The role of inflammation in core features of depression: Insights from paradigms using exogenously-induced inflammation.

In the paper

“There is evidence that somatic symptoms follow a different temporal course than depressed mood following inflammatory challenge and may have distinct neurobiological underpinnings.”

In the paper

“Support for this idea derives from IFN-α studies, which show that although the large majority of patients rapidly develop somatic symptoms (e.g., fatigue), only a subgroup go on to develop other symptoms (e.g., feelings of guilt, suicidality) severe enough to qualify for a major depression diagnosis (Capuron et al., 2002; Capuron and Miller, 2004; Musselman et al., 2001).”

What the sources say

• Not checked yetcites Capuron et al., 2002 source
• Not checked yetcites Capuron and Miller, 2004
• Not checked yetcites Musselman et al., 2001 source

In the paper

“For example, IFN-α therapy resulted in the emergence of a cluster of somatic symptoms that appeared in the majority of patients within two weeks of treatment initiation (including symptoms of anorexia, fatigue, and pain), as well as cluster of affective/cognitive symptoms that emerged in a smaller proportion of patients (including symptoms of negative mood, anxiety, and cognitive dysfunction) (Cap”

What the sources say

• Not checked yetcites Capuron et al., 2002 source

In the paper

“Further, patients receiving (low-dose) IFN-α treatment for Hepatitis C exhibit increases in fatigue and decreases in vigor within four hours of initial injection that continue to rise across the 8 weeks of treatment (Dowell et al., 2016).”

What the sources say

• Not checked yetcites Dowell et al., 2016 source

In the paper

“In general, research also supports an effect of inflammation on negative reactivity and reward processing, with most studies focusing on neural processes.”

In the paper

“Indeed, the association between inflammation and both attentional bias and fatigue remain when accounting for concurrent depressed mood (Bower et al., 2009; Boyle et al., 2017).”

What the sources say

• Not checked yetcites Bower et al., 2009 source
• Not checked yetcites Boyle et al., 2017 source

In the paper

“Similar findings have been observed in cancer patients, where paroxetine led to reductions in depressed mood but not fatigue in patients undergoing chemotherapy (Morrow et al., 2003).”

What the sources say

• Not checked yetcites Morrow et al., 2003 source

In the paper

“Further, chronic treatment with IFN-α in non-human primates leads to decreases in the synthesis and availability of dopamine in the striatum, which are correlated with reductions in effort-dependent sucrose consumption (Felger et al., 2013).”

What the sources say

• Not checked yetcites Felger et al., 2013 source

In the paper

“Of note, inflammation and IDO can both influence glutamate metabolism, which may also play a role in depression”

In the paper

“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).”

What the sources say

• Not checked yetcites Fried and Nesse, 2015 source
• Not checked yetcites Young et al., 2014 source
• Not checked yetcites Biesheuvel-Leliefeld et al., 2015 source

In the paper

“Of particular relevance for this review, peripheral inflammation has been shown to induce depressive-like behaviors in animal models, including anhedonia (e.g., reduced sucrose consumption), decreases in exploratory, novelty-seeking and social behaviors, reduced food intake; and sleep disturbance (Anisman and Matheson, 2005; De La Garza, 2005; Dunn et al., 2005; Larson and Dunn, 2001; Pecchi et al”

What the sources say

• Not checked yetcites Anisman and Matheson, 2005 source
• Not checked yetcites De La Garza, 2005 source
• Not checked yetcites Dunn et al., 2005 source

In the paper

“This process can become self-perpetuating because chronically elevated glucocorticoids can stimulate production of neuroinflammation by activating microglia (Frank et al., 2013; Nair and Bonneau, 2006), the resident immune cells of the brain.”

What the sources say

• Not checked yetcites Frank et al., 2013 source
• Not checked yetcites Nair and Bonneau, 2006

In the paper

“To summarize briefly, glutamate is released at a higher rate under conditions of stress (Goshen and Yirmiya, 2009), and excess presence of synaptic glutamate can lead to excitotoxicity and neuronal death (Ankarcrona et al., 1995).”

What the sources say

• Not checked yetcites Goshen and Yirmiya, 2009 source
• Not checked yetcites Ankarcrona et al., 1995 source

In the paper

“Typhoid vaccination caused greater negative mood following two stress tasks (a Stroop color-word task and a simulated public speaking exercise) compared to a placebo group; elevations in negative mood were driven by increases in fatigue and confusion (Brydon et al., 2009).”

What the sources say

• Not checked yetcites Brydon et al., 2009 source

In the paper

“Anhedonia, the loss of pleasure or interest in previously rewarding stimuli, is a hallmark of depression and is one of the core diagnostic criteria for major depression (American Psychiatric Association, 2013).”

What the sources say

• Not checked yetcites American Psychiatric Association, 2013

In the paper

“Typhoid vaccination leads to a modest, short-term inflammatory response; for example, an average increase of 0.82 pg/mL (a 106% increase) in IL-6 at 3 hours post-vaccination (Wright et al., 2005) and increases in inflammation resolve within 24 hours following typhoid vaccination (Paine et al., 2013).”

What the sources say

• Not checked yetcites Wright et al., 2005 source
• Not checked yetcites Paine et al., 2013 source

In the paper

“Moreover, the exaggerated amygdala response to socially threatening images was associated with increased feelings of social disconnection (Inagaki et al., 2012); thus, inflammation may upregulate amygdala reactivity to social threats, resulting in the experience of social disconnection and withdrawal.”

What the sources say

• Not checked yetcites Inagaki et al., 2012 source

In the paper

“For example, compared to non-depressed controls, individuals with depression exhibit more negative facial expressions in response to unpleasant images (Sloan et al., 1997), report greater perceived stress in response to a laboratory stress tasks (de Rooij et al., 2010), and display greater increases in negative affect in response to daily stressors (Myin-Germeys et al., 2003).”

What the sources say

• Not checked yetcites Sloan et al., 1997 source
• Not checked yetcites de Rooij et al., 2010 source
• Not checked yetcites Myin-Germeys et al., 2003 source

In the paper

“For example, although endotoxin did not increase self-reported affective reactivity to social stress, endotoxin did lead to exaggerated activation of threat-related neural circuits, including greater activation of the amygdala and dACC (Muscatell et al., 2016).”

What the sources say

• Not checked yetcites Muscatell et al., 2016 source

In the paper

“These studies have shown that endotoxin administration leads to symptoms of depression including negative mood, anhedonia, cognitive impairment, fatigue, reduced food intake, altered sleep, and social withdrawal, as well as anxiety symptoms (DellaGioia and Hannestad, 2010; Eisenberger et al., 2010a; Reichenberg et al., 2001).”

What the sources say

• Not checked yetcites DellaGioia and Hannestad, 2010 source
• Not checked yetcites Eisenberger et al., 2010a
• Not checked yetcites Reichenberg et al., 2001 source

In the paper

“Yet, there is also evidence that the inflammation-depression pathway is bidirectional as depressive symptoms predict increases in inflammation in some samples (Huang et al., 2017; Matthews et al., 2010; Stewart et al., 2009).”

What the sources say

• Not checked yetcites Huang et al., 2017 source
• Not checked yetcites Matthews et al., 2010 source
• Not checked yetcites Stewart et al., 2009 source

In the paper

“Additionally, unlike IFN-α treatment or endotoxin, vaccines do not typically lead to fever, nausea, or other physical illness symptoms. Therefore, any effects on mood and cognition are not simply attributable to illness symptoms, but rather to more direct effects of cytokines on the brain.”

In the paper

“Studies of patients receiving this treatment have shown that IFN-α can induce symptoms of depressed mood, fatigue, sleep disturbance, loss of appetite, pain, anxiety, anhedonia, anger, hostility, cognitive impairment, and suicidal ideation (Capuron et al., 2002; Janssen et al., 1994; Lotrich et al., 2007).”

What the sources say

• Not checked yetcites Capuron et al., 2002 source
• Not checked yetcites Janssen et al., 1994 source
• Not checked yetcites Lotrich et al., 2007 source

In the paper

“Additionally, participants with larger vaccine-induced IL-6 responses exhibited elevated systolic blood pressure responses to stress tasks, as well as elevated post-stress cortisol and a marker of noradrenaline (Brydon et al., 2009).”

What the sources say

• Not checked yetcites Brydon et al., 2009 source

In the paper

“Importantly, these alterations in reward processing precede and potentially contribute to the etiology of depression in at-risk groups (Gotlib et al., 2010), and number of prospective studies have shown that self-reported anhedonia (less frequent and intense positive affect) is a strong predictor of subsequent increases in depression severity (Morris et al., 2009).”

What the sources say

• Not checked yetcites Gotlib et al., 2010

In the paper

“Thus, inflammation may impact not only consummatory but also anticipatory reward processes, potentially leading to behavioral manifestations of depressed mood.”

In the paper

“Impaired cognitive control is heritable”

What the sources say

• Not checked yetcites Friedman et al., 2008 source

In the paper

“Much of this work has shown attenuated reward-related neural activity following an inflammatory stimulus, which is generally consistent with preclinical research on inflammation and reward (See Swardfager et al., 2016 for review).”

What the sources say

• Not checked yetcites Swardfager et al., 2016 source

In the paper

“Anhedonia is often conceptualized as the behavioral manifestation of altered reward processing in depressed patients (Beck, 2004; Nutt et al., 2007; Webb et al., 2016; Winer and Salem, 2015), and may underlie many of the profound social impairments that are central to depression (Kupferberg et al., 2016).”

What the sources say

• Not checked yetcites Beck, 2004
• Not checked yetcites Nutt et al., 2007 source
• Not checked yetcites Webb et al., 2016 source

In the paper

“Anhedonia is a broad construct that includes deficits in anticipation of, motivation toward, and responsiveness to reward, as well as deficits in reward learning (ability to recall and make decisions based on past rewarding experiences) (Treadway and Zald, 2011) and is estimated to be 46% heritable in studies of monozygotic twins (Bogdan and Pizzagalli, 2009).”

What the sources say

• Not checked yetcites Bogdan and Pizzagalli, 2009

In the paper

“However, several other studies of IFN-α treated hepatitis C patients have found no significant performance deficits on the Trail Making Test part B (Amodio et al., 2005; Drozdz et al., 2008; Fontana et al., 2007), the Wisconsin Card Sorting task (Fontana et al., 2007), or on the Intradimensional/Extradimensional Shift task (Majer et al., 2008).”

What the sources say

• Not checked yetcites Amodio et al., 2005 source
• Not checked yetcites Drozdz et al., 2008
• Not checked yetcites Fontana et al., 2007 source

In the paper

“substantia nigra-hippocampus connectivity to novelty was increased in the placebo condition and attenuated in the vaccine condition (Harrison et al., 2015)”

What the sources say

• Not checked yetcites Harrison et al., 2015 source

In the paper

“which is relevant to reductions in motivational and approach behavior seen in depression”

In the paper

“Anhedonia is a broad construct that includes deficits in anticipation of, motivation toward, and responsiveness to reward, as well as deficits in reward learning (ability to recall and make decisions based on past rewarding experiences) (Treadway and Zald, 2011) and is estimated to be 46% heritable in studies of monozygotic twins (Bogdan and Pizzagalli, 2009).”

What the sources say

• Not checked yetcites Treadway and Zald, 2011 source

In the paper

“We conclude that inflammation likely plays a role in exaggerated reactivity to negative information, altered reward reactivity, and somatic symptoms.”

In the paper

“In a study in which participants were explicitly asked to sustain their positive mood following the presentation of positive stimuli, depressed individuals failed to sustain NAc activation over time compared with controls; moreover, this reduced capacity was associated with lower self-reported positive affect (Heller et al., 2009).”

What the sources say

• Not checked yetcites Heller et al., 2009 source

In the paper

“Deficits in cognitive control are among the most frequent complaints for individuals with depression (Simons et al., 2009).”

What the sources say

• Not checked yetcites Simons et al., 2009 source

In the paper

“the only published study examining the role of inflammation in performance on behavioral tasks of updating found that moderate inflammation facilitated (rather than slowed) updating speed (Grigoleit et al., 2011)”

• Also stated in: § Inflammation and cognitive control deficits. · plain

  “the moderate-dose endotoxin group exhibited significantly faster reaction times on the n-back task compared to the placebo condition (with comparable levels of accuracy across the two groups) (Grigoleit et al., 2011)”

What the sources say

• Not checked yetcites Grigoleit et al., 2011 source

In the paper

“A meta-analysis of 113 studies found significant deficits in executive functioning among depressed individuals compared to non-depressed controls, including deficits in updating, shifting, inhibition, working memory, planning, and verbal fluency, with effect sizes ranging from d = 0.32 – 0.97 (Snyder, 2014).”

What the sources say

• Not checked yetcites Snyder, 2014 source

In the paper

“Novel stimuli are high in intrinsic reward value, thereby motivating adaptive behaviors such as exploration and social approach (Kakade and Dayan, 2002).”

What the sources say

• Not checked yetcites Kakade and Dayan, 2002

In the paper

“Thus, a role of inflammation in shifting ability impairments is mixed, with the majority of studies finding no effect of inflammation on shifting ability.”

In the paper

“A large epidemiological study of more than 1800 depressed patients found that 73% reported feeling tired, and that this was the second most commonly endorsed symptom, after low mood (Tylee et al., 1999).”

What the sources say

• Not checked yetcites Tylee et al., 1999

In the paper

“Thus, inflammation did not impair inhibitory control, but rather led to an overall psychomotor slowing and/or decrease in motivation (Brydon et al., 2008).”

What the sources say

• Not checked yetcites Brydon et al., 2008 source

In the paper

“Fatigue is a prevalent presenting symptom of major depressive disorder (Demyttenaere et al., 2005).”

What the sources say

• Not checked yetcites Demyttenaere et al., 2005 source

In the paper

“A large epidemiological study of more than 1800 depressed patients found that 73% reported feeling tired, and that this was the second most commonly endorsed symptom, after low mood (Tylee et al., 1999).”

What the sources say

• Not checked yetcites Tylee et al., 1999

In the paper

“In IFN-α models, fatigue is the most commonly reported symptom, affecting an estimated 80% of patients (Capuron et al., 2002).”

What the sources say

• Not checked yetcites Capuron et al., 2002 source

In the paper

“Persistent fatigue can lead to substantial impairment in fulfilling social, familial, and work roles, and patients with residual fatigue are more likely to experience depression recurrence despite continued prophylactic treatment (Targum and Fava, 2011).”

What the sources say

• Not checked yetcites Targum and Fava, 2011

In the paper

“In addition, conceptual models have suggested a role for the anterior insula and the dorsal ACC in fatigue, particularly in the context of inflammation (Dantzer et al., 2014; Karshikoff et al., 2017), while the basal ganglia and frontal lobes have been implicated in diseases such chronic fatigue syndrome (DeLuca et al., 2009).”

What the sources say

• Not checked yetcites DeLuca et al., 2009 source

In the paper

“Psychomotor retardation, defined as a slowing of motor activity and difficulty responding quickly and spontaneously to environmental cues, is a common symptom of depression (Taylor et al., 2006).”

What the sources say

• Not checked yetcites Taylor et al., 2006 source

In the paper

“Common sleep alterations in depression include difficulty initiating sleep, frequent nocturnal awakenings, and early morning awakenings.”

In the paper

“Sleep deprivation appears to cause alterations to neural processes that underlie a wide range of cognitive tasks, including attentional control, memory, reward processing, and emotion discrimination which involve multiple brain regions and the connectivity between them (Krause et al., 2017).”

What the sources say

• Not checked yetcites Krause et al., 2017 source

In the paper

“Hypersomnia can also accompany depression, though it is somewhat less common (Garvey et al., 1984; Tsuno et al., 2005).”

What the sources say

• Not checked yetcites Garvey et al., 1984 source
• Not checked yetcites Tsuno et al., 2005 source

In the paper

“Notably, increases in IL-6 and decreases in motor speed were both associated with altered activation patterns (enhanced activation) in the substantia nigra (Brydon et al., 2008).”

What the sources say

• Not checked yetcites Brydon et al., 2008 source

In the paper

“Psychomotor slowing involves disruptions in dopamine functioning and the basal ganglia circuit; dopaminergic abnormalities underlie the psychomotor slowing seen in depression as they do in Parkinson’s disease (Rogers et al., 1987).”

What the sources say

• Not checked yetcites Rogers et al., 1987 source

In the paper

“Common sleep alterations in depression include difficulty initiating sleep, frequent nocturnal awakenings, and early morning awakenings.”

In the paper

“An estimated 50–90% of individuals with diagnosed depression complain of poor sleep quality (Casper et al., 1985; Hetta et al., 1985; Kupfer et al., 1969; Riemann et al., 2001).”

What the sources say

• Not checked yetcites Casper et al., 1985 source
• Not checked yetcites Hetta et al., 1985
• Not checked yetcites Kupfer et al., 1969 source

In the paper

“Common sleep alterations in depression include difficulty initiating sleep, frequent nocturnal awakenings, and early morning awakenings.”

In the paper

“The classic example of these adaptive behavioral changes is fatigue, which can promote recovery by driving the organism to rest and thereby allow the body to devote its energy to healing.”

In the paper

“Blunted responsivity to rewards may be similarly adaptive, minimizing an organism’s pursuit of rewards in favor of rest; the exception to this blunted reward responsivity could be social rewards, due to the likely benefits of having close others nearby for caretaking purposes (Eisenberger et al., 2016).”

What the sources say

• Not checked yetcites Eisenberger et al., 2016

In the paper

“Taken together, results suggest that inflammation can disrupt sleep in ways that mirror the sleep disruptions observed in depression, including reductions in sleep quality, increases in NREM sleep, and decreases in REM sleep latency following IFN-α and moderate doses of endotoxin.”

In the paper

“In the short-term, these adaptations serve a clear benefit to the individual, but if sustained (such as through ongoing stress or immune dysregulation) could be iatrogenic in the long-term.”

In the paper

“In some ways, this is puzzling given that inflammatory processes have been shown to regulate learning and memory (e.g., Yirmiya and Goshen, 2011) and that correlational studies have identified associations between mild elevations in inflammatory markers and both self-reported (Davis et al., 2018; Kuhlman et al., 2018) and objective (Marsland et al., 2015) measures of cognitive function.”

What the sources say

• Not checked yetcites Yirmiya and Goshen, 2011 source

In the paper

“Specifically, low-level immune activation leads to increased non-rapid eye movement (NREM) sleep, while decreasing or having no effect on REM sleep; in contrast, more robust immune activation decreased both NREM and REM sleep (Mullington et al., 2000).”

What the sources say

• Not checked yetcites Mullington et al., 2000 source

In the paper

“For example, heightened reactivity to negative stimuli may be beneficial when the threat is present, but not when an organism perceives safety.”

In the paper

“Inflammation may only be relevant for some individuals with depression, while also being relevant to specific aspects of depression and not others.”

In the paper

“and the recent findings indicating that inflammation can lead to heightened VS reactivity specifically to social rewards (Inagaki et al., 2015; Muscatell et al., 2016)”

What the sources say

• Not checked yetcites Inagaki et al., 2015 source
• Not checked yetcites Muscatell et al., 2016 source

In the paper

“Genetic factors interact with psychological, environmental, and other biological factors and exert their influences at multiple points throughout the course of disorders.”

What the sources say

• Not checked yetcites Miller and Rockstroh, 2013

In the paper

“For example, early life exposure to immune activation and exposure to chronic stress alter the density and morphology of microglia, particularly in regions of the brain involved in emotion and emotion regulation (Bilbo and Schwarz, 2012; Tynan et al., 2010).”

What the sources say

• Not checked yetcites Bilbo and Schwarz, 2012
• Not checked yetcites Tynan et al., 2010 source

In the paper

“Taken together, these factors provide insight into how some individuals with depression do not exhibit elevated peripheral markers of inflammation while some individuals without depression do.”

In the paper

“Despite the fact that depression is more prevalent among women than men (Kuehner, 2003; Nolen-Hoeksema, 2001, 1987)”

What the sources say

• Not checked yetcites Kuehner, 2003 source
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Nolen-Hoeksema, 2001, 1987

In the paper

“Additionally, among females but not males, endotoxin-induced increases in IL-6 have been associated with increased activation of threat-related neural regions (dACC, anterior insula), which mediate the relationship between IL-6 levels and depressed mood (Eisenberger et al., 2009).”

What the sources say

• Not checked yetcites Eisenberger et al., 2009 source

In the paper

“Based on our review of the causal role of inflammation on core features of depression, we would expect anti-inflammatory treatments to benefit patients presenting with exaggerated reactivity to negative information, altered reward processes, and somatic symptoms but not necessarily those presenting primarily with difficulties in cognitive control.”

In the paper

“Depressed individuals attend selectively to negative information (Gotlib and Joormann, 2010; Joormann and Quinn, 2014)”

What the sources say

• Not checked yetcites Gotlib and Joormann, 2010
• Not checked yetcites Joormann and Quinn, 2014

In the paper

“Much of the work on reactivity to negative information has focused on the impact of endotoxin-induced inflammation on negative reactivity to social threats (social evaluation, social exclusion, images of fearful faces) and sensitivity to social rewards.”

In the paper

“Early exploration of these pathways in preclinical models suggests that males have more microglia in early life and females have more activated or primed microglia during adolescence and adulthood (Schwarz et al., 2012).”

What the sources say

• Not checked yetcites Schwarz et al., 2012 source

In the paper

“The current body of evidence indicates that inflammation is linked, in many cases causally, to alterations in core affective and cognitive processes (e.g., anhedonia; negative reactivity bias) and their neural circuits that are strongly implicated in current models of the etiology and treatment of depression.”