Role of Translocator Protein Density, a Marker of Neuroinflammation, in the Brain During Major Depressive Episodes
Open accessAbstract
IMPORTANCE: The neuroinflammatory hypothesis of major depressive disorder is supported by several main findings. First, in humans and animals, activation of the immune system causes sickness behaviors that present during a major depressive episode (MDE), such as low mood, anhedonia, anorexia, and weight loss. Second, peripheral markers of inflammation are frequently reported in major depressive disorder. Third, neuroinflammatory illnesses are associated with high rates of MDEs. However, a fundamental limitation of the neuroinflammatory hypothesis is a paucity of evidence of brain inflammation during MDE. Translocator protein density measured by distribution volume (TSPO VT) is increased in activated microglia, an important aspect of neuroinflammation. OBJECTIVE: To determine whether TSPO VT is elevated in the prefrontal cortex, anterior cingulate cortex (ACC), and insula in patients with MDE secondary to major depressive disorder. DESIGN, SETTING, AND PARTICIPANTS: Case-control study in a tertiary care psychiatric hospital from May 1, 2010, through February 1, 2014. Twenty patients with MDE secondary to major depressive disorder and 20 healthy control participants underwent positron emission tomography with fluorine F 18-labeled N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide ([18F]FEPPA). Patients with MDE were medication free for at least 6 weeks. All participants were otherwise healthy and nonsmokers. MAIN OUTCOMES AND MEASURES: Values of TSPO VT in the prefrontal cortex, ACC, and insula. RESULTS: In MDE, TSPO VT was significantly elevated in all brain regions examined (multivariate analysis of variance, F15,23 = 4.5 [P = .001]). The magnitude of TSPO VT elevation was 26% in the prefrontal cortex (mean [SD] TSPO VT, 12.5 [3.6] in patients with MDE and 10.0 [2.4] in controls), 32% in the ACC (mean [SD] TSPO VT, 12.3 [3.5] in patients with MDE and 9.3 [2.2] in controls), and 33% in the insula (mean [SD] TSPO VT, 12.9 [3.7] in patients with MDE and 9.7 [2.3] in controls). In MDE, greater TSPO VT in the ACC correlated with greater depression severity (r = 0.63 [P = .005]). CONCLUSIONS AND RELEVANCE: This finding provides the most compelling evidence to date of brain inflammation, and more specifically microglial activation, in MDE. This finding is important for improving treatment because it implies that therapeutics that reduce microglial activation should be promising for MDE. The correlation between higher ACC TSPO VT and the severity of MDE is consistent with the concept that neuroinflammation in specific regions may contribute to sickness behaviors that overlap with the symptoms of MDE.
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Not all studies have revealed increased TSPO binding in patients with depression, possibly owing to effects of medication and/or a paucity of subjects with increased inflammation.
“not all studies have revealed increased TSPO binding in patients with depression, possibly owing to effects of medication and/or a paucity of subjects with increased inflammation61,62.”
From The role of inflammation in depression: from evolutionary imperative to modern treatment target (2016) · cites this paper as [61]
The Introduction (page unavailable) reports an earlier negative TSPO PET study and identifies ongoing antidepressant use as a possible bias. It also notes that the earlier sample included people who were almost asymptomatic, but does not establish that the study had too few subjects with increased inflammation or identify that as a reason for its negative result. (LLM, conf=0.84)
Experimental — accuracy not yet measuredPET imaging studies have found an increased uptake of TSPO ligands in the prefrontal cortex, anterior cingulate cortex, and the hippocampal formation in depressed compared to non-depressed patients.
“PET imaging studies have found an increased uptake of TSPO ligands in the prefrontal cortex, anterior cingulate cortex, and the hippocampal formation in depressed compared to non-depressed patients indicating that microglial activation leads to neuroinflammation (92).”
From Chronic stress, neuroinflammation, and depression: an overview of pathophysiological mechanisms and emerging anti-inflammatories (2023) · cites this paper as [92]
The Abstract Results report elevated TSPO distribution volume in the prefrontal and anterior cingulate cortices during major depressive episodes compared with controls. The paper identifies the insula, not the hippocampal formation, as its third principal region; a search for the hippocampal formation found no corresponding result. The Discussion treats microglial activation as the most supported interpretation of increased TSPO binding, not proof that it causes neuroinflammation. (LLM, conf=0.88)
Experimental — accuracy not yet measuredA well-controlled PET study using a radiolabelled TSPO tracer revealed increased immune activation in the brains of patients with major depressive disorder compared with control subjects.
“a well-controlled neuroimaging study using positron emission tomography (PET) and a radiolabelled tracer for the translocator protein (TSPO) — which is overexpressed in activated microglia, macrophages and astrocytes — revealed increased immune activation in the brains of patients with major depressive disorder compared with control subjects61.”
From The role of inflammation in depression: from evolutionary imperative to modern treatment target (2016) · cites this paper as [61]
The Methods describe [18F]FEPPA TSPO PET in patients experiencing a major depressive episode and healthy controls, and the Results report significantly elevated TSPO binding in the patient group. The Discussion interprets this as evidence of microglial activation, but cautions that PET cannot identify the cell type: astrocyte activation is presented as a possibility under certain conditions, and the paper does not establish the parenthetical claim about activated macrophages. (LLM, conf=0.82)
Experimental — accuracy not yet measuredFludrocortisone improves cognitive function in depressed patients in an experimental study.
“and to improve cognitive function in depressed patients in an experimental study 80”
From Major depressive disorder (2016) · cites this paper as [80]
The Materials and Methods > Participants section describes a PET study of medication-free participants with major depressive episodes, not a fludrocortisone experiment. Searches for fludrocortisone and cognitive improvement found no passage in our copy reporting the claimed effect; page numbers were not available. (LLM, conf=0.78)
Experimental — accuracy not yet measuredRecent imaging studies report greater neuroinflammation in the hippocampus and medial prefrontal cortex of depressed people than in healthy controls.
“recent imaging studies in depressed individuals have reported enhanced neuroinflammation in the hippocampus and mPFC compared to HCs (93,94).”
From The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology (2019) · cites this paper as [93]
There is a significant association between activated microglia and major depression in several brain regions linked with depression.
“Perhaps the most compelling evidence to date comes from a recent neuroimaging study demonstrating significant association between activated microglia and major depression in several brain regions linked with depression (Setiawan et al, 2015).”
From Repeated Social Defeat, Neuroinflammation, and Behavior: Monocytes Carry the Signal (2017) · cites this paper as Setiawan et al, 2015
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The neuroimmunology of social-stress-induced sensitization
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Mapping inflammation onto mood: inflammatory mediators of anhedonia
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- Authors
- Setiawan, E., Wilson, A. A., Mizrahi, R., Rusjan, P. M., Miler, L., Rajkowska, G., Suridjan, I., Kennedy, J. L., Rekkas, P. V., Houle, S., & Meyer, J. H.
- Affiliations
- Centre for Addiction and Mental Health (CA)
- Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson
- ORCID
- Venue
- JAMA Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2015-03-01
- Volume
- 72
- Issue
- 3
- Pages
- 268
- ISSN
- 2168-622X (ISSN-L)
- PMC
- PMC4836849
- OpenAlex
- W1990151307
- Cited by
- 939
- References
- 43
- Citations by year
- 2026: 63 · 2025: 79 · 2024: 76 · 2023: 78 · 2022: 82 · 2021: 122 · 2020: 80 · 2019: 84 · 2018: 92 · 2017: 67 · 2016: 75 · 2015: 36 · 2014: 2
- FWCI
- 29.82
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- JAMA Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Fondation Brain Canada
- Centre for Addiction and Mental Health
- Canadian Institutes of Health Research
- National Institute of General Medical Sciences (P30GM103328)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- major depressive episode, neuroinflammation, translocator protein (TSPO), microglial activation, prefrontal cortex, anterior cingulate cortex, insula, sickness behavior, anorexia and weight loss, anhedonia, depression biomarkers
- MeSH terms
- Adult, Anilides, Cerebral Cortex, Major Depressive Disorder, Female, Gyrus Cinguli, Humans, Inflammation, Male, Middle Aged, Pyridines, Severity of Illness Index, Biomarkers, Case-Control Studies, Prefrontal Cortex, Microglia, Receptors, GABA, Positron-Emission Tomography
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