Blood test to diagnose bipolar disorder – skepticism among researchers remains

Blood test to diagnose bipolar disorder – skepticism among researchers remains

A novel blood test that uses biomarkers to distinguish bipolar disorder from depression could cut the time needed for an accurate diagnosis from years to weeks, according to the company that developed the test. However, some scientists express concerns about the test's validity.

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

However, some researchers are concerned about the small number of subjects in the studies on which the test is based, as well as the lack of independent reviews of these studies. The test's developers, the French start-up Alcediag based in Montpellier, claim that their studies are valid and reproducible.

This dispute raises a broader discussion about the potential of biomarkers – biological characteristics that can indicate a specific health condition – to enable earlier diagnoses and personalized treatments for psychiatric disorders. “There is a role for biomarker research,” says Suresh Sundram, a psychiatrist at Monash University in Melbourne, Australia. “But this is a very sensitive area.”

Slow diagnoses

Bipolar disorder, a spectrum of disorders characterized by mood swings between mania and depression, is difficult to diagnose. About 40 million people worldwide live with the disease, and the diagnostic process, which often involves multiple sessions with a psychiatrist, takes an average of seven to ten years. During this time, many patients are mistakenly labeled with conditions such as Depression diagnosed and receiving inappropriate or ineffective treatments.

Alcediag hopes to change this bleak picture. The company claims its EDIT-B blood test, which costs 900 euros ($980), can help differentiate bipolar disorder from depression through the use of biomarkers. EDIT-B differentiates the two diseases by identifying subtle differences in the RNA editing measures – a regulatory process that alters various cellular mechanisms, including gene expression, which in turn influences neurological function.

Several studies have suggested that differences in RNA editing may play a role in autoimmune diseases, cancer, as well as psychiatric disorders. In initial research, Alcediag scientists identified distinct RNA editing patterns affecting eight genes that appear to vary between healthy individuals and those suffering from depression. Among depressed patients, six of these genes also show variations that distinguish those with depression from those with bipolar disorder. These differences result in a unique combination – or signature – of biomarkers that the company discovered using an artificial intelligence algorithm it developed.

“We have a signature for depressed people, a signature for controls and one for bipolar disorder,” says Dinah Weissmann, co-founder and chief scientific officer of Alcediag. In a 2022 study of 410 participants, the algorithm was able to distinguish the 160 people with depression and the 95 people with bipolar disorder with high accuracy 1.

About 80 people have used the test since EDIT-B was commercialized in France and Italy, Weissmann said, and feedback so far has been positive. She cites the anecdotal report of one person who reported being switched to a more effective medication after receiving a positive test result. "The patient wrote to his doctor: 'It's great, I'm on my feet again. I'm living normally again,'" says Weissmann.

Potential risks

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

On the other hand, there is a chance that a faulty blood test could misdiagnose or miss disorders, warns Boris Chaumette, a psychiatrist at the French National Institute of Health and Medical Research in Paris.

There is no evidence to date that any EDIT-B result has led to an incorrect diagnosis. However, Chaumette and others raise concerns about the methods of certain studies used to demonstrate the effectiveness of the EDIT-B test. He points out the “inherent limitations” of the 2022 study with 410 participants. "You have a data set with a lot of variables and not a lot of patients, and you ask an algorithm to classify people. It's bound to find things that classify them, and it's bound to find things in common," he says. “In reality, what is observed could reflect the effects of treatments.”

Chaumette adds that, aside from the control group, every person who participated in Alcediag's studies was taking medication (as is often the case in psychiatric research). These drugs could affect the levels of some biomarkers, says Sundram, “so that the algorithm could capture the effect of the drug.”

Weissmann explains that the study participants with bipolar disorder and those with depression were taking a variety of different medications. If the algorithm had differentiated people based on their treatments, it would have classified them by therapeutic class. Also, stable patients - those with a diagnosis but who had no symptoms at the time of the study - had a different biomarker signature than the control group, suggesting that their medication suppressed symptoms without affecting markers of the underlying disease. She says Alcediag's trials included hundreds of participants and that the company is conducting a new clinical trial involving 436 patients; the results are expected next year.

Questions about reproducibility

Some aspects of Alcediag's studies make it difficult for independent researchers to review the work, Chaumette says. The algorithm and its underlying code have not been disclosed, and follow-up studies conducted after the original 2022 study used slightly different versions of the test. For example, in a study the company published this year, one biomarker was removed from the original combination and three new ones were added 2.

This issue led to the French National Health Authority (HAS), an independent body evaluating health products, rejecting Alcediag's request for reimbursement of the test by the French health authorities. “There were performance variations between the three versions and we lacked justification as to why this version was chosen and not another,” says Cédric Carbonneil, who heads the HAS department responsible for evaluating new medical devices and procedures. It is not uncommon for companies in early stages of development to initially have applications rejected. HAS expects Alcediag to reapply, he adds. Alcediag explains that it made changes to the biomarkers to improve the performance of the test and that the algorithm was not disclosed for commercial reasons.

Chaumette says he would have liked to see larger studies supporting the test before it was distributed to patients, and he hopes Alcediag will make its technology available to independent groups to replicate the results. “If you commercialize it quickly and patent everything without sharing anything, it becomes opaque.”

1. Salvetat, N. et al. Transl. Psychiatry 12, 182 (2022).

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2. Salvetat, N. et al. J. Affect. Disord. 356, 385–393 (2024).

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