An extensive push to identify and validate blood biomarkers for mood disorders has resulted in a blood test, composed of RNA biomarkers, that can distinguish how severe a patient’s depression is. The test also can predict their risk of severe depression in the future, and their risk of future bipolar disorder, or manic-depressive illness, as well as informs tailored medication choices for patients.

The work1 builds on previous research into blood biomarkers2 that track suicidality as well as pain, post-traumatic stress disorder, and Alzheimer’s disease3.

We have pioneered the area of precision medicine in psychiatry over the last two decades, particularly over the last 10 years. This study represents a current state-of-the-art outcome of our efforts. This is part of our effort to bring psychiatry from the 19th century into the 21st century, to help it become like other contemporary fields such as oncology. Ultimately, the mission is to save and improve lives,

says Alexander B. Niculescu, professor of psychiatry at the Indiana University School of Medicine.

Worldwide, 1 in 4 people will suffer from a depressive episode in their lifetime, but current diagnosis and treatment approaches are largely trial and error.

The current study took place over four years, with over 300 participants recruited primarily from the patient population at the Richard L. Roudebush VA Medical Center in Indianapolis. The team used a careful four-step approach of discovery, prioritization, validation, and testing.

Discovery cohort longitudinal within-subject analysis

Discovery cohort longitudinal within-subject analysis. Credit: Le-Niculescu, et al. CC-BY

First, researchers followed the participants over time, observing them in both high and low mood states. Each time, the researchers recorded what changed in terms of the biomarkers in their blood between the highs and lows.

Validation And Testing

Next, Niculescu’s team used large databases developed from all previous studies in the field to cross-validate and prioritize their findings. From here, the researchers validated the top 26 candidate biomarkers in independent cohorts of people with clinically severe depression or mania.

Last, the researchers tested the biomarkers in additional independent cohorts to determine how strongly they predicted who is ill, and who will become ill in the future.

matching with medications

New repurposed drugs using the panels of markers. There is overlap between depression, bipolar and mania biomarkers. Credit: Le-Niculescu, et al. CC-BY

This approach enabled the researchers to demonstrate how to match patients with medications — even finding a new potential medication to treat depression.

Through this work, we wanted to develop blood tests for depression and for bipolar disorder, to distinguish between the two, and to match people to the right treatments. Blood biomarkers are emerging as important tools in disorders where subjective self-report by an individual, or a clinical impression of a health care professional, are not always reliable. These blood tests can open the door to precise, personalized matching with medications, and objective monitoring of response to treatment,

Niculescu says.

Circadian Clock Genes

In addition to the diagnostic and therapeutic advances discovered in their latest study, Niculescu’s team found that circadian clock genes — the genes that regulate seasonal, day-night and sleep-wake cycles — underline mood disorders.

That explains why some patients get worse with seasonal changes, and the sleep alterations that occur in mood disorders,

Niculescu says.

The work opens the door for the findings to be translated into clinical practice as well as help with new drug development.

Blood biomarkers offer real-world clinical practice advantages. The brain cannot be easily biopsied in live individuals, so we’ve worked hard over the years to identify blood biomarkers for neuropsychiatric disorders,

concludes Niculescu.


  1. Le-Niculescu, H., Roseberry, K., Gill, S.S. et al. Precision medicine for mood disorders: objective assessment, risk prediction, pharmacogenomics, and repurposed drugs. Mol Psychiatry (2021). ↩︎

  2. Le-Niculescu H, Kurian SM, Yehyawi N, Dike C, Patel SD, Edenberg HJ, et al. Identifying blood biomarkers for mood disorders using convergent functional genomics. Mol Psychiatry. 2009;14:156–74 ↩︎

  3. Niculescu AB, Le-Niculescu H, Roseberry K, Wang S, Hart J, Kaur A, et al. Blood biomarkers for memory: toward early detection of risk for Alzheimer disease, pharmacogenomics, and repurposed drugs. Mol Psychiatry. 2019;25:1651–72 ↩︎


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