The DOI matches its Crossref record; 455 of the 459 references it cites were found in a registry or an index.
Is serotonin an upper or a downer? The evolution of the serotonergic system and its role in depression and the antidepressant response.
Abstract
The role of serotonin in depression and antidepressant treatment remains unresolved despite decades of research. In this paper, we make three major claims. First, serotonin transmission is elevated in multiple depressive phenotypes, including melancholia, a subtype associated with sustained cognition. The primary challenge to this first claim is that the direct pharmacological effect of most symptom-reducing medications, such as the selective serotonin reuptake inhibitors (SSRIs), is to increase synaptic serotonin. The second claim, which is crucial to resolving this paradox, is that the serotonergic system evolved to regulate energy. By increasing extracellular serotonin, SSRIs disrupt energy homeostasis and often worsen symptoms during acute treatment. Our third claim is that symptom reduction is not achieved by the direct pharmacological properties of SSRIs, but by the brain's compensatory responses that attempt to restore energy homeostasis. These responses take several weeks to develop, which explains why SSRIs have a therapeutic delay. We demonstrate the utility of our claims by examining what happens in animal models of melancholia and during acute and chronic SSRI treatment.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
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 the citing paper
“‘depression’ (a disorder characterized by cognitive rumination) confers specific social advantages to help keep social problems in mental focus”
From Hypernatural Monitoring: A Social Rehearsal Account of Smartphone Addiction (2018) · cites this paper as Andrews et al., 2015
Citations
Cites
Diagnostic and Statistical Manual of Mental Disorders
Williams, J. B. W., & First, M. B. (2013) · Oxford University Press eBooks · doi:10.1093/acrefore/9780199975839.013.104 · Cited by 109,845
From inflammation to sickness and depression: when the immune system subjugates the brain
Dantzer, R., O'Connor, J. C., Freund, G. G., Johnson, R. W., & Kelley, K. W. (2008) · Nature Reviews Neuroscience · doi:10.1038/nrn2297 · Cited by 7,395
Helplessness: On Depression, Development, and Death
Seligman, M. E. P. (1975) · CERN Document Server (European Organization for Nuclear Research) · Cited by 6,181
Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants
Santarelli, L., Saxe, M., Gross, C., Surget, A., Battaglia, F., Dulawa, S., Weisstaub, N., Lee, J., Duman, R., Arancio, O., et al. (2003) · Science · doi:10.1126/science.1083328 · Cited by 4,321
Boore, J. L. (1999) · Nucleic Acids Research · doi:10.1093/nar/27.8.1767 · Cited by 3,715
THE CATECHOLAMINE HYPOTHESIS OF AFFECTIVE DISORDERS: A REVIEW OF SUPPORTING EVIDENCE
Schildkraut, J. J. (1965) · American Journal of Psychiatry · doi:10.1176/ajp.122.5.509 · Cited by 3,568
Stress and disorders of the stress system
Chrousos, G. P. (2009) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2009.106 · Cited by 3,215
A review of central 5-HT receptors and their function
Barnes, N. M., & Sharp, T. (1999) · Neuropharmacology · doi:10.1016/s0028-3908(99)00010-6 · Cited by 3,211
The molecular neurobiology of depression
Krishnan, V., & Nestler, E. J. (2008) · Nature · doi:10.1038/nature07455 · Cited by 2,889
Rasch, B., & Born, J. (2013) · Physiological Reviews · doi:10.1152/physrev.00032.2012 · Cited by 2,783 · cited 1×
“Finally, the increase in REM sleep also points to complex nformation processing, because REM sleep promotes consolidaion of hippocampal memory representations encoding complex nformation (Rasch and Born, 2013).”
Background
Research works printed but not linked: 2
- Ayd, 1958, Drug-induced depression: fact or fallacy?, N. Y. State J. Med., 58, 354
- Everett, 1959, Mode of action of Rauwolfia alkaloids and motor activity, Biol. Psychiatry, 1
Cited by
Sorted by citations
Learned helplessness at fifty: Insights from neuroscience.
Maier, S. F., & Seligman, M. E. P. (2016) · Psychological Review · doi:10.1037/rev0000033 · Cited by 1,031
Rethinking IL-6 and CRP: Why they are more than inflammatory biomarkers, and why it matters
Del Giudice, M., & Gangestad, S. W. (2018) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2018.02.013 · Cited by 779
Serotonin and brain function: a tale of two receptors
Carhart-Harris, R., & Nutt, D. (2017) · Journal of Psychopharmacology · doi:10.1177/0269881117725915 · Cited by 739
Beck, A. T., & Bredemeier, K. (2016) · Clinical Psychological Science · doi:10.1177/2167702616628523 · Cited by 510
Prospective biomarkers of major depressive disorder: A systematic review and meta-analysis
Kennis, M., Gerritsen, L., van Dalen, M., Williams, A., Cuijpers, P., & Bockting, C. (2020) · Molecular Psychiatry · doi:10.1038/s41380-019-0585-z · Cited by 435
Metadata
- Authors
- Andrews, P. W., Bharwani, A., Lee, K. R., Fox, M., & Thomson, J. A.
- Affiliations
- McMaster University (CA)
- University of California, Irvine (US)
- University of Virginia (US)
- Corresponding author
- Andrews, Paul W.
- Venue
- Neuroscience & Biobehavioral Reviews
- Publisher
- Elsevier BV
- Published
- 2015-04
- Volume
- 51
- Pages
- 164-188
- ISSN
- 0149-7634 (ISSN-L)
- OpenAlex
- W2163250198
- Cited by
- 281
- References
- 459
- Citations by year
- 2026: 12 · 2025: 13 · 2024: 25 · 2023: 21 · 2022: 20 · 2021: 34 · 2020: 31 · 2019: 36 · 2018: 37 · 2017: 24 · 2016: 17 · 2015: 10
- FWCI
- 3.69
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuroscience & Biobehavioral Reviews (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › 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
- serotonin, depression, antidepressant response, selective serotonin reuptake inhibitors, melancholia, energy homeostasis, treatment delay, animal models of depression
- MeSH terms
- Animals, Antidepressive Agents, Brain, Depressive Disorder, Humans, Serotonin, Selective Serotonin Reuptake Inhibitors
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
