The role of corticotropin-releasing factor in depression and anxiety disorders

Arborelius, L; Owens, MJ; Plotsky, PM; Nemeroff, CB

doi:10.1677/joe.0.1600001

Cited by 1,378Stress Responses and CortisolNeuropeptides and Animal PhysiologyNeuroendocrine regulation and behavior

The role of corticotropin-releasing factor in depression and anxiety disorders

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Arborelius, L, Owens, MJ, Plotsky, PM, Nemeroff, CB·1999·Journal of Endocrinology

DOI 10.1677/joe.0.1600001

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Abstract

Corticotropin-releasing factor (CRF), a 41 amino acid-containing peptide, appears to mediate not only the endocrine but also the autonomic and behavioral responses to stress. Stress, in particular early-life stress such as childhood abuse and neglect, has been associated with a higher prevalence rate of affective and anxiety disorders in adulthood. In the present review, we describe the evidence suggesting that CRF is hypersecreted from hypothalamic as well as from extrahypothalamic neurons in depression, resulting in hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and elevations of cerebrospinal fluid (CSF) concentrations of CRF. This increase in CRF neuronal activity is also believed to mediate certain of the behavioral symptoms of depression involving sleep and appetite disturbances, reduced libido, and psychomotor changes. The hyperactivity of CRF neuronal systems appears to be a state marker for depression because HPA axis hyperactivity normalizes following successful antidepressant treatment. Similar biochemical and behavioral findings have been observed in adult rats and monkeys that have been subjected to early-life stress. In contrast, clinical studies have not revealed any consistent changes in CSF CRF concentrations in patients with anxiety disorders; however, preclinical findings strongly implicate a role for CRF in the pathophysiology of certain anxiety disorders, probably through its effects on central noradrenergic systems. The findings reviewed here support the hypothesis that CRF receptor antagonists may represent a novel class of antidepressants and/or anxiolytics.

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Alterations of the HPA axis is one of the most notable neurobiological findings in psychiatry.
“Alterations of the hypothalamic–pituitary–adrenal (HPA) axis is one of the most notable neurobiological findings in psychiatry (1, 2).”
From Childhood Trauma, the HPA Axis and Psychiatric Illnesses: A Targeted Literature Synthesis (2022) · cites this paper as [1]
The Clinical findings in depression section describes HPA-axis hyperactivity in depressed patients as supported by a compelling number of studies, including repeatedly replicated cortisol findings. The Summary calls it well documented. Those passages support its importance in depression, but do not establish that HPA-axis alterations are among the most notable neurobiological findings across psychiatry. (LLM, conf=0.82)
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There is an excitatory reciprocal interaction between the HPA axis and the brainstem sympathetic locus coeruleus-norepinephrine system: CRH activates the LC, and NE activates hypothalamic CRH.
“An important interplay is also the excitatory reciprocal interaction between the HPA axis and the brainstem sympathetic locus coeruleus (LC)-norepinephrine (NE) system: CRH activates the LC; in turn, NE, a known wake-promoting neurotransmitter, activates hypothalamic CRH [9, 10].”
From Impact of Sleep and Its Disturbances on Hypothalamo-Pituitary-Adrenal Axis Activity (2010) · cites this paper as [10]

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Authors: Arborelius, L., Owens, M., Plotsky, P., & Nemeroff, C.
Affiliations: Emory University (US)
Venue: Journal of Endocrinology
Publisher: Bioscientifica
Published: 1999-01-01
Volume: 160
Issue: 1
Pages: 1-12
ISSN: 0022-0795 (ISSN-L)
1479-6805
DOI: 10.1677/joe.0.1600001
OpenAlex: W2143629083
Cited by: 1,378
References: 106
Citations by year: 2026: 8 · 2025: 20 · 2024: 29 · 2023: 24 · 2022: 35 · 2021: 34 · 2020: 34 · 2019: 44 · 2018: 31 · 2017: 48 · 2016: 36 · 2015: 49 · 2014: 63 · 2013: 58 · 2012: 59
FWCI: 4.58
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Endocrinology (publishedVersion)
PubMed (publishedVersion)
Funders: Swedish Institute
National Institutes of Health (DS-08705, MH-42088)
Medical Research Council
National Institute of Mental Health (R01MH042088, MH-50113, MH42088, R01MH050113)
Topics: Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
Keywords: corticotropin-releasing factor, depression, anxiety disorders, hypothalamic-pituitary-adrenal axis, early life stress, childhood abuse and neglect, CRF receptor antagonists, antidepressants, anxiolytics, noradrenergic system, psychomotor changes
MeSH terms: Adult, Animals, Anxiety Disorders, Child, Preschool, Corticotropin-Releasing Hormone, Depression, Disease Models, Animal, Humans, Hypothalamo-Hypophyseal System, Infant, Maternal Deprivation, Neurons, Pituitary-Adrenal System, Stress, Psychological, Receptors, Corticotropin-Releasing Hormone, Rats

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The role of corticotropin-releasing factor in depression and anxiety disorders

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