The cellular and molecular basis of major depressive disorder: towards a unified model for understanding clinical depression
Open accessAbstract
Major depressive disorder (MDD) is considered a serious public health issue that adversely impacts an individual's quality of life and contributes significantly to the global burden of disease. The clinical heterogeneity that exists among patients limits the ability of MDD to be accurately diagnosed and currently, a symptom-based approach is utilized in many cases. Due to the complex nature of this disorder, and lack of precise knowledge regarding the pathophysiology, effective management is challenging. The aetiology and pathophysiology of MDD remain largely unknown given the complex genetic and environmental interactions that are involved. Nonetheless, the aetiology and pathophysiology of MDD have been the subject of extensive research, and there is a vast body of literature that exists. Here we overview the key hypotheses that have been proposed for the neurobiology of MDD and highlight the need for a unified model, as many of these pathways are integrated. Key pathways discussed include neurotransmission, neuroinflammation, clock gene machinery pathways, oxidative stress, role of neurotrophins, stress response pathways, the endocannabinoid and endovanilloid systems, and the endogenous opioid system. We also describe the current management of MDD, and emerging novel therapies, with particular focus on patients with treatment-resistant depression (TRD).
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In ADHD comorbid disease, major depressive disorder, activated astrocytes can reduce glutamate on the synaptic cleft via EAATs and convert it to glutamine in the cytosol.
“In an ADHD comorbid disease, major depressive disorder, activated astrocytes can reduce glutamate on the synaptic cleft via excitatory amino acid transporters (EAATs) and convert it to glutamine in the cytosol [162].”
From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [162]
Cites
The role of inflammation in depression: from evolutionary imperative to modern treatment target
Miller, A. H., & Raison, C. L. (2016) · Nature Reviews Immunology · doi:10.1038/nri.2015.5 · Cited by 3,942 · see citing works
Cytokines sing the blues: inflammation and the pathogenesis of depression
Raison, C. L., Capuron, L., & Miller, A. H. (2006) · Trends in Immunology · doi:10.1016/j.it.2005.11.006 · Cited by 3,009 · see citing works
Mayberg, H. S., Liotti, M., Brannan, S. K., McGinnis, S., Mahurin, R. K., Jerabek, P. A., Silva, J. A., Tekell, J. L., Martin, C. C., Lancaster, J. L., et al. (1999) · American Journal of Psychiatry · doi:10.1176/ajp.156.5.675 · Cited by 2,416 · see citing works
Allelic Variation of Human Serotonin Transporter Gene Expression
Heils, A., Teufel, A., Petri, S., Stöber, G., Riederer, P., Bengel, D., & Lesch, K. P. (1996) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1996.66062621.x · Cited by 2,221 · see citing works
2-Arachidonoylgylcerol: A Possible Endogenous Cannabinoid Receptor Ligand in Brain
Sugiura, T., Kondo, S., Sukagawa, A., Nakane, S., Shinoda, A., Itoh, K., Yamashita, A., & Waku, K. (1995) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1995.2437 · Cited by 2,196 · see citing works
Cytokine-Associated Emotional and Cognitive Disturbances in Humans
Reichenberg, A., Yirmiya, R., Schuld, A., Kraus, T., Haack, M., Morag, A., & Pollmächer, T. (2001) · Archives of General Psychiatry · doi:10.1001/archpsyc.58.5.445 · Cited by 1,365 · see citing works
Binder, E. B. (2009) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2009.05.021 · Cited by 968 · see citing works
Hasler, G., van der Veen, J. W., Tumonis, T., Meyers, N., Shen, J., & Drevets, W. C. (2007) · Archives of General Psychiatry · doi:10.1001/archpsyc.64.2.193 · Cited by 846 · see citing works
Daly, E. J., Trivedi, M. H., Janik, A., Li, H., Zhang, Y., Li, X., Lane, R., Lim, P., Duca, A. R., Hough, D., et al. (2019) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2019.1189 · Cited by 795 · see citing works
Radley, J. J., Sisti, H. M., Hao, J., Rocher, A. B., McCall, T., Hof, P. R., McEwen, B. S., & Morrison, J. H. (2004) · Neuroscience · doi:10.1016/j.neuroscience.2004.01.006 · Cited by 769 · see citing works
The neurobiology of depression: An integrated view
Dean, J., & Keshavan, M. (2017) · Asian Journal of Psychiatry · doi:10.1016/j.ajp.2017.01.025 · Cited by 765 · see citing works
Examining emotion regulation in depression: A review and future directions
Joormann, J., & Stanton, C. H. (2016) · Behaviour Research and Therapy · doi:10.1016/j.brat.2016.07.007 · Cited by 749 · see citing works
Clark, L. A., Cuthbert, B., Lewis-Fernández, R., Narrow, W. E., & Reed, G. M. (2017) · Psychological Science in the Public Interest · doi:10.1177/1529100617727266 · Cited by 688 · see citing works
Wochnik, G. M., Rüegg, J., Abel, G. A., Schmidt, U., Holsboer, F., & Rein, T. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m407498200 · Cited by 638 · see citing works
Circadian patterns of gene expression in the human brain and disruption in major depressive disorder
Li, J. Z., Bunney, B. G., Meng, F., Hagenauer, M. H., Walsh, D. M., Vawter, M. P., Evans, S. J., Choudary, P. V., Cartagena, P., Barchas, J. D., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1305814110 · Cited by 589 · see citing works
The role of 5-HT receptors in depression
Yohn, C. N., Gergues, M. M., & Samuels, B. A. (2017) · Molecular Brain · doi:10.1186/s13041-017-0306-y · Cited by 485 · see citing works
Wu, J. C., Kelsoe, J. R., Schachat, C., Bunney, B. G., DeModena, A., Golshan, S., Gillin, J. C., Potkin, S. G., & Bunney, W. E. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.02.018 · Cited by 263 · see citing works
Regulation of Neurogenesis by Neurotrophins during Adulthood: Expected and Unexpected Roles
Vilar, M., & Mira, H. (2016) · Frontiers in Neuroscience · doi:10.3389/fnins.2016.00026 · Cited by 235 · see citing works
Fava, M., Memisoglu, A., Thase, M. E., Bodkin, J. A., Trivedi, M. H., de Somer, M., Du, Y., Leigh-Pemberton, R., DiPetrillo, L., Silverman, B., et al. (2016) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2015.15070921 · Cited by 232 · see citing works
Mechanisms of action of antidepressants: from neurotransmitter systems to signaling pathways
Taylor, C., Fricker, A. D., Devi, L. A., & Gomes, I. (2005) · Cellular Signalling · doi:10.1016/j.cellsig.2004.12.007 · Cited by 186 · see citing works
Korgaonkar, M. S., Grieve, S. M., Etkin, A., Koslow, S. H., & Williams, L. M. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2012.252 · Cited by 135 · see citing works
Slavich, G. M., Tartter, M. A., Brennan, P. A., & Hammen, C. (2014) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2014.07.009 · Cited by 83 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Quintero, J., Gutiérrez-Casares, J. R., & Álamo, C. (2022) · Neurology and Therapy · doi:10.1007/s40120-022-00392-2 · Cited by 70 · see citing works
“In an ADHD comorbid disease, major depressive disorder, activated astrocytes can reduce glutamate on the synaptic cleft via excitatory amino acid transporters (EAATs) and convert it to glutamine in the cytosol [162].”
BackgroundCanbeyli, R. (2022) · European Journal of Neuroscience · doi:10.1111/ejn.15507 · Cited by 48 · see citing works
The importance of epigenetics in diagnostics and treatment of major depressive disorder
Czarny, P., Białek, K., Ziółkowska, S., Strycharz, J., Barszczewska, G., & Sliwinski, T. (2021) · Journal of Personalized Medicine · doi:10.3390/jpm11030167 · Cited by 37 · see citing works
Dam, V. H., Stenbæk, D. S., Köhler-Forsberg, K., Ip, C., Ozenne, B., Sahakian, B. J., Knudsen, G. M., Jørgensen, M. B., & Frokjaer, V. G. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-02240-1 · Cited by 27 · see citing works
- Authors
- Pitsillou, E., Bresnehan, S. M., Kagarakis, E. A., Wijoyo, S. J., Liang, J., Hung, A., & Karagiannis, T. C.
- Affiliations
- The University of Melbourne (AU)
- Monash University (AU)
- RMIT University (AU)
- Corresponding author
- Karagiannis, Tom C.
- Venue
- Molecular Biology Reports
- Published
- 2019-10-14
- Volume
- 47
- Issue
- 1
- Pages
- 753-770
- ISSN
- 0301-4851 (ISSN-L)
- 1573-4978
- OpenAlex
- W2979595541
- Cited by
- 206
- References
- 22
- Citations by year
- 2026: 16 · 2025: 42 · 2024: 38 · 2023: 33 · 2022: 37 · 2021: 22 · 2020: 17 · 2019: 1
- FWCI
- 2.47
- Type
- journal article
- Language
- en
- Open access
- green
- figshare.com
- Locations
- Molecular Biology Reports (publishedVersion)
- PubMed (publishedVersion)
- RMIT Research Repository (RMIT University Library) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- major depressive disorder, depression pathophysiology, neurobiology of depression, neurotransmission, neuroinflammation, clock genes, oxidative stress, neurotrophins, stress response, endocannabinoid system, endogenous opioid system, treatment-resistant depression, depression treatment, gene-environment interaction
- MeSH terms
- Animals, Antidepressive Agents, Depression, Major Depressive Disorder, Humans, Inflammation, Models, Biological, Synapses, Signal Transduction, Neurotransmitter Agents, Oxidative Stress, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
