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Cited by 1,180Tryptophan and brain disordersStress Responses and CortisolTreatment of Major Depression

Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications

Open access
Felger, J.C., Lotrich, F.E.·2013·Neuroscience
DOI 10.1016/j.neuroscience.2013.04.060PMC PMC3741070
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Abstract

Mounting evidence indicates that inflammatory cytokines contribute to the development of depression in both medically ill and medically healthy individuals. Cytokines are important for development and normal brain function, and have the ability to influence neurocircuitry and neurotransmitter systems to produce behavioral alterations. Acutely, inflammatory cytokine administration or activation of the innate immune system produces adaptive behavioral responses that promote conservation of energy to combat infection or recovery from injury. However, chronic exposure to elevated inflammatory cytokines and persistent alterations in neurotransmitter systems can lead to neuropsychiatric disorders and depression. Mechanisms of cytokine behavioral effects involve activation of inflammatory signaling pathways in the brain that results in changes in monoamine, glutamate, and neuropeptide systems, and decreases in growth factors, such as brain-derived neurotrophic factor. Furthermore, inflammatory cytokines may serve as mediators of both environmental (e.g. childhood trauma, obesity, stress, and poor sleep) and genetic (functional gene polymorphisms) factors that contribute to depression's development. This review explores the idea that specific gene polymorphisms and neurotransmitter systems can confer protection from or vulnerability to specific symptom dimensions of cytokine-related depression. Additionally, potential therapeutic strategies that target inflammatory cytokine signaling or the consequences of cytokines on neurotransmitter systems in the brain to prevent or reverse cytokine effects on behavior are discussed.

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Written from the paper’s full text.

TL;DR

This review argues that inflammatory cytokines contribute to a subtype of depression by altering neurotransmitter, neuropeptide, growth-factor, and glutamate systems, with evidence drawn from human and animal studies. It proposes that cytokine-related depression may be identified through inflammatory biomarkers and genetic variants and treated by targeting inflammation or its downstream neural effects.

Key findings

  • Elevated proinflammatory cytokines and markers—including IL-1, IL-6, TNF-alpha, CRP, and PGE2—are reported in idiopathic major depression and in medically ill populations; cancer patients show elevated cytokines and depression/fatigue rates approaching 50%, and IFN-alpha treatment induces depression in 30–50% of patients depending on dose.
  • Peripheral cytokines can reach the brain through circumventricular organs, active transport, vagal afferents, endothelial/perivascular activation, and immune-cell recruitment, then amplify local inflammatory signaling involving COX-2/PGE2, microglia, IDO/KYN metabolites, iNOS, and reactive oxygen/nitrogen species.
  • Specific polymorphisms are linked to particular symptom dimensions: IL-6 rs1800795 with depression but not worsening fatigue during IFN-alpha therapy; TNF-alpha A-308G rs1800629 with irritable anger rather than depression; 5-HTTLPR with neurovegetative symptoms; BDNF Met with more psychological/cognitive symptoms; and IDO1 rs9657182 with IFN-alpha-induced depression in Caucasian C-risk-allele carriers but not African Americans.
  • Therapeutic implications include SSRIs being more effective for mood, anxiety, and cognitive symptoms than for fatigue/neurovegetative symptoms; the TNF antagonist infliximab improved depressive symptoms in treatment-resistant patients only when baseline CRP was high (hsCRP >5 mg/L); other candidates include COX inhibitors, omega-3 fatty acids, p38 MAPK/NF-kB inhibitors, BH4/monoamine-synthesis support, IDO/KYN inhibitors, and NMDA antagonists.

Methods

  • Narrative review synthesizing human clinical studies—including idiopathic major depression, medically ill populations, IFN-alpha-treated patients, CSF and blood biomarker studies, neuroimaging, and genetic association studies—alongside animal and preclinical mechanistic work.
  • The paper integrates evidence across proposed pathways: cytokine access to the brain, monoamine and glutamate neurotransmission, BDNF, CRH/HPA-axis function, and inflammatory signaling.
  • Main analysis is qualitative synthesis; no systematic search strategy, meta-analysis, or formal risk-of-bias assessment is described.

Limitations

  • The paper states that much of the vulnerability and treatment literature relies on correlative relationships among SNPs, inflammatory or neurotransmitter biomarkers, and behavioral symptoms, so mechanistic animal/translational studies and subsequent clinical trials are needed.
  • The paper also states that more human neuroimaging is needed, that peripheral transcriptomic findings should be integrated with brain imaging, and that many studies did not examine biomarkers or polymorphisms in relation to specific depressive symptom dimensions.
  • Evident from the text: as a narrative review, it lacks a systematic search and inclusion process, and many cited findings come from specific populations or preclinical models, which may limit generalizability.

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Integrity signals

Registry

Crossref · 10.1016/j.neuroscience.2013.04.060

Cites

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Statistics

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Claims the paper makes

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  • Interpretationcitation

    It is biologically plausible that inflammatory cytokines serve as mediators of both environmental and genetic factors that may trigger depressive disorders.

    “Nonetheless, it is biologically plausible that inflammatory cytokines serve as mediators of both environmental and genetic factors that may trigger the development of depressive disorders (Raison and Miller, 2011).”
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  • Interpretationreasoning

    Chronic exposure to elevated inflammatory cytokines and persistent alterations in neurotransmitter function and behavior can lead to neuropsychiatric dysfunction, especially depression.

    “However, under conditions of chronic exposure to elevated inflammatory cytokines, persistent alterations in neurotransmitter function and behavior can lead to the development neuropsychiatric dysfunction, and especially depression.”
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  • Premisecitation

    Administration of cytokines to humans and laboratory animals produces neuropsychiatric symptoms and behavioral alterations consistent with depression.

    “Furthermore, administration of cytokines to humans and laboratory animals produces neuropsychiatric symptoms and behavioral alterations consistent with depression (Miller et al., 2009).”
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  • Interpretationnone given

    Inflammatory cytokines contribute to the development of depression in both medically ill and medically healthy individuals.

    “Mounting evidence indicates that inflammatory cytokines contribute to the development of depression in both medically ill and medically healthy individuals.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Cytokines can influence neurocircuitry and neurotransmitter systems to produce behavioral alterations.

    “Cytokines also have the capability of influencing neurocircuitry and neurotransmitter systems to produce behavioral alterations (Miller et al., 2009, Haroon et al., 2012).”
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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Not all types of depression necessarily involve cytokines, such as post-partum, peri-menopausal, hypothyroidism, cocaine withdrawal, and vascular depression.

    “We should note that not all types of depression necessarily involve cytokines, e.g. post-partum and peri-menopausal depression, hypothyroidism, depression secondary to cocaine withdrawal, and vascular depression to name just a few.”
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    Premisecitation

    Not all subjects exhibiting increased inflammatory cytokines develop depression; there are vulnerability and resilience factors for cytokine-induced depression.

    “That is, not all subjects exhibiting increased inflammatory cytokines develop depression, and there are numerous vulnerability and resilience factors for cytokine-induced depression (Kendler et al., 2001, Caspi et al., 2003, Duman and Monteggia, 2006, Heim et al., 2008, Lotrich, 2011)”
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    Premisenone given

    Factors that may precipitate inflammation and influence depression include medical illness, obesity, psychosocial stress, sleep disturbance, and gastrointestinal inflammation.

    “Factors that may precipitate inflammation and influence the development of depression include medical illness, obesity, psychosocial stress, sleep disturbance, and gastrointestinal inflammation, and will be discussed herein.”
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    Premisecitation

    All major pathophysiologic pathways implicated in depression-including monoaminergic dysfunction, HPA-axis dysfunction, changes in growth factors and neuropeptides, altered glutamate neurotransmission, and decreased neurogenesis-are affected by inflammatory cytokines.

    “Interestingly, all of these pathways have been demonstrated to be affected by inflammatory cytokines (Pace et al., 2007, Dantzer et al., 2008, Miller et al., 2009, Haroon et al., 2012) (Figure 1).”
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    Premisecitation

    A functional polymorphism in the promoter region of the IL-6 gene (rs1800795), the genotype that produces more IL-6, was found to be associated with depression but not the fatigue that worsens during IFN-alpha therapy.

    “Consistent with the relationship between circulating IL-6 and IFN-alpha-induced depression, a functional polymorphisms in the promoter region of the IL-6 gene (rs1800795), the genotype that produces more IL-6, was found to be associated with depression but not the fatigue that worsens during IFN-alpha therapy (Bull et al., 2008).”
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    Premisecitation

    Cancer patients exhibit elevated circulating proinflammatory cytokines and develop depression and fatigue at rates approaching 50%.

    “For example, cancer patients exhibit elevated circulating proinflammatory cytokines and develop depression and fatigue at rates approaching 50% (Musselman et al., 2001b, Massie, 2004, Jehn et al., 2006).”
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    Premisecitation

    IFN-alpha produces behavioral symptoms including fatigue, neurovegetative symptoms, cognitive and sleep changes, anxiety, and anhedonia, and induces depression in 30-50% of treated patients depending on dose.

    “IFN-alpha is notorious for producing behavioral symptoms including fatigue and neurovegetative symptoms, cognitive and sleep changes, anxiety, and anhedonia, and induces depression in 30–50% of treated-patients depending on the dose (Capuron et al., 2002, Maddock et al., 2005, Raison et al., 2005a, Lotrich, 2009).”
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    Premisecitation

    Omega-3 fatty acids are reduced in major depression and predict vulnerability to cytokine-induced depression.

    “Interestingly, omega-3 fatty acids are reduced in major depression and also predict vulnerability to cytokine-induced depression (Su et al., 2010, Lotrich et al., 2012, McNamara and Lotrich, 2012).”
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    Interpretationcitation

    DAMPs and NLRP3 inflammasome may serve as a primary link by which chronic psychological or physical stress is translated into damage signals that promote inflammatory activity, and may contribute to depression and associated comorbid medical illnesses.

    “Therefore, DAMPS and the NLRP3 inflammasome may serve as a primary link by which chronic psychological or physical stress is translated into damage signals that promote inflammatory activity, and may contribute to depression as well as associated co-morbid medical illnesses related to chronic stress (Iwata et al., 2012).”
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    Premisecitation

    Inflammatory cytokine administration and low-grade chronic inflammation increase IDO activity and the peripheral metabolism of tryptophan to KYN.

    “Inflammatory cytokine administration and low-grade chronic inflammation have been shown to increase IDO activity and the metabolisms of tryptophan, the primary amino-acid precursor of serotonin, to KYN in the periphery (Capuron et al., 2003a, Raison et al., 2010b, Capuron et al., 2011a).”
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    Premisecitation

    Obesity is associated with increased circulating cytokines, and BMI significantly influences concentrations of IL-6 and other inflammatory markers.

    “Finally, obesity is associated with increased circulating cytokines, and BMI significantly influences concentrations of L-6 and other inflammatory markers (Khaodhiar et al., 2004).”
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    SSRIs alleviate cytokine-induced depression, with depressive and anxiety symptoms most responsive, while fatigue and neurovegetative symptoms are less responsive.

    “Interestingly, selective serotonin (5-HT) reuptake inhibitors (SSRIs) have been shown to alleviate cytokine-induced depression (Musselman et al., 2001a, Raison et al., 2007), and depressive and anxiety symptoms appear to be most responsive, while fatigue and neurovegetative symptoms are less responsive (Capuron et al., 2002, Raison et al., 2005b, McNutt et al., 2012).”
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    Premisecitation

    In the brain, IDO activity is significantly increased at 24 hours and peaks at 48 hours after LPS administration, corresponding to the expression of some depressive-like behaviors in laboratory animals.

    “In the brain, IDO activity is significantly increased at 24 hr and peaks at 48 hr in response to LPS administration, corresponding to the expression of some depressive-like behaviors, e.g. increased immobility in the forced-swim and tail suspension tests, in laboratory animals (Lestage et al., 2002, O'Connor et al., 2008).”
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    Interpretationreasoning

    Neuroactive KYN metabolites KA and QUIN are likely responsible for many behavioral changes associated with cytokine-induced IDO activity, and may involve effects on other neurotransmitter systems.

    “These finding suggest that neuroactive KYN metabolites, KA and QUIN, are likely responsible for many behavioral changes associated with cytokine-induced IDO activity, and may involve effects on other neurotransmitter systems (see Section 3.3 for discussion).”
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    Premisecitation

    Inflammatory cytokines including IL-6 increase 5-HTT expression and function, an effect mediated by induction of p38 MAPK both in vitro and in vivo.

    “Interestingly, inflammatory cytokines, including IL-6, have been shown to increase 5-HTT expression and function (Morikawa et al., 1998, Mossner et al., 1998, Sakai et al., 2003, Tsao et al., 2008) (see Figure 1), an effect found to be mediated by induction of p38 mitogen-activated protein kinase (MAPK), both in vitro and in vivo (Zhu et al., 2005, Zhu et al., 2006, Zhu et al., 2010a).”
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    Interpretationcitation

    IFN-alpha may act directly on the CNS, but may also exert indirect effects via activation of other peripheral and central inflammatory cytokines.

    “In terms of immunologic mechanisms of IFN-alpha-induced depression, IFN-alpha may act directly on the central nervous system (CNS), but may also exert indirect effects via the activation of other peripheral and central inflammatory cytokines (Raison et al., 2009).”
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    Premisecitation

    A polymorphism (rs9657182) in the promoter region of the gene encoding IDO1 was found to be associated with IFN-alpha-induced depression in Caucasian subjects homozygous for the C risk allele, but not African Americans who exhibited a markedly lower frequency of the risk allele at this locus.

    “Interestingly, a polymorphism (rs9657182) in the promoter region of the gene encoding IDO1 was found to be associated with IFN-alpha-induced depression in Caucasian subjects homozygous for the C risk allele, but not African Americans who exhibited a markedly lower frequency of the risk allele at this locus (Smith et al., 2012)(see Table 1 for details).”
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    Interpretationcitation

    These metabolites can interact with neurotransmitter systems in the brain, particularly glutamate, and are thought to be involved in the behavioral effects of cytokines.

    “These metabolites can then interact with neurotransmitter systems in the brain, particularly glutamate (see Section 3.3), and are thought to be involved in the behavioral effects of cytokines (Dantzer et al., 2011, Haroon et al., 2012).”
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    Premisecitation

    In HCV patients treated chronically with IFN-alpha, CSF IL-6 concentrations negatively correlate with 5-HIAA concentrations, which in turn negatively correlate with IFN-alpha-induced depression severity.

    “In patients treated chronically with IFN-alpha for hepatitis C virus (HCV), CSF concentrations of IL-6 negatively correlated with 5-HIAA concentrations, which in turn negatively correlated with IFN-alpha-induced depression severity (Raison et al., 2009).”
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    Premisecitation

    Cytokines released by peripheral immune cells or adipose tissue can access the CNS to initiate local immune activation by several mechanisms including passage through leaky BBB at circumventricular organs, active uptake across BBB, local actions at peripheral vagal nerve afferents, activation of endothelial cells and perivascular macrophages, and recruitment of activated immune cells.

    “Cytokines released by peripheral immune cells or adipose tissue can access the CNS to initiate local immune activation by several mechanisms, including 1.) passage through leaky regions in the blood-brain-barrier at circumventricular organs”
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    Premisecitation

    The gut is another source of inflammatory cytokines, and intestinal microorganisms influence immune responses.

    “Another source of inflammatory cytokines is the gut, and there has been attention paid to the role of intestinal microorganisms in influencing the immune responses of an organism (Lee and Mazmanian, 2010).”
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    Interpretationreasoning

    Differential responsiveness of symptom dimensions coupled with association of specific gene loci with behavioral symptoms suggests that distinct mechanisms may mediate various aspects of cytokine-induced depression, and understanding these mechanisms may improve treatment strategies.

    “Therefore, differential responsiveness of symptom dimensions coupled with the association of specific gene loci with behavioral symptoms suggests that distinct mechanisms may mediate the various aspects of cytokine-induced depression, and understanding these mechanisms may improve treatment strategies.”
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    Interpretationcitation

    HPA-mediated vulnerability to cytokine-induced depression likely represents a more general hyper-responsiveness and pre-existing vulnerability to stress or inflammatory challenge, possibly mediated by changes in GR expression or function.

    “Therefore, it is reasonable that HPA-mediated vulnerability to cytokine-induced depression represents a more general hyper-responsiveness and pre-existing vulnerability to stress or inflammatory challenge, which may be mediated by changes in glucocorticoid receptor (GR) expression or function (Pace et al., 2007).”
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    Premisecitation

    Inflammatory cytokines activate IDO and KYN pathways in the brain that affect glutamate neurotransmission and may contribute to glutamate dysfunction in depression.

    “Inflammatory cytokines activate IDO and KYN pathways in the brain that effect glutamate neurotransmission and may contribute to glutamate dysfunction in depression (McNally et al., 2008, Dantzer et al., 2011, Haroon et al., 2012).”
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    Interpretationreasoning

    Increased FDOPA uptake and decreased turnover suggest a potential depletion of DA in DAergic terminals and increased synthetic capacity following IFN-alpha exposure.

    “Increased uptake and decreased turnover of FDOPA suggests a potential depletion of DA in DAergic terminals and increased synthetic capacity following IFN-alpha exposure.”
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    Premisecitation

    Acutely, cytokines and immune activation increase locus coeruleus activity and NE release in the hippocampus and hypothalamus, relevant to HPA-axis activation, fever, and metabolic change.

    “Acutely, cytokines and immune activation increase locus coeruleus activity and NE release in the hippocampus and hypothalamus. This increase in NE activity is relevant to HPA-axis activation, fever, and metabolic change associated with immune activation (Dunn et al., 1999, Dunn et al., 2005).”
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    Premisecitation

    Inflammatory cytokines induce GTP-cyclohydrolase I, but inflammation-mediated increases in ROS/RNS can oxidize BH4, and increased iNOS activity can usurp BH4, reducing its availability for DA synthesis.

    “Although inflammatory cytokines have been shown to induce GTP-cyclohydrolase I, the enzyme necessary for BH4 synthesis, inflammation-mediated. increases in ROS/RNS can oxidize BH4, whereas increased inducible NOS (iNOS) activity can usurp BH4 (see Figure 1), thus reducing it’s availability for DA synthesis (Cunnington and Channon, 2010).”
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    Monkeys displaying huddling behavior in response to IFN-alpha have significantly lower CSF concentrations of HVA and DOPAC, which correlate with reduced locomotor activity.

    “Monkeys that display huddling behavior in response to IFN-alpha have been found to exhibit significantly lower CSF concentrations of the dopamine metabolites, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) (Felger et al., 2007, Felger and Miller, 2012), which correlated with reduced locomotor activity (Felger and Miller, 2012).”
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    Rhesus monkeys expressing functional IFNARs exhibit immune, neuroendocrine, and behavioral responses to human IFN-alpha similar to humans, including decreased psychomotor activity and increased depressive-like huddling behavior in about 50% of animals.

    “Rhesus monkeys that express functional IFNARs and activate relevant signal transduction pathways in response to human IFN-alpha (Felger et al., 2007), exhibit immune, neuroendocrine, and behavioral responses to IFN-alpha similar to humans, including decreases in psychomotor activity and increases in depressive-like huddling behavior (in ~50% of animals) (Felger et al., 2007, Felger and Miller, 201”
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    Premisecitation

    Plasma Phen/Tyr ratios are increased in IFN-alpha-treated subjects compared to controls, negatively correlate with CSF DA and HVA, and positively correlate with fatigue.

    “Plasma Phen/Tyr ratios were increased in IFN-alpha-treated subjects compared to controls (Felger et al., 2012b, Zoller et al., 2012), and negatively correlated with CSF concentrations of DA and HVA, and positively correlated with fatigue, in IFN-alpha-treated patients (Felger et al., 2012b).”
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    Premisecitation

    CSF BH2 concentrations are significantly increased in IFN-alpha-treated patients compared to controls, and decreased CSF BH4 concentrations correlate with increased CSF IL-6.

    “Furthermore, CSF concentrations of BH2 were significantly increased in IFN-alpha-treated patients compared to controls, and decreased CSF BH4 concentrations correlated with increased CSF IL-6 (Felger et al., 2012b).”
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    Premisecitation

    In IFN-alpha-treated HCV+ subjects, FDOPA PET showed increased uptake and decreased turnover in the caudate, putamen, and ventral striatum.

    “Interestingly, both increased uptake and decreased turnover of FDOPA in the caudate, putamen and ventral striatum of IFN-alpha-treated patients was found (Capuron et al., 2012).”
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    Premisecitation

    Both KA and QUIN are increased in CSF of IFN-alpha-treated patients, and CSF QUIN correlates with depressive symptoms during IFN-alpha administration.

    “Both KA and QUIN have been observed to be increased in the CSF of IFN-alpha-treated patients (Schwarcz and Pellicciari, 2002, Raison et al., 2010b), and CSF QUIN correlated with depressive symptoms during IFN-alpha administration (Raison et al., 2010b).”
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    Premisecitation

    IFN-alpha administration decreases systemic BDNF levels in humans, as do other inflammatory cytokines and LPS injections.

    “IFN-alpha administration has also been found to decrease systemic BDNF levels in humans (Kenis et al., 2010, Lotrich et al., 2013) (see Figure 1), as can other inflammatory cytokines and LPS injections (Tong et al., 2008, Cortese et al., 2011) (Guan and Fang, 2006).”
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    Premisecitation

    Inflammatory cytokines influence neuronal development and apoptosis, and both stress and inflammatory cytokine activity may adversely influence neurogenesis and neuroplasticity.

    “Inflammatory cytokines have repeatedly been observed to influence both neuronal development and apoptosis (Chawla-Sarkar et al., 2003, Hayley et al., 2005) (Mehler and Kessler, 1997, Zhao and Schwartz, 1998), (Peng et al., 2008, Anisman, 2009, Koo et al., 2010b). In fact, both stress and subsequent inflammatory cytokine activity may adversely influence neurogenesis and neuroplasticity (Patel et al”
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    Premisecitation

    SSRIs are very effective in treating anxiety, depressed mood, and cognitive aspects of cytokine-induced depression, but not as effective for fatigue and neurovegetative symptoms.

    “In terms of the role of 5-HT in the treatment of cytokine-induced depression, SSRIs have been very effective in treating anxiety, depressed mood, and cognitive aspects of cytokine-induce depression, but not as effective for fatigue and neurovegetative symptoms (Capuron et al., 2002, Raison et al., 2005b, McNutt et al., 2012).”
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    Premisecitation

    A direct comparison found the 5-HTTLPR Short allele specifically associated with risk for neurovegetative symptoms of depression, while the BDNF Met allele was primarily associated with cognitive symptoms.

    “It is noteworthy that a direct comparison of the 5-HTTLPR and the met/val allele of BDNF found that the 5-HTTLPR Short allele was specifically associated with risk for neurovegetative symptoms of depression, while the BDNF Met allele was primarily associated with the cognitive symptoms (Lotrich et al., 2013).”
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    Interpretationreasoning

    Peripheral cytokine effects on basal ganglia function generalize to multiple inflammatory stimuli and may be relevant to depression, specifically to symptoms of fatigue and psychomotor slowing.

    “Taken together, these data suggest that peripheral cytokine effects on basal ganglia function generalize to multiple inflammatory stimuli, and may be relevant to depression and specifically to symptoms of fatigue and psychomotor slowing.”
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  • May combine two claims.

    Interpretationcitation

    The fatigue of depression, often a residual symptom of SSRI therapy, is a prominent feature of cytokine-induced depression and may represent cytokine effects on basal ganglia and dopamine function.

    “The fatigue of depression, which is often a residual symptom of SSRI therapy, is a prominent feature of cytokine-induced depression, and may represent cytokine effects on the basal ganglia and dopamine (DA) function (Capuron et al., 2001, Majer et al., 2008, Capuron et al., 2009).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Capuron et al., 2001 source

      Not checked in the free run.

    • cites Majer et al., 2008 source

      Not checked in the free run.

    • cites Capuron et al., 2009 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Inflammation is associated with decreased peripheral conversion of Phen to Tyr, which may be associated with reduced DA in the brain and behavioral symptoms such as anhedonia and fatigue.

    “These results indicate that inflammation is associated with decreased peripheral conversion of Phen to Tyr, which may in turn be associated with reduced DA in the brain as well as behavioral symptoms such as anhedonia and fatigue.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In IFN-alpha-treated patients, CSF MHPG was not related to behavioral symptoms, and DBH SNPs were not associated with development of depression.

    “MHPG has been examined in the CSF of IFN-alpha-treated patients but was not related to behavioral symptoms (Raison et al., 2009). SNPs of the gene for DA beta-hydroxylase, the enzyme that converts DA to NE, was examined in IFN-alpha-treated HCV+ subjects but was not associated with the development of depression (Smith et al., 2012).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Raison et al., 2009 source

      Not checked in the free run.

    • cites Smith et al., 2012 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Baseline circulating cytokines such as IL-6 and inflammation markers like CRP may help identify patients who will fail current antidepressant therapies and guide novel treatment strategies.

    “baseline concentrations of circulating cytokines, such as IL-6, and markers of inflammation, like CRP, may be useful for indentifying subjects that will fail to respond to current antidepressant therapies”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Quinolinic acid has been implicated in several neurodegenerative diseases, including Huntington's disease, amyotrophic lateral sclerosis, Alzheimer's disease, and HIV-associated dementia.

    “QUIN has been implicated in a number of neurodegenerative diseases, including Huntington’s disease, Amyotrophic Lateral Sclerosis, Alzheimer’s disease, and dementia secondary to infection with HIV”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Schwarcz and Pellicciari, 2002

      Not checked in the free run.

    • cites Guidetti and Schwarcz, 2003

      Not checked in the free run.

    • cites Guillemin et al., 2005a

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IFN-alpha strongly induces ADAR1 mRNA, which edits the AMPA glutamate receptor.

    “the mRNA specific adenosine deaminase 1 (ADAR1), which edits the AMPA glutamate receptor, is strongly induced by IFN-alpha”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Liu and Samuel, 1999

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    People with a history of childhood trauma tend to have higher adult inflammatory biomarkers and higher rates of depression.

    “persons with a history of childhood trauma tend to have higher inflammatory biomarkers as adults and also exhibit higher rates of depression”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Danese et al., 2007 source

      Not checked in the free run.

    • cites Danese et al., 2008 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Quinolinic acid and inflammatory cytokines increase glutamate release and reduce astrocytic glutamate uptake via the excitatory amino acid transporter.

    “QUIN and inflammatory cytokines have also been shown to increase glutamate release and decrease the astrocytic uptake of glutamate by the excitatory amino acid transporter”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Tavares et al., 2002 source

      Not checked in the free run.

    • cites Tilleux and Hermans, 2007 source

      Not checked in the free run.

    • cites Ida et al., 2008 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Cytokines may influence the glutamatergic system through multiple routes and conceivably increase depression risk.

    “Thus there are a variety of routes by which cytokines may influence the glutamatergic system and conceivably increase risk for depression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    This makes glutamate more available to extrasynaptic NMDA receptors and contributes to glutamate toxicity.

    “thus making glutamate more available to extrasynaptic NMDARs and contributing to glutamate toxicity”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hardingham et al., 2002 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Parkinson's-like symptoms occur in some patients during IFN-alpha administration and have been successfully treated with levodopa.

    “Parkinson’s-like symptoms have been observed in some patients during IFN-alpha administration, and these symptoms have been successfully treated with levodopa”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Mizoi et al., 1997

      Not checked in the free run.

    • cites Sarasombath et al., 2002

      Not checked in the free run.

    • cites Bersano et al., 2008 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Many biomarkers and gene polymorphisms that increase vulnerability to cytokine-induced depression have been identified and may help identify at-risk patients.

    “numerous biomarkers and gene polymorphisms that confer vulnerability to cytokine-induced depression have been indentified, and may be useful in identifying at-risk patients”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    IDO-deficient mice are resistant to behavioral changes after BCG infection while showing a normal inflammatory cytokine response to BCG.

    “IDO-deficient mice are resistant to behavioral changes following infection with bacille Calmette–Guerin (BCG), while showing a normal inflammatory cytokine response to BCG administration”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites O'Connor et al., 2009a

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Low serum folate is associated with depression and resistance to antidepressant treatment.

    “low serum folate has been associated with depression and with resistance to antidepressant treatment”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Fava et al., 1997 source

      Not checked in the free run.

    • cites Papakostas et al., 2004a

      Not checked in the free run.

    • cites Gilbody et al., 2007a

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Memantine prevented the onset of dopamine deficits in SIV-infected macaques, an effect mediated by increased BDNF.

    “inhibition of the NMDA receptor with memantine prevented the onset of DA deficits in the brains of SIV-infected macaques, and effect mediated by increased BDNF”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Meisner et al., 2008 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sapropterin is the first non-dietary FDA-approved synthetic BH4 for phenylketonuria and lowers blood phenylalanine by stabilizing and increasing PAH activity.

    “Sapropterin (Kuvan) is the first non-dietary, FDA-approved, synthetic form of BH4 for patients with phenylketonuria that is effective in lowering blood Phen levels by stabilizing and increasing PAH activity”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Trefz et al., 2009 source

      Not checked in the free run.

    • cites Burton et al., 2010 source

      Not checked in the free run.

    • cites Utz et al., 2012 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Peripheral cytokines are able to reach the brain and trigger local central inflammatory networks, altering neurotransmitter function.

    “Peripheral cytokines can access the brain and activate local CNS inflammatory networks to produce alterations in neurotransmitter function.”
    Quote in the paperSubstantial claim
55 of 55

  • The paper relies on this without support.

    SSRIs and other classical antidepressants targeting the 5-HT system are efficacious for many aspects of major depression and cytokine-induced depression.

    “Although SRRIs and other classical antidepressants that target the 5-HT system are efficacious in treating many aspects of both major depression and cytokine-induced depression”

  • The paper relies on this without support.

    Knockout mice lacking the ATP P2X7 receptor, which stimulates inflammasome-mediated IL-1beta release, show an antidepressant-like profile with increased mobility in tail suspension and forced swim tests.

    “knockout mice for the ATP P2X7 receptor that stimulates inflammasome-mediated IL-1beta release exhibit an antidepressant-like profile, including increased mobility in the tail suspension and forced swim tests”

  • The paper relies on this without support.

    Classic stimulants increase dopamine release and block DAT function.

    “Classic stimulants act to increase DA release and block DAT function”
3 of 3

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?

  • Chronic exposure to elevated inflammatory cytokines can lead to depression.

    “It has been shown that chronic exposure to elevated inflammatory cytokines can lead to depression (108).”

    From Vagus Nerve as Modulator of the Brain–Gut Axis in Psychiatric and Inflammatory Disorders (2018) · cites this paper as [108]

  • Pro-inflammatory cytokines contribute to the pathogenesis of psychiatric diseases such as depression.

    “Growing evidence suggests that pro-inflammatory cytokines contribute to the pathogenesis of psychiatric diseases such as depression [137,138]”

    From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [137]

  • Increased circulating cytokines are detected in depression and anxiety.

    “The idea that stress itself induces endocrine mediators like IL6, which is traditionally associated with inflammation, has since been supported by the detection of increased circulating cytokines in depression and anxiety (Felger and Lotrich, 2013; Khandaker et al., 2014), and by the association of IL6 polymorphisms in individuals with depression (Zhang et al., 2016).”

    From Origin and function of stress-induced IL-6 in murine models (2020) · cites this paper as Felger and Lotrich, 2013

  • Secretion of IL-1β, IL-6 and TNF-α with macrophage-associated proinflammatory cytokines is synchronized with M1 activation in MDD patients.

    “Secretion of IL-1β, IL-6 and TNF-α with macrophage-associated proinflammatory cytokines was synchronized with M1 activation in MDD patients [15].”

    From Neuron secrete exosomes containing miR-9-5p to promote polarization of M1 microglia in depression (2022) · cites this paper as [15]

Cites

Flagged first, then by citations

7 of the 445 references couldn’t be matched to a known paper.

Research works printed but not linked: 4

  1. Capuron, 2011, Chronic low-grade inflammation in elderly persons is associated with altered tryptophan and tyrosine metabolism: role in neuropsychiatric symptoms, Biol Psychiatry, 70, 175, 10.1016/j.biopsych.2010.12.006 · DOI · Paper page
  2. Koo, 2010, Nuclear factor-kb is a critical mediator of stress-impaired neurogenesis and depressive behavior, Proc Natl Acad Sci U.., 107, 2669, 10.1073/pnas.0910658107 · DOI · Paper page
  3. O’Connor, 2009, Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice, Mol Psychiatry, 14, 511, 10.1038/sj.mp.4002148 · DOI · Paper page
  4. Zhu, 2010, Interleukin-1 receptor activation by systemic lipopolysaccharide induces behavioral despair linked to MAPK regulation of CNS serotonin transporters, Neuropsychopharmacology, 35, 2510, 10.1038/npp.2010.116 · DOI · Paper page

Cited by

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Related

Authors
Felger, J. C., & Lotrich, F. E.
Affiliations
  • Emory University (US)
  • University of Pittsburgh (US)
ORCID
Felger, J.C.
Venue
Neuroscience
Publisher
Elsevier BV
Published
2013-08
Volume
246
Pages
199-229
ISSN
0306-4522 (ISSN-L)
DOI
10.1016/j.neuroscience.2013.04.060
PMC
PMC3741070
OpenAlex
W2004243143
Cited by
1,180
References
445
Citations by year
2026: 97 · 2025: 125 · 2024: 99 · 2023: 98 · 2022: 127 · 2021: 107 · 2020: 86 · 2019: 104 · 2018: 101 · 2017: 70 · 2016: 60 · 2015: 61 · 2014: 31 · 2013: 12
FWCI
3.84
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • NIMH (R090250)
  • the Glenn Family Breast Fund
  • the Winship Cancer Institute
Topics
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Keywords
inflammatory cytokines, depression, neuroinflammation, innate immune system, monoaminergic systems, glutamatergic system, neuropeptides, brain-derived neurotrophic factor, genetic polymorphism, childhood trauma, obesity, stress, sleep, neurotransmitter systems, cytokine signaling, anti-inflammatory therapy
MeSH terms
Animals, Antidepressive Agents, Brain, Depression, Humans, Inflammation, Biomarkers, Cytokines, Inflammation Mediators

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-04.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-04.

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