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Researchers Develop Promising Blood Test for Depression & Bipolar Disorder; May Open Door to Precise, Personalized Matching with Medications, and Objective Monitoring of Response to Treatment

Worldwide, 1 in 4 people will suffer from a depressive episode in their lifetime. While current diagnosis and treatment approaches are largely trial and error, a breakthrough study by Indiana University (IU) School of Medicine researchers sheds new light on the biological basis of mood disorders, and offers a promising blood test aimed at a precision medicine approach to treatment. Led by Alexander B. Niculescu, MD, PhD, Professor of Psychiatry at IU School of Medicine, the study was published online on April 8, 2021 in Molecular Psychiatry. The work builds on previous research conducted by Dr. Niculescu and his colleagues into blood biomarkers (focused on gene expression from immune cells) that track suicidality, as well as pain, post-traumatic stress disorder, and Alzheimer's disease. The ability to identify peripheral gene expression changes that reflect brain activities is likely due to the fact that the brain and immune system have developmental commonalities, marked by shared reactivity and ensuing gene expression patterns, the authors stated. The open-access Molecular Psychiatry article is titled “Precision Medicine for Mood Disorders: Objective Assessment, Risk Prediction, Pharmacogenomics, and Repurposed Drugs” ( "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," said Dr. Niculescu. "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." The team's work describes the development of a blood test, composed of gene expression biomarkers, that can distinguish how severe a patient's depression is, the risk of the patient developing severe depression in the future, and the risk of future bipolar disorder (manic-depressive illness). The test also informs tailored medication choices for patients.


This comprehensive 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 of candidate biomarkers.


First, the participants were followed over time, with researchers observing them in both high and low mood states--each time recording what changed in terms of the biomarkers in their blood between the two states.

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

In their abstract, the authors wrote: “Adding the scores from the first three steps into an overall convergent functional evidence (CFE) score, we ended up with 26 top candidate blood gene expression biomarkers that had a CFE score as good as or better than SLC6A4, an empirical finding which we used as a de facto positive control and cutoff. Notably, there was among them an enrichment in genes involved in circadian mechanisms. We further analyzed the biological pathways and networks for the top candidate biomarkers, showing that circadian, neurotrophic, and cell differentiation functions are involved, along with serotonergic and glutamatergic signaling, supporting a view of mood as reflecting energy, activity and growth.”

“Fourth, we tested, in independent cohorts of psychiatric patients, the ability of each of these 26 top candidate biomarkers to assess state [mood (SMS-7), depression (HAMD), mania (YMRS)], and to predict clinical course (future hospitalizations for depression, future hospitalizations for mania]. We conducted our analyses across all patients, as well as personalized by gender and diagnosis, showing increased accuracy with the personalized approach, particularly in women."


“Again, using SLC6A4 as the cutoff, 12 top biomarkers had the strongest overall evidence for tracking and predicting depression after all four steps: NRG1, DOCK10, GLS, PRPS1, TMEM161B, GLO1, FANCF, HNRNPDL, CD47, OLFM1, SMAD7, and SLC6A4. Of these 12, 6 had the strongest overall evidence for tracking and predicting both depression and mania, hence bipolar mood disorders. There were also two biomarkers (RLP3 and SLC6A4) with the strongest overall evidence for mania. These panels of biomarkers have practical implications for distinguishing between depression and bipolar disorder.”


“Next, we evaluated the evidence for our top biomarkers being targets of existing psychiatric drugs, which permits matching patients to medications in a targeted fashion, and the measuring of response to treatment. We also used the biomarker signatures to bioinformatically identify new/repurposed candidate drugs. Top drugs of interest as potential new antidepressants were pindolol, ciprofibrate, pioglitazone and adiphenine, as well as the natural compounds asiaticoside and chlorogenic acid. The last three had also been identified by our previous suicidality studies.”


“Finally, we provide an example of how a report to doctors would look for a patient with depression, based on the panel of top biomarkers (12 for depression and bipolar, 1 for mania), with an objective depression score, risk for future depression, and risk for bipolar switching, as well as personalized lists of targeted prioritized existing psychiatric medications and new potential medications.”


“Overall, our studies provide objective assessments, targeted therapeutics, and monitoring of response to treatment, that enable precision medicine for mood disorders.”

"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," said Dr. Niculescu. "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, is not always reliable. These blood tests can open the door to precise, personalized matching with medications, and objective monitoring of response to treatment."

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

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


According to Dr. Niculescu, the work done by his team has opened the door for their findings to be translated into clinical practice, as well as help with new drug development. Focusing on collaboration with pharmaceutical companies and other doctors in a push to start applying some of their tools and discoveries in real-world scenarios, Dr. Niculescu said he believes the work being done by his team is vital in improving the quality of life for countless patients.


"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," said Dr. Niculescu. "Given the fact that 1 in 4 people will have a clinical mood disorder episode in their lifetime, the need for and importance of efforts such as ours cannot be overstated."

[News release] [Molecular Psychiatry article]