The endogenous and reactive depression subtypes revisited: integrative animal and human studies implicate multiple distinct molecular mechanisms underlying major depressive disorder

Abstract

Background: Traditional diagnoses of major depressive disorder (MDD) suggested that the presence or absence of stress prior to onset results in either 'reactive' or 'endogenous' subtypes of the disorder, respectively. Several lines of research suggest that the biological underpinnings of 'reactive' or 'endogenous' subtypes may also differ, resulting in differential response to treatment. We investigated this hypothesis by comparing the gene-expression profiles of three animal models of 'reactive' and 'endogenous' depression. We then translated these findings to clinical samples using a human post-mortem mRNA study.

Methods: Affymetrix mouse whole-genome oligonucleotide arrays were used to measure gene expression from hippocampal tissues of 144 mice from the Genome-based Therapeutic Drugs for Depression (GENDEP) project. The study used four inbred mouse strains and two depressogenic 'stress' protocols (maternal separation and Unpredictable Chronic Mild Stress) to model 'reactive' depression. Stress-related mRNA differences in mouse were compared with a parallel mRNA study using Flinders Sensitive and Resistant rat lines as a model of 'endogenous' depression. Convergent genes differentially expressed across the animal studies were used to inform candidate gene selection in a human mRNA post-mortem case control study from the Stanley Brain Consortium.

Results: In the mouse 'reactive' model, the expression of 350 genes changed in response to early stresses and 370 in response to late stresses. A minimal genetic overlap (less than 8.8%) was detected in response to both stress protocols, but 30% of these genes (21) were also differentially regulated in the 'endogenous' rat study. This overlap is significantly greater than expected by chance. The VAMP-2 gene, differentially expressed across the rodent studies, was also significantly altered in the human study after correcting for multiple testing.

Conclusions: Our results suggest that 'endogenous' and 'reactive' subtypes of depression are associated with largely distinct changes in gene-expression. However, they also suggest that the molecular signature of 'reactive' depression caused by early stressors differs considerably from that of 'reactive' depression caused by late stressors. A small set of genes was consistently dysregulated across each paradigm and in post-mortem brain tissue of depressed patients suggesting a final common pathway to the disorder. These genes included the VAMP-2 gene, which has previously been associated with Axis-I disorders including MDD, bipolar depression, schizophrenia and with antidepressant treatment response. We also discuss the implications of our findings for disease classification, personalized medicine and case-control studies of MDD.

Figures

Figure 1

This figure shows the stress administration regime for the unpredictable chronic mild stress paradigm. The duration of the stress regime was for two consecutive weeks and the order of the different stressors was randomized. This figure shows the stressors and time/duration of administration for each of the two weeks.

Figure 2

Venn diagram showing the number of genes significantly altered in response each depressogenic protocol. A compelling finding is the limited number of overlapping genes (approximately 8.8%) suggesting that etiologically different molecular mechanisms underpin a congruent set of behaviors.

Figure 3

Venn diagram showing the number of genes overlapping across all rodent studies. Only 67 genes were differentially regulated in response to both early (MS) and late stressors (UCMS) pointing at minimal genetic overlap. However, many of these genes (approximately 30%) were also differentially regulated in an endogenous rat model of depression. The replication of these genes in a different organism that shows congenital depression-like symptoms, points at molecular mechanisms that may be involved in the human pathology.

Figure 4

Network analysis performed on converging genes differentially regulated in response to different stresses in mouse and between different selected Flinders lines. The pathway comprises over half the reference molecules uploaded to the Ingenuity database system (12 out of the 21 reference molecules). The pathway implicates a number of genes previously associated with MDD and antidepressant treatment response, including Ppm1a, Ywhaz, NkFb and Mapk.