Patient-specific modeling of the neuroendocrine HPA-axis and its relation to depression: ultradian and circadian oscillations
Abstract
In the Western world approximately 10% of the population experience severe depression at least once in their lifetime and many more experience a mild form of depression. Depression has been associated with malfunctions in the hypothalamus-pituitary-adrenal (HPA) axis. We suggest a novel mechanistic non-linear model capable of showing both circadian as well as ultradian oscillations of the hormone concentrations related to the HPA-axis. The fast ultradian rhythm is assumed to originate from the hippocampus whereas the slower circadian rhythm is assumed to be caused by the circadian clock. The model is able to describe the oscillatory patterns in hormone concentration data from 29 patients and healthy controls. Using non-linear mixed effects modeling with statistical hypothesis testing, three of the model parameters are identified to be related to depression. These parameters represent underlying physiological mechanisms controlling the average levels as well as the ultradian frequencies and amplitudes of the hormones ACTH and cortisol. The results are promising since they point toward an exact etiology for depression. As a consequence new biomarkers and pharmaceutical targets may be identified.
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The antecedent model was superior to the rest in fitting data.
“Like the previous model [17], this model was superior to the rest in fitting data.”
From Patient specific modeling of the HPA axis related to clinical diagnosis of depression (2017) · cites this paper as [17]
To the authors' knowledge only one other model shares most of the same properties, namely the one presented by Gudmand-Hoeyer et al. [17].
“To our knowledge only one other model share most of the same properties, namely the one presented by Gudmand-Hoeyer et al. [17].”
From Patient specific modeling of the HPA axis related to clinical diagnosis of depression (2017) · cites this paper as [17]
Amongst earlier models, only Gudmand-Hoeyer et al. [17] have been able to fit individual data from a group of subjects equally well.
“Amongst earlier models, only Gudmand-Hoeyer et al. [17] have been able to fit individual data from a group of subjects equally well.”
From Patient specific modeling of the HPA axis related to clinical diagnosis of depression (2017) · cites this paper as [17]
The Gudmand-Hoeyer et al. [17] model is based on the physiological paradigm that ultradian oscillation is due to a corticotropin-releasing hormone pulse generator in macaque hypothalamus.
“However, that model is based on the physiological paradigm that ultradian oscillation is due to a corticotropin-releasing hormone pulse generator in macaque hypothalamus (referring to Mershon et al. [34])”
From Patient specific modeling of the HPA axis related to clinical diagnosis of depression (2017) · cites this paper as [17]
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The HPA axis in bipolar disorder: Systematic review and meta-analysis
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Patient specific modeling of the HPA axis related to clinical diagnosis of depression
Bangsgaard, E. O., & Ottesen, J. T. (2017) · Mathematical Biosciences · doi:10.1016/j.mbs.2016.10.007 · Cited by 31 · see citing works
Self-citationModel Predictive Controller to Regulate Cortisol Levels in Individuals With Adrenal Insufficiency
Joshi, R., Saha, N., Srinivasan, V., Zak, S. H., & Mariash, C. N. (2026) · arXiv
“In the patient-specific modeling, Gudmand-Hoeyer et al. (2014) identified three potential biomarkers of depression through parameter analysis.”
- Authors
- Gudmand-Hoeyer, J., Timmermann, S., & Ottesen, J. T.
- Affiliations
- Lundbeck (Denmark) (DK)
- Roskilde University (DK)
- Corresponding author
- Ottesen, Johnny T.
- ORCID
- Ottesen, Johnny T.
- Venue
- Mathematical Biosciences
- Publisher
- Elsevier BV
- Published
- 2014-11
- Volume
- 257
- Pages
- 23-32
- ISSN
- 0025-5564 (ISSN-L)
- OpenAlex
- W2121598606
- Cited by
- 22
- References
- 16
- Citations by year
- 2024: 1 · 2023: 2 · 2022: 3 · 2021: 2 · 2020: 3 · 2019: 1 · 2018: 3 · 2017: 3 · 2016: 2 · 2015: 2
- FWCI
- 1.14
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Mathematical Biosciences (publishedVersion)
- PubMed (publishedVersion)
- RUCforsk (Roskilde University) (submittedVersion)
- Funders
- The Danish Society for the Protection of Laboratory Animals
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- depression, hypothalamic-pituitary-adrenal axis, ultradian rhythms, circadian rhythm, ACTH, cortisol, hippocampus, circadian clock, patient-specific modeling, nonlinear mixed-effects models, biomarkers, therapeutic target
- MeSH terms
- Circadian Rhythm, Depression, Humans, Hypothalamo-Hypophyseal System, Models, Biological, Periodicity, Pituitary-Adrenal System
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