Bipolar disorder (BD), which affects 1% of the population, is often confused with major depressive disorder (MDD) due to similar symptoms and the prevalence of consultations during depressive episodes. Researchers at the University of Cambridge have identified a panel of biomarkers in blood samples that can differentiate BD from MDD with good accuracy.
Bipolar disorder (BD) is a neuropsychiatric condition that affects around 1% of the population worldwide but presents significant diagnostic challenges due to its similarity to other disorders, such as major depressive disorder (MDD).
Around 40% of patients with BD are initially misdiagnosed with MDD, which is because many seek medical care during depressive episodes, while manic episodes—a hallmark of BD—may be less noticeable or reported.
In addition, psychiatric assessments often rely on subjective reports, further complicating correct identification.
To overcome these challenges, researchers are exploring the use of biomarkers, biological molecules found in blood, or other bodily fluids that can indicate specific processes in the body.
Biomarkers have the potential to provide an early, objective method of differentiating BD from MDD, overcoming the subjectivity of traditional methods. However, previous studies have faced challenges such as interference from mood-stabilizing medications and a lack of independent validation cohorts.
Researchers at the University of Cambridge conducted a study to address these limitations using metabolomic analysis of dried blood spots (DBS). This study is part of the Delta project, which ran in the UK between 2018 and 2020 and was designed to identify specific biomarkers that could differentiate BD from MDD in patients who were initially misdiagnosed.
Participants were recruited online and included people recently diagnosed with MDD (within the past five years) who were currently experiencing depressive symptoms. They completed an adaptive questionnaire with 635 questions, covering everything from mental well-being to aspects of mood, such as items from the Mood Disorders Questionnaire (MDQ).
In addition, fasting blood samples were collected via mailed kits.
These samples were analyzed to identify 630 different metabolites using an advanced mass spectrometry platform. Mood disorder diagnoses were subsequently confirmed by telephone interviews using the Composite International Diagnostic Interview (CIDI), a reference standard for clinical diagnosis.
The study analyzed two cohorts:
1 - Discovery cohort: 241 participants, of whom 67 were later diagnosed with BD and 174 confirmed with MDD.
2 - Validation cohort: 30 participants, of whom 9 had BD and 21 had MDD.
The analysis revealed a panel of 17 biomarkers that helped distinguish BD from MDD, with an accuracy assessed by the receiver operating characteristic curve (AUROC) of 0.71, indicating good diagnostic performance.
The strongest biomarker identified was ceramide d18:0/24:1, a molecule involved in cellular and inflammatory processes.
Dried Blood Spot Metabolomic Signature Distinguishing Bipolar Disorder from Major Depressive Disorder in Patients with Current Depressive Symptoms. A) Area under the receiver operating characteristic curve (AUROC) indicating the diagnostic performance of the biomarker panel identified in the discovery cohort (67 patients with misdiagnosed BD and 174 with MDD). B) AUROC in the validation cohort (9 patients with BD and 21 with MDD clinically diagnosed with a mood disorder during the 1-year follow-up period). C) Relative importance of individual biomarkers in the classification model. GCA indicates glycocholic acid; 3-IAA, indoleacetic acid; 3-IPA, indolepropionic acid; TMAO, trimethylamine N-oxide.
By combining biomarker data with patient self-reported information, diagnostic performance was further improved, demonstrating the value of an integrated approach.
The identified biomarkers were particularly associated with lifetime manic episodes, a key feature of BD. These results were validated in patients who had received updated diagnoses of BD or MDD over the past year, with an AUROC of 0.73, reinforcing the robustness of the biomarker panel.
In addition to offering a promising tool for differential diagnosis, the study highlighted the potential role of ceramides in the pathophysiological mechanisms underlying mood disorders, suggesting new avenues for research and treatment.
This study represents a breakthrough in the development of accessible and objective tests to distinguish BD from MDD, potentially revolutionizing the way these disorders are diagnosed.
By reducing misdiagnosis, it is possible to improve treatments and prognosis, directly benefiting patients. Furthermore, elucidating the role of ceramides opens the door to new treatments targeting specific metabolic pathways involved in BD.
READ MORE:
Metabolomic Biomarker Signatures for Bipolar and Unipolar Depression
Jakub Tomasik; Scott J. Harrison; Nitin Rustogi; Tony Olmert; Giles Barton-Owen; Sung Yeon Sarah Han; Jason D. Cooper; Paweł Eljasz; Lynn P. Farrag; Lauren V. Friend; Emily Bell; Dan Cowell; Sabine Bahn
JAMA Psychiatry. 2024;81(1):101-106.
doi:10.1001/jamapsychiatry.2023.4096
Abstract:
Importance Bipolar disorder (BD) is frequently misdiagnosed as major depressive disorder (MDD) because of overlapping symptoms and the lack of objective diagnostic tools. To identify a reproducible metabolomic biomarker signature in patient dried blood spots (DBSs) that differentiates BD from MDD during depressive episodes and assess its added value when combined with self-reported patient information. This diagnostic analysis used samples and data from the Delta study, conducted in the UK between April 27, 2018, and February 6, 2020. The primary objective was to identify BD in patients with a recent (within the past 5 years) diagnosis of MDD and current depressive symptoms (Patient Health Questionnaire–9 score of 5 or more). Participants were recruited online through voluntary response sampling. The analysis was carried out between February 2022 and July 2023. Patient data were collected using a purpose-built online questionnaire (n = 635 questions). DBS metabolites (n = 630) were analyzed using a targeted mass spectrometry–based platform. Mood disorder diagnoses were established using the Composite International Diagnostic Interview. Of 241 patients in the discovery cohort, 170 (70.5%) were female; 67 (27.8%) were subsequently diagnosed with BD and 174 (72.2%) were confirmed as having MDD; and the mean (SD) age was 28.1 (7.1) years. Of 30 participants in the validation cohort, 16 (53%) were female; 9 (30%) were diagnosed with BD and 21 (70%) with MDD; and the mean (SD) age was 25.4 (6.3) years. DBS metabolite levels were assessed in 241 patients with depressive symptoms with a recent diagnosis of MDD, of whom 67 were subsequently diagnosed with BD by the Composite International Diagnostic Interview and 174 were confirmed as having MDD. The identified 17-biomarker panel provided a mean (SD) cross-validated area under the receiver operating characteristic curve (AUROC) of 0.71 (SD, 0.12; P < .001), with ceramide d18:0/24:1 emerging as the strongest biomarker. Combining biomarker data with patient-reported information significantly enhanced diagnostic performance of models based on extensive demographic data, PHQ-9 scores, and the outcomes from the Mood Disorder Questionnaire. The identified biomarkers were correlated primarily with lifetime manic symptoms and were validated in a separate group of patients who received a new clinical diagnosis of MDD (n = 21) or BD (n = 9) during the study’s 1-year follow-up period, with a mean (SD) AUROC of 0.73 (0.06; P < .001). This study provides a proof of concept for developing an accessible biomarker test to facilitate the differential diagnosis of BD and MDD and highlights the potential involvement of ceramides in the pathophysiological mechanisms of mood disorders.
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