Deep brain stimulation of the lateral habenula in treatment resistant major depression
Abstract
The burden of depression as a severe illness with high suicidality and prevalence is immense. Despite substantial advancement in psychopharmacology and psychotherapy over the last decades a residual group of very ill patients with a chronic disease and high suicidal risk remains. Modern theories about the pathophysiology of depression are derived from studies examining the mechanism of antidepressants influencing the serotonergic (5-HT) and noradrenergic (NE) systems. Serotonergic fibers originate from the dorsal raphe nuclei (DRN), noradrenergic fibers from the locus coeruleus (LC). Both nuclei represent relatively small brain regions and both are controlled to some extent by the habenular complex. We propose the hypothesis of an overactivation of the habenula in human major depressive episodes (MDE's). Increased activation of the lateral habenular nucleus leads to the down regulation of the serotonergic, noradrenergic, dopaminergic systems and stimulation of the hypothalamic-pituitary-adrenal (HPA) axis. Functional inhibition of the lateral habenula via deep brain stimulation (DBS) has antidepressive properties. The hypothesis is based on the findings of a clinical imaging study examining the habenular after tryptophan depletion and on several animal studies which are discussed. Providing that our hypothesis will be validated by an analogous tyrosine depletion study and additional preclinical studies, the next logical step would be to directly test our hypothesis in patients. Possible criteria for patient selection, ethical issues and locus of DBS are carefully discussed.
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Over-activation of the lateral habenula has been proposed to be involved in depression and as a site of antidepressant action of conventional antidepressant drugs.
“The lateral habenula signals negative valence to monoaminergic systems and over-activation of the lateral habenula has recently been proposed to be involved in depression as well as to be a site of antidepressant action of conventional antidepressant drugs (Proulx et al., 2014; Sartorius and Henn, 2007).”
From BDNF - a key transducer of antidepressant effects (2016) · cites this paper as Sartorius and Henn, 2007
The lateral habenula signals negative valence to monoaminergic systems.
“The lateral habenula signals negative valence to monoaminergic systems and over-activation of the lateral habenula has recently been proposed to be involved in depression as well as to be a site of antidepressant action of conventional antidepressant drugs (Proulx et al., 2014; Sartorius and Henn, 2007).”
From BDNF - a key transducer of antidepressant effects (2016) · cites this paper as Sartorius and Henn, 2007
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- Authors
- Sartorius, A., & Henn, F. A.
- Affiliations
- Central Institute of Mental Health (DE)
- Brookhaven National Laboratory (US)
- Corresponding author
- Sartorius, Alexander
- ORCID
- Sartorius, Alexander
- Venue
- Medical Hypotheses
- Publisher
- Elsevier BV
- Published
- 2007-01
- Volume
- 69
- Issue
- 6
- Pages
- 1305-1308
- ISSN
- 0306-9877 (ISSN-L)
- OpenAlex
- W2032715840
- Cited by
- 251
- References
- 1
- Citations by year
- 2026: 7 · 2025: 3 · 2024: 9 · 2023: 8 · 2022: 15 · 2021: 10 · 2020: 11 · 2019: 12 · 2018: 12 · 2017: 21 · 2016: 22 · 2015: 12 · 2014: 21 · 2013: 22 · 2012: 15
- FWCI
- 7.64
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Medical Hypotheses (publishedVersion)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Topics
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Neurology › Transcranial Magnetic Stimulation Studies
- Keywords
- deep brain stimulation, lateral habenula, treatment-resistant depression, major depressive episode, serotonergic system, noradrenergic system, dorsal raphe nucleus, locus coeruleus, hypothalamic-pituitary-adrenal axis, tryptophan depletion, depression pathophysiology, patient selection
- MeSH terms
- Animals, Antidepressive Agents, Depression, Depressive Disorder, Major, Major Depressive Disorder, Electric Stimulation, Electrophysiology, Humans, Models, Theoretical, Synaptic Transmission, Serotonin, Tryptophan, Tyrosine, Habenula, Deep Brain Stimulation, Positron-Emission Tomography
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