Inflammatory cytokines in depression: Neurobiological mechanisms and therapeutic implications

In the paper

“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”

What the sources say

• Partly supported

  The Results section reports that memantine prevented dopamine deficits in the putamen of SIV-infected macaques and increased BDNF. The Discussion explicitly says that, despite the correlation between BDNF and dopamine, the authors cannot establish a causal effect. Thus, the claim that increased BDNF mediated the protection overstates the paper. (LLM, conf=0.94)

  cites Meisner et al., 2008 sourceExperimental — accuracy not yet measured

In the paper

“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.”

In the paper

“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)”

What the sources say

• Not checked yetcites Kendler et al., 2001 source
• Not checked yetcites Caspi et al., 2003 source
• Not checked yetcites Duman and Monteggia, 2006 source

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites Pace et al., 2007 source
• Not checked yetcites Dantzer et al., 2008 source
• Not checked yetcites Miller et al., 2009 source

In the paper

“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).”

What the sources say

• Not checked yetcites Bull et al., 2008

In the paper

“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).”

What the sources say

• Not checked yetcites Musselman et al., 2001b
• Not checked yetcites Massie, 2004 source
• Not checked yetcites Jehn et al., 2006 source

In the paper

“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).”

What the sources say

• Not checked yetcites Capuron et al., 2002 source
• Not checked yetcites Maddock et al., 2005 source
• Not checked yetcites Raison et al., 2005a

In the paper

“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).”

What the sources say

• Not checked yetcites Su et al., 2010
• Not checked yetcites Lotrich et al., 2012
• Not checked yetcites McNamara and Lotrich, 2012

In the paper

“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).”

What the sources say

• Not checked yetcites Iwata et al., 2012

In the paper

“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).”

What the sources say

• Not checked yetcites Capuron et al., 2003a
• Not checked yetcites Raison et al., 2010b
• Not checked yetcites Capuron et al., 2011a

In the paper

“Finally, obesity is associated with increased circulating cytokines, and BMI significantly influences concentrations of L-6 and other inflammatory markers (Khaodhiar et al., 2004).”

What the sources say

• Not checked yetcites Khaodhiar et al., 2004 source

In the paper

“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).”

What the sources say

• Not checked yetcites Musselman et al., 2001a
• Not checked yetcites Raison et al., 2007 source
• Not checked yetcites Capuron et al., 2002 source

In the paper

“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).”

What the sources say

• Not checked yetcites Lestage et al., 2002 source
• Not checked yetcites O'Connor et al., 2008

In the paper

“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).”

In the paper

“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).”

What the sources say

• Not checked yetcites Morikawa et al., 1998 source
• Not checked yetcites Zhu et al., 2005 source
• Not checked yetcites Zhu et al., 2006 source

In the paper

“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).”

What the sources say

• Not checked yetcites Raison et al., 2009 source

In the paper

“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).”

What the sources say

• Not checked yetcites Smith et al., 2012 source

In the paper

“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).”

What the sources say

• Not checked yetcites Dantzer et al., 2011 source
• Not checked yetcites Haroon et al., 2012 source

In the paper

“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).”

What the sources say

• Not checked yetcites Raison et al., 2009 source

In the paper

“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”

What the sources say

• Not checked yetcites Katsuura et al., 1990
• Not checked yetcites Banks et al., 1995 source
• Not checked yetcites Bluthe et al., 1994

In the paper

“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).”

What the sources say

• Not checked yetcites Lee and Mazmanian, 2010

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites Pace et al., 2007 source

In the paper

“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).”

What the sources say

• Not checked yetcites McNally et al., 2008 source
• Not checked yetcites Dantzer et al., 2011 source
• Not checked yetcites Haroon et al., 2012 source

In the paper

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

In the paper

“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).”

What the sources say

• Not checked yetcites Dunn et al., 1999 source
• Not checked yetcites Dunn et al., 2005 source

In the paper

“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).”

What the sources say

• Not checked yetcites Cunnington and Channon, 2010

In the paper

“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).”

What the sources say

• Not checked yetcites Felger et al., 2007 source
• Not checked yetcites Felger and Miller, 2012

In the paper

“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”

What the sources say

• Not checked yetcites Felger et al., 2007 source
• Not checked yetcites Felger and Miller, 2012

In the paper

“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).”

What the sources say

• Not checked yetcites Felger et al., 2012b
• Not checked yetcites Zoller et al., 2012 source

In the paper

“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).”

What the sources say

• Not checked yetcites Felger et al., 2012b

In the paper

“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).”

What the sources say

• Not checked yetcites Capuron et al., 2012 source

In the paper

“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).”

What the sources say

• Not checked yetcites Schwarcz and Pellicciari, 2002
• Not checked yetcites Raison et al., 2010b

In the paper

“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).”

What the sources say

• Not checked yetcites Kenis et al., 2010 source
• Not checked yetcites Lotrich et al., 2013 source
• Not checked yetcites Tong et al., 2008 source

In the paper

“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”

What the sources say

• Not checked yetcites Chawla-Sarkar et al., 2003 source
• Not checked yetcites Hayley et al., 2005 source
• Not checked yetcites Patel et al., 2003 source

In the paper

“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).”

What the sources say

• Not checked yetcites Capuron et al., 2002 source
• Not checked yetcites Raison et al., 2005b
• Not checked yetcites McNutt et al., 2012 source

In the paper

“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).”

What the sources say

• Not checked yetcites Lotrich et al., 2013 source

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites Capuron et al., 2001 source
• Not checked yetcites Majer et al., 2008 source
• Not checked yetcites Capuron et al., 2009 source

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites Raison et al., 2009 source
• Not checked yetcites Smith et al., 2012 source

In the paper

“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”

In the paper

“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”

What the sources say

• Not checked yetcites Schwarcz and Pellicciari, 2002
• Not checked yetcites Guidetti and Schwarcz, 2003
• Not checked yetcites Guillemin et al., 2005a

In the paper

“the mRNA specific adenosine deaminase 1 (ADAR1), which edits the AMPA glutamate receptor, is strongly induced by IFN-alpha”

What the sources say

• Not checked yetcites Liu and Samuel, 1999

In the paper

“persons with a history of childhood trauma tend to have higher inflammatory biomarkers as adults and also exhibit higher rates of depression”

What the sources say

• Not checked yetcites Danese et al., 2007 source
• Not checked yetcites Danese et al., 2008 source

In the paper

“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”

What the sources say

• Not checked yetcites Tavares et al., 2002 source
• Not checked yetcites Tilleux and Hermans, 2007 source
• Not checked yetcites Ida et al., 2008 source

In the paper

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

In the paper

“thus making glutamate more available to extrasynaptic NMDARs and contributing to glutamate toxicity”

What the sources say

• Not checked yetcites Hardingham et al., 2002 source

In the paper

“Parkinson’s-like symptoms have been observed in some patients during IFN-alpha administration, and these symptoms have been successfully treated with levodopa”

What the sources say

• Not checked yetcites Mizoi et al., 1997
• Not checked yetcites Sarasombath et al., 2002
• Not checked yetcites Bersano et al., 2008 source

In the paper

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

In the paper

“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”

What the sources say

• Not checked yetcites O'Connor et al., 2009a

In the paper

“low serum folate has been associated with depression and with resistance to antidepressant treatment”

What the sources say

• Not checked yetcites Fava et al., 1997 source
• Not checked yetcites Papakostas et al., 2004a
• Not checked yetcites Gilbody et al., 2007a

In the paper

“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”

What the sources say

• Not checked yetcites Trefz et al., 2009 source
• Not checked yetcites Burton et al., 2010 source
• Not checked yetcites Utz et al., 2012 source

In the paper

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