The DOI matches its Crossref record; 299 of the 300 references it cites were found in a registry or an index.
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
Abstract
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.
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“More than that, oxidative stress evaluation through F2-isoprostanes quantification [269] in depressed patients treated with sertraline or bupropion for eight months revealed high rates of oxidation, despite some psychiatric improvements [139].”
From Oxidative Stress Implications in the Affective Disorders: Main Biomarkers, Animal Models Relevance, Genetic Perspectives, and Antioxidant Approaches (2016) · cites this paper as [139]
In the citing paper
“Curcumin is a pleiotropic agent that targets immune-inflammatory and oxidative and nitrosative stress pathways and promotes neuroprotection and improved neurogenesis [165, 166].”
From Cognitive remission: a novel objective for the treatment of major depression? (2016) · cites this paper as [166]
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Cites
3 retracted
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Kelly, J. R., Borre, Y., O' Brien, C., Patterson, E., El Aidy, S., Deane, J., Kennedy, P. J., Beers, S., Scott, K., Moloney, G., et al. (2016) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2016.07.019 · Cited by 1,683
So depression is an inflammatory disease, but where does the inflammation come from?
Berk, M., Williams, L. J., Jacka, F. N., O’Neil, A., Pasco, J. A., Moylan, S., Allen, N. B., Stuart, A. L., Hayley, A. C., Byrne, M. L., et al. (2013) · BMC Medicine · doi:10.1186/1741-7015-11-200 · Cited by 1,423
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Antioxidant and anti-inflammatory effects of zinc. Zinc-dependent NF-κB signaling
Jarosz, M., Olbert, M., Wyszogrodzka, G., Młyniec, K., & Librowski, T. (2017) · Inflammopharmacology · doi:10.1007/s10787-017-0309-4 · Cited by 784
Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways
Maes, M., Berk, M., Goehler, L., Song, C., Anderson, G., Gałecki, P., & Leonard, B. (2012) · BMC Medicine · doi:10.1186/1741-7015-10-66 · Cited by 629
Self-citation
Metadata
- Authors
- Maes, M., Fišar, Z., Medina, M., Scapagnini, G., Nowak, G., & Berk, M.
- Affiliations
- University of Molise (IT)
- Jagiellonian University (PL)
- Mental Health Research Institute (AU)
- Corresponding author
- Maes, Michael
- Venue
- Inflammopharmacology
- Published
- 2012-01-24
- Volume
- 20
- Issue
- 3
- Pages
- 127-150
- ISSN
- 0925-4692 (ISSN-L)
- 1568-5608
- OpenAlex
- W2008971294
- Cited by
- 325
- References
- 300
- Citations by year
- 2026: 4 · 2025: 14 · 2024: 11 · 2023: 19 · 2022: 21 · 2021: 14 · 2020: 32 · 2019: 19 · 2018: 18 · 2017: 26 · 2016: 31 · 2015: 29 · 2014: 29 · 2013: 36 · 2012: 21
- FWCI
- 4.26
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Inflammopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacological Receptor Mechanisms and Effects
- Keywords
- depression, antidepressant targets, neuroinflammation, inflammatory cytokines, cell-mediated immunity, oxidative stress, nitrosative stress, mitochondrial dysfunction, antioxidant pathways, neurodegeneration, apoptosis, neurogenesis, Nrf2 activators, GSK-3 inhibitors, minocycline, ketamine, omega-3 polyunsaturated fatty acids, neurotrophic factors
- MeSH terms
- Animals, Antioxidants, Depression, Humans, Immunity, Cellular, Mitochondria, Nitrosation, Drug Delivery Systems, Oxidative Stress, Disease Progression, Inflammation Mediators, Glycogen Synthase Kinase 3, NF-E2-Related Factor 2
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