Depression Diagnostics Could Get Boost with Discovery of New Biomarker

Having a simple, biochemical marker for depression is crucial for disease diagnostics and vital to track drug therapies for their effectiveness in treating the neurochemical aspects of the disorder. As such, investigators at the University of Illinois, Chicago (UIC) have just released data from a new study, which identifies a biomarker in human platelets that tracks the extent of depression.

The research builds on previous studies by several investigators that have shown in humans and animal models that depression is consistent with decreased adenylyl cyclase—a small molecule inside the cell that is made in response to neurotransmitters such as serotonin and epinephrine.

“When you are depressed, adenylyl cyclase is low. The reason adenylyl cyclase is attenuated is that the intermediary protein that allows the neurotransmitter to make the adenylyl cyclase, Gs alpha (Gsα), is stuck in a cholesterol-rich matrix of the membrane—a lipid raft—where they don’t work very well,” explained senior study investigator Mark Rasenick, PhD, professor of physiology, biophysics, and psychiatry at UIC.

Findings from the new study—published recently in Molecular Psychiatry through an article titled, “A Novel Peripheral Biomarker for Depression and Antidepressant Response”—have identified the cellular biomarker for translocation of Gs alpha from lipid rafts. The biomarker can be identified through a blood test.

“What we have developed is a test that can not only indicate the presence of depression, but it can also indicate therapeutic response with a single biomarker, and that is something that has not existed to date,” said Rasenick, who is also a research career scientist at Jesse Brown VA Medical Center.

The researchers hypothesized they will be able to use this blood test to determine if antidepressant therapies are working, perhaps as soon as one week after beginning treatment. Previous research had shown that when patients showed improvement in their depression symptoms, the Gs alpha was out of the lipid raft. However, in patients who took antidepressants but showed no improvement in their symptoms, the Gs alpha was still stuck in the raft—meaning simply having antidepressants in the bloodstream was not good enough to improve symptoms.

“In this small proof-of-concept study, we examined the hypothesis that translocation of Gsα from lipid rafts toward a more facile activation of adenylyl cyclase is a biomarker for clinical response to antidepressants,” the authors wrote. “There were 49 subjects with MDD (HamD17 score ≥15) and 59 healthy controls at the screening visit. The AlphaScreen assay measured both basal activity and prostaglandin E1 (PGE1) stimulation of Gsα-adenylyl cyclase to assess the extent of coupling of Gsα with adenylyl cyclase. At the screen, platelet samples obtained from MDD subjects revealed significantly lower PGE1 activation of adenylyl cyclase activity than controls (p = 0.02).”

The authors continued, stating that “subsequently, 19 consenting MDD subjects completed a six-week open-label antidepressant treatment trial. The 11 antidepressant responders (HamD17 improvement ≥50% from the screen) revealed a significant increase in PGE1-stimulated adenylyl cyclase compared to non-responders (p = 0.05) with an effect size of 0.83 for the PGE1/Gsα lipid-raft biomarker. PGE1 stimulation increased by ≥30% from screen assessment in eight responders (72.7%) and two non-responders (25.0%) [Fisher exact = 0.07] with a positive predictive value for the response of 80.0%. In this small pilot study, increased PGE1 stimulated adenylyl cyclase was associated with antidepressant response in MDD subjects.”

A blood test may show whether or not the Gs alpha was out of the lipid raft after one week.

“Because platelets turn over in one week, you would see a change in people who were going to get better. So you’d be able to see the biomarker that should presage successful treatment,” Rasenick noted.

Currently, patients and their physicians have to wait several weeks, sometimes months, to determine if antidepressants are working, and when it is determined they aren’t working, different therapies are tried.

“About 30% of people don’t get better—their depression doesn’t resolve. Perhaps, failure begets failure, and both doctors and patients make the assumption that nothing is going to work,” Rasenick concluded. “Most depression is diagnosed in primary care doctor’s offices where they don’t have sophisticated screening. With this test, a doctor could say, ‘Gee, they look like they are depressed, but their blood doesn’t tell us they are. So, maybe we need to re-examine this.’”

Depression Diagnostics Could Get Boost with Discovery of New Biomarker

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