Role of norepinephrine in the pathophysiology and treatment of mood disorders
Abstract
For four decades, norepinephrine (NE) has been postulated to play an important, possibly primary, role in the pathophysiology and subsequent treatment of mood disorders. The long-held hypothesis was that depression and pathological elation are direct functions of low and high activity of norepinephrine-containing neurons, respectively. Decades of research in this field have been devoted to further clarifying this relationship. However, there continues to be inconsistencies in the data, with different studies finding significant differences in NE metabolites and changes in receptor populations. Furthermore, antidepressants that do not act directly on the NE system appear to be quite effective in the treatment of depression. Although differential NE activity and treatment response may be partially due to different subtypes of depression, this clearly does not explain all the data. This review attempts to consolidate the relevant physiology of the NE system with the pathological changes found in depression. Norepinephrine clearly has an important role in this disease, but absolute changes in its activity are less likely to be the primary cause of the disorder. Evidence for dysregulation of the locus ceruleus-NE system in depression is quite apparent, however, contributing to disrupted attention, concentration, memory, arousal, and sleep. Homeostatic changes likely occur after chronic treatment with antidepressants, allowing a new regulatory state to occur in which NE modulation is once again effective. The availability of new tools such as selective ligands for the NE transporter that can be utilized with positron emission tomography imaging will undoubtedly advance the field.
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These neurotransmitters play a key role in mood regulation, cognition, and perception.
“These neurotransmitters play a key role in mood regulation (Ressler and Nemeroff, 1999), cognition(Hoshino, 2005) and perception (Mather et al., 2016).”
From Efficacy, acceptability and side-effects of oral versus long-acting- injectables antipsychotics: Systematic review and network meta-analysis (2024) · cites this paper as Ressler and Nemeroff, 1999
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Biology of Depressive Disorders. Part A
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Cytokines and major depression
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Familial orthostatic tachycardia due to norepinephrine transporter deficiency
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“These neurotransmitters play a key role in mood regulation (Ressler and Nemeroff, 1999), cognition(Hoshino, 2005) and perception (Mather et al., 2016).”
BackgroundIncreased plasma norepinephrine concentration in psychotic depression
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- Authors
- Ressler, K. J., & Nemeroff, C. B.
- Affiliations
- Emory University (US)
- Corresponding author
- Nemeroff, Charles B
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 1999-11
- Volume
- 46
- Issue
- 9
- Pages
- 1219-1233
- ISSN
- 0006-3223 (ISSN-L)
- OpenAlex
- W2004974601
- Cited by
- 307
- References
- 117
- Citations by year
- 2026: 8 · 2025: 17 · 2024: 14 · 2023: 4 · 2022: 8 · 2021: 8 · 2020: 7 · 2019: 7 · 2018: 12 · 2017: 11 · 2016: 5 · 2015: 8 · 2014: 8 · 2013: 8 · 2012: 12
- FWCI
- 1.79
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r24mh051761-05)
- National Institute of Mental Health (R01MH042088, MH 51761, MH42088)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- norepinephrine, mood disorders, depression, mania, locus coeruleus, norepinephrine transporter, antidepressants, norepinephrine metabolites, norepinephrine receptors, treatment response, homeostatic regulation
- MeSH terms
- Antidepressive Agents, Depression, Humans, Locus Coeruleus, Norepinephrine, Mood Disorders
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 ›
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