Gene-expression study indicates greater dysregulation of glutamate system in depressed females

Written by Courtney Johnson

A new study of postmortem tissue, carried out recently at the University of Illinois (IL, USA), has determined that the expression of glutamate receptor (GluRs) genes is elevated in the brains of females with major depressive disorder (MDD). Results also showed that a subset of these genes were elevated in males with MDD as well as in individuals who had died as a result of suicide. These data may offer a novel explanation for the higher incidence of suicide attempts among females as well as a potentially heightened predisposition to depression.
Pre-existing data has associated an elevated suicide risk with neurotransmitter system dysregulation. Abnormalities in the glutamate system in particular – involving the major excitatory neurotransmitter glutamate – is implied in several neurological disorders, for example, epilepsy, Alzheimer’s and schizophrenia.

In the current study, post hoc gene-expression analysis results indicated that the expression of several glutamate receptor genes is elevated in the postmortem brain tissue of subjects who suffered from MDD. The results were compared with those of a control cohort of subjects who had never suffered from psychiatric illness. Elevated levels of GRIN1, GRIN2A–D, GRIA2–4, GRIK1–2, GRM1, GRM4, GRM5 and GRM7 were observed in female subjects with MDD. The expression of GRM5 was, however, determined to be lower in depressed male subjects compared to controls. Subsequent to examination of the suicide and non-suicide cohort of depressed subjects, the expression of genes GRIN2B, GRIK3 and GRM2 were observed to be elevated in the suicide group.

Overall, the results offer further evidence to support the key role of disruption of the glutamate system in depression and consequently suicide risk. While recent targeting of the N-methyl-d-aspartate (NMDA) glutamate receptor through drugs such as ketamine has been highly successful, the more generalized disturbance of GluR gene expression in females suggests that targeting of the AMPA receptor and the metabotropic GluRs in addition to this, could be a potential way forward in treating depression in females.

Monsheel Sodhi (University of Illinois) indicated that only around one-third of patients that receive conventional treatments currently achieve substantial remission of their depression. This can take several weeks or longer, posing a potential risk in terms of suicide.

Greater than 41,000 individuals in the USA commit suicide each year, 90% of whom suffer from mental illness, largely depression. With such incidence rates rising, the importance of developing more rapidly acting antidepressants cannot be underestimated.

“Our data indicate that females with major depression who are at high risk of suicide may have the greatest antidepressant benefit from drugs that act on the glutamate system, such as ketamine,” commented Sodhi. In addition, Sodhi highlighted that the current study shows alternative GluR targets for antidepressants as well as novel biochemical markers for assessing suicide risk.

Sources: University of Illinois at Chicago press release; Gray AL, Hyde TM, Deep-Soboslay A, Kleinman JE, Sodhi MS. Sex differences in glutamate receptor gene expression in major depression and suicide. Mol. Psychiatry doi:10.1038/mp.2015.114 (2015) (Epub ahead of print)