New Biomarker Found for Depression and Antidepressant Response

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A biomarker in human platelets that tracks the extent of depression has been found by researchers at the University of Chicago. This proof-of-concept study builds off of previous work that has 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.

“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 Mark Rasenick, University of Illinois Chicago distinguished professor of physiology and biophysics and psychiatry, and senior author of the study, in a press statement.

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.

The new study appears in Molecular Psychiatry. It describes the cellular biomarker for translocation of Gs alpha from lipid rafts, which are complexes of cholesterol and other compounds that exist in the lipid bilayer. The biomarker can be identified through a blood test.

“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, is stuck in a cholesterol-rich matrix of the membrane — a lipid raft — where they don’t work very well,” said Rasenick.

The study included 49 subjects with major depressive order (MDD) and 59 healthy controls. The researchers used the AlphaScreen (PerkinElmer) assay to measure basal activity and prostaglandin E1 (PGE1) stimulation of Gsα-adenylyl cyclase to assess the extent of coupling of Gsα with adenylyl cyclase.

Platelet samples obtained from MDD subjects revealed significantly lower PGE1 activation of adenylyl cyclase activity than controls. Next, 19 MDD subjects completed a 6-week open label antidepressant treatment trial. The 11 antidepressant responders revealed significant increase in PGE1-stimulated adenylyl cyclase compared to non-responders.

The researchers hypothesize 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 has 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.

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

These data suggest that a simple, high-throughput-capable assay for depression and antidepressant response can be developed.

“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 said. “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.'”

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