Blood transcriptomic biomarkers in adult primary care patients with major depressive disorder undergoing cognitive behavioral therapy

Abstract

An objective, laboratory-based diagnostic tool could increase the diagnostic accuracy of major depressive disorders (MDDs), identify factors that characterize patients and promote individualized therapy. The goal of this study was to assess a blood-based biomarker panel, which showed promise in adolescents with MDD, in adult primary care patients with MDD and age-, gender- and race-matched nondepressed (ND) controls. Patients with MDD received cognitive behavioral therapy (CBT) and clinical assessment using self-reported depression with the Patient Health Questionnaire–9 (PHQ-9). The measures, including blood RNA collection, were obtained before and after 18 weeks of CBT. Blood transcript levels of nine markers of ADCY3, DGKA, FAM46A, IGSF4A/CADM1, KIAA1539, MARCKS, PSME1, RAPH1 and TLR7, differed significantly between participants with MDD (N=32) and ND controls (N=32) at baseline (q< 0.05). Abundance of the DGKA, KIAA1539 and RAPH1 transcripts remained significantly different between subjects with MDD and ND controls even after post-CBT remission (defined as PHQ-9 <5). The ROC area under the curve for these transcripts demonstrated high discriminative ability between MDD and ND participants, regardless of their current clinical status. Before CBT, significant co-expression network of specific transcripts existed in MDD subjects who subsequently remitted in response to CBT, but not in those who remained depressed. Thus, blood levels of different transcript panels may identify the depressed from the nondepressed among primary care patients, during a depressive episode or in remission, or follow and predict response to CBT in depressed individuals.

Translational identification of transcriptional signatures of major depression and antidepressant response

“…In a series of experiments, Redei et al (2014) used genetic models of depression and chronic stress on different strains of rats to separately profile transcriptional signatures of depression in the brain and the blood, and test whether a subset of transcripts that differentiated depressed-like rats from non-depressed-like rats would also differentiate human patients with early-onset MDD from those without any disorder. The same gene candidates were tested for their capacity to follow and predict response to a cognitive behavioral therapy Pajer et al, 2012;Redei et al, 2014;Redei and Mehta, 2015;Mehta-Raghavan et al, 2016). Although characteristics of the animal model we used and that of our human validation cohort were different, it turned out that some variations in transcriptional signatures were shared between the different animal models and the human cohorts.…”

“…For example, CMAS, encoding cytidine monophosphate N-acetylneuraminic acid synthetase, regulates brain sialylation, which is important for the development of brain structure and function (Yoo et al, 2015). CMAS was among the short list of blood-based biomarkers from the Redei et al (2014) studies, as well as among the candidate gene list from a transcriptome analysis on a naturalistic cohort of MDE patients responding to antidepressant treatment (Belzeaux et al, 2012). CMAS is also part of the most dysregulated transcripts in the UCMS procedure between stressed mice responding to fluoxetine and stressed mice that were either untreated or not responding to fluoxetine (Supplementary Table S5).…”

The Promise of Biomarkers in Diagnosing Major Depression in Primary Care: the Present and Future

“…It can be unbiased, such as genome-wide expression analyses in human samples [33••, 55], in samples from a valid animal model [40,41], or a combination of both [56]. An alternate, unbiased process integrates genome-wide expression and genetic findings to identify biomarkers [39].…”

“…Our group took a different route to MDD biomarker discovery [40]. We identified a prospective panel of blood transcriptomic biomarkers by genome-wide expression analysis of both a genetic and a chronic stress-induced animal model of depression.…”

“…Some suggest that diagnosing major depression is an art not science, while others discount conclusions from an independent study [50] when it does not replicate their initial findings [51•]. Animal studies are dismissed as having limited direct relevance or specificity to the human condition [51], even if the results can be translated into humans [40]. Sometimes, the replication studies are done in subjects with differing diagnosis from the original discovery population [39,52].…”