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Glutamate receptor genes more active in females with major depressive disorder

Analyses of brain tissue from postmortem subjects indicate disruption of the glutamase system occurs in the dorsolateral prefrontal cortex of patients with major depressive disorder and those who commit suicide, and the disruption may be more severe in female patients.

“The rapid antidepressant efficacy of ketamine may depend on increased glutamate neurotransmission through the activity of multiple [glutamate receptor] subtypes, possibly leading to optimal levels of synaptogenesis,” the researchers wrote. “Reduced numbers of synapses have been reported in the [dorsolateral prefrontal cortex] of patients with [major depressive disorder] and also in rodent models of stress. Conventional antidepressant drugs appear to reverse these neuronal deficits after a time delay, whereas ketamine rapidly induces synaptogenesis and reverses the synaptic deficits caused by chronic stress in animal models of depression.”

To determine if glutamate receptor gene expression is altered in the dorsolateral prefrontal cortex of patients with major depressive disorder (MDD), researchers evaluated postmortem brain tissue from 53 patients with MDD and 32 mentally healthy patients. Thirty-four of the patients with MDD committed suicide. Gene expression was measured via Applied Biosystems assays.

Patients with MDD exhibited higher expression levels in most glutamatergic genes tested in the dorsolateral prefrontal cortex (P = .006).

Gene expression differences occurred mostly in female patients, according to post hoc analysis. Higher expression levels of GRIN1, GRIN2A-D, GRIA2-4, GRIK1-2, GRM1, GRM4, GRM5 and GRM7 were detected among female patients with MDD.

Monsheel Sodhi

GRM5 expression was lower among male patients with MDD than healthy males.

Patients with MDD who committed suicide had higher expression levels of GRIN2B, GRIK3 and GRM2 compared with patients with MDD who did not commit suicide.

“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,” study researcher Monsheel Sodhi, PhD, of the University of Illinois at Chicago, said in a press release.

“These data may indicate that specific abnormalities occur directly in the glutamatergic system in the [dorsolateral prefrontal cortex] in MDD and that these abnormalities are most severe in female patients. Our findings may also reveal novel biomarkers for MDD and suicide. The mechanisms underlying the effects detected require further investigation,” Sodhi and colleagues concluded. – by Amanda Oldt

Disclosure: The researchers report no relevant financial disclosures.