The trial, led by Raoul Belzeaux, Erica Fongaro and Leena Endrey of Montpellier University Hospital together with Nicolas Glaichenhaus of the Côte d’Azur University and more than two dozen collaborating investigators across France, is registered on ClinicalTrials.gov under number NCT07031817 and was registered on May 30, 2025. Its central question is deceptively simple: can a combination of five circulating immune-inflammatory proteins, a handful of clinical variables and the Mood Disorder Questionnaire reliably distinguish bipolar disorder from unipolar major depression in adults who present with a major depressive episode and are eligible for antidepressant treatment? If the answer is yes, the implications for everyday psychiatric practice could be transformative, because the tool would give general practitioners an objective, biologically grounded signal where today they have only clinical intuition.

The scientific logic behind the device rests on a growing body of evidence that bipolar disorder is not merely a pattern of symptoms but a condition with measurable biological signatures. Researchers have repeatedly found altered concentrations of immune signaling molecules in the blood of people with bipolar disorder, including interleukin-6, interleukin-10, interleukin-15, interleukin-27 and the chemokine CXCL10. These molecules, known as cytokines and chemokines, are the messengers of the immune system, and their dysregulation is thought to reflect the low-grade inflammatory state that has been documented in subsets of patients with mood disorders. Individually, none of these proteins is specific enough to serve as a diagnostic marker. The trial’s designers, however, are betting that a composite in vitro diagnostic algorithm, one that integrates the combined pattern of these serum biomarkers with clinical variables such as age and psychotropic treatment status, will achieve a level of diagnostic accuracy that no single component could reach alone.

The Mood Disorder Questionnaire, or MDQ, is the third pillar of the device. This thirteen-item self-report instrument, widely used in primary care, asks patients about symptoms of hypomania, whether those symptoms cluster together and whether they cause problems. The MDQ is cheap, fast and easy to administer, but its real-world performance has been inconsistent, with sensitivity and specificity varying widely across settings and populations. The trial’s hypothesis is that the questionnaire’s weaknesses can be compensated by the biological signal from the blood biomarkers, and that the resulting composite device will outperform the MDQ alone in a real-world primary-care pathway. This is a critical distinction, because the trial is not testing the tool in an idealized research setting but in the messy, time-pressured environment of everyday general practice.

The study design reflects this real-world ambition. General practitioners and primary-care centers across France will prescreen adults aged 18 to 65 who, in their clinical assessment, are experiencing a major depressive episode and are eligible for antidepressant treatment. After referral, participants will attend a specialized outpatient psychiatric center where they will undergo a structured diagnostic interview using the Mini International Neuropsychiatric Interview, complete clinician-rated and self-rated scales and provide fasting blood samples. The composite diagnostic algorithm will then be applied to the resulting data, and its performance will be assessed against an expert diagnosis based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, at baseline and again at a follow-up visit seven to nine weeks later. The planned sample size is 623 participants, a figure chosen to provide adequate precision for sensitivity and specificity estimates under an expected bipolar disorder prevalence of roughly 10 percent in this population.

Diagnostic performance will be evaluated using standard metrics, including sensitivity, specificity, positive and negative predictive values and the area under the receiver operating characteristic curve, a measure that captures the trade-off between correctly identifying true cases and avoiding false alarms across all possible diagnostic thresholds. Secondary objectives are equally ambitious. The researchers plan to characterize the false positives and false negatives produced by the device, to assess whether the tool can predict which patients will experience a hypomanic switch or depressive improvement after eight weeks of treatment, to evaluate the analytical variability of the biomarker measurements and the acceptability of the device from the patient’s perspective, and to compare the device’s diagnostic judgement with that of the treating general practitioner. These secondary analyses are designed to reveal not only whether the device works but how it fails, which patients it misses and which it wrongly flags, information that will be essential for responsible clinical deployment.

Two parallel studies are planned alongside the main trial. An acceptability study will examine how patients and clinicians respond to the device in practice, probing whether people are willing to provide blood samples and whether general practitioners find the tool useful in their decision-making. A medico-economic modelling study will use the French national health database, known as the Système National des Données de Santé, to estimate the device’s impact on care pathways and healthcare costs. This economic analysis is a crucial component, because even a diagnostically accurate tool must be shown to be cost-effective if it is to be adopted at scale in national health systems. The modelling will draw on real-world data from millions of French patients, providing a level of economic evidence that is rarely available for psychiatric diagnostic tools.

The trial is sponsored by Montpellier University Hospital and funded by the Erié Fund, hosted by the King Baudouin Foundation, and by FondaMental through the Prix Marcel Dassault 2022, with external peer review of the submitted protocol built into the funding programs. Ethical approval was granted by the CPP Ouest IV ethics committee, and informed consent will be collected from all participants before any trial-specific procedure begins. The study’s protocol version 4.1, dated August 12, 2026, reflects a level of methodological rigor that is essential for a trial of this scale, involving a data monitoring committee, a clinical research unit with a methodologist, statistician and data manager, and electronic case report forms to ensure data quality across the many participating centers.

The stakes of this trial extend far beyond the borders of France. Bipolar disorder affects roughly one percent of the population worldwide and is among the leading causes of disability in young adults, yet the average delay between the first depressive episode and a correct bipolar diagnosis is estimated at six to ten years. During that interval, patients are frequently treated with antidepressants alone, which can trigger hypomanic or manic episodes, worsen the long-term course of the illness and increase suicide risk. Early and accurate identification of bipolar disorder in adults presenting with a major depressive episode could improve prognosis, reduce suicide risk and lower healthcare and societal costs, according to the trial’s designers. A validated composite diagnostic device could support earlier and more precise diagnosis, inform treatment decisions and provide data to model its impact on care pathways and costs, potentially reshaping the way depression is diagnosed and treated in primary care around the world.

The trial’s publication as an open-access study protocol in BMC Psychiatry, with a permanent DOI and full transparency about its methods, reflects a broader movement toward open science in psychiatric research. The article was received on August 28, 2026, accepted on October 3, 2026, and published on October 16, 2026, and the full protocol is freely available to researchers, clinicians and patients everywhere. If the trial succeeds, it will represent one of the first clinically validated composite diagnostic medical devices in psychiatry, a field that has long lagged behind oncology and cardiology in the development of objective diagnostic tools. The device would not replace clinical judgement but would augment it, giving general practitioners a biologically informed second opinion at the moment when it matters most, before the first antidepressant prescription is written. For the millions of patients whose bipolar disorder hides behind a mask of ordinary depression, that second opinion could not come soon enough.

Subject of Research: Clinical validation of a composite medical device combining blood biomarkers, a decision algorithm, and the Mood Disorder Questionnaire to support the differential diagnosis of bipolar disorder in primary-care patients with a major depressive episode: a study protocol

Article Title: Clinical validation of a composite medical device combining blood biomarkers, a decision algorithm, and the Mood Disorder Questionnaire to support the differential diagnosis of bipolar disorder in primary-care patients with a major depressive episode: a study protocol

Article References: Belzeaux, R., Fongaro, E., Endrey, L., Bourla, A., Buresi, A., Conejero, I., Higelin, A. C., Dias-Alves, M., Drapier, D., Dupouy, J., Durand-Zaleski, I., Odoul, A.-S., Haoui, R., Klein, R., Lefrere, A., Lutz, P.-E., Mesmoudi, S., Olivier, F., Oriol, N., … Glaichenhaus, N. (2026). Clinical validation of a composite medical device combining blood biomarkers, a decision algorithm, and the Mood Disorder Questionnaire to support the differential diagnosis of bipolar disorder in primary-care patients with a major depressive episode: a study protocol. BMC Psychiatry. https://doi.org/10.1186/s12888-026-08751-1

Image Credits: AI Generated

DOI: 10.1186/s12888-026-08751-1

Keywords: Clinical, validation, composite, medical, device, combining, blood, biomarkers, decision, algorithm, Mood, Disorder