"My colleagues and I have been studying G protein signaling in the nervous system for the past 40 years," Dr. Mark Rasenick of the University of Illinois at Chicago told Reuters Health by email. "We (did) a series of preclinical studies in rodents and cultured cells showing that a signature of antidepressant action is the increased efficiency of a particular G protein, Gsalpha. The first paper on this was published by David Menkes and me in 1983." (https://bit.ly/3sK3N8f)
Regarding the current study, he said, "While we were not surprised by the results, we were surprised by the statistical power of this small sample size. Of course, a larger study is needed to confirm both the validity and potential of the biomarker."
Dr. Rasenick and colleagues explain in Molecular Psychiatry that in patients with major depressive disorder (MDD), in contrast to healthy controls, Gsalpha is ensconced in lipid rafts, resulting in impaired stimulation of adenylyl cyclase. Levels of the enzyme are low in people with depression.
The team investigated the hypothesis that freeing Gsalpha from the lipid rafts so it can more easily activate adenylyl cyclase is a biomarker for clinical response to antidepressants.
First, 49 individuals with MDD (HamD17 score of 15 or more) and 59 controls attended a screening visit. The AlphaScreen assay measured both basal activity and prostaglandin E1 (PGE1) stimulation of Gsalpha-adenylyl cyclase to assess the extent of Gsalpha coupling with adenylyl cyclase.
Platelet samples obtained from those with MDD showed significantly lower PGE1 activation of adenylyl cyclase activity than controls.
Next, 19 individuals with MDD (age range, 35-60; 13 women) completed a 6-week open-label antidepressant treatment trial. The 11 responders (HamD17 improvement of at least 50% from screen) had a significant increase in PGE1-stimulated adenylyl cyclase compared to non-responders, with an effect size of 0.83 for a PGE1/Gsalpha lipid-raft biomarker.
PGE1 stimulation increased by at least 30% from screen assessment in eight responders (72.7%) and two non-responders (25.0%), for a positive predictive value for response of 80.0%.
Summing up, the authors state, "In this small, pilot study, increased PGE1 stimulated adenylyl cyclase was associated with antidepressant response in MDD subjects. These data suggest that a simple, high-throughput-capable assay for depression and antidepressant response can be developed."
Dr. Rasenick added, "The methodology to screen individual patient samples is in place, but we currently lack facilities and personnel. In addition to validating the assay, we want to determine whether it will serve as an early indicator (1 week vs. the current 2 months) of treatment efficacy."
"Longer term plans are an 'ex-vivo' screen to personalize antidepressant therapy for individual patients and new molecular approaches to therapeutics based on G protein signaling targets," he concluded.
Dr. Alan Schatzberg, a professor in the Department of Psychiatry and Behavioral Sciences at Stanford University School of Medicine, commented on the study in an email to Reuters Health.
"The findings are important and reasonable," he said. "As with other research, they build on findings from a number of groups in the past, including from Mooney and myself some 30 years back." (https://bit.ly/3B8WkTL)
"The data are clear: effective antidepressant trials are associated with signature changes in lipid rafts that contain key receptors and their coupled G-proteins," he said. "The test can be used to assess the likelihood of a drug working in a clinical trial and whether an individual patient has been treated with an effective agent and for sufficient duration."
"What is needed next is replication as a marker of treatment and possible extension of it to a diagnostic for patients who may have major depression," Dr. Schatzberg concluded.
SOURCE: https://go.nature.com/3gzNqoO Molecular Psychiatry, online January 5, 2022.
By Marilynn Larkin
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