Brain and Blood Biomarkers Identified for Major Depressive Disorder

Emerging evidence suggests major depressive disorder may be detectable through shared molecular changes in brain and blood, with multiomic data revealing overlapping genetic and epigenetic signatures that could pave the way for clinically useful biomarkers. A systematic review published in JAMA Psychiatry found differentially expressed and differentially methylated genes in major depressive disorder brain and blood that also have variants associated with the disorder in genome-wide association study databases.

Major depressive disorder is a heterogeneous and debilitating psychiatric illness associated with substantial morbidity and suicide risk. Genome wide association studies have demonstrated that major depressive disorder is polygenic, involving thousands of small effect variants. Environmental influences further shape disease risk through epigenetic mechanisms, including altered DNA methylation and gene expression. Despite this complexity, no validated biomarkers exist for major depressive disorder.

The systematic review included 54 studies, comprising 30 brain studies, 20 blood studies, and 4 analysing both tissues. Across datasets, 744 differentially expressed genes were altered in the same direction in brain and blood, 43 of which overlapped with GWAS identified MDD risk loci. Additionally, 544 differentially methylated genes were altered in the same direction in brain and blood, 34 of which overlapped with GWAS identified MDD risk loci. Identified hub genes converged on developmental, inflammatory, transcriptional, apoptotic, and mitochondrial pathways. These findings indicate that major depressive disorder involves coordinated molecular dysregulation detectable across tissues.

While the individual dysregulated genes are highly variable across studies and brain regions, converging pathways and hub gene functions, including those related to neurodevelopment, mitochondria, neuroinflammation, apoptosis, and transcriptional regulation emerge across studies.

In a separate study published in Nature, researchers identified a brain-enriched circular RNA, CDR1as, that is associated with symptomatic response to SSRI treatment. Expression of CDR1as was found to be regulated by serotonin and Brain-Derived Neurotrophic Factor receptor activity. Using circRNA-specific PCR in baseline whole blood samples from two independent cohorts, drawn from the Establishing moderators and biosignatures of antidepressant response in clinical care (EMBARC) and the Biomarkers of ANTidepressant RESponse (ANTARES) clinical studies, researchers showed that before treatment CDR1as is differentially expressed between future symptomatic responders and non-responders to treatment with the SSRI sertraline.

CDR1as levels were altered following sertraline treatment in responders with the trajectory of change post-treatment associated with long-term remission. Levels of CDR1as in the blood can specifically predict remission with SSRI treatment, but not response or remission with Placebo or Bupropion treatments. Animal mechanistic and neuronal culture studies suggest mouse Cdr1as is strongly regulated by 5-HT2A and BDNF receptor signaling.

The identification of overlapping gene expression and methylation signatures suggests major depressive disorder may have measurable peripheral biomarkers reflecting central nervous system pathology. Such biomarkers could support earlier diagnosis, enable phenotypical stratification, and inform precision medicine approaches. Cell-type specific multiomic studies involving understudied brain regions are needed to better understand the pathophysiology of major depressive disorder and identify relevant biomarkers and treatment targets. If validated, blood-based molecular markers could complement clinical assessment and improve treatment selection, ultimately advancing personalised care for major depressive disorder.