Metabolic Brain Disease

, Volume 24, Issue 1, pp 27–53 | Cite as

The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression

  • Michael MaesEmail author
  • Raz Yirmyia
  • Jens Noraberg
  • Stefan Brene
  • Joe Hibbeln
  • Giulia Perini
  • Marta Kubera
  • Petr Bob
  • Bernard Lerer
  • Mario Maj
Original Paper


Despite extensive research, the current theories on serotonergic dysfunctions and cortisol hypersecretion do not provide sufficient explanations for the nature of depression. Rational treatments aimed at causal factors of depression are not available yet. With the currently available antidepressant drugs, which mainly target serotonin, less than two thirds of depressed patients achieve remission. There is now evidence that inflammatory and neurodegenerative (I&ND) processes play an important role in depression and that enhanced neurodegeneration in depression may–at least partly–be caused by inflammatory processes. Multiple inflammatory-cytokines, oxygen radical damage, tryptophan catabolites–and neurodegenerative biomarkers have been established in patients with depression and these findings are corroborated by animal models of depression. A number of vulnerability factors may predispose towards depression by enhancing inflammatory reactions, e.g. lower peptidase activities (dipeptidyl-peptidase IV, DPP IV), lower omega-3 polyunsaturated levels and an increased gut permeability (leaky gut). The cytokine hypothesis considers that external, e.g. psychosocial stressors, and internal stressors, e.g. organic inflammatory disorders or conditions, such as the postpartum period, may trigger depression via inflammatory processes. Most if not all antidepressants have specific anti-inflammatory effects, while restoration of decreased neurogenesis, which may be induced by inflammatory processes, may be related to the therapeutic efficacy of antidepressant treatments. Future research to disentangle the complex etiology of depression calls for a powerful paradigm shift, i.e. by means of a high throughput-high quality screening, including functional genetics and genotyping microarrays; established and novel animal and ex vivo–in vitro models for depression, such as new transgenic mouse models and endophenotype-based animal models, specific cell lines, in vivo and ex vivo electroporation, and organotypic brain slice culture models. This screening will allow to: 1) discover new I&ND biomarkers, both at the level of gene expression and the phenotype; and elucidate the underlying molecular I&ND pathways causing depression; and 2) identify new therapeutic targets in the I&ND pathways; develop new anti-I&ND drugs for these targets; select existing anti-I&ND drugs or substances that could augment the efficacy of antidepressants; and predict therapeutic response by genetic I&ND profiles.


Depression Inflammation Cytokines Neurodegeneration Oxidative stress Nitrosative stress Tryptophan Serotonin IDO. 


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Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Michael Maes
    • 1
    Email author
  • Raz Yirmyia
    • 2
  • Jens Noraberg
    • 3
    • 4
  • Stefan Brene
    • 5
  • Joe Hibbeln
    • 6
  • Giulia Perini
    • 7
  • Marta Kubera
    • 8
  • Petr Bob
    • 9
  • Bernard Lerer
    • 10
  • Mario Maj
    • 11
  1. 1.Clinical Research Center for Mental HealthAntwerp WilrijkBelgium
  2. 2.Department of PsychologyThe Hebrew UniversityJerusalemIsrael
  3. 3.Molecular Neurobiology Laboratory, Medical Biotechnology CenterUniversity of Southern DenmarkOdenseDenmark
  4. 4.Department of Anatomy and NeurobiologyUniversity of Southern DenmarkOdenseDenmark
  5. 5.Department of Neurobiology, Care Sciences and SocietyKarolinska University Hospital, MR CenterStockholmSweden
  6. 6.Section on Nutritional NeurochemistryLMBB, DICBR, NIAAA, NIHWashington DCUSA
  7. 7.Department of PsychiatryUniversity of PadovaPadovaItaly
  8. 8.Institute of PharmacologyPolish Academy of ScienceKrakowPoland
  9. 9.Psychiatric Department1st Medical Faculty Charles University in PraguePragueCzech Republic
  10. 10.Hadassah Biological Psychiatry LaboratoryHadassah-Hebrew UniversityJerusalemIsrael
  11. 11.Department of PsychiatryUniversity of Naples SUNNaplesItaly

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