Scientists have developed a panel of blood biomarkers that they claim can diagnose major depressive disorder (MDD) in adolescents and young adults (early-onset MDD). The set of 11 gene transcript biomarkers was initially discovered through combined studies in both genetic and environmental stress-related rat models of MDD, and subsequently validated in initial studies in human patients.
In addition to identifying and validating an 11-gene panel for diagnosing early-onset MDD, the Northwestern University-led team found a partially overlapping, 18-gene panel of biomarkers that could distinguish between patients exhibiting just early-onset MDD, and those with major depression and anxiety disorder. The authors describe their research in Translational Psychiatry, in a paper titled “Discovery of blood transcriptomic markers for depression in animal models and pilot validation in subjects with early-onset major depression.”
Early-onset MDD is currently diagnosed through patient self-reporting and clinical observation. Two different approaches have been used to try and identify blood-based biochemical markers for the disorder and its stratification. One is based on screening for markers suggested by current knowledge of MDD etiology, such as cortisol or brain-derived neurotrophic factor. The other has focused on the use of omic technologies such as proteomic profiling or trancriptomic profiling of bipolar disorder, psychosis, or mood disorders. Unfortunately, the Northwestern team writes, neither approach has yielded selective and reproducibly demonstrable biomarkers for early-onset MDD.
Because evidence suggests that MDD has both genetic and environmental stress-related etiologies, the authors generated both a genetic, and different chronic stress-based rat models of MDD. They then carried out genome-wide expression analyses in these animals, compared with normal controls, to identify a set of candidate transcripts that could be also be measured in human blood. “The core hypothesis for this study was that the combined list of transcripts that differentiated depressed-like from non-depressed-like rats would also differentiate human subjects with early-onset MDD from those without any disorder,” the investigators note.
A panel of eleven transcripts found at increased levels in the blood and brains of either the genetic or stress-induced MDD animals was also found to differentiate between a cohort of 14 adolescent patients with diagnosed MDD, and healthy controls. The transcripts included MARCKS, MAF, FAM46A, NAGA, UBE3A, CD59, ATP11C, RAPH1, SCAPER/ZNF291, TLR7, and IGSF4A/CADM1A. A separate, and partially overlapping panel of 18 biomarkers was subsequently found to delineate between patients with MDD and those exhibiting MDD associated with anxiety disorders. This set of biomarkers included CD59, FAM46A, IGSF4A/CADM1, NAGA, TLR7, ZNF291/SCAPER, AHSP, AMFR, CAT, CDR2, CMAS, DGKA, GCLM, GGA3, IRF3, KIAA1539, PSME1, and SLC4A1.
Interestingly, the authors write, the 11-transcript diagnostic panel comprised markers derived almost 50/50 from the genetic and chronic stress models, and includes transcripts belonging to three broad functional gene categories: transption, neurodevelopment, and neurodegeneration. Only 6 of the 18 biomarker transcripts distinguishing between patients with MDD, from those with MDD and anxiety, were also found in the original 11-transcript biomarker panel. The other 12 were unique to the MDD-anxiety diagnostic category. “Furthermore, the panel differentiating MDD youths with and without comorbid anxiety disorders had a substantially higher number of genes derived from the chronic stress model than from the genetic model,” the researchers note. “These latter observations support the longstanding clinical impression that MDD with comorbid anxiety disorders is a unique phenotype.”
They claim the next step will be to test the findings in a larger sample of youths with MDD and MDD with comorbid anxiety, as well as those with other psychiatric disorders. “These 11 genes are probably the tip of the iceberg because depression is a complex illness,” professor Redei admits. “But its an entree into a much bigger phenomenon that has to be explored...right now, depression is treated with a blunt instrument. The early diagnosis and specific classification of early major depression could lead to a larger repertoire of more effective treatments and enhanced individualized care.”