title: 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.
authors.affiliation: 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. karim.malki@kcl.ac.uk.
authors.forename: Karim
authors.initials: K
authors.lastname: Malki
authors.forename: Robert
authors.initials: R
authors.lastname: Keers
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Tosto
authors.forename: Anbarasu
authors.initials: A
authors.lastname: Lourdusamy
authors.forename: Lucia
authors.initials: L
authors.lastname: Carboni
authors.forename: Enrico
authors.initials: E
authors.lastname: Domenici
authors.forename: Rudolf
authors.initials: R
authors.lastname: Uher
authors.forename: Peter
authors.initials: P
authors.lastname: McGuffin
authors.forename: Leonard C
authors.initials: LC
authors.lastname: Schalkwyk
mesh_terms: D000275:Adjustment Disorders / Q000235:genetics*; D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use; D001921:Brain / Q000473:pathology; D016022:Case-Control Studies; D003863:Depression / Q000175:diagnosis / Q000235:genetics; D003866:Depressive Disorder / Q000175:diagnosis / Q000235:genetics*; D003865:Major Depressive Disorder / Q000145:classification / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation; D006624:Hippocampus; D006801:Humans; D008297:Male; D008426:Maternal Deprivation; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D051381:Rats; D013315:Stress, Psychological / Q000235:genetics*; D050988:Vesicle-Associated Membrane Protein 2 / Q000235:genetics
chemical_list: D000928:Antidepressive Agents; D012333:RNA, Messenger; C494807:VAMP2 protein, human; D050988:Vesicle-Associated Membrane Protein 2; C494808:vesicle-associated membrane protein 2, mouse