A blood test can help diagnose bipolar disorder, but some researchers are skeptical.

A first-of-its-kind blood test that uses biomarkers to distinguish between bipolar disorder and depression could cut the time it takes to make an accurate diagnosis from years to weeks, according to the company that developed the test, but some scientists have expressed concerns. about its reality.

The test uses biomarkers associated with RNA editing to diagnose the disease. It has been available in France since March and in Italy since October 2023, having received regulatory approval in both countries.

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However, some researchers are concerned about the small size of the studies on which the test is based and the lack of independent verification of the studies. The test’s developer, Montpellier-based French startup Alcediag, says its tests are valid and reproducible.

The series highlights a broader debate about the potential of biomarkers—biological characteristics that may indicate a particular medical condition—to allow earlier diagnosis and more personalized treatment for mental health disorders.

“Biomarker research has a role,” says Suresh Sundram, a psychiatrist at Monash University in Melbourne, Australia. “But this is a very dangerous area.”

Slow diagnosis

Bipolar disorder, a spectrum of conditions characterized by mood swings alternating between mania and depression, is difficult to diagnose. About 40 million people worldwide live with the condition, and the diagnostic process, which often involves several visits to a psychiatrist, takes an average of seven to ten years, during which time people are often misdiagnosed as depression and received inappropriate or ineffective treatment.

Alcediag hopes to change this grim picture. The company says its €900 ($980) EDIT-B blood test can help differentiate bipolar disorder from depression using biomarkers. EDIT-B differentiates the two by measuring subtle differences in RNA editing is a regulatory process that alters various cellular mechanisms, including gene expression, which in turn affects neurological functioning.

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Several studies have shown that differences in RNA editing may play a role in autoimmune diseases and cancer, as well as psychiatric diseases. In a preliminary study, Alcediag scientists identified distinct RNA editing patterns affecting eight genes that appear to differ between healthy people and those with depression. Among patients with depression, six of these genes also show variations that distinguish people with depression from people with bipolar disorder. These differences create a unique combination (or signature) of biomarkers, which the company says it discovered using an artificial intelligence (AI) algorithm it developed.

“We have a signature for those with depression, a signature for control and… one for bipolar disorder,” says Dina Weissmann, co-founder and chief scientific officer of Alcediag. In a 2022 study of 410 participants, the algorithm distinguished 160 people with depression and 95 people with bipolar disorder with high accuracy.¹.

According to Weissmann, about 80 people have used EDIT-B since its commercialization in France and Italy, and the feedback so far has been positive. She cites an anecdotal account of a man who, after testing positive, said he switched to a more effective drug. “The patient wrote to his doctor: “Everything is fine, I’m back on my feet. I’m living normally again,” Weissmann says.

Potential Risks

For many people with bipolar disorder, a faster and more accurate diagnosis would allow them to access “the right medication at the right time,” says Marion Leboyer, a psychiatrist and executive director of the FondaMental Foundation, a research organization based near Paris.

On the other hand, if a blood test gives an incorrect result, there is a risk that disorders may be misdiagnosed or missed, says Boris Chaumette, a psychiatrist at the French National Institute of Health and Medical Research in Paris.

There is no indication that the EDIT-B result led to an incorrect diagnosis. But Chaumette and others are concerned about some of the research methodologies used to demonstrate the effectiveness of the EDIT-B test. He points to the “inherent limitations” of the 2022 study with 410 participants. “You take a data set with many variables and a small number of patients and ask the algorithm to classify people. It will inevitably find things that classify them, it will inevitably reveal commonalities,” he says. “In fact, what you are seeing may be a treatment effect.”

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He adds that, except for the control group, all participants in Alcediaga’s studies were taking medications (as is often the case in psychiatric studies). These drugs can affect the levels of certain biomarkers, Sundram says, “so that the algorithm can pick up the effect of the drug.”

Weissmann says the study participants with bipolar disorder and those with depression were taking a number of different medications, so if the algorithm were to differentiate between people based on the treatment they were on, it would classify them into therapeutic classes. Stable patients—those who were diagnosed but not experiencing symptoms at the time of the study—also had a different biomarker signature from the control group, she adds, indicating that their medications suppressed symptoms without affecting markers of the underlying disease. She says Alcediag’s studies have included hundreds of participants and that the company is conducting a new clinical trial involving 436 patients; they plan to publish the results next year.

Replication Questions

Some aspects of Alcediaga’s research make it difficult for independent researchers to verify the work, Chaumette says. The algorithm and the underlying code have not been disclosed, and subsequent studies conducted after the first 2022 test used slightly different versions of the test. For example, in a study published this year, the company removed one biomarker from the original combination and added three new ones.².

The issue led France’s National Health Authority (HAS), an independent body that evaluates health products, to reject Alcediag’s application to have people undergoing the test reimbursed by French health authorities. “The effectiveness of the three versions varied, and we had no rationale for why this version was chosen over another,” says Cedric Carbonneil, who heads the HAS division responsible for evaluating new medical devices and procedures. It is not uncommon for early-stage companies to have their applications initially rejected, and HAS expects Alcediag to reapply, he adds. Alcediag said it made changes to the biomarkers to improve the test’s performance and did not disclose the algorithm for commercial reasons.

Chaumette says he would like to see larger studies validating the test before it is used in patients, and he hopes Alcediag will make its technology available to independent groups so they can replicate the results. “If you quickly commercialize it and patent everything without sharing anything, then it becomes opaque.”