Current approaches to diagnosing and treating depressive disorders are based largely on trial and error, but a newly reported study by a team at Indiana University School of Medicine has shed new light on the biological basis of mood disorders. Through their research, reported in Molecular Psychiatry, the team has developed a blood test for a panel of RNA biomarkers, which can distinguish how severe a patient’s depression is, indicate the risk of them developing severe depression in the future, and also the risk of future bipolar disorder. The test could feasibly help clinicians better tailor existing treatments to individual patients.

“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 research lead Alexander B. Niculescu, MD, PhD, Professor of Psychiatry at IU School of Medicine. “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 and colleagues report on their findings in a paper titled, “Precision medicine for mood disorders: objective assessment, risk prediction, pharmacogenomics, and repurposed drugs.”

Worldwide, one in four people will be affected by a mood disorder (depression, bipolar disorders), in their lifetime, the authors noted. Depression, in particular, is a leading cause of disability for people aged 15–44 years. However, there are currently no objective measures, such as blood tests, that are used in clinical practice, and available treatments don’t work for everyone. “Due to the lack of objective tests and the perceived presence of stigma, mood disorders are often underdiagnosed or misdiagnosed (depression instead of bipolar disorder),” the authors wrote. “They are also sub-optimally treated, can lead to self-medication with alcohol and drugs, and may culminate in some cases with suicide.”

In contrast, blood biomarkers could feasibly “open the door” to precise, personalized treatment, and objective monitoring of treatment response, the team noted. “The development of blood tests, as well as matching of patients with existing and new treatments, in a precise, personalized and preventive fashion, would make a significant difference at an individual and societal level.”

Alexander B. Niculescu, MD, PhD, [IU School of Medicine]

Previous research conducted by Niculescu and colleagues had identified blood gene expression biomarkers that track suicidality. “More recently, we have conducted such studies also for pain, for stress disorders , and for memory/Alzheimer’s Disease,” they stated. “We have pioneered the area of precision medicine in psychiatry over the last two decades, particularly over the last 10 years,” Niculescu commented.

 

For their newly reported work, the team looked to identify more definitive biomarkers for mood disorders in general, and depression in particular. “We endeavored to use a similar comprehensive approach to identify more definitive biomarkers for mood disorders, that are transdiagnostic, by studying mood in psychiatric disorders patients.”

The study, carried out over four years, involved more than 300 participants, recruited primarily from the patient population at the Richard L. Roudebush VA Medical Center in Indianapolis. Their strategy involved a four-step process of discovery, prioritization, validation and testing.

First, the participants were followed over time, with researchers observing them in both high and low mood states, each time recording changes in blood biomarkers between the two states. Next, the team utilized large databases developed from all previous studies in the field, to cross-validate and prioritize their findings. From here, they were able to validate the top 26 candidate biomarkers in independent cohorts of people with severe depression or mania. “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,” they noted. Lastly, the biomarkers were tested in additional independent cohorts to determine how strongly they could predict who was ill, and who would become ill in the future.

The researchers in addition demonstrated how the biomarker panel could be used in a clinical setting to identify patients with depression, indicate a risk for future depression and bipolar switching, and generate a personalized lists of targeted psychiatric drugs. Through their results the team also identified new potential drug candidates for treating depression. “We also used the biomarker signatures to bioinformatically identify new/repurposed candidate drugs,” they explained. “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 3 had also been identified by our previous suicidality studies.”

Interestingly, the study findings indicated a potential role for circadian clock genes—the genes that regulate seasonal, day-night and sleep-wake cycle—in mood disorders. Eight out of 23 genes identified had biological roles related to the circadian clock. “That explains why some patients get worse with seasonal changes, and the sleep alterations that occur in mood disorders,” Niculescu said.

He maintains that the team’s findings could pave the way for translation into clinical practice, as well as help with new drug development. “This study represents a current state-of-the-art outcome of our efforts,” he said. “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.”

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, 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. 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.”

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