, Volume 20, Issue 3, pp 127–150 | Cite as

New drug targets in depression: inflammatory, cell-mediated immune, oxidative and nitrosative stress, mitochondrial, antioxidant, and neuroprogressive pathways. And new drug candidates—Nrf2 activators and GSK-3 inhibitors

  • Michael MaesEmail author
  • Zdenĕk Fišar
  • Miguel Medina
  • Giovanni Scapagnini
  • Gabriel Nowak
  • Michael Berk
Inflammation in Acute and Chronic Neurological and Psychiatric Diseases


This paper reviews new drug targets in the treatment of depression and new drug candidates to treat depression. Depression is characterized by aberrations in six intertwined pathways: (1) inflammatory pathways as indicated by increased levels of proinflammatory cytokines, e.g. interleukin-1 (IL-1), IL-6, and tumour necrosis factor α. (2) Activation of cell-mediated immune pathways as indicated by an increased production of interferon γ and neopterin. (3) Increased reactive oxygen and nitrogen species and damage by oxidative and nitrosative stress (O&NS), including lipid peroxidation, damage to DNA, proteins and mitochondria. (4) Lowered levels of key antioxidants, such as coenzyme Q10, zinc, vitamin E, glutathione, and glutathione peroxidase. (5) Damage to mitochondria and mitochondrial DNA and reduced activity of respiratory chain enzymes and adenosine triphosphate production. (6) Neuroprogression, which is the progressive process of neurodegeneration, apoptosis, and reduced neurogenesis and neuronal plasticity, phenomena that are probably caused by inflammation and O&NS. Antidepressants tend to normalize the above six pathways. Targeting these pathways has the potential to yield antidepressant effects, e.g. using cytokine antagonists, minocycline, Cox-2 inhibitors, statins, acetylsalicylic acid, ketamine, ω3 poly-unsaturated fatty acids, antioxidants, and neurotrophic factors. These six pathways offer new, pathophysiologically guided drug targets suggesting that novel therapies could be developed that target these six pathways simultaneously. Both nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activators and glycogen synthase kinase-3 (GSK-3) inhibitors target the six above-mentioned pathways. GSK-3 inhibitors have antidepressant effects in animal models of depression. Nrf2 activators and GSK-3 inhibitors have the potential to be advanced to phase-2 clinical trials to examine whether they augment the efficacy of antidepressants or are useful as monotherapy.


Depression Antidepressants Inflammation Cytokines Serotonin Oxidative and nitrosative stress Neuroprogression 



Miguel Medina is a full employee of Noscira S.A.. Michael Berk has received Grant/Research Support from the NIH, Simons Autism Foundation, Cancer Council of Victoria, Stanley Medical Research Foundation, MBF, NHMRC, Beyond Blue, Geelong Medical Research Foundation, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Organon, Novartis, Mayne Pharma and Servier, has been a speaker for Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck, Merck, Pfizer, Sanofi Synthelabo, Servier, Solvayand Wyeth, and served as a consultant to Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck and Servier. Michael Berk is a co-inventor of two provisional patents regarding the use of NAC and related compounds for psychiatric indications, which, while assigned to the Mental Health Research Institute, could lead to personal remuneration upon a commercialization event. This research was supported by Grant No MSM0021620849 given to Dr. Zdenĕk Fišar by the Ministry of Education, Youth and Sports of the Czech Republic.


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Copyright information

© Springer Basel AG 2012

Authors and Affiliations

  • Michael Maes
    • 1
    Email author
  • Zdenĕk Fišar
    • 2
  • Miguel Medina
    • 3
  • Giovanni Scapagnini
    • 4
  • Gabriel Nowak
    • 5
  • Michael Berk
    • 6
    • 7
    • 8
  1. 1.Maes Clinics@TRIABangkokThailand
  2. 2.Department of Psychiatry, First Faculty of MedicineCharles University in Prague, General University Hospital in PraguePragueCzech Republic
  3. 3.NosciraTres CantosSpain
  4. 4.Department of Health SciencesUniversity of MoliseCampobassoItaly
  5. 5.Department of PharmacobiologyJagiellonian University Medical College, Institute of Pharmacology PASKrakowPoland
  6. 6.Department of Clinical and Biomedical SciencesThe University of MelbourneMelbourneAustralia
  7. 7.Orygen Research Centre, Centre for Youth Mental HealthThe University of MelbourneMelbourneAustralia
  8. 8.Mental Health Research InstituteMelbourneAustralia

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