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Clinical and Biochemical Manifestations of Depression: Relation to the Neurobiology of Stress
Open accessAbstract
Major depressive disorder (MDD) is a chronic, recurrent, and severe psychiatric disorder with high mortality and medical comorbidities. Stress-related pathways have been directly involved in the pathophysiology and treatment of MDD. The present paper provides an overview on the stress system as a model to understand key pathophysiological paradigms in MDD. These mechanisms involve behavioral, cognitive, and systemic manifestations and are also associated with the mechanisms of action of effective antidepressants. Aspects such as depression subtypes, inflammation, insulin resistance, oxidative stress, and prothrombotic states in critical brain circuits and periphery are critically appraised. Finally, new strategies for approaching treatment-resistant major depression and potential adverse effects associated with this complex and intricate network are highlighted. The authors used PubMed as the database for this review. Each author extracted relevant data and assessed the methodological quality of each study.
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“Hypercortisolism is one of the relevant mechanisms involved in response to stress and is present in many people with MDD and in animals subjected to stress in the laboratory.”
From Stress and serum cortisol levels in major depressive disorder: a cross-sectional study (2020) · cites this paper as [9]
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“Chronic stress throughout life involves several biological changes, which are underlying MDD in many patients and in laboratory animals [4],[6],[9].”
From Stress and serum cortisol levels in major depressive disorder: a cross-sectional study (2020) · cites this paper as [9]
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“Insulin resistance and inflammation can cause anxiety [47]”
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“Experiential avoidance seeks to control the way or frequency of aversive private experiences [37] and has been associated with anxiety [38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54].”
From The Effect of Anxiety and Nutritional Habits on the Body Distortion of Athletes. (2025) · cites this paper as [47]
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InfluentialRoss, A. B., Shertukde, S. P., Livingston Staffier, K., Chung, M., Jacques, P. F., & McKeown, N. M. (2023) · Advances in Nutrition · doi:10.1016/j.advnut.2023.04.003 · Cited by 41
Skin conductance responses in Major Depressive Disorder (MDD) under mental arithmetic stress
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Social Determinants of Health: An Overview for the Primary Care Provider
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Sex differences in sleep, anhedonia, and HPA axis activity in a rat model of chronic social defeat
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“Poor sleep may be antecedent to depression or co-morbid with depression (Gold et al., 2015; Palagini et al., 2013; Pillai et al., 2011).”
BackgroundNeurochemistry of Neurochemicals: Messengers of Brain Functions
Uddin, M. S., Mamun, A. A., Kabir, M. T., Nasrullah, M., Wahid, F., Begum, M. M., Labu, Z. K., Rahman, M. S., Islam, M. T., Amran, M. S., et al. (2018) · Journal of Intellectual Disability - Diagnosis and Treatment · doi:10.6000/2292-2598.2017.05.04.6 · Cited by 36
“Depression [71, 72] Critical aberrations in cholinergic, catecholaminergic (i.”
BackgroundDistinctive stress sensitivity and anxiety-like behavior in female mice: Strain differences matter
Marchette, R. C. N., Bicca, M. A., Santos, E. C. D. S., & de Lima, T. C. M. (2018) · Neurobiology of Stress · doi:10.1016/j.ynstr.2018.08.002 · Cited by 41
“In stress-related disorders such as melancholic depression, the activities of central glutamate, norepinephrine, central cytokines and pro-inflammatory mediators are significantly and persistently increased (Gold et al., 2015).”
Influential(2019) · PubMed Central · Cited by 37
Algamal, M., Ojo, J. O., Lungmus, C., Muza, P. M., Cammarata, C., Owens, M. J., Mouzon, B., Diamond, D. M., MULLAN, M. J., & Crawford, F. (2018) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2018.00150 · Cited by 38
HPA Axis Interactions with Behavioral Systems
Packard, A. E. B., Egan, A. E., & Ulrich‐Lai, Y. M. (2016) · Comprehensive physiology · doi:10.1002/cphy.c150042 · Cited by 138
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Adaptação psicossocial e saúde física em crianças de pais separados
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Anxiety-Related Bleeding and Thrombosis
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“[2] The monoamine hypothesis of depression states that it is caused by functional deficit of monoamines (norepinephrine, serotonin and dopamine) at certain sites in the brain.[3] Previously study presented the first evidence for a dopaminergic dysfunction in depression.”
The Effect of Swimming on Anxiety-Like Behaviors and Corticosterone in Stressed and Unstressed Rats
Safari, M. A., Jahromi, M. K., Rezaei, R., Aligholi, H., & Brand, S. (2020) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph17186675 · Cited by 29
“Elevated plasma cortisol levels are common in patients with anxiety [40].”
BackgroundOlayinka, J. N., Akawa, O. B., Ogbu, E. K., Eduviere, A. T., Ozolua, R. I., & Soliman, M. E. S. (2023) · Current Research in Pharmacology and Drug Discovery · doi:10.1016/j.crphar.2023.100161 · Cited by 30
“Moreover, a growing body of evidence has shown the association between increased levels of biomarkers of oxidative stress and development of depression (Milne et al., 2005; Black et al., 2015; Gold et al., 2015).”
BackgroundMood Therapeutics: Novel Pharmacological Approaches for Treating Depression
Henter, I. D., SOUSA, R. T. D., Gold, P. W., Brunoni, A. R., Zarate, C. A., & Machado‐Vieira, R. (2016) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2017.1253472 · Cited by 29
“increased glutamate release, as well as oxidative stress [76,95].”
BackgroundAssociation of PDE11A global haplotype with major depression and antidepressant drug response
Wong, M. (2009) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s4771 · Cited by 28
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Inflammation and Depression: A Nervous Plea for Psychiatry to Not Become Immune to Interpretation
Konsman, J. P. (2019) · Pharmaceuticals · doi:10.3390/ph12010029 · Cited by 27
High prevalence of fatigue in adults with a 22q11.2 deletion syndrome
Vergaelen, E., Claes, S. J., Kempke, S., & Swillen, A. (2017) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.38094 · Cited by 26
“Several psychiatric disorders including depression and schizophrenia have been associated with changes in the stress system and a proinflammatory state of the immune system [Gibney and Drexhage, 2013; Gold et al., 2015].”
BackgroundPathophysiology of Major Depression by Clinical Stages
de Menezes Galvão, A. C., Almeida, R. N., de Sousa, G. M., Leocadio-Miguel, M. A., Palhano-Fontes, F., de Araujo, D. B., Lobão-Soares, B., Maia-de-Oliveira, J. P., Nunes, E. A., Hallak, J. E. C., et al. (2021) · Frontiers in Psychology · doi:10.3389/fpsyg.2021.641779 · Cited by 31
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Lima, A. R., Mello, M. F., Andreoli, S. B., Fossaluza, V., de Araújo, C. M., Jackowski, A. P., Bressan, R. A., & Mari, J. D. J. (2014) · PLoS ONE · doi:10.1371/journal.pone.0087117 · Cited by 24
“Paradoxically, impairments in HPA negative feedback inhibition and subsequent hypercortisolemia, which have been described in studies of major depression [9,10], have not been observed in PTSD patients.”
Background
Metadata
- Authors
- Gold, P. W., Machado-Vieira, R., & Pavlatou, M. G.
- Affiliations
- National Institutes of Health (US)
- National Institute of Mental Health Intramural Research Program, National Institutes of Health, Bethesda, MD 20892, USA
- Corresponding author
- Gold, Phillip W.
- ORCID
- Pavlatou, Maria G.
- Venue
- Neural Plasticity
- Publisher
- Hindawi Limited
- Published
- 2015
- Volume
- 2015
- Pages
- 1-11
- ISSN
- 1687-5443 (ISSN-L)
- 2090-5904
- PMC
- PMC4387963
- OpenAlex
- W2055457894
- Cited by
- 259
- References
- 53
- Citations by year
- 2026: 12 · 2025: 12 · 2024: 15 · 2023: 17 · 2022: 17 · 2021: 26 · 2020: 24 · 2019: 24 · 2018: 27 · 2017: 29 · 2016: 20 · 2015: 6
- FWCI
- 3.43
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Neural Plasticity (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- major depressive disorder, stress system, neurobiology of stress, depression pathophysiology, antidepressant mechanism, depression subtypes, inflammation, insulin resistance, oxidative stress, hypercoagulability, treatment-resistant depression, antidepressant side effects
- MeSH terms
- Animals, Brain, Depressive Disorder, Homeostasis, Humans, Inflammation, Neuronal Plasticity, Stress, Physiological, Stress, Psychological, Oxidative Stress, Neurogenesis
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