Open Access Highly Accessed Research article

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

Karim Malki1*, Robert Keers1*, Maria Grazia Tosto12, Anbarasu Lourdusamy3, Lucia Carboni4, Enrico Domenici56, Rudolf Uher17, Peter McGuffin1 and Leonard C Schalkwyk1

Author Affiliations

1 King’s College London, MRC Social, Genetic and Developmental Psychiatry Centre, at Institute of Psychiatry, SGDP Research Centre (PO80), De Crespigny Park, Denmark Hill, London SE5 8AF, UK

2 Department of Psychology, University of York, York, UK

3 Queen’s Medical Centre, University of Nottingham, Nottingham, UK

4 Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, Bologna, Italy

5 Center of Excellence for Drug Discovery in Neuroscience, GlaxoSmithKline Medicines Research Centre, Verona, Italy

6 Current address: Pharma Research and Early Development, F. Hoffmann–La Roche, Basel, Switzerland

7 Department of Psychiatry, Dalhousie University, Halifax, NS, Canada

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BMC Medicine 2014, 12:73  doi:10.1186/1741-7015-12-73

Published: 7 May 2014



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.


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.


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.


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.

Endogenous Depression; Reactive Depression; GENDEP; VAMP-2; DSM-IV; Stanley Brain Consortium; mRNA; Stress