Rising Star Awardee Dr. Maze aims to determine whether testing the blood for reduced levels of a serotonin-modified protein could help to predict susceptibility to depression under stress, to diagnose major depressive disorder, and/or to predict whether antidepressant medications might help specific patients.
Major Depressive Disorder (MDD) afflicts over 300 million people worldwide, but current antidepressant medications work to relieve symptoms in only a fraction of these, and then, generally only after weeks to months of treatment. What if a simple blood test were available that could not only indicate whether a person would respond favorably to medications, but could also reveal someone’s individual level of vulnerability to MDD under stress before it even begins? Such a test could potentiate proactive lifestyle changes to help at-risk people ward off MDD, while potentially saving newly-diagnosed patients months of trying different medications in favor of alternative (e.g. psychosocial) treatments that might help them more efficiently.
Recent research in the lab of Ian Maze, Ph.D., Assistant Professor, Departments of Neuroscience and Pharmacological Sciences at the Icahn School of Medicine at Mount Sinai, suggests that the expression of a chemically modified protein (called histone H3 serotonylation; H3Q5ser) involved in serotonergic neuronal activity in the brain displays characteristics that make it opportune to assess in just such a blood test: H3Q5ser is not only expressed differently in the brains of people with MDD vs. non-afflicted people in a way that correlates with responsiveness to antidepressants, but it also shows up in concordant proportions in the blood. Now, Dr. Maze has won the 2017 One Mind Rising Star Early Diagnostics Basic Research Award for his ambitious proposal to investigate this modified protein as a potential blood biomarker that could help doctors to eventually predict depression vulnerability, and antidepressant responsiveness, in individual patients.
To test this possibility, Dr. Maze proposes a sequence of three research aims. First, Dr. Maze and his team will ascertain whether H3Q5ser can serve as a biomarker to predict stress susceptibility in a rodent model. In a model called “chronic social defeat stress” (CSDS), where each member of a cohort of experimental mice is exposed to a larger, more aggressive mouse repeatedly, the resulting social stress can serve as a trigger for some of the mice (noted as “susceptible” to stress) to develop depression-like symptoms. Dr. Maze’s team will test the blood levels of H3Q5ser in these mice before, within, and after a period of repeated CSDS sessions, and correlate these levels at each time point with the evolution of the mice’s depressive-like behaviors. This experiment should reveal whether changes in H3Q5ser expression precede, coincide with, or follow changes in behavior—and resolve the question of whether a blood test for this modified protein’s expression can be used to predict the development of depression-like behavior in this mouse model.
In their second aim, Maze and his team will use a similar process on this same mouse model to evaluate whether measuring H3Q5ser expression in the blood can be used to predict the susceptible mice’s response to antidepressant treatment. By measuring the blood levels of H3Q5ser in these mice before, during, and after treatment with antidepressant medications, and observing whether changes in this protein’s expression precede, coincide with, or follow ameliorations in the animals’ behavior, Dr. Maze’s team will discover whether such H3Q5ser measurement can help to predict antidepressant efficacy in this mouse model.
Third, Dr. Maze will track H3Q5ser expression in humans over time: 100 each of healthy controls, untreated MDD patients, and MDD patients taking antidepressants will undergo blood tests regularly over a few months. The treated MDD patients will concurrently be assessed for changes in symptoms, with these changes analyzed against their H3Q5ser expression levels. These observations should shed invaluable light on the relationships between H3Q5ser expression, the presence/absence of MDD, and the efficacy of medications for individual patients.
Says Dr. Maze, “Our studies aim to fully test the hypothesis that H3Q5ser may be used as a biomarker for MDD and/or antidepressant efficacy in human patients. If true, the existence of such a marker will prove useful in both the diagnosis of MDD and in its treatment.”
From a patient’s perspective, such a discovery could help to bring about recovery faster. We at One Mind Institute are excited to watch how Dr. Maze’s research will play out, and we extend our heartfelt appreciation to our donors for enabling us to support this Rising Star’s work.