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VCU Team Searching For Methylation Signature to Predict Chronic Depression

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Researchers from Virginia Commonwealth University are planning a study of DNA methylation, with the hope that it will yield a molecular signature that can be used to personalize treatment for depression by distinguishing those who are likely to have a chronic form of the disease from those with a shorter or more episodic type of depression.

The team received a $3 million grant from the National Institute of Mental Health earlier this month to support the project, which will use next-gen sequencing to examine patterns of methylation in retrospective samples from 1,500 cases and controls, and then validate any resulting predictive signature in a separate set.

According to Edwin van den Oord, director of the VCU Center for Biomarker Research and Personalized Medicine and principal investigator on the study, the group is optimistic about the methylome sequencing approach, because it has had "very promising" results using the same technique in the context of schizophrenia.

The team's schizophrenia results are not yet published, van den Oord told PGx Reporter. But he said that that the previous work yielded important insight into the causes of the schizophrenia, and that the group was able to successfully replicate its findings in independent samples in that study.

Based on this success, he said, the group wanted to apply the same approach to another disease, choosing to target major depressive disorder, with the hope that the research might reveal a methylation pattern that could be used to predict patients' disease course, and therefore personalize their care and treatment.

Though he declined to detail whether specific depression medications have been associated with different efficacy in chronic versus non-chronic major depression, he said the team believes that by enabling doctors to more precisely characterize the severity of the disease, they can then treat those likely to suffer chronic depression more aggressively, or choose specific drugs they are likely to respond well to based on their methylation status and associated risk for persistent depression.

According to the VCU group, methylation markers are stable in blood and easy and inexpensive to measure, making them a great candidate for a clinical assay. In their grant abstract, the team also claimed that methylation markers may have better predictive power than gene mutations, because methylation is "directly related to gene expression."

Further, "methylation studies may improve disease understanding as they can account for a range of clinical disease features," the group wrote.

In the VCU team's new five-year, NIMH-funded effort, the researchers plan to apply the same sequencing approach they used in their schizophrenia research, a technique called MBD-seq, to analyze 1,500 samples from The Netherlands Study of Depression and Anxiety, or NESDA, van den Oord said.

The group plans to compare patients followed over a six-year time period to look for methylation patterns associated with different clinical MDD trajectories—distinguishing those who experienced chronic depression from those with more of a short-duration or episodic form of the disease.

According to the group's grant abstract, the study will use DNA collected from the same subjects at baseline and again after six years, dividing them into three groups: controls with no MDD, cases with MDD at baseline who showed full remission by the six-year follow up, and cases with chronic MDD.

The NESDA group will send samples to VCU for sequencing, and both the VCU team and their partners in The Netherlands will collaborate in analyzing the data.

In parallel, van den Oord said the researchers also plan to examine post-mortem brain samples to attempt to compare their results in blood with an analysis of brain tissue.

"Looking at blood is a meaningful exercise, but since depression is not a disease of the blood, looking at brain tissue in parallel will allow us to look at and answer scientific questions about correspondence between the two tissues," he said.

According to van den Oord, the discovery portion of the study will likely take the first two years of the five-year effort. Then, over the third year, the researchers will attempt to replicate and validate the predictive power of the 50 most promising methylation sites they identify in 1,500 additional independent samples.

The promise of molecular tools to guide psychiatric care has fueled many other efforts. For example, an international team has been working since 2012 looking for biomarkers to predict patients' responses to specific depression medications (PGx Reporter 5/9/2012).

Rather than look for predictors of response to particular depression medications, the VCU study is focused, more simply, on the differentiation of chronic versus non-chronic depression as a tool for personalizing care.

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