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Cited by 422Tryptophan and brain disordersTreatment of Major DepressionStress Responses and Cortisol

A Review of the Relationship between Proinflammatory Cytokines and Major Depressive Disorder

Open access
Young, Juan Joseph, Bruno, Davide, Pomara, Nunzio·2014·Journal of Affective Disorders
DOI 10.1016/j.jad.2014.07.032
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Abstract

Background Determining etiological factors and reviewing advances in diagnostic modalities sensitive and specific to Major Depressive Disorder (MDD) is of importance in its evaluation and treatment. The inflammatory hypothesis is one of the most prevalent topics concerning MDD and may provide insight into the pathogenesis of depression, development of biomarkers, and ultimately production of more effective depression therapies. Method We reviewed several studies to evaluate contemporary concepts concerning proinflammatory cytokines and their relationship to various depressive disorders, the use of anti-inflammatory therapies in MDD treatment, and the application of neuroimaging in conjunction with cytokine profiles from both plasma and CSF as possible diagnostic tools. Results Proinflammatory cytokines in both plasma and CSF have been found to influence the progression and severity of depressive disorders in different populations. Studies have shown elevated serum levels of IL-1, IL-6, TNF-α, CRP, and MCP-1 in depressed patients, but have presented mixed results with IL-8 serum levels, and with IL-6 and MCP-1 CSF levels. Anti-inflammatory treatment of MDD may have adjuvant properties with current depression medications. MRI and NIRS neuroimaging confirm neurological abnormalities in the presence of elevated proinflammatory cytokines in depressed or stressed patients. Limitations Heterogeneity of MDD and limited CSF cytokine research complicate the study of MDD pathogenesis. Conclusion There is significant evidence that inflammatory processes influence the development and progression of MDD. Future studies with larger arrays of cytokine profiles aided by neuroimaging may provide more sensitive and specific modes of diagnostics in determining MDD etiology and provide guidance in individual therapies.

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Crossref · 10.1016/j.jad.2014.07.032

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Claims the paper makes

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  • Findingown data

    The review identified a single study that reported markedly higher CSF MCP-1 in depressed subjects.

    “However, this review was able to find only one article showing significantly elevated CSF MCP-1 levels in subjects with depression.”
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  • Findingnone given

    Fewer studies examine brain parenchyma disruption alongside elevated proinflammatory cytokines.

    “Less prevalent are studies dedicated to the observation of brain parenchyma disruption in relation to increases in proinflammatory cytokine levels.”
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  • Findingown data

    The described MRI and fMRI studies did not report CSF cytokine measurements.

    “none of the MRI or fMRI studies described included results concerning cytokine levels in the CSF.”
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  • Findingreasoning

    The review found no studies linking altered CSF inflammatory cytokines to functional brain abnormalities on neuroimaging.

    “this review has not been able to find studies that corroborate increased or decreased inflammatory CSF cytokines and functional abnormalities in the brain using neuroimaging modalities.”
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  • Findingreasoning

    Apart from the structural MRI study, these imaging findings came from healthy volunteers undergoing stress tasks to induce inflammation, not from diagnosed MDD patients.

    “with the exception of the structural MRI study, these neuroimaging results did not involve diagnosed MDD patients but healthy volunteers that participated in stressinducing tasks to invoke proinflammatory states.”
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    Findingnone given

    The authors know of no study identifying cytokines with high sensitivity or specificity for MDD.

    “no research known to the authors has found cytokines that are highly sensitive or specific to MDD.”
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    Premisecitation

    Sympathetic nervous system activation by inflammatory signaling releases norepinephrine into peripheral tissues, causing β-adrenergic receptor stimulation and further upregulation of IL-1, TNF, and IL-6.

    “the sympathetic nervous system activated by the same initial inflammatory signaling processes leads to a release of norepinephrine into the peripheral tissues causing β-adrenergic receptor stimulation and further upregulation of IL-1, TNF, and IL-6 (Slavich and Irwin, 2014).”
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    Interpretationreasoning

    Nonphysiologic conditions may upregulate transporters throughout the blood-brain barrier, allowing cytokine levels in CSF to rise.

    “Alternatively, nonphysiologic conditions may cause an upregulation of transporters throughout the BBB thus allowing the elevation of cytokine levels in the CSF.”
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    Premisecitation

    TNF-α and IL-1β can affect the CNS through permeable regions, but typically only at high levels that influence central immune behavior through receptor-induced cascades rather than local peripheral immune responses.

    “Proinflammatory cytokines such as TNF-α and IL-1β have been found to affect the CNS in this way, but typically only in high levels that influence central immune behavior through receptorinduced cascade reactions rather than the more locally-oriented immune responses found in the periphery (Woodroofe, 1995).”
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    Premisecitation

    One proposed mechanism is that proinflammatory cytokines stimulate indoleamine 2,3-dioxygenase in glial cells, converting tryptophan to kynurenine, which is then transformed into neurotoxic quinolinic acid in the brain.

    “one hypothesis postulates that proinflammatory cytokines stimulate indoleamine 2,3-dioxygenase (IDO) in glial cells to convert tryptophan to kynurenine which is transformed into the neurotoxic quinolinic acid inside the brain (Müller and Schwarz, 2007;Walker et al., 2014).”
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    Animal studies support an association between inflammatory states and depressive symptoms, reduced hippocampal volumes, and sickness behavior.

    “A number of animal studies also support the association of inflammatory states with depressive symptoms, decreased hippocampal volumes, and “sickness behavior” (Goshen et al., 2008;Goshen and Yirmiya, 2009;Lawson et al., 2013).”
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    IL-2, which is typically not found in the CNS, can appear in CSF in persistent disease states such as cancer, suggesting that the blood-brain barrier may become compromised in similar disease states and allow peripheral cytokine access.

    “researchers (Saris et al, 1988) have shown that IL-2, a cytokine that is typically not found in the CNS, could be present in the CSF in persistent disease states such as those found in cancer patients, suggesting that the BBB may become compromised during similar diseased states thus allowing peripheral cytokine access into the central immune system.”
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    Premisecitation

    IL-1 receptors in vagal sensory neurons and perineural sheath macrophages and dendritic cells within vagal branches are postulated to mediate neural transmission during inflammation.

    “It has been postulated that the expression of IL-1 receptors in vagal sensory neurons and the presence of perineural sheath macrophages and dendritic cells within vagal branches mediate the neural transmission during inflammation (Banks, 2005).”
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    In mice, vagotomy reduces pain, fever, and glucocorticoid responses and produces less sickness behavior.

    “Studies in mice have indicated that vagotomy decreased response to pain, fever, and glucocorticoid levels while also resulting in less sickness behavior (Maier and Watkins, 1998).”
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    LPS binds TLR4 and induces production of the proinflammatory cytokines IL-1α and IL-1β.

    “LPS is recognized by and binds to TLR4, thereby inducing the production of proinflammatory cytokines IL-1α and IL-1β (Barton and Kagan, 2009;Dantzer, 2006).”
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    Premisecitation

    Elevated plasma proinflammatory cytokine levels have been observed in diagnosed MDD patients who attempted suicide, had suicidal ideation, or had geriatric depression, suggesting a positive association between inflammatory mechanisms and different depressive disorder subsets.

    “studies have also shown elevated plasma levels of proinflammatory cytokines in diagnosed MDD patients who had attempted suicide, with suicidal ideation, and geriatric depression suggesting that inflammatory mechanisms may be positively associated with different subsets of depressive disorders (Miller et al., 2006;O'Donavan et al., 2013;Sublette et al., 2011).”
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    Premisecitation

    HPA axis hyperfunction is linked to reduced hippocampal volumes, impaired neuronal plasticity, and decreased neurochemical functioning that result in depressive symptoms.

    “A review of cytokine-induced alterations in neuroplasticity has suggested that HPA axis hyperfunction is linked to a reduction of hippocampal volumes, impaired neuronal plasticity, and decreased neurochemical functioning resulting in depressive symptoms (Hayley et al., 2005).”
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    Cytokines that reach the CNS affect the HPA axis, promoting fever, reduced food intake, excessive CRH release, disruption of the HPA negative feedback loop, and glucocorticoid resistance.

    “Once these cytokines are able to influence the CNS, they exert an effect on the HPA axis, promoting fever, decreased food intake, and excessive release of corticotrophin release hormone (CRH), thus leading to the disruption of the negative feedback loop to the HPA axis and the promotion of glucocorticoid resistance within the immune system (Dantzer, 2006).”
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    Quinolinic acid binds NMDA receptors and depletes tryptophan, leading to lower serotonin levels and higher glutamatergic activity that is commonly associated with depression.

    “Quinolinic acid binds to N-methyl-D-aspartate receptors while also depleting tryptophan leading to a decrease in overall serotonin levels and an increase in glutamatergic activity commonly associated with depression (Sublette et al., 2011).”
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    Interactions between antidepressant medications and inflammatory signaling pathways have been suggested, but results are inconsistent.

    “Interactions between antidepressant medications and inflammatory signaling pathways have been suggested in a recent review (McNamara and Lotrich, 2012), although with caution due to inconsistent results.”
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    Premisecitation

    Vagal innervation has anti-inflammatory effects on the immune system, indicating multiple vagal functions and heterogeneity in mechanisms affecting CNS immune behavior.

    “other studies have reported vagal anti-inflammatory influences on the immune system suggesting multiple functions of vagal innervation, and highlighting the heterogeneity of mechanisms affecting CNS immune behavior (Christmas et al., 2013;Friebe et al., 2013;Raison et al., 2006).”
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    In a small group of unmedicated, acutely depressed patients, CSF IL-1β levels were higher and IL-6 levels were lower than in healthy controls, with no significant difference in CSF TNF-α.

    “This study found higher levels of IL-1β and decreased levels of IL-6 in the CSF of depressed patients compared to healthy controls while there was no significant difference of CSF TNF-α between the two groups.”
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    In the same study, MDD patients had smaller volumes in the anterior cingulate, dorsomedial prefrontal cortex, and basal ganglia.

    “MDD subjects also exhibited decreased anterior cingulated cortex, dorsomedial prefrontal cortex (DMPFC), and basal ganglia volumes”
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    Interpretationreasoning

    There may be treatment-resistant depression populations that are uniquely responsive to anti-inflammatory intervention, suggesting a need for appropriate screening and treatment.

    “these findings raise the possibility of TRD populations who could be uniquely responsive to antiinflammatory intervention, thus suggesting the need for appropriate screenings and treatment.”
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    Interpretationreasoning

    Inconsistency in CSF IL-6 results may be due to differences in cytokine gene expression between acute and chronic inflammatory stimuli or to different depressive etiologic factors affecting IL-6 production.

    “The inconsistency in the results may be attributable to the differences in cytokine gene expression in response to an acute inflammatory stimulus versus a chronic one, or may be the result of different depressive etiologic factors on IL-6 production.”
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    Interpretationnone given

    Heterogeneity of MDD and limited CSF cytokine research complicate the study of MDD pathogenesis.

    “Heterogeneity of MDD and limited CSF cytokine research complicate the study of MDD pathogenesis.”
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    Premisecitation

    In vitro, citalopram and mirtazapine increase inflammatory cytokine production, whereas escitalopram decreases cytokine concentrations.

    “in an in vitro investigation of citalopram, mirtazapine, and escitalopram stimulation of cytokine production, researchers have shown that Citalopram and Mirtazapine increased inflammatory cytokine production, whereas escitalopram administration decreased cytokine concentrations (Munzer et al., 2013).”
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    Data on microglial dysregulation are limited, and results are mixed regarding increased microglial densities and activation in diagnosed MDD patients in clinical and post-mortem examinations.

    “A review (Frick et al., 2013) detailing studies concerning cytokine effects on different immune cells indicated that data on microglial dysregulation are “limited” and reported mixed results relating to increased microglial densities and activation in diagnosed MDD patients in both clinical and post-mortem examinations.”
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    Adding NSAIDs to SSRI therapy reduces depression severity as measured by the Hamilton Depression Scale, implying increased antidepressant effects.

    “Studies have reported that adding NSAIDs to SSRI therapy decreases severity of depression, as measured with the Hamilton Depression Scale, implying increases in antidepressant effects (Akhondzadeh et al., 2009;Müller, 2013).”
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    IL-8 is a neutrophil chemokine central to neutrophil recruitment and infiltration during acute inflammation and has been implicated in depressive episodes.

    “IL-8, on the other hand, is a known neutrophil chemokine that has a central role in the recruitment and infiltration of neutrophils into inflammatory sites during acute inflammation and has been implicated in depressive episodes (Harada et al., 1994).”
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    In patients with unipolar MDD, there are no differences in IL-6 levels between healthy controls and depressed patients.

    “another study of patients with unipolar MDD determined that there were no differences in IL-6 levels between healthy controls and depressed patients (Carpenter et al., 2004).”
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    Structural abnormalities in emotion-processing brain regions make people more prone to negative symptoms and poorer emotional control.

    “There is significant evidence that anatomical disturbances in the neural structures involved in experiencing and processing emotion predispose individuals to the development of negative symptoms and impair emotional regulation (Gotlib and Hamilton, 2008).”
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    MCP-1 induces leukocyte infiltration and neuronal damage during CNS inflammation and is associated with neurodegeneration in multiple sclerosis, Alzheimer's disease, brain ischemia, and trauma.

    “MCP-1 is a known chemokine that induces leukocyte infiltration and neuronal damage during CNS inflammation and has been associated with neurodegeneration in multiple sclerosis, Alzheimer's disease, brain ischemia, and trauma (Banisadr et al., 2005).”
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    Premisecitation

    CSF IL-6 levels positively correlate with depressive symptoms and suicidal behavior.

    “one study showed a positive correlation between CSF IL-6 levels and depressive symptoms, and suicidal behavior (Lindqvist et al., 2009)”
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    Interpretationcitation

    Escitalopram, but not the other studied drugs, reduced recurrence of major depressive episodes, suggesting that antidepressant efficacy may depend on reducing inflammatory cytokine secretion.

    “Critically, escitalopram,but not the other drugs, decreased recurrence of MDEs, suggesting that the efficacy of antidepressant medications may depend upon reduction of inflammatory cytokine secretion.”
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    Activity changes in particular brain regions depend on how recent the depressive episode is and whether treatment is used.

    “the increase or decrease in activity of individual structures vary according to the closeness of depressive episodes and type of treatment (or lack thereof) (Gotlib and Hamilton, 2008)”
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    Structural MRI research found reduced hippocampal volume and lower glucocorticoid activation in patients diagnosed with MDD.

    “Structural MRI studies demonstrated smaller hippocampal volumes and decreased glucocorticoid activation in MDD diagnosed patients (Frodl and Amico, 2014).”
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    NIRS has limitations in low spatial resolution.

    “though limitations in its low spatial resolution are noted (Takizawa et al., 2014)”
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    NIRS non-invasively detects haemoglobin changes near the cortical surface without disrupting cognitive or brain activity.

    “NIRS can measure haemoglobin concentration changes in the immediate cortical surface areas non-invasively, without interfering with cognitive or brain processes”
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34 of 34

  • The paper relies on this without support.

    MDD is a heterogeneous condition.

    “The heterogeneity of the disease complicates the task”

  • The paper relies on this without support.

    MDD cases have high comorbidity and are difficult to differentially diagnose.

    “Considering the high level of comorbidity and difficult differential diagnosis for cases with MDD, the imperative to develop reliable diagnostic tools to evaluate MDD is high.”
2 of 2

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?

  • Depression is highly heterogeneous, as shown by mixed symptom phenotypes and mixed treatment effectiveness.

    “However, depression is an exceedingly heterogeneous disorder as evidenced by the mixed symptom phenotypes that qualify for the disorder (Fried and Nesse, 2015; Young et al., 2014) and the mixed effectiveness of existing treatments (Biesheuvel-Leliefeld et al., 2015; Cipriani et al., 2018; Piet and Hougaard, 2011; Shea et al., 1992; Vittengl et al., 2007).”

    From The role of inflammation in core features of depression: Insights from paradigms using exogenously-induced inflammation. (2018) · cites this paper as Young et al., 2014

  • Overexpression of IL-6 led to a reduction in depressive behaviors in animal models.

    “At the same time, overexpression of IL-6 led to a reduction in these behaviors [83,84].”

    From Selected biomarkers of depression: what are the effects of cytokines and inflammation (2022) · cites this paper as [83]

  • In animal models of depression, IL-6 was reduced in the CA1 region of the hippocampus of rats exhibiting depressive behaviors.

    “In animal models of depression, IL-6 was reduced in the CA1 region of the hippocampus of rats exhibiting depressive behaviors and IL-6 knockdown facilitated development of depressive behaviors.”

    From Selected biomarkers of depression: what are the effects of cytokines and inflammation (2022) · cites this paper as [83]

  • IL-6 knockdown facilitated development of depressive behaviors in animal models.

    “In animal models of depression, IL-6 was reduced in the CA1 region of the hippocampus of rats exhibiting depressive behaviors and IL-6 knockdown facilitated development of depressive behaviors.”

    From Selected biomarkers of depression: what are the effects of cytokines and inflammation (2022) · cites this paper as [83]

  • Increased levels of pro-inflammatory cytokines IL-1β, IL-6, IL-18, TNF-α and IFNγ have been consistently reported in the blood of depressed patients.

    “Increased levels of pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, IL-18, tumor necrosis factor-α (TNF-α) and interferon-γ (IFNγ) have been consistently reported in the blood of depressed patients [138,139,140]”

    From P2X7 Receptor Signaling in Stress and Depression (2019) · cites this paper as [138]

The citation lists haven’t been fetched yet

References 60 · Cited by 422

Authors
Young, J. J., Bruno, D., & Pomara, N.
Affiliations
  • Nathan Kline Institute for Psychiatric Research (US)
  • Liverpool Hope University (GB)
Corresponding author
Pomara, Nunzio
ORCID
Venue
Journal of Affective Disorders
Publisher
Elsevier BV
Published
2014-12
Volume
169
Pages
15-20
ISSN
0165-0327 (ISSN-L)
DOI
10.1016/j.jad.2014.07.032
OpenAlex
W2035981398
Cited by
422
References
60
Citations by year
2026: 12 · 2025: 27 · 2024: 32 · 2023: 33 · 2022: 30 · 2021: 56 · 2020: 42 · 2019: 37 · 2018: 40 · 2017: 34 · 2016: 44 · 2015: 28 · 2014: 4 · 2013: 1
FWCI
2.89
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Journal of Affective Disorders (publishedVersion)
  • PubMed (publishedVersion)
  • Liverpool John Moores University (acceptedVersion)
  • Hope's Institutional Research Archive (Liverpool Hope University) (acceptedVersion)
Topics
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
major depressive disorder, inflammatory cytokines, anti-inflammatory therapy, cytokine biomarkers, cerebrospinal fluid cytokines, plasma cytokines, interleukin-6, interleukin-1, TNF-α, C-reactive protein, MCP-1, interleukin-8, neuroimaging, depression pathogenesis, depression diagnosis
MeSH terms
Adult, Anti-Inflammatory Agents, Brain, Major Depressive Disorder, Depressive Disorder, Major, Humans, Cytokines, Disease Progression, Inflammation Mediators, Neuroimaging

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