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Bipolar disorder (BD) is a severe mental disorder associated with functional impairment, high disability and premature mortality. Modifications of editing in mRNA of serotonin receptor subtype 2C (5-HTR2c) was reported by us in depressed suicide decedents. We have also identified a panel of RNA editing-based blood biomarkers for the diagnosis of BD, which also allowed to discriminate unipolar depression from BD with high sensivity and specificity.
Objectives
Herein, aiming to confirm the diagnostic value of this panel, a new cohort of BD patients was recruited in Brazil.
Methods
This study is based on the analysis of 47 control patients (CTRL) compared to 40 patients with bipolar disorder (BD). BD patients (BP) were classified into 4 subgroups: euthymic (BP_EUT, n = 17), depressive (BP_DEP, n = 11), manic/hypomanic (BP_HM, n = 7) and mixed (BP_MIX, n = 5). The diagnostic value of a panel of RNA editing-based blood biomarkers for the diagnosis of BD, which includes a set of eight genes, namely PDE8A, CAMK1D (calcium/calmodulin-dependent protein kinase type 1D); GAB2 (growth factor receptor bound protein 2-associated protein 2); IFNAR1 (interferon alpha/beta receptor 1); KCNJ15 (ATP-sensitive inward rectifier potassium channel 15); LYN (tyrosine-protein kinase Lyn); MDM2 (E3 ubiquitin-protein ligase Mdm2); PRKCB (protein kinase C beta type), which was able to discriminate unipolar depression from BD with high sensivity and specificity, was confirmed here by testing an independent cohort of patients suffering from BD recruited in a well-known genetic admixed ancestry population, which is typical in South America, more specifically in Brazil.
Results
We identified new combinations allowing a clear discrimination of euthymic versus depressed bipolar patients, and euthymic versus healthy controls, confirming that RNA editing is a key mechanism in the physiopathology of mental disorders, in particular in BD.
Conclusions
In conclusion of this study, we confirm that RNA editing is a key mechanism in the physiopathology of mental disorders in general, and in BD in particular, and that measuring changes in this mechanism at the peripheral level allowed us to stratify BD patients not only with respect to their symptomatology, but also with respect to the pathophysiology, thus paving the way for personalised medicine in psychiatry.
Bipolar disorder (BD) is a psychiatric disorder characterized by alternating episodes of high mood and low mood similar to depression. To differentiate BD patients from unipolar (UN) depressed patients remains a challenge and the clinical scales available failed to distinguish these 2 populations. ALCEDIAG developed EDIT-B, the first blood test able to make a differential diagnosis of BD. Based on RNA editing modifications measurement and AI, the test requires a simple blood draw and equipment available in most central laboratories. A first study on 160 UN and 95 BD patients allowed a differential diagnosis with an AUC of 0.935 and high specificity (Sp=84.6%) and sensitivity (Se=90.9%). A multicentric clinical study has been set up to validate these performances.
Objectives
The objective of this project is to run a multicentric clinical study in Europe and assess the performances of the test.
Methods
The EDIT-B project, led by Alcediag, is supported by EIT-Health grant (European institute of Innovation and Technology) and gathers 4 clinical centers in 3 countries (France, Spain, Danemark), a CRO for the clinical study management (Aixial), a CRO for the development of a diagnostic kit (Veracyte), a diagnostic lab for molecular biology analyses (Synlab), and a regulatory company (PLG).
Results
At the end of the study, the EDIT-B performance will be confirmed and the test will be CE-marked.
Conclusions
This test will address the needs of millions of patients suffering from misdiagnosis and therefore allow them to receive the correct treatment.
In clinical practice, differentiating Bipolar Disorder (BD) from unipolar depression is challenging due to the depressive symptoms, which are the core presentations of both disorders. Patients with BD are often misdiagnosed during depressive episodes resulting in a delay in proper treatment and a poor management of their condition.
Objectives
The aim of the present study is to discriminate between unipolar depression and BD using a panel of RNA edited blood biomarkers.
Methods
Depressed patients were classified according to clinical scores in MADRS and IDSC-30 depression scales. After blood collection and RNA extraction, we used whole-transcriptome sequencing to identify differential A-to-I editing events, and Targeted Next Generation Sequencing to validate those biomarkers.
Results
We discovered 646 variants differentially edited between depressed patients and control in a discovery cohort of 57 participants. After using stringent criteria and biological pathway analysis, 6 biomarker candidates were singled out and tested in a validation cohort of 160 patients suffering from unipolar depression and 95 BD patients in a depressive episode, which allowed a differential diagnosis of BD with an AUC of 0.935 and high specificity (Sp=84.6%) and sensitivity (Se=90.9%).
Conclusions
We have shown that a combination of 6 blood RNA editing-related biomarkers allows to discriminate unipolar and bipolar depression This 6 BMKs panel may be crucial to improve BD diagnosis and orientate the treatment therefore addressing the needs of millions of patients suffering from misdiagnosis and incorrect treatment for their diseases. This will change the game for the management of patients.
Predicting suicidal behaviors is one of the most complex challenges of daily psychiatric practices. Alterations of RNA editing of neurotransmitter receptors and other proteins have been shown to be involved in etiology of different psychiatric disorders and linked to suicidal behavior. Additionally, an increase in expression levels of ADARs, the RNA editing enzymes, has also been observed.
Objective
The objective of the present study was to test whether modifications in RNA editing profile of prime targets allow identifying disease-relevant blood biomarkers and evaluating suicide risk in patients.
Methods
A clinical study was performed to identify an RNA editing signature in blood of depressed patients with and without history of suicide attempts. Patient's samples were drawn in PAXgene tubes and analyzed on Alcediag's proprietary RNA editing platform using NGS. In addition, gene expression analysis by quantitative PCR was performed.
Results
We generated a predictive algorithm comprising various selected biomarkers to detect patients with a high risk to attempt suicide. We evaluated the diagnostic performance using the relative proportion of the phosphodiesterase 8A (PDE8A) mRNA editing at different sites as well as the expression of PDE8A and the ADARs. The significance of these biomarkers for suicidality was evaluated using the receiver–operating characteristic (ROC) curve. The generated algorithm comprising the biomarkers was found to have strong diagnostic performances with high specificity and sensitivity.
Conclusions
We developed tools to measure disease–specific biomarkers in blood samples of patients for identifying individuals at the greatest risk for future suicide attempts.
Disclosure of interest
The authors have not supplied their declaration of competing interest.
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