Markers of central inflammation in major depressive disorder: a systematic review and meta-analysis of studies examining cerebrospinal fluid, positron emission tomography and post-mortem brain tissue

Enache, Daniela; Pariante, Carmine M.; Mondelli, Valeria

doi:10.1016/j.bbi.2019.06.015

Cited by 615Tryptophan and brain disordersNeuroinflammation and Neurodegeneration MechanismsTreatment of Major Depression

Markers of central inflammation in major depressive disorder: a systematic review and meta-analysis of studies examining cerebrospinal fluid, positron emission tomography and post-mortem brain tissue

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Enache, Daniela, Pariante, Carmine M., Mondelli, Valeria·2019·Brain, Behavior, and Immunity

DOI 10.1016/j.bbi.2019.06.015

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Abstract

BACKGROUND Increased peripheral inflammation has been consistently reported in patients with major depressive disorder (MDD). However, only few studies have explored markers of central (brain) inflammation in patients with MDD. The aim of this study is to systematically review in vivo and post-mortem markers of central inflammation, including studies examining cerebrospinal fluid (CSF), positron emission tomography, and post-mortem brain tissues in subjects suffering with MDD compared with controls. METHODS PubMed and Medline databases were searched up to December 2018. We included studies measuring cerebrospinal fluid (CSF) cytokines and chemokines, positron emission tomography (PET) studies; and post-mortem studies measuring cytokines, chemokines and cell-specific markers of microglia and astrocytes, all in MDD. A meta-analysis was performed only for CSF and PET studies, as studies on post-mortem markers of inflammation had different cell-specific markers and analysed different brain regions. RESULTS A total of 69 studies met the inclusion criteria. CSF levels of IL-6 and TNF-α were higher in patients with MDD compared with controls (standardised mean difference SMD 0.37, 95%CI: 0.17-0.57 and SMD 0.58, 95%CI 0.26-0.90, respectively). CSF levels of IL-6 were increased in suicide attempters regardless of their psychiatric diagnosis. Translocator protein, a PET marker of central inflammation, was elevated in the anterior cingulate cortex and temporal cortex of patients with MDD compared with controls (SMD 0.78, 95%CI: 0.41-1.16 and SMD 0.52, 95%CI: 0.19-0.85 respectively). Abnormalities in CSF and PET inflammatory markers were not correlated with those in peripheral blood. In post-mortem studies, two studies found increased markers of microglia in MDD brains, while four studies found no MDD related changes. Of the studies investigating expression of cell-specific marker for astrocytes, thirteen studies reported a decreased expression of astrocytes specific markers, two studies reported increased expression of astrocytes specific markers, and eleven studies did not detect any difference. Four out of six studies reported decreased markers of oligodendrocytes in the prefrontal cortex. Post-mortem brain levels of tumor necrosis alpha (TNF-α) were also found increased in MDD. CONCLUSIONS Our review suggests the presence of an increase in IL-6 and TNF-alpha levels in CSF and brain parenchyma, in the context of a possible increased microglia activity and reduction of astrocytes and oligodendrocytes markers in MDD. The reduced number of astrocytes may lead to compromised integrity of blood brain barrier with increased monocyte recruitment and infiltration, which is partly supported by post-mortem studies and by PET studies showing an increased TSPO expression in MDD.

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BackgroundInfluential
White Matter Abnormalities in First-Episode, Treatment-Naive Young Adults With Major Depressive Disorder
Ma, N. (2007) · American Journal of Psychiatry · doi:10.1176/appi.ajp.164.5.823 · Cited by 152 · see citing works
Glial fibrillary acidic protein is differentially expressed across cortical and subcortical regions in healthy brains and downregulated in the thalamus and caudate nucleus of depressed suicides
Torres-Platas, S. G., Nagy, C., Wakid, M., Turecki, G., & Mechawar, N. (2016) · Molecular Psychiatry · doi:10.1038/mp.2015.65 · Cited by 148 · cited 3× · see citing works
“Two studies found similar mRNA or protein levels of GFAP between MDD and controls in cerebellar cortex, primary motor cortex (Brodmann’s area-BA- 4), primary visual cortex (BA 17) (Torres-Platas et al., 2016), and in anterior cingulate cortex (Webster et al.”
BackgroundResultInfluential
Astrogliopathology
Verkhratsky, A., Rodriguez, J. J., & Steardo, L. (2013) · The Neuroscientist · doi:10.1177/1073858413510208 · Cited by 146 · cited 1× · see citing works
“Additionally, the GAP junction between astrocytes and astrocytes and between astrocytes and neurons may be affected and this would lead to an impairment in the ion homeostasis and synaptic circuit (Rajkowska and Stockmeier, 2013; Verkhratsky et al., 2014).”
Background
Glial fibrillary acidic protein is reduced in cerebellum of subjects with major depression, but not schizophrenia
Fatemi, S. H., Laurence, J. A., Araghi‐Niknam, M., Stary, J. M., Schulz, S. C., Lee, S. S., & Gottesman, I. I. (2003) · Schizophrenia Research · doi:10.1016/j.schres.2003.08.014 · Cited by 141 · cited 2× · see citing works
“, 2017), lateral cerebellum (Fatemi et al., 2004), and white matter in ventral prefrontal cortex (Rajkowska et al.”
Background
Translocator protein (18 kDa TSPO) binding, a marker of microglia, is reduced in major depression during cognitive-behavioral therapy
Li, H., Sagar, A. P., & Kéri, S. (2017) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2017.12.011 · Cited by 134 · cited 6× · see citing works
“First (Holmes et al., 2018; Su et al., 2016) and second (Hannestad et al., 2013; Li et al., 2018; Richards et al., 2018; Setiawan et al., 2018) generation TSPO PET tracers were used.”
BackgroundMethodInfluential
PROINFLAMMATORY AND “RESILIENCY” PROTEINS IN THE CSF OF PATIENTS WITH MAJOR DEPRESSION: Cytokines, Resiliency Proteins and Major Depression
Martinez, J. M., Garakani, A., Yehuda, R., & Gorman, J. M. (2012) · Depression and Anxiety · doi:10.1002/da.20876 · Cited by 131 · cited 6× · see citing works
“Some studies, which found a decreased in neurotrophic factors in patients with MDD, argue that in patients with MDD there is primarily an impairment in synaptic plasticity and neuroplasticity (Martinez et al., 2012)(Rajkowska and Stockmeier, 2013).”
BackgroundResultInfluential
CSF and plasma cytokines at delivery and postpartum mood disturbances
Boufidou, F., Lambrinoudaki, I., Argeitis, J., Zervas, I. M., Pliatsika, P., Leonardou, A. A., Petropoulos, G., Hassiakos, D., Papadias, K., & Nikolaou, C. (2008) · Journal of Affective Disorders · doi:10.1016/j.jad.2008.07.008 · Cited by 118 · cited 2× · see citing works
“9 We included 12 studies which investigated cytokines, chemokines and complement C5 in CSF of MDD patients (Blasko et al., 2006; Boufidou et al., 2009; Carpenter et al., 2004; Hestad et al., 2016; Ishii et al., 2018; Kern et al., 2014; Levine et al., 1999; Lindqvist et al., 2009; Martinez et al., 2012; Palhagen et al.…”
Background
Regionally-specific changes in levels of tumour necrosis factor in the dorsolateral prefrontal cortex obtained postmortem from subjects with major depressive disorder
Dean, B., Tawadros, N., Scarr, E., & Gibbons, A. S. (2009) · Journal of Affective Disorders · doi:10.1016/j.jad.2009.04.027 · Cited by 110 · see citing works
Reduced connexin 43 immunolabeling in the orbitofrontal cortex in alcohol dependence and depression
Miguel-Hidalgo, J. J., Wilson, B. A., Hussain, S., Meshram, A., Rajkowska, G., & Stockmeier, C. A. (2014) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2014.04.007 · Cited by 110 · see citing works
Toll-Like Receptors 2, -3 and -4 Prime Microglia but not Astrocytes Across Central Nervous System Regions for ATP-Dependent Interleukin-1β Release
Facci, L., Barbierato, M., Marinelli, C., Argentini, C., Skaper, S. D., & Giusti, P. (2014) · Scientific Reports · doi:10.1038/srep06824 · Cited by 109 · see citing works
Innate immunity in the postmortem brain of depressed and suicide subjects: Role of Toll-like receptors
Pandey, G. N., Rizavi, H. S., Bhaumik, R., & Ren, X. (2018) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2018.09.024 · Cited by 108 · cited 1× · see citing works
“, 2019, 2014) found similar levels of toll like receptor 1, 2, 3, 4 mRNA in MDD suicide victims and MDD no suicide victims, but increased levels of protein toll like receptor 3, 4 and 6 in MDD suicide victims compared with MDD non-suicide victims (Pandey et al., 2019).”
Result
S100B-immunopositive astrocytes and oligodendrocytes in the hippocampus are differentially afflicted in unipolar and bipolar depression: A postmortem study
Gos, T., Schroeter, M. L., Lessel, W., Bernstein, H.-G., Dobrowolny, H., Schiltz, K., Bogerts, B., & Steiner, J. (2013) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2013.07.005 · Cited by 106 · cited 4× · see citing works
“We included 12 studies which measured oligodendrocytes in post-mortem MDD brains (Aston et al., 2005; Barley et al., 2009; Gos et al., 2013; Hayashi et al., 2011; Honer et al., 1999; Lutz et al., 2017; Miguel-Hidalgo et al., 2017; Rajkowska et al., 2015; Tanti et al., 2018; Uranova et al., 2004; Vostrikov et al., 2007…”
BackgroundInfluential
Role of Complex Epigenetic Switching in Tumor Necrosis Factor-α Upregulation in the Prefrontal Cortex of Suicide Subjects
Wang, Q., Roy, B., Turecki, G., Shelton, R. C., & Dwivedi, Y. (2018) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2017.16070759 · Cited by 101 · cited 16× · see citing works
“CSF levels of IL-6 and TNF-α were higher in patients with MDD compared with controls (standardised mean difference SMD 0.37, 95%CI: 0.17-0.57 and SMD 0.58, 95%CI 0.26-0.90, respectively).”
BackgroundInfluential
Gene expression deficits in pontine locus coeruleus astrocytes in men with major depressive disorder
Chandley, M., Szebeni, K., Szebeni, A., Crawford, J. D., Stockmeier, C. A., Turecki, G., Miguel-Hidalgo, J. J., & Ordway, G. A. (2013) · Journal of Psychiatry and Neuroscience · doi:10.1503/jpn.120110 · Cited by 100 · cited 5× · see citing works
“We included 24 studies which assessed astrocytes in postmortem brains of patients with MDD (Altshuler et al., 2010; Barley et al., 2009; Bernard et al., 2011; Chandley et al., 2013; Cobb et al., 2016; Damadzic et al., 2001; Davis et al., 2002; Fatemi et al., 2004; Gos et al., 2013; Miguel-Hidalgo et al., 2014, 2011, 2…”
BackgroundInfluential
Different changes in cortical tumor necrosis factor-α-related pathways in schizophrenia and mood disorders
Dean, B., Gibbons, A. S., Tawadros, N., Brooks, L., Everall, I., & Scarr, E. (2012) · Molecular Psychiatry · doi:10.1038/mp.2012.95 · Cited by 99 · cited 2× · see citing works
“Ten studies measured cytokines (Clark et al., 2016; Dean et al., 2013, 2010; Hoyo-Becerra et al., 2013; Pandey et al., 2019, 2012; Pantazatos et al., 2017; Tonelli et al., 2008; Wang et al., 2018) and chemokines (Clark et al., 2016; Torres-Platas et al., 2014) expression in postmortem brains of MDD…”
BackgroundResult
Oligodendrocyte morphometry and expression of myelin – Related mRNA in ventral prefrontal white matter in major depressive disorder
Rajkowska, G., Mahajan, G., Maciąg, D., Sathyanesan, M., Iyo, A. H., Moulana, M., Kyle, P. B., Woolverton, W. L., Miguel-Hidalgo, J. J., Stockmeier, C. A., et al. (2015) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2015.04.010 · Cited by 99 · cited 3× · see citing works
“We included 12 studies which measured oligodendrocytes in post-mortem MDD brains (Aston et al., 2005; Barley et al., 2009; Gos et al., 2013; Hayashi et al., 2011; Honer et al., 1999; Lutz et al., 2017; Miguel-Hidalgo et al., 2017; Rajkowska et al., 2015; Tanti et al., 2018; Uranova et al., 2004; Vostrikov et al., 2007…”
Background
Glial fibrillary acidic protein and glutamine synthetase in subregions of prefrontal cortex in schizophrenia and mood disorder
Toro, C. T., Hallak, J. E. C., Dunham, J. S., & Deakin, J. F. W. (2006) · Neuroscience Letters · doi:10.1016/j.neulet.2006.05.067 · Cited by 95 · see citing works
Higher CSF Interleukin-6 and CSF Interleukin-8 in Current Depression in Older Women. Results from a Population-Based Sample
Kern, S., Skoog, I., Börjesson-Hanson, A., Blennow, K., Zetterberg, H., Östling, S., Kern, J., Gudmundsson, P., Marlow, T., Rosengren, L., et al. (2014) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2014.05.006 · Cited by 94 · see citing works
Low plasma vascular endothelial growth factor (VEGF) associated with completed suicide
Isung, J., Mobarrez, F., Nordström, P., Åsberg, M., & Jokinen, J. (2012) · The World Journal of Biological Psychiatry · doi:10.3109/15622975.2011.624549 · Cited by 94 · cited 3× · see citing works
“Seven studies found no correlation between markers of central inflammation (CSF cytokines or PET TSPO) and peripheral inflammation (Bay-Richter et al., 2015; Hannestad et al., 2013; Holmes et al., 2018; Isung et al., 2012; Lindqvist et al., 2009; Sasayama et al., 2013; Setiawan et al., 2015).”
BackgroundResult
Reduced kynurenine pathway metabolism and cytokine expression in the prefrontal cortex of depressed individuals
Clark, S. M., Pocivavsek, A., Nicholson, J. D., Notarangelo, F. M., LANGENBERG, P. W., McMahon, R. P., Kleinman, J. E., Hyde, T. M., Stiller, J. W., Postolache, T. T., et al. (2016) · Journal of Psychiatry and Neuroscience · doi:10.1503/jpn.150226 · Cited by 92 · cited 5× · see citing works
“Clark et al reported an increase in the proportion of IBA1-positive amoebian (active) microglia in the ventrolateral prefrontal cortex of patients with MDD compared with controls and similar density of hypertrophic (non-active) microglia (Clark et al., 2016).”
BackgroundInfluential
Myelination
Barnett, S. C., & Linington, C. (2012) · The Neuroscientist · doi:10.1177/1073858412465655 · Cited by 83 · cited 1× · see citing works
“Furthermore, an increased level of cytokines and impairment in astrocytes function may lead to an impairment of the myelination and reduced oligodendrocytes density (Barnett and Linington, 2013; Rajkowska et al., 2018).”
Background
Prefrontal changes in the glutamate-glutamine cycle and neuronal/glial glutamate transporters in depression with and without suicide
Zhao, J., Verwer, R. W. H., van Wamelen, D. J., Qi, X.-R., Gao, S.-F., Lucassen, P. J., & Swaab, D. F. (2016) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2016.06.017 · Cited by 83 · see citing works
Cerebrospinal fluid interleukin (IL)-6 in unipolar major depression
Carpenter, L. L., Heninger, G. R., Malison, R. T., Tyrka, A. R., & Price, L. H. (2004) · Journal of Affective Disorders · doi:10.1016/s0165-0327(02)00460-3 · Cited by 79 · cited 2× · see citing works
“9 We included 12 studies which investigated cytokines, chemokines and complement C5 in CSF of MDD patients (Blasko et al., 2006; Boufidou et al., 2009; Carpenter et al., 2004; Hestad et al., 2016; Ishii et al., 2018; Kern et al., 2014; Levine et al., 1999; Lindqvist et al., 2009; Martinez et al., 2012; Palhagen et al.…”
Background
Monoamines, BDNF, IL-6 and corticosterone in CSF in patients with Parkinson’s disease and major depression
Pålhagen, S., Qi, H., Mårtensson, B., Wålinder, J., Granérus, A., & Svenningsson, P. (2009) · Journal of Neurology · doi:10.1007/s00415-009-5353-6 · Cited by 77 · cited 2× · see citing works
“9 We included 12 studies which investigated cytokines, chemokines and complement C5 in CSF of MDD patients (Blasko et al., 2006; Boufidou et al., 2009; Carpenter et al., 2004; Hestad et al., 2016; Ishii et al., 2018; Kern et al., 2014; Levine et al., 1999; Lindqvist et al., 2009; Martinez et al., 2012; Palhagen et al.…”
BackgroundResult
A quantitative immunohistochemical study of astrocytes in the entorhinal cortex in schizophrenia, bipolar disorder and major depression: absence of significant astrocytosis
Damadzic, R., Bigelow, L. B., Krimer, L. S., Goldenson, D. A., Saunders, R. C., Kleinman, J. E., & Herman, M. M. (2001) · Brain Research Bulletin · doi:10.1016/s0361-9230(01)00529-9 · Cited by 77 · cited 2× · see citing works
“, 2006), entorhinal cortex (Damadzic et al., 2001), substantia nigra (Williams et al.”
Background
Neuroinflammatory and morphological changes in late-life depression: the NIMROD study
Su, L., Faluyi, Y. O., Hong, Y. T., Fryer, T. D., Mak, E., Gabel, S., Hayes, L., Soteriades, S., Williams, G. B., Arnold, R. J., et al. (2016) · The British Journal of Psychiatry · doi:10.1192/bjp.bp.116.190165 · Cited by 77 · see citing works
Glial fibrillary acidic protein in late life major depressive disorder: an immunocytochemical study
Davis, S. (2002) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.73.5.556 · Cited by 77 · cited 3× · see citing works
“, 2002); and only one study showed higher GFAP immunoreactivity in dorsolateral prefrontal cortex in brains of elderly patients with MDD (Davis et al., 2002).”
Background
Child abuse associates with an imbalance of oligodendrocyte-lineage cells in ventromedial prefrontal white matter
Tanti, A., Kim, J. J., Wakid, M., Davoli, M.-A., Turecki, G., & Mechawar, N. (2017) · Molecular Psychiatry · doi:10.1038/mp.2017.231 · Cited by 76 · see citing works
Decreased quinolinic acid in the hippocampus of depressive patients: evidence for local anti-inflammatory and neuroprotective responses?
Busse, M., Busse, S., Myint, A., Gos, T., Dobrowolny, H., Müller, U. J., Bogerts, B., Bernstein, H., & Steiner, J. (2015) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-014-0562-0 · Cited by 74 · cited 3× · see citing works
“We included 8 studies which investigated microglial markers in post-mortem brains of patients with MDD (Brisch et al., 2017; Busse et al., 2015; Clark et al., 2016; Foster et al., 2006; Steiner et al., 2011, 2008; Torres-Platas et al., 2014; Wesseling et al., 2014)(Table 4).”
Background
Astrocyte pathology in the ventral prefrontal white matter in depression
Rajkowska, G., Legutko, B., Moulana, M., Syed, M., Romero, D. G., Stockmeier, C. A., & Miguel-Hidalgo, J. J. (2018) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2018.04.005 · Cited by 70 · cited 5× · see citing works
“We included 24 studies which assessed astrocytes in postmortem brains of patients with MDD (Altshuler et al., 2010; Barley et al., 2009; Bernard et al., 2011; Chandley et al., 2013; Cobb et al., 2016; Damadzic et al., 2001; Davis et al., 2002; Fatemi et al., 2004; Gos et al., 2013; Miguel-Hidalgo et al., 2014, 2011, 2…”
BackgroundInfluential
Altered Chemokine Levels in the Cerebrospinal Fluid and Plasma of Suicide Attempters
Janelidze, S., Ventorp, F., Erhardt, S., Hansson, O., Minthon, L., Flax, J., Samuelsson, M., Traskman-Bendz, L., & Brundin, L. (2013) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2012.09.010 · Cited by 69 · see citing works
Clinical Findings Documenting Cellular and Molecular Abnormalities of Glia in Depressive Disorders
Czéh, B., & Nagy, S. A. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00056 · Cited by 64 · cited 2× · see citing works
“6 a systematic review and did not present the large amount of inconclusive post-mortem studies on glial markers in patients with MDD and bipolar disorder (Czeh and Nagy, 2018).”
Background
Calprotectin in microglia from frontal cortex is up‐regulated in schizophrenia: evidence for an inflammatory process?
Foster, F., Kandanearatchi, A., Beasley, C. L., Williams, B. P., Khan, N., Fagerhol, M. K., & Everall, I. (2006) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2006.05219.x · Cited by 62 · cited 1× · see citing works
“We included 8 studies which investigated microglial markers in post-mortem brains of patients with MDD (Brisch et al., 2017; Busse et al., 2015; Clark et al., 2016; Foster et al., 2006; Steiner et al., 2011, 2008; Torres-Platas et al., 2014; Wesseling et al., 2014)(Table 4).”
Background
Microglia in the dorsal raphe nucleus plays a potential role in both suicide facilitation and prevention in affective disorders
Brisch, R., Steiner, J., Mawrin, C., Krzyżanowska, M., Jankowski, Z., & Gos, T. (2017) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-017-0774-1 · Cited by 60 · cited 3× · see citing works
“We included 8 studies which investigated microglial markers in post-mortem brains of patients with MDD (Brisch et al., 2017; Busse et al., 2015; Clark et al., 2016; Foster et al., 2006; Steiner et al., 2011, 2008; Torres-Platas et al., 2014; Wesseling et al., 2014)(Table 4).”
Background
Interleukin-6 and the soluble IL-6 receptor are decreased in cerebrospinal fluid of geriatric patients with major depression: no alteration of soluble gp130
Stübner, S., Schön, T., Padberg, F., Teipel, S. J., Schwarz, M. J., Haslinger, A., Buch, K., Dukoff, R., Lasser, R., Müller, N., et al. (1999) · Neuroscience Letters · doi:10.1016/s0304-3940(98)00916-1 · Cited by 59 · see citing works
Targeted Multiplexed Selected Reaction Monitoring Analysis Evaluates Protein Expression Changes of Molecular Risk Factors for Major Psychiatric Disorders
Wesseling, H., Gottschalk, M. G., & Bahn, S. (2014) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyu015 · Cited by 54 · cited 4× · see citing works
“We included 8 studies which investigated microglial markers in post-mortem brains of patients with MDD (Brisch et al., 2017; Busse et al., 2015; Clark et al., 2016; Foster et al., 2006; Steiner et al., 2011, 2008; Torres-Platas et al., 2014; Wesseling et al., 2014)(Table 4).”
BackgroundResultInfluential
Increased cerebrospinal fluid complement C5 levels in major depressive disorder and schizophrenia
Ishii, T., Hattori, K., Miyakawa, T., Watanabe, K., Hidese, S., Sasayama, D., Ota, M., Teraishi, T., Hori, H., Yoshida, S., et al. (2018) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2018.02.131 · Cited by 53 · cited 1× · see citing works
“9 We included 12 studies which investigated cytokines, chemokines and complement C5 in CSF of MDD patients (Blasko et al., 2006; Boufidou et al., 2009; Carpenter et al., 2004; Hestad et al., 2016; Ishii et al., 2018; Kern et al., 2014; Levine et al., 1999; Lindqvist et al., 2009; Martinez et al., 2012; Palhagen et al.…”
Background
A novel, rapid, quantitative cell-counting method reveals oligodendroglial reduction in the frontopolar cortex in major depressive disorder
Hayashi, Y., Nihonmatsu-Kikuchi, N., Yu, X., Ishimoto, K., Hisanaga, S.-I., & Tatebayashi, Y. (2011) · Molecular Psychiatry · doi:10.1038/mp.2011.84 · Cited by 52 · cited 3× · see citing works
“, 2007), and in the frontopolar prefrontal cortex (BA 10) (Hayashi et al., 2011) .”
Background
Neuropathological changes in the substantia nigra in schizophrenia but not depression
Williams, M. R., Galvin, K., O'Sullivan, B., Macdonald, C., Ching, E. W. K., Turkheimer, F., Howes, O., Pearce, R. K., Hirsch, S., & Maier, M. (2014) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-013-0479-z · Cited by 51 · cited 4× · see citing works
“We included 12 studies which measured oligodendrocytes in post-mortem MDD brains (Aston et al., 2005; Barley et al., 2009; Gos et al., 2013; Hayashi et al., 2011; Honer et al., 1999; Lutz et al., 2017; Miguel-Hidalgo et al., 2017; Rajkowska et al., 2015; Tanti et al., 2018; Uranova et al., 2004; Vostrikov et al., 2007…”
BackgroundInfluential
Concomitant interferon alpha stimulation and TLR3 activation induces neuronal expression of depression-related genes that are elevated in the brain of suicidal persons
Hoyo-Becerra, C., Huebener, A., Trippler, M., Lutterbeck, M., Liu, Z. J., Truebner, K., Bajanowski, T., Gerken, G., Hermann, D. M., & Schlaak, J. F. (2013) · PLoS ONE · doi:10.1371/journal.pone.0083149 · Cited by 49 · cited 2× · see citing works
“Although IL-6 mRNA was no different between depressed and controls subjects, IL-6 mRNA has been reported to be increased in suicide victims (Hoyo-Becerra et al., 2013; Pandey et al., 2012).”
Background
MicroRNA-21: Expression in oligodendrocytes and correlation with low myelin mRNAs in depression and alcoholism
Miguel-Hidalgo, J. J., Hall, K. O., Bonner, H., Roller, A., Syed, M., Park, C. J., Ball, J. P., Rothenberg, M. E., Stockmeier, C. A., & Romero, D. G. (2017) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2017.08.009 · Cited by 45 · see citing works
Patients with depression display cytokine levels in serum and cerebrospinal fluid similar to patients with diffuse neurological symptoms without a defined diagnosis
Hestad, K. A., Engedal, K., Whist, J. E., Aukrust, P., Farup, P. G., Mollnes, T. E., & Ueland, T. (2016) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s101925 · Cited by 42 · cited 10× · see citing works
“A recent meta-analysis focused specifically on CSF cytokines in patients with MDD, schizophrenia and bipolar disorder, and found increased CSF levels of IL-6 and IL8 in these patients (Wang and Miller, 2018); however, this systematic review and metaanalysis did not include two previous studies, which focused exclusive…”
BackgroundResultInfluential
Glucocorticoid programming of neuroimmune function
Walker, D. J., & Spencer, K. A. (2017) · General and Comparative Endocrinology · doi:10.1016/j.ygcen.2017.07.016 · Cited by 40 · see citing works
Vascular and extravascular immunoreactivity for intercellular adhesion molecule 1 in the orbitofrontal cortex of subjects with major depression: Age-dependent changes
Miguel-Hidalgo, J. J., Overholser, J. C., Jurjus, G., Meltzer, H. Y., Dieter, L., Konick, L. C., Stockmeier, C. A., & Rajkowska, G. (2011) · Journal of Affective Disorders · doi:10.1016/j.jad.2011.03.052 · Cited by 31 · see citing works

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2 of the 97 references couldn’t be matched to a known paper.

Sorted by citations

COVID-19 pandemic and mental health consequences: Systematic review of the current evidence
Vindegaard, N., & Benros, M. E. (2020) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2020.05.048 · Cited by 3,221 · see citing works
The Bidirectional Relationship of Depression and Inflammation: Double Trouble
Beurel, E., Toups, M., & Nemeroff, C. B. (2020) · Neuron · doi:10.1016/j.neuron.2020.06.002 · Cited by 2,136 · see citing works
“Furthermore, a recent meta-analysis suggests increased microglial activity is associated with increased IL-6, IL-8, and TNF levels in CSF and brain parenchyma of MDD patients (Wang and Miller, 2018) and reduced astrocytes and oligodendrocytes numbers in MDD patients (Enache et al., 2019).”
Background
Major depressive disorder
Marx, W., Penninx, B. W. J. H., Solmi, M., Furukawa, T. A., Firth, J., Carvalho, A. F., & Berk, M. (2023) · Nature Reviews Disease Primers · doi:10.1038/s41572-023-00454-1 · Cited by 850 · see citing works
Comorbid depression in medical diseases
Gold, S. M., Köhler‐Forsberg, O., Moss-Morris, R. E., Mehnert, A., Miranda, J. J., Bullinger, M., Steptoe, A., Whooley, M. A., & Otte, C. (2020) · Nature Reviews Disease Primers · doi:10.1038/s41572-020-0200-2 · Cited by 547 · see citing works
Persistent psychopathology and neurocognitive impairment in COVID-19 survivors: effect of inflammatory biomarkers at three-month follow-up
Mazza, M. G., Palladini, M., De Lorenzo, R., Magnaghi, C., Poletti, S., Furlan, R., Ciceri, F., Rovere-Querini, P., & Benedetti, F. (2021) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2021.02.021 · Cited by 513 · see citing works
“Depressed patients are characterized by higher levels of cytokines when compared to healthy controls with consistent results in literature when considering IL-1β, IL6, IL-10, CCL2, TNF-α, and transforming growth factor-β (TGF-β) (Enache et al., 2019; Eyre et al., 2016; Howren et al., 2009; Kohler et al., 2017; Poletti…”
Depression Heterogeneity and Its Biological Underpinnings: Toward Immunometabolic Depression
Milaneschi, Y., Lamers, F., Berk, M., & Penninx, B. W. J. H. (2020) · Biological Psychiatry · doi:10.1016/j.biopsych.2020.01.014 · Cited by 433 · see citing works
Immune targets for therapeutic development in depression: towards precision medicine
Drevets, W. C., Wittenberg, G. M., Bullmore, E. T., & Manji, H. K. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00368-1 · Cited by 348 · see citing works
Major Depressive Disorder: Advances in Neuroscience Research and Translational Applications
Li, Z., Ruan, M., Chen, J., & Fang, Y. (2021) · Neuroscience Bulletin · doi:10.1007/s12264-021-00638-3 · Cited by 352 · see citing works
Microglia in depression: current perspectives
Jia, X., Gao, Z., & Hu, H. (2020) · Science China Life Sciences · doi:10.1007/s11427-020-1815-6 · Cited by 283 · see citing works
“In meta-analysis of depression studies, patients with depression showed consistently upregulated levels of pro-inflammatory cytokines such as TNF-α and IL-6 (Dowlati et al., 2010; Enache et al., 2019).”
Background
Neuroinflammation in psychiatric disorders: PET imaging and promising new targets
Meyer, J. H., Červenka, S., Kim, M.-J., Kreisl, W. C., Henter, I. D., & Innis, R. B. (2020) · The Lancet Psychiatry · doi:10.1016/s2215-0366(20)30255-8 · Cited by 274 · see citing works
Oligodendrocyte lineage cells and depression
Zhou, B., Zhu, Z., Ransom, B. R., & Tong, X. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-00930-0 · Cited by 239 · see citing works
Gut microbiota–brain axis in depression: the role of neuroinflammation
Carlessi, A. S., Borba, L. A., Zugno, A. I., Quevedo, J., & Réus, G. Z. (2021) · European Journal of Neuroscience · doi:10.1111/ejn.14631 · Cited by 243 · see citing works
Augmentation therapy with minocycline in treatment-resistant depression patients with low-grade peripheral inflammation: results from a double-blind randomised clinical trial
Nettis, M. A., Lombardo, G., Hastings, C., Zajkowska, Z., Mariani, N., Nikkheslat, N., Worrell, C., Enache, D., McLaughlin, A., Kose, M., et al. (2021) · Neuropsychopharmacology · doi:10.1038/s41386-020-00948-6 · Cited by 235 · see citing works
Self-citation
The intestinal barrier in disorders of the central nervous system
Pellegrini, C., Fornai, M., D'Antongiovanni, V., Antonioli, L., Bernardini, N., & Derkinderen, P. (2023) · The Lancet Gastroenterology & Hepatology · doi:10.1016/s2468-1253(22)00241-2 · Cited by 239 · see citing works
Omega-3 polyunsaturated fatty acids protect against inflammation through production of LOX and CYP450 lipid mediators: relevance for major depression and for human hippocampal neurogenesis
Borsini, A., Nicolaou, A., Camacho‐Muñoz, D., Kendall, A. C., Benedetto, M. G. D., Giacobbe, J., Su, K., & Pariante, C. M. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01160-8 · Cited by 235 · see citing works
Self-citation
Psychiatric face of COVID-19
Steardo, L., Steardo, L., & Verkhratsky, A. (2020) · Translational Psychiatry · doi:10.1038/s41398-020-00949-5 · Cited by 222 · see citing works
Post-COVID-19 Depressive Symptoms: Epidemiology, Pathophysiology, and Pharmacological Treatment
Mazza, M. G., Palladini, M., Poletti, S., & Benedetti, F. (2022) · CNS Drugs · doi:10.1007/s40263-022-00931-3 · Cited by 233 · see citing works
“Accordingly, increased microglial activation in association with high levels of IL-6 and TNF-α have been observed in MDD episodes [82], whereas microglia activation has been implicated in both acute and chronic neurological complications of COVID-19 [83], and increased microglial activation has been demonstrated in po…”
Background
Microglial ERK-NRBP1-CREB-BDNF Signaling in Sustained Antidepressant Actions of (R)-Ketamine
Yao, W., Cao, Q., Luo, S., He, L., Yang, C., Chen, J., Qi, Q., Hashimoto, K., & Zhang, J.-C. (2022) · Molecular Psychiatry · doi:10.1038/s41380-021-01377-7 · Cited by 217 · see citing works
“A recent meta-analysis using positron emission tomography data showed increased expression of microglia in the brain of patients with depression [71].”
Method
PI3K/AKT signaling pathway: Molecular mechanisms and therapeutic potential in depression
Guo, N., Wang, X., Xu, M., Bai, J., Yu, H., & Zhang, L. (2024) · Pharmacological Research · doi:10.1016/j.phrs.2024.107300 · Cited by 232 · see citing works
Biological factors influencing depression in later life: role of aging processes and treatment implications
Szymkowicz, S. M., Gerlach, A., Homiack, D., & Taylor, W. D. (2023) · Translational Psychiatry · doi:10.1038/s41398-023-02464-9 · Cited by 212 · see citing works
“Studies of individuals with depression and suicide attempts report increased microglial activation in the anterior cingulate cortex (ACC), a key hub of both the ASN and CCN, in individuals with depression and suicide attempts [131, 132].”
Background
Climate change, environment pollution, COVID-19 pandemic and mental health
Marazziti, D., Cianconi, P., Mucci, F., Crowther, L. F., Chiarantini, I., & Vecchia, A. D. (2021) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2021.145182 · Cited by 193 · see citing works
“Depression was associated with elevated IL-6 concentrations in both plasma and brain (Lindqvist et al., 2009; Sasayama et al., 2013; Kern et al., 2014; Enache et al., 2019; Boufidou et al., 2009; Hodes et al., 2016).”
Psycho-Neuroendocrine-Immune Interactions in COVID-19: Potential Impacts on Mental Health
Raony, Í., de Figueiredo, C. S., Pandolfo, P., Giestal-de-Araujo, E., Oliveira-Silva Bomfim, P., & Savino, W. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01170 · Cited by 185 · see citing works
How inflammation affects the brain in depression: a review of functional and structural MRI studies
Han, K.-M., & Ham, B.-J. (2021) · Journal of Clinical Neurology · doi:10.3988/jcn.2021.17.4.503 · Cited by 187 · see citing works
Depression, dementia and immune dysregulation
Hayley, S., Hakim, A. M., & Albert, P. R. (2021) · Brain · doi:10.1093/brain/awaa405 · Cited by 186 · see citing works
“, 2017), post-mortem studies in human brain have detected inflammatory cytokines and microglial activation markers in depression and suicide (Enache et al., 2019).”
Background
The role of exercise in the treatment of depression: biological underpinnings and clinical outcomes
Ross, R. E., VanDerwerker, C. J., Saladin, M. E., & Gregory, C. M. (2023) · Molecular Psychiatry · doi:10.1038/s41380-022-01819-w · Cited by 176 · see citing works
A specific inflammatory profile underlying suicide risk? Systematic review of the main literature findings
Serafini, G., Parisi, V. M., Aguglia, A., Amerio, A., Sampogna, G., Fiorillo, A., Pompili, M., & Amore, M. (2020) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph17072393 · Cited by 172 · see citing works
“[52] supported the existence of abnormally increased IL-6 and TNF-α concentrations in CSF and brain parenchyma, together with an increased microglia activity and abnormally reduced astrocytes/oligodendrocytes markers levels in MDD.”
Background
Past, Present and (Foreseeable) Future of Biological Anti-TNF Alpha Therapy
Leone, G. M., Mangano, K., Petralia, M. C., Nicoletti, F., & Fagone, P. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12041630 · Cited by 171 · see citing works
Depression in Alzheimer’s Disease: Epidemiology, Mechanisms, and Treatment
Huang, Y.-Y., Gan, Y.-H., Yang, L., Cheng, W., & Yu, J.-T. (2024) · Biological Psychiatry · doi:10.1016/j.biopsych.2023.10.008 · Cited by 164 · see citing works
Inflammatory mediators in major depression and bipolar disorder
Poletti, S., Mazza, M. G., & Benedetti, F. (2024) · Translational Psychiatry · doi:10.1038/s41398-024-02921-z · Cited by 179 · see citing works
The Ketogenic Diet for Refractory Mental Illness: A Retrospective Analysis of 31 Inpatients
Danan, A., Westman, E. C., Saslow, L. R., & Ede, G. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.951376 · Cited by 151 · see citing works
Stress-induced NLRP3 inflammasome activation negatively regulates fear memory in mice
Dong, Y., Li, S., Lu, Y., Li, X., Liao, Y., Peng, Z., Li, Y., Hou, L., Yuan, Z., & Cheng, J. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01842-0 · Cited by 146 · see citing works
The SARS-CoV-2 and mental health: From biological mechanisms to social consequences
Szcześniak, D. M., Gładka, A., Misiak, B., Cyran, A., & Rymaszewska, J. (2020) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2020.110046 · Cited by 152 · see citing works
Neuroinflammation—A Crucial Factor in the Pathophysiology of Depression—A Comprehensive Review
Sălcudean, A., Bodo, C.-R., Popovici, R. A., Lica, M. M., Păcurar, M., Crăciun, R.-E., Crișan, A., ENĂTESCU, V. R., Marinescu, I. P., Cîmpian, D. M., et al. (2025) · Biomolecules · doi:10.3390/biom15040502 · Cited by 165 · see citing works
Gut-derived systemic inflammation as a driver of depression in chronic liver disease
Kronsten, V. T., Tranah, T. H., Pariante, C. M., & Shawcross, D. L. (2021) · Journal of Hepatology · doi:10.1016/j.jhep.2021.11.008 · Cited by 134 · see citing works
Self-citation
“Inflamed” depression: A review of the interactions between depression and inflammation and current anti-inflammatory strategies for depression
Yin, Y., Ju, T., Zeng, D., Duan, F., Zhu, Y., Liu, J., Li, Y., & Lu, W. (2024) · Pharmacological Research · doi:10.1016/j.phrs.2024.107322 · Cited by 152 · see citing works
Novel neuroimmunologic therapeutics in depression: A clinical perspective on what we know so far
Roman, M., & Irwin, M. R. (2020) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2019.09.016 · Cited by 132 · see citing works
“This increase of CSF levels of TNFα and Il-6 in depressed individuals was further corroborated by a systematic review and meta-analysis of 69 studies, which also demonstrated an increase of these two inflammatory markers in the brain parenchyma in depression (Enache et al., 2019).”
Result
The complex interplay between depression and multimorbidity in late life: risks and pathways
Triolo, F., Harber-Aschan, L., Murri, M. B., Calderón‐Larrañaga, A., Vetrano, D. L., Sjöberg, L., Marengoni, A., & Dekhtyar, S. (2020) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2020.111383 · Cited by 136 · see citing works
“…been linked with subsequent depression and multimorbidity, with evidence pointing to the relevance of critical windows of stress in childhood, as well as over prolonged life periods (Brodbeck et al., 2018; England-Mason et al., 2018; Henchoz et al., 2019; Sinnott et al., 2015; Triolo et al., 2020).”
Background
Peripheral and central kynurenine pathway abnormalities in major depression
Paul, E. R., Schwieler, L., Erhardt, S., Boda, S., Trepci, A., Kämpe, R., Asratian, A., Holm, L., Yngve, A., Dantzer, R., et al. (2022) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2022.01.002 · Cited by 134 · see citing works
“Increased circulating pro-inflammatory cytokines are among the most reliably observed findings in the biologicalpsychiatry of MDD (Dowlati et al., 2010; Enache et al., 2019; Köhler et al., 2017).”
Toll-Like Receptor Signaling in Depression
Figueroa‐Hall, L. K., Paulus, M. P., & Savitz, J. B. (2020) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2020.104843 · Cited by 121 · see citing works
“A number of systematic reviews and meta-analyses have shown that interleukin 6 (IL-6), IL-1β, C-reactive protein (CRP), tumor necrosis factor (TNF), and IL-1 receptor antagonist (IL-1Ra) are positively associated with MDD (Dowlati et al., 2010; Enache et al., 2019; Goldsmith et al., 2016; Haapakoski et al., 2015).”
Background
Aiding and Abetting Anhedonia: Impact of Inflammation on the Brain and Pharmacological Implications
Lucido, M. J., Bekhbat, M., Goldsmith, D. R., Treadway, M. T., Haroon, E., Felger, J. C., & Miller, A. H. (2021) · Pharmacological Reviews · doi:10.1124/pharmrev.120.000043 · Cited by 130 · see citing works
“microglia, the immune cells of the brain (Pandey et al., 2014, 2017; Torres-Platas et al., 2014a,b; Enache et al., 2019).”
Background
The immunology of stress and the impact of inflammation on the brain and behaviour
Ravi, M., Miller, A. H., & Michopoulos, V. (2021) · BJPsych Advances · doi:10.1192/bja.2020.82 · Cited by 130 · see citing works
“Increased microglia activation, the central mediators of the immune system, as assessed by PET neuroimaging, and greater expression of TNF and TLR4 in post-mortem brain tissue have also been described in individuals with depression (27).”
Blood–Brain Barrier Dysfunction in the Pathogenesis of Major Depressive Disorder
Wu, S., Yin, Y., & Du, L. (2021) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-021-01153-9 · Cited by 126 · see citing works
Blood brain barrier and inflammation in depression
Medina-Rodriguez, E. M., & Beurel, E. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105926 · Cited by 123 · see citing works
Depression: Biological markers and treatment
Erjavec, G. N., Šagud, M., Perković, M. N., Štrac, D. Š., Konjevod, M., Tudor, L., Uzun, S., & Pivac, N. (2020) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2020.110139 · Cited by 120 · see citing works
Psychological Symptoms in COVID-19 Patients: Insights into Pathophysiology and Risk Factors of Long COVID-19
Thye, A. Y.-K., Law, J. W., Tan, L. T., Pusparajah, P., Ser, H., Thurairajasingam, S., Letchumanan, V., & Lee, L. (2022) · Biology · doi:10.3390/biology11010061 · Cited by 115 · see citing works
Dihydrolipoic acid protects against lipopolysaccharide-induced behavioral deficits and neuroinflammation via regulation of Nrf2/HO-1/NLRP3 signaling in rat
Bian, H., Wang, G., Huang, J., Liang, L., Zheng, Y., Wei, Y., Wang, H., Xiao, L., & Wang, H. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01836-y · Cited by 112 · see citing works
The molecular pathophysiology of depression and the new therapeutics
Tian, H., Hu, Z., Xu, J., & Wang, C. (2022) · MedComm · doi:10.1002/mco2.156 · Cited by 122 · see citing works
Immuno-metabolic depression: from concept to implementation
Penninx, B. W. J. H., Lamers, F., Jansen, R., Berk, M., Khandaker, G. M., Picker, L. D., & Milaneschi, Y. (2024) · The Lancet Regional Health - Europe · doi:10.1016/j.lanepe.2024.101166 · Cited by 126 · see citing works
Sick for science: experimental endotoxemia as a translational tool to develop and test new therapies for inflammation-associated depression
Lasselin, J., Lekander, M., Benson, S., Schedlowski, M., & Engler, H. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-00869-2 · Cited by 114 · see citing works
“This TSPO binding pattern was similar to those in patients with MDD, for which a meta-analysis reported increased TSPO expression in ACC, frontal lobe, prefrontal and temporal cortices, insula, and hippocampus when compared to healthy controls [71].”
Result
Possible antidepressant mechanisms of omega-3 polyunsaturated fatty acids acting on the central nervous system
Zhou, L., Xiong, J., Chai, Y.-Q., Huang, L., Tang, Z.-Y., Zhang, X., Liu, B., & Zhang, J.-T. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.933704 · Cited by 115 · see citing works
Choroid plexus enlargement is associated with neuroinflammation and reduction of blood brain barrier permeability in depression
Althubaity, N., Schubert, J. J., Martins, D., Yousaf, T., Nettis, M. A., Mondelli, V., Pariante, C. M., Harrison, N. A., Bullmore, E. T., Dima, D., et al. (2021) · NeuroImage Clinical · doi:10.1016/j.nicl.2021.102926 · Cited by 108 · see citing works
Self-citation
Neuroimmune Mechanisms Underlying Neuropathic Pain: The Potential Role of TNF-α-Necroptosis Pathway
Duan, Y.-W., Chen, S., Li, Q., & Zang, Y. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23137191 · Cited by 116 · see citing works
Inflammation as a treatment target in mood disorders: review
Jones, B. D. M., Daskalakis, Z. J., Carvalho, A. F., Strawbridge, R., Young, A. H., Mulsant, B. H., & Husain, M. I. (2020) · BJPsych Open · doi:10.1192/bjo.2020.43 · Cited by 106 · see citing works
Neuroinflammation, Pain and Depression: An Overview of the Main Findings
Campos, A. C. P., Antunes, G. F., Matsumoto, M., Pagano, R. L., & Martinez, R. C. R. (2020) · Frontiers in Psychology · doi:10.3389/fpsyg.2020.01825 · Cited by 102 · see citing works
“Neuroimaging and postmortem studies have shown an increase in mitochondrial translocator protein (tryptophan-rich sensory proteins -TSPO) in subjects with major depressive disorder (Enache et al., 2019).”
Background
Ketamine’s effect on inflammation and kynurenine pathway in depression: A systematic review
Kopra, E. I., Mondelli, V., Pariante, C. M., & Nikkheslat, N. (2021) · Journal of Psychopharmacology · doi:10.1177/02698811211026426 · Cited by 102 · see citing works
“Increased inflammatory markers, specifically C-reactive protein (CRP), interleukin (IL)-1, IL-6, and tumornecrosis factor alpha (TNF-α), have been observed in the blood and cerebrospinal fluid (CSF) as well as in postmortem brain samples of MDD and BD patients (Enache et al., 2019; Osimo et al., 2020; Raison et al., 2…”
BackgroundSelf-citation
Targeting neuroinflammation by polyphenols: A promising therapeutic approach against inflammation-associated depression
Tayab, M. A., Islam, M. N., Chowdhury, K. A. A., & Tasnim, F. M. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.112668 · Cited by 98 · see citing works
Cerebrospinal Fluid Biomarkers in Patients With Unipolar Depression Compared With Healthy Control Individuals
Mousten, I. V., Sørensen, N. V., Christensen, R. H. B., & Benros, M. E. (2022) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2022.0645 · Cited by 97 · see citing works
Sex differences in the blood–brain barrier: Implications for mental health
Dion‐Albert, L., Binder, L. B., Daigle, B., Hong-Minh, A., Lebel, M., & Ménard, C. (2022) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2022.100989 · Cited by 89 · see citing works
“Changes in central and peripheral inflammatory mediators have been observed in MDD (Enache et al., 2019; Schiepers et al., 2005), BD (O’Brien et al.”
Background
Systems biology dissection of PTSD and MDD across brain regions, cell types, and blood
Daskalakis, N. P., Iatrou, A., Chatzinakos, C., Jajoo, A., Snijders, C., Wylie, D., DiPietro, C. P., Tsatsani, I., Chen, C.-Y., Pernia, C. D., et al. (2024) · Science · doi:10.1126/science.adh3707 · Cited by 99 · see citing works
Single-cell mass cytometry of microglia in major depressive disorder reveals a non-inflammatory phenotype with increased homeostatic marker expression
Böttcher, C., Fernández‐Zapata, C., Snijders, G. J. L., Schlickeiser, S., Sneeboer, M. A. M., Kunkel, D., de Witte, L. D., & Priller, J. (2020) · Translational Psychiatry · doi:10.1038/s41398-020-00992-2 · Cited by 91 · see citing works
Ketogenic diet as a metabolic treatment for mental illness
Norwitz, N. G., Sethi, S., & Palmer, C. (2020) · Current Opinion in Endocrinology Diabetes and Obesity · doi:10.1097/med.0000000000000564 · Cited by 87 · see citing works
Increased serum peripheral C-reactive protein is associated with reduced brain barriers permeability of TSPO radioligands in healthy volunteers and depressed patients: implications for inflammation and depression
Turkheimer, F., Althubaity, N., Schubert, J. J., Nettis, M. A., Cousins, O., Dima, D., Mondelli, V., Bullmore, E. T., Pariante, C. M., & Veronese, M. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.10.025 · Cited by 87 · see citing works
Self-citation
Noteworthy perspectives on microglia in neuropsychiatric disorders
Zhu, H., Guan, A., Liu, J., Li, P., Zhang, Z., & Wang, S. (2023) · Journal of Neuroinflammation · doi:10.1186/s12974-023-02901-y · Cited by 90 · see citing works
“…in post-mortem brains of MDD individuals, may cause disruption of BBB integrity and subsequently infiltration of monocytes into the CNS, which can also display increased TSPO in PET [236]; on the other hand, microglia activation may not persist but assume a role at specific stages of MDD [235].”
Background
Impaired regulatory T cell control of astroglial overdrive and microglial pruning in schizophrenia
Zuelli, F. M. D. G. C., & Deakin, J. F. W. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.03.004 · Cited by 86 · see citing works
The cytokine network in the pathogenesis of major depressive disorder. Close to translation?
Petralia, M. C., Mazzon, E., Fagone, P., Basile, M. S., Lenzo, V., Quattropani, M. C. A., Nuovo, S. D., Bendtzen, K., & Nicoletti, F. (2020) · Autoimmunity Reviews · doi:10.1016/j.autrev.2020.102504 · Cited by 86 · see citing works
Evidence for the Role of Mitochondrial DNA Release in the Inflammatory Response in Neurological Disorders
Moya, G. E., Rivera, P. D., & Dittenhafer‐Reed, K. E. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22137030 · Cited by 88 · see citing works
Is there neuroinflammation in depression? Understanding the link between the brain and the peripheral immune system in depression
Nettis, M. A., & Pariante, C. M. (2020) · International review of neurobiology · doi:10.1016/bs.irn.2019.12.004 · Cited by 81 · see citing works
Self-citation
Increased GFAP concentrations in the cerebrospinal fluid of patients with unipolar depression
Michel, M., Fiebich, B. L., Kuzior, H., Meixensberger, S., Berger, B., Maier, S., Nickel, K., Runge, K., Denzel, D., Pankratz, B., et al. (2021) · Translational Psychiatry · doi:10.1038/s41398-021-01423-6 · Cited by 79 · see citing works
Is depression the missing link between inflammatory mediators and cancer?
Polityńska, B., Pokorska, O., Wojtukiewicz, A. M., Sawicka, M., Mysliwiec, M., Honn, K. V., Tucker, S. C., & Wojtukiewicz, M. Z. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2022.108293 · Cited by 80 · see citing works
Major depressive disorder as a neuro-immune disorder: Origin, mechanisms, and therapeutic opportunities
Réus, G. Z., Manosso, L. M., Quevedo, J., & Carvalho, A. F. (2023) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2023.105425 · Cited by 89 · see citing works
A systematic review of the association between biological markers and environmental stress risk factors for adolescent depression
Zajkowska, Z., Walsh, A. E. L., Zonca, V., Gullett, N., Pedersen, G. A., Kieling, C., Swartz, J. R., Karmacharya, R., Fisher, H. L., Kohrt, B. A., et al. (2021) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2021.04.003 · Cited by 82 · see citing works
Self-citation
Translational evidence for the Inflammatory Response System (IRS)/Compensatory Immune Response System (CIRS) and neuroprogression theory of major depression
Debnath, M., Berk, M., & Maes, M. H. J. (2021) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2021.110343 · Cited by 75 · see citing works
Beyond the neuron: Role of non-neuronal cells in stress disorders
Cathomas, F., Holt, L. M., Parise, E. M., Liu, J., Murrough, J. W., Casaccia, P., Nestler, E. J., & Russo, S. J. (2022) · Neuron · doi:10.1016/j.neuron.2022.01.033 · Cited by 70 · see citing works
TSPO PET brain inflammation imaging: A transdiagnostic systematic review and meta-analysis of 156 case-control studies
Picker, L. D., Morrens, M., Branchi, I., Haarman, B. C. M., Terada, T., Kang, M. S., Boche, D., Tremblay, M., Leroy, C., Bottlaender, M., et al. (2023) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2023.07.023 · Cited by 78 · see citing works
Microglial Inflammatory-Metabolic Pathways and Their Potential Therapeutic Implication in Major Depressive Disorder
Rahimian, R., Belliveau, C., Chen, R., & Mechawar, N. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.871997 · Cited by 73 · see citing works
Anti-inflammatory properties of commonly used psychiatric drugs
Patel, S., Keating, B. A., & Dale, R. C. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.1039379 · Cited by 70 · see citing works
How Oxidative Stress Induces Depression?
Ji, N., Lei, M., Chen, Y., Tian, S., Li, C., & Zhang, B. (2023) · ASN NEURO · doi:10.1177/17590914231181037 · Cited by 82 · see citing works
“…IL-6 and TNF-α in the serum Lindqvist et al. (2017); Zou et al. (2018) Increased IL-6, TNF-α and TSPO in multiple brain subregions (ACC/PFC/hippocampus) Enache et al. (2019); Gritti et al. (2021) Behavioral therapy reduces peripheral IL-6 Ma et al. (2022) Fluoxetine reduces IL-1β, IL-6 and TNF-α…”
Background
Neuroinflammation in Major Depressive Disorder: A Review of PET Imaging Studies Examining the 18-kDa Translocator Protein
Gritti, D., Delvecchio, G., Ferro, A., Bressi, C., & Brambilla, P. (2021) · Journal of Affective Disorders · doi:10.1016/j.jad.2021.06.001 · Cited by 66 · see citing works
Stress-Related Dysfunction of Adult Hippocampal Neurogenesis—An Attempt for Understanding Resilience?
Leschik, J., Lutz, B., & Gentile, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22147339 · Cited by 70 · see citing works
Distinct non-inflammatory signature of microglia in post-mortem brain tissue of patients with major depressive disorder
Snijders, G. J. L., Sneeboer, M. A. M., Fernández-Andreu, A., Udine, E., (NBB-Psy), P. D. P. O. T. N. B. B., Boks, M. P., Ormel, P. R., van Berlekom, A. B., van Mierlo, H. C., Böttcher, C., et al. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-00896-z · Cited by 65 · see citing works
Cannabidiol antidepressant-like effect in the lipopolysaccharide model in mice: Modulation of inflammatory pathways
Florensa-Zanuy, E., Garro-Martínez, E., Adell, A., Castro, E., Díaz, Á., Pazos, Á., MacDowell, K. S., Martín‐Hernández, D., & Pilar-Cuéllar, F. (2021) · Biochemical Pharmacology · doi:10.1016/j.bcp.2021.114433 · Cited by 68 · see citing works
How environmental enrichment balances out neuroinflammation in chronic pain and comorbid depression and anxiety disorders
Kimura, L. F., Novaes, L. S., Picolo, G., Munhoz, C. D., Cheung, C. W., & Camarini, R. (2021) · British Journal of Pharmacology · doi:10.1111/bph.15584 · Cited by 70 · see citing works
Novel rapid-acting glutamatergic modulators: Targeting the synaptic plasticity in depression
Wang, Y., Wang, X., Feng, S., Chen, N., Wang, Z., & Zhang, Y. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105761 · Cited by 68 · see citing works
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“Meta-analyses of the literature have indicated that depressed individuals tend to have elevated concentrations of various inflammatory markers, both peripherally and in the brain (Haapakoski et al., 2015; Enache et al., 2019).”
Background
Longitudinal relationships of cytokines, depression and anhedonia in depressed adolescents
Rengasamy, M. L., Marsland, A. L., McClain, L. L., Kovats, T., Walko, T. D., Pan, L. A., & Price, R. B. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.09.004 · Cited by 65 · see citing works
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Background
Advancing an Inflammatory Subtype of Major Depression
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Paeoniflorin exerts antidepressant-like effects through enhancing neuronal FGF-2 by microglial inactivation
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Sickness behaviour and depression: An updated model of peripheral-central immunity interactions
Turkheimer, F., Veronese, M., Mondelli, V., Cash, D., & Pariante, C. M. (2023) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2023.03.031 · Cited by 66 · see citing works
“, 2009) but results in MDD were mixed with 2/3 of the studies reporting reductions or no-change of IL-6 and TNF- concentrations and the remaining registering moderate increases (Enache et al., 2019).”
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Pro-inflammatory cytokines in stress-induced depression: Novel insights into mechanisms and promising therapeutic strategies
Chang, J., Jiang, T., Shan, X., Zhang, M., Li, Y. Y., Qi, X., Bian, Y., & Zhao, L. (2024) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2023.110931 · Cited by 70 · see citing works
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Authors: Enache, D., Pariante, C. M., & Mondelli, V.
Affiliations: King's College London (GB)
National Health Service (GB)
Corresponding author: Mondelli, Valeria
ORCID: Enache, Daniela
Pariante, Carmine M.
Mondelli, Valeria
Venue: Brain, Behavior, and Immunity
Publisher: Elsevier BV
Published: 2019-10
Volume: 81
Pages: 24-40
ISSN: 0889-1591 (ISSN-L)
DOI: 10.1016/j.bbi.2019.06.015
OpenAlex: W2953025937
Semantic Scholar: 83e5363ffd00c2dba7a412e43a5a292f085d67ed
Cited by: 615
References: 97
Citations by year: 2026: 54 · 2025: 74 · 2024: 160 · 2023: 91 · 2022: 86 · 2021: 87 · 2020: 52 · 2019: 11
FWCI: 3.71
Type: journal article
Language: en
Open access: green
kclpure.kcl.ac.uk
Licence: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Brain Behavior and Immunity (publishedVersion)
PubMed (publishedVersion)
Research Portal (King's College London) (submittedVersion, cc-by-nc-nd)
Funders: GlaxoSmithKline foundation
South London and Maudsley NHS Foundation Trust
Kingâs College London
Svenska LÃ¤karesÃ¤llskapet (MQBF1)
National Institute for Health Research
Medical Research Foundation (MRF-160-0005)
H. Lundbeck A/S
Wellcome Trust
Medical Research Council
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 disorder, neuroinflammation, cerebrospinal fluid cytokines, interleukin-6, TNF-α, translocator protein (TSPO), positron emission tomography, microglia, astrocytes, oligodendrocytes, suicide attempters, postmortem brain, peripheral inflammation, prefrontal cortex, anterior cingulate cortex
MeSH terms: Astrocytes, Autopsy, Brain, Major Depressive Disorder, Female, Humans, Inflammation, Male, Oligodendroglia, Tumor Necrosis Factor-alpha, Biomarkers, Interleukin-6, Cytokines, Prefrontal Cortex, Microglia, Receptors, GABA, Chemokines, Positron-Emission Tomography

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Markers of central inflammation in major depressive disorder: a systematic review and meta-analysis of studies examining cerebrospinal fluid, positron emission tomography and post-mortem brain tissue

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