A first-of-its-kind blood test that uses biomarkers to distinguish bipolar disorder from depression could shorten the time it takes to get an accurate diagnosis from years to weeks, according to the company that developed the test; However, some scientists have expressed concerns about its validity.

The test uses biomarkers related to RNA editing to diagnose the condition and has been given regulatory approval in both countries, being available in France since March and Italy since October 2023.

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But some researchers are concerned about the small size of the studies on which the test is based and the lack of independent validation of the studies. The test’s developer, French start-up Alcediag in Montpellier, says the trials are valid and reproducible.

This line underscores a broader debate about the potential of biomarkers (biological characteristics that can indicate a particular medical condition). early diagnosis and more personalized treatments for psychiatric disorders.

“There is a role for researching biomarkers,” says Suresh Sundram, a psychiatrist at Monash University in Melbourne, Australia. “But this is an area of ​​great concern.”

slow diagnosis

Bipolar disorder, a set of conditions characterized by mood swings that alternate between mania and depression, is difficult to diagnose. Approximately 40 million people worldwide live with the disease, and the diagnostic process, which often involves multiple meetings with a psychiatrist, takes an average of seven to ten years; During this time, people are often misdiagnosed with conditions such as: depression and given inappropriate or ineffective treatments.

Alcediag hopes to change this horrific landscape. The company says its 900-euro ($980) blood test EDIT-B can help distinguish bipolar disorder from depression using biomarkers. EDIT-B distinguishes between the two by measuring subtle differences. RNA editing — a regulatory process that alters various cellular mechanisms, including the expression of genes, ultimately affecting neurological functioning.

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

“We have a signature for patients with depression, we have a signature for controls, and… we have a signature for bipolar,” says Dinah Weissmann, co-founder and chief scientific officer of Alcediag. In a 2022 study involving 410 participants, the algorithm distinguished 160 people with depression from 95 people with bipolar disorder with high accuracy¹.

Weissmann says about 80 people have used EDIT-B since its commercialization in France and Italy, and so far the feedback has been positive. He cites an anecdotal report from one person who said he switched to more effective medications after receiving a positive test result. “The patient wrote to his doctor: ‘Great, I can stand on my feet again. I’m living normally again,’” says Weissmann.

Potential risks

For many people with bipolar disorder, a faster and more accurate diagnosis would allow them to access “the right medicine 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, if a blood test gives an incorrect result, there is a risk of diseases being 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 misdiagnosis. But Chaumette and others are concerned about some of the research methodologies used to demonstrate the effectiveness of the EDIT-B test. He points out the “natural limits” of the 2022 study with 410 participants. “You take a data set with lots of variables and not a lot of patients, and you ask an algorithm to classify people. It will inevitably find things that classify them, it will inevitably identify things they have in common,” he says. “What you actually observe may be the effect of treatments.”

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He adds that everyone in Alcediag’s studies, except for the control group, was on medication (as is often the case in psychiatric research). These drugs can affect the levels of some biomarkers, so “the algorithm can capture the effect of the drug,” Sundram says.

Study participants with bipolar disorder and depression were on a number of different medications, Weissmann says, so if the algorithm were separating people based on their treatment, it would classify them into therapeutic classes. He adds that stable patients (those diagnosed at the time of the study but not experiencing symptoms) had a different biomarker signature than the control group, indicating that their medications suppressed symptoms without affecting markers of the underlying disease. Alcediag’s studies have included hundreds of participants, he says, and the company is conducting a new clinical trial with 436 patients; They expect to publish the results next year.

Replication questions

Chaumette says some aspects of Alcediag’s work make it difficult for independent researchers to verify the work. The algorithm and underlying code have not yet been shared, and follow-up studies after the first trial in 2022 used slightly different versions of the test. For example, in a study published this year, the company removed one biomarker from the initial combination and added three new ones.².

This issue led the French National Health Authority (HAS), an independent body that evaluates health products, to reject Alcediag’s application for people who took the test to be reimbursed by French health authorities. “There were performance differences between the three versions, and we lacked justification to explain why this version was chosen over another,” says Cédric Carbonneil, head of the HAS department responsible for the evaluation of new medical devices and procedures. He added that it was not unusual for applications from companies in the early stages of development to be initially rejected, and that HAS expected Alcediag to re-apply. Alcediag says it made changes to the biomarkers to improve the performance of the test and does not share the algorithm for commercial reasons.

Chaumette said he would like to see larger studies supporting the test before it is applied to patients, and he hopes Alcediag will make its technology available to independent groups to allow them to replicate the findings. “If you commercialize quickly and patent everything without sharing anything, then it won’t be transparent.”