researchers have found patterns of gene activity linked to depression and the likelihood of  death by suicide that differ between men and women.

Looking at postmortem brain tissue of males and females with major depression -- some of whom had died of suicide -- the researchers found different expression patterns for genes that encode docking ports on a type of nerve cell activated by the excitatory neurotransmitter glutamate. This is notable because recent clinical research indicates that drugs acting on the glutamate system have more rapid antidepressant effects than conventional treatments.

The findings were reported in  Molecular Psychiatry on July 14, 2015 by A.L. Gray and colleagues at the University of Illinois at Chicago.  The senior author and team leader was 2004 and 2006 NARSAD Young Investigator grantee Monsheel Sodhi, Ph.D., of the University of Illinois at Chicago. The team also included 1989 Young Investigator grantee Thomas M. Hyde, M.D., Ph.D., and 2013 Distinguished Investigator grantee Joel E. Kleinman, M.D., Ph.D.

Their study, the first on the topic to include large numbers of women, examined the expression of glutamate receptor-encoding genes in a part of the brain called the dorsolateral prefrontal cortex.  This brain region is important in the regulation of mood and cognition, which are disrupted in patients with depression.  

The team uncovered unique abnormalities in the glutamate system among women. Compared to their non-depressed counterparts, women with depression showed higher expression for 14 of the 21 genes tested. This pattern included all but one of the genes that instruct cells to produce a type of docking port for glutamate called NMDA receptors.  A gene that encodes part of another class of glutamate receptors, called AMPA receptors, also showed high expression among depressed women.

Among men with depression, the study replicated previous findings showing lower than average activity in a gene called GRM5.  Its activity helps cells generate another important receptor, called mGluR5, which has been previously implicated in studies of depression in mice models.  

For both men and women, the expression of the GRIN2B, another gene whose activity generates an important component of the NMDA receptor, was higher among those who had died by suicide. This points to GRIN2B as a possible marker and target for future therapies for the prevention of suicide.

These findings add to growing support for the strategy of targeting glutamate receptors in the treatment of depression and suicidal behavior. Conventional antidepressants focus on the neurotransmitter serotonin — which only indirectly affects the glutamate system — and typically take weeks or months to improve symptoms, when they are effective.

The researchers caution that the brain tissue they studied may have been altered by long-term antidepressant use.  It’s possible, therefore, that their findings are in some part reflective of drug effects rather than caused directly by depression itself. More work is needed to investigate this possibility.

Read the paper.