Keywords

1 Introduction

A growing body of evidence suggests that inflammation plays a role in psychiatric illnesses and especially major depressive disorder (MDD) (Howren et al. 2009; Miller et al. 2017). Inflammatory markers, including cytokines, chemokines, and acute phase reactants like C-reactive protein (CRP), are reliably increased in a number of depressed patients with respect to controls (Howren et al. 2009; Maes et al. 1997; Haapakoski et al. 2015). Furthermore, elevated CRP and other peripheral blood markers of inflammation have been found to predict future development of depression (Wium-Andersen et al. 2013; Gimeno et al. 2009; Au et al. 2015). Although not every patient with MDD has increased inflammation, it is thought that elevated levels of inflammation may contribute to the disease process and to specific symptoms in a subgroup of patients within this complex and heterogeneous disease.

Recent data indicate that increasing plasma CRP (as well as cytokines and their soluble receptors) is associated with decreased functional connectivity within corticostriatal reward and motor circuitry and with increased central nervous system (CNS) glutamate in patients with MDD, which correlates with symptoms of anhedonia and motor slowing (Felger et al. 2016; Haroon et al. 2016). These findings in depressed patients with elevated levels of inflammation are strikingly similar to the effects of peripheral administration of inflammatory stimuli on neural activity in reward and motor circuitry, as well as the effects of exogenously administered inflammatory stimuli on CNS neurotransmitters such as glutamate and dopamine (DA) (Felger et al. 2013a; Capuron et al. 2012; Eisenberger et al. 2010; Harrison et al. 2015a; Haroon et al. 2015). Therefore, elevated levels of inflammation in the blood of patients with MDD may reflect increased inflammatory activity in the CNS and its effects on neural systems and neurotransmitters (Felger et al. 2018). Interestingly in this regard, MDD patients with high levels of CRP and other markers of peripheral inflammation have been found to exhibit resistance to conventional antidepressant therapies (Strawbridge et al. 2015; Cattaneo et al. 2013, 2016). This chapter will review the sources of inflammation in depression, its consequences on the brain, and how it has led to trials of novel immune-based therapies and treatments that reverse the effects of inflammation on neurotransmitter systems (Fig. 1).

Fig. 1
figure 1

Mechanisms of inflammation effects on the brain and behavior and targets for intervention in depression. Inflammation is increased in patients with major depressive disorder (MDD) due to environmental exposures, genetics, psychosocial stressors, diet, and other lifestyle factors (i.e., smoking) and medical illnesses. Innate immune cell activation and the release of inflammatory cytokines cause both increased CRP production from the liver and effects on brain neurotransmitters and circuits to drive relevant behavioral changes. Evidence indicates that inflammation and cytokines may preferentially affect dopamine and glutamate systems to disrupt circuits involved in reward and motor activity, as well as those involved anxiety and emotional regulation. In terms of potential novel therapies that may target inflammation or its effects on the brain, there is current interest in treatment strategies that affect the immune system to decrease inflammation (1), drugs that increase dopamine synthesis or synaptic availability or that decrease glutamate signaling (2), and lifestyle changes or alternative therapies that modify the sources of inflammation in MDD patients (3). CRP C-reactive protein, dACC dorsal anterior cingulate cortex, vmPFC ventromedial prefrontal cortex

Full size image

2 Evidence of Increased Inflammation in Depression and Treatment Implications

2.1 Increased Peripheral and Central Inflammation

Numerous studies have reported increased circulating inflammatory cytokines, such as interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF), their soluble receptors, and acute phase reactants, like C-reactive protein (CRP), in patients with MDD (Maes 1999; Maes et al. 1992; Sluzewska 1999). These findings have been corroborated by meta-analyses (Howren et al. 2009; Dowlati et al. 2010). The American Heart Association considers peripheral CRP >3 mg/L, e.g., “high CRP,” to be associated with the greatest risk for development of cardiovascular disease relative to concentrations considered low (<1 mg/L) and moderate (1–3 mg/L) (Ridker 2003). These guidelines for risk of heart disease are consistent with emerging evidence that inflammation serves as a common mechanism of disease affecting multiple bodily systems, including the brain (Couzin-Frankel 2010). Not every MDD patient exhibits high concentrations of inflammatory markers or CRP, yet “high” CRP >3 mg/L is detected in a substantial proportion of patients, 20–50% depending on the sample. Even higher CRP concentrations are observed in patients who are resistant to standard antidepressant therapies (Felger et al. 2016; Haroon et al. 2016; Rapaport et al. 2016; Raison et al. 2013a; Uher et al. 2014). CRP, an acute phase reactant produced by the liver in response to innate immune cytokines, notably IL-6 and TNF, is used in clinical practice as a biomarker of systemic inflammation. Although CRP does play a role in activating the complement system (Rhodes et al. 2011; Devaraj et al. 2009), it is not thought to be a primary driver of inflammation effects on the brain. Rather, cytokines and downstream inflammatory mediators are known to exert effects on neurons and glia, which then drive changes in brain function. Nevertheless, CRP is associated with the activity of other inflammatory molecules, is routinely measured across medical centers and research laboratories (Aziz et al. 2003; Coventry et al. 2009), and is being used in clinical trials in MDD to target anti-cytokine therapies in patients with elevated levels of inflammation (Miller et al. 2017; Raison et al. 2013a).

With such strong evidence for increased inflammatory markers in the periphery of patients with psychiatric illness, there has been growing interest in finding ways to more directly measure the activation of inflammatory processes in the brain. Increased inflammatory cytokine concentrations in the cerebrospinal fluid (CSF) of patients with MDD have been observed (Levine et al. 1999; Schwieler et al. 2015; Garver et al. 2003; Soderlund et al. 2009, 2011). Additionally, increased CSF cytokines have been associated with the severity of depression and with improvement in symptoms in response to successful treatment (Levine et al. 1999; Lindqvist et al. 2009; Martinez et al. 2012). Despite intense efforts to measure inflammation in the brain by neuroimaging, positron emission tomography (PET) for imaging upregulation of the translocator protein (TSPO) on activated microglia and macrophages using ligands such as [11C]PK 11195 (Venneti et al. 2007; Cagnin et al. 2007), [11C]PBR28 (Imaizumi et al. 2007), and [18F]FEPPA (Wilson et al. 2008) in MDD patients has yielded mixed results. For example, in a sample of patients with mild to moderate MDD using [11C]PBR28, no differences were found between patients and controls, though the sample was small and the depression severity was relatively low (Hannestad et al. 2012a). In contrast, the use of [18F]FEPPA in a more severely depressed sample showed significantly increased binding in the striatum, hippocampus, insula, and prefrontal cortex (Setiawan et al. 2015), yet no significant relationship was found between peripheral inflammatory markers and central TSPO binding. These findings are in contrast to studies in nonhuman primates (NHP) and in healthy humans where peripheral inflammatory cytokines were increased in response to a peripheral inflammatory challenge in association with increased [11C]PBR28 (Hannestad et al. 2012a; Sandiego et al. 2015), which was found primarily in microglia (Hannestad et al. 2012a). These data raise questions regarding what specifically TSPO binding is measuring in patients. More studies are likely needed prior to the use of such techniques in clinical trials exploring novel anti-inflammatory therapies.

2.2 Sources of Innate Immune Activation and Inflammation

Depressed patients who are otherwise medically healthy may experience chronic levels of increased innate immune system activation and inflammation due to a variety of environmental exposures including psychosocial stress (and particularly early life stress and trauma), sleep disturbance, inflammatory diet, gastrointestinal permeability, obesity, and other lifestyle factors such as smoking (Berk et al. 2013). History of childhood trauma is often associated with elevated inflammatory biomarkers and higher rates of depression as adults (Danese et al. 2008). Thus a “biological embedding” or imprinting of stress through inflammatory processes in childhood has been described (Danese et al. 2011). MDD patients with a history of early life stress have been shown to respond to psychological stress (the Trier Social Stress Test) with exaggerated circulating IL-6 production and increased DNA binding of nuclear factor (NF)-kB in peripheral blood mononuclear cells compared to non-depressed controls (Pace et al. 2006). In adolescents with a history of childhood adversity, high IL-6 production has been shown to precede subsequent development of depression 6 months later (Miller and Cole 2012), indicating causal relationships between early life stress, increased inflammation, and depression. Regarding mechanisms, recent work has demonstrated that stress can activate the inflammatory response through sterile inflammatory processes using signals called damage-associated molecular patterns (DAMPs), as well as by bacteria and bacterial products such as microbial-associated molecular patterns (MAMPs) leaked from the gut (Wong et al. 2016; Fleshner 2011, 2013). DAMPS refer to molecules produced as a function of cellular stress and accelerated metabolism, such as uric acid, adenosine triphosphate (ATP), glucose, and heat shock proteins (Fleshner 2013; Maslanik et al. 2012). DAMPS and MAMPS can then lead to stimulation of the NLRP3 inflammasome and NF-kB in monocytes, ultimately leading to the production of inflammatory cytokines including IL-1, IL-18, IL-6, and TNF (Maslanik et al. 2012; Iwata et al. 2013).

Additional environmental and lifestyle factors such as sleep disturbance may also contribute to increased inflammation in depression (Opp et al. 2007; Suarez 2008). Disturbed sleep increases circulating IL-6, TNF, and CRP (Meier-Ewert et al. 2004; Vgontzas et al. 2004), and sleep impairments in psychiatric illnesses such as depression have been associated with increased inflammation (Opp et al. 2007; Motivala et al. 2005). Furthermore, inflammatory diets that promote gut permeability and changes in the microbiota, smoking, and increased body mass index (BMI) all contribute to increased inflammation and may interact with genetics and stress to contribute to behavioral symptoms and poor overall health outcomes in patients with psychiatric illness (Berk et al. 2013; Jamal et al. 2014). For example, obesity from consumption of a high-fat diet in rodents induces changes in the gut microbiota and increases ileal inflammation and permeability (de La Serre et al. 2010). Obesity and high BMI are associated with increased concentrations of IL-6 and other inflammatory markers in humans (Khaodhiar et al. 2004; Lim et al. 2005) thought to be the result of macrophage accumulation in adipose tissue, and especially visceral adiposity, which can release cytokines into the portal circulation (Weisberg et al. 2003; Suganami and Ogawa 2010; Park et al. 2005).

2.3 Gene Expression and Genetic Predisposition

Several functional allelic variants and single-nucleotide polymorphisms (SNPs) of genes encoding immune and inflammatory molecules have been associated with depression, including those encoding expression of inflammatory cytokines, major histocompatibility complex proteins, B and T cells, and inflammatory mediators like cyclooxygenase-2 (Bosker et al. 2011; Raison and Miller 2013; Bufalino et al. 2012). These findings have engendered speculation as to whether alleles that promote enhanced inflammatory cytokine secretion were evolutionarily advantageous and thus conserved (Raison and Miller 2013). Indeed, heightened inflammatory responses to environmental stimuli may have improved survival by conferring greater protection from bacterial and viral infection (Raison and Miller 2013). Further, genetic priming to respond to stress and the environment with increased inflammatory and antiviral responses could contribute to the high prevalence of psychiatric disorders comorbid with medical illnesses that are associated with inflammation (e.g., cardiovascular disease, metabolic disorders, and autoimmune disorders) (Yirmiya et al. 1999, 2000; Raison and Miller 2003; Evans et al. 1999; Pollak and Yirmiya 2002; Shelton and Miller 2010). In addition to genetic polymorphisms, increased inflammatory gene expression has been found in circulating immune cells80 as well as in brains of patients with MDD (Shelton et al. 2011).

2.4 Influence of High Inflammation on Antidepressant Treatment Response

Current antidepressant therapies are effective for many patients with MDD. However, up to 30% fail to achieve remission, and even antidepressant responders often exhibit significant residual symptoms consistent with many of those caused by exposure to cytokines and inflammation, such as anhedonia, fatigue, and psychomotor retardation (Targum and Fava 2011; Rush 2007; Dunlop and Nemeroff 2007; Trivedi et al. 2008; Nierenberg 2015). Nonresponsiveness of inflammation-related symptoms to standard antidepressant therapies has been exemplified in cancer patients and in those patients receiving IFN-α therapy treated with SSRIs to alleviate inflammation-related depression and fatigue (Bower et al. 2002; Miller et al. 2008; Ahles et al. 2002). SSRIs alleviated cancer-related or IFN-α-induced anxiety and some depressive symptoms, but not those of fatigue or psychomotor retardation (Capuron et al. 2002a; Raison et al. 2005a; Morrow et al. 2003). A similar lack of response to SSRIs in patients with increased inflammation has also been observed in MDD. For instance, patients with higher levels of CRP (>1 mg/L) have been found to demonstrate worse response to the SSRI escitalopram but to have more favorable responses to the noradrenergic antidepressant nortriptyline (Uher et al. 2014; Jha et al. 2017). Measurement of inflammatory cytokine mRNA expression in peripheral immune cells was even more predictive than CRP of this effect (Cattaneo et al. 2013, 2016). Additionally, MDD patients with high inflammation have been shown to respond better to adjuvant or novel therapies that boost monoamine availability or that target glutamate (Jha et al. 2017; Yang et al. 2015; Shelton et al. 2015). Therefore, it is important to better understand the mechanisms by which inflammation affects the brain in order to develop novel therapies or to appropriately target existing therapies to patients with elevated levels of inflammation.

3 Inflammation Effects on the Brain and Behavior

3.1 Immunologic Mechanisms

Immune Signaling in the Brain

Peripheral inflammation and cytokines may signal the CNS to initiate local immune activation by several mechanisms, including (1) passage of cytokines through leaky regions in the blood-brain barrier at circumventricular organs (Katsuura et al. 1990; Pan and Kastin 2003), (2) active uptake mechanisms of cytokines across the blood-brain barrier (Banks and Erickson 2010; Banks et al. 1995, 2002), and (3) local actions at peripheral vagal nerve afferents that relay inflammatory signals to relevant brain regions, including the nucleus of the solitary tract and hypothalamus (the so-called neural route) (Bluthe et al. 1994; Ericsson et al. 1994; Watkins et al. 1994, 1995). However, recent translational data indicate that during peripheral inflammation, activated monocytes/macrophages traffic to the brain in response to monocyte chemoattractant protein (MCP-1), a chemokine produced by activated microglial cells in response to cytokine signaling from the periphery (D’Mello et al. 2009, 2015). These monocytes/macrophages traffic primarily to perivascular and meningeal spaces and have been shown to contribute to behavioral changes in rodent models of stress-induced depressive and anxiety behaviors (Wohleb et al. 2012, 2014; Hodes et al. 2014). Interestingly, patterns of gene expression in the peripheral blood of patients with psychiatric disorders exhibit increased signatures consistent with pro-inflammatory “M1” activation of monocyte/macrophages (Mostafavi et al. 2014; Brambilla et al. 2014; Drago et al. 2015). Furthermore, recruitment of activated peripheral macrophages to perivascular spaces, as well as localized activation of microglia neighboring these blood vessels and increased expression of MCP-1, has been observed in the dorsal anterior cingulate cortex (dACC) of postmortem tissue from patients with depression (MDD or bipolar disorder) who completed suicide (Steiner et al. 2011; Torres-Platas et al. 2014). These findings indicate that accumulation of peripheral immune cells in vascular compartments in association with restricted and/or regionally specific activation of microglia may be characteristic of patients with depression who exhibit elevated levels of inflammation.

T Cells and Cytokines Promote Cognition and Plasticity

A large body of work has found that CD4 T effector cells that traffic to the brain vasculature have beneficial effects on brain function by promoting tissue repair processes after injury, boosting cognitive function, reducing depressive or anxiety behaviors, and increasing neurogenesis (Derecki et al. 2010; Wolf et al. 2009; Schwartz and Shechter 2010; Lewitus et al. 2008). Relevant to depression and behavior, T cells traffic to the brain to reduce stress-induced anxiety-like behavior and reverse stress-induced decreases in brain-derived neurotrophic factor (BDNF), which is known to stimulate neurogenesis and possess antidepressant effects (Lewitus et al. 2008). T cells may also be required for normal cognitive function considering that T cell-deficient animals exhibit impaired learning and memory in water tests and mazes that can be reversed by the adoptive transfer of T cells (Kipnis et al. 2004; Ziv et al. 2006). T cells trafficking to the brain vasculature and meningeal space can produce IL-4 which stimulates astrocytes to produce growth factors including BDNF while also leading to the skewing of meningeal macrophages from a pro-inflammatory M1 phenotype to an anti-inflammatory, neuroprotective M2 phenotype (Derecki et al. 2010). A rich literature has also described the impact of a cytokines, including TNF and IL-1, on synaptic plasticity and learning and memory (del Rey et al. 2013). For example, mice depleted of the IL-1 type 1 receptor exhibit significant decreases in learning and memory and impaired long-term potentiation (LTP) (Yirmiya and Goshen 2011). Similar to IL-1, deletion of TNF receptors 1 and 2 has been associated with cognitive deficits (Naude et al. 2014), which may be due to their role in strengthening of excitatory synapses and plasticity by induction of surface expression of AMPA receptors (Stellwagen and Malenka 2006; Beattie et al. 2002) and stimulation of synaptic scaling (Stellwagen and Malenka 2006).

3.2 Neurobiological Mechanisms: Inflammation Effects on Circuits

A wealth of clinical and translational work has demonstrated that peripheral inflammation impacts brain regions relevant to both reward and threat sensitivity. PET and fMRI neuroimaging studies in humans have involved either the acute administration of inflammatory stimuli, such as endotoxin or vaccination, or chronic exposure to inflammatory cytokines, such as interferon [IFN]-α, as therapy for cancers and infectious diseases like hepatitis C virus (Capuron et al. 2007, 2012). Inflammation has consistently been found to affect both corticostriatal reward and motor circuits to drive reduced motivation and motor activity, as well as anxiety-related brain regions including the amygdala, insula, and ACC, which may result from cytokine effects on monoamines and glutamate (Fig. 1). Recent work has aimed to translate these findings to the investigation of relationships between increased inflammation and altered neurocircuits in patients with MDD.

Reward and Motor Circuits

Findings from numerous laboratories have consistently indicated that innate immune activation and the release of inflammatory cytokines preferentially affect reward and motor circuits and DA in the basal ganglia to contribute to reduced motivation and motor slowing (Capuron et al. 2007, 2012; Eisenberger et al. 2010; Harrison et al. 2015a; Felger and Miller 2012; Brydon et al. 2008; Majer et al. 2008; Goldsmith et al. 2016). Much of this work has stemmed from patients administered with IFN-α, up to 50% of whom met symptom criteria for major depression (depending on the dosing) and up to 80% of whom experienced significant fatigue, lack of energy, and motor slowing during treatment (Capuron et al. 2002a, b, 2003; Donnelly 1998; Musselman et al. 2001; Raison et al. 2005b, 2009, 2010a). Reduced motivation and anhedonia were also frequently reported in IFN-α-treated patients (Capuron et al. 2002a, 2012; Majer et al. 2008). Indeed, the Snaith-Hamilton Pleasure Scale (SHAPS) and the Reduced Motivation subscale of the Multidimensional Fatigue Inventory (MFI) yielded comparable effect sizes (all r = 0.47–0.49) for increases in self-reported depression or fatigue scores after chronic IFN-α treatment (Capuron et al. 2012; Majer et al. 2008). In IFN-α-treated patients, whole-brain analysis of fluorine-18-labeled fluorodeoxyglucose (FDG) PET found that, in addition to decreased metabolism in PFC, increased glucose metabolism was found in the basal ganglia and particularly the DA-rich putamen (Capuron et al. 2007; Juengling et al. 2000). Increased glucose metabolism in the left putamen and left nucleus accumbens (NAcc) correlated with fatigue in these patients, as assessed by the “energy” subscale of the Visual Analog Scale of Fatigue (VAS-F) (Capuron et al. 2007). This pattern of increased glucose metabolism in the basal ganglia is similar to that seen in Parkinson’s disease (PD) (Spetsieris et al. 1995; Eidelberg et al. 1994; Mentis et al. 2002), where it is thought to reflect increased oscillatory burst activity in relevant nuclei secondary to loss of inhibitory nigral DA input (Wichmann and DeLong 1999, 2003). Interestingly, this pattern of increased metabolism in the striatum is also similar to the effects of transient catecholamine depletion in patients with MDD, which correlated with anhedonic symptoms (Hasler et al. 2008). Functional magnetic resonance imaging (fMRI) has also demonstrated decreased neural activation in the basal ganglia, including ventral striatum, with unexpected delivery of reward (winning in a gambling task) (Reuter et al. 2005) in patients undergoing IFN-α administration, which correlated with reduced motivation (Capuron et al. 2012). Acute administration of IFN-α has also been shown to induce a change in striatal microstructure, as measured by quantitative magnetization transfer (qMT) imaging that predicted development of fatigue symptoms during treatment (Dowell et al. 2016).

Administration of the cytokine inducers endotoxin and typhoid vaccination to healthy volunteers produces similar effects on the ventral striatum in response to rewarding stimuli, suggesting that findings from IFN-α generalize to other inflammatory stimuli (Eisenberger et al. 2010; Harrison et al. 2015a). Indeed, endotoxin administration led to reduced activation of the ventral striatum to reward-predicting cues during a monetary incentive delay task (MIDT), which was associated with increases in self-reported depressed mood as measured by the Profile of Mood States (POMS) depression subscale (Eisenberger et al. 2010). Similar blunting of neural responses to reward anticipation has been observed following dietary depletion of precursors for DA synthesis (Bjork et al. 2014). Moreover, typhoid vaccination was found to cause a shift in reward versus punishment sensitivity in a probabilistic instrumental learning task combined with fMRI (Harrison et al. 2015a). Compared to saline control, typhoid vaccination reduced the behavioral attractiveness of rewards while making punishments more aversive, effects that were related to decreased neural activation of the ventral striatum to reward prediction errors and increased activation of the anterior insula to punishment prediction errors (Harrison et al. 2015a). Of relevance to the potential effects of inflammation on DA, the magnitude of response to prediction error signaling is fundamentally modulated by DA-dependent striatal activity as determined by the administration of drugs that enhance (l-DOPA) or inhibit (haloperidol) DAergic function (Pessiglione et al. 2006). Additionally, typhoid vaccination compared with saline has been shown to affect activity in the substantia nigra, including increased activation during a cognitive Stroop task and decreased activation in response to visual or novel stimuli, which correlated with both psychomotor slowing and increased peripheral blood concentrations of IL-6 (Brydon et al. 2008; Harrison et al. 2015b).

In medically stable patients with MDD, a relationship was observed between increased inflammation and decreased functional connectivity within reward-related corticostriatal neurocircuitry (Felger et al. 2016). Indeed, increased inflammation (plasma concentrations of CRP as well as cytokines and their soluble receptors) was associated with decreased functional connectivity between the ventral striatum and vmPFC and decreased connectivity between the dorsal striatum and the vmPFC and pre-supplementary motor area (pre-SMA), which correlated with self-reported symptoms of anhedonia and objective measures of psychomotor slowing, respectively (Felger et al. 2016). Interestingly, dorsal striatum and pre-SMA/SMA are key components of corticostriatal circuitry involved in linking motivation to motor output (Haber and Knutson 2010; Samanez-Larkin and Knutson 2015). Like the ventral striatum, vmPFC is part of the classic reward circuitry that receives significant mesocorticolimbic DA innervation (Russo and Nestler 2013; Diekhof et al. 2012).

Fear and Anxiety Circuits

A number of studies have examined the effects of inflammation on the activation of brain regions that contribute to fear, anxiety, and emotional processing, such as the amygdala, insula, or dorsal anterior cingulate cortex (dACC). In addition, other studies have examined changes in the function of circuitry involving these regions. Inflammation has been shown to not only increase amygdala activity but to also increase amygdala responsiveness to stress that drives increased production of inflammatory cytokines (Harrison et al. 2009a; Inagaki et al. 2012; Muscatell et al. 2015). Increased IL-6 and TNF after administration of endotoxin to healthy subjects has been shown to increase amygdala activity in response to socially threatening images, which was associated with enhanced feelings of social disconnection (Inagaki et al. 2012). Administration of typhoid vaccination, which increases IL-6 and induces behavioral changes including cognitive disturbances and fatigue, also increased activation of the amygdala during presentation of congruent and incongruent stimuli (Harrison et al. 2009b). In terms of stress sensitivity and neural pathways involved in the inflammatory response to stress, heightened neural activity in the amygdala in response to a psychosocial laboratory stressor was associated with greater stress-induced increases in IL-6 (Muscatell et al. 2015).

Several studies have also reported relationships between peripheral inflammatory cytokines and activity of medial prefrontal cortical regions, including the subgenual ACC, either in individuals undergoing stress or following administration of cytokine inducers (Harrison et al. 2009a; O’Connor et al. 2009c). Indeed, administration of typhoid vaccination to healthy controls induced mood changes that correlated with enhanced activity within the subgenual ACC during an implicit emotional face perception task. Typhoid vaccination also reduced task-related functional connectivity of the subgenual ACC to the amygdala and other medial prefrontal cortical regions, as well as the NAcc and superior temporal sulcus, which correlated with peripheral blood IL-6 (Harrison et al. 2009a). As mentioned above, heightened neural activity in the amygdala was associated with increased IL-6 responses to a psychosocial laboratory stressor. Functional connectivity analyses also indicated that individuals who showed a heightened inflammatory response to the stressor exhibited stronger coupling between the amygdala and the dorsomedial prefrontal cortex (Muscatell et al. 2015). In addition to activation of the amygdala, administration of typhoid vaccination increased activation of the insula during presentation of congruent and incongruent stimuli (Harrison et al. 2009b). Among females but not males administered endotoxin, increases in IL-6 were associated with increases in neural activity in brain regions including the anterior insula in response to social exclusion during a virtual ball-tossing game (Eisenberger et al. 2009). Endotoxin administration has also been shown to increase cerebral glucose metabolism in the insula as measured by PET (Hannestad et al. 2012b). Therefore, heightened sensitivity of the insula to inflammatory cytokines in the periphery, particularly in the presence of emotional stimuli, may contribute to altered neural circuitry involving the amygdala, medial prefrontal cortex, and ACC to precipitate symptoms of anxiety and emotional disturbance that contribute to MDD.

3.3 Neurobiological Mechanisms: Inflammation Effects on Neurotransmitters

Inflammation Effects on Monoamine Metabolism and Neurotransmission

Although most recent studies examining the effect of cytokines or inflammatory stimuli on monoamine release, tissue content, or turnover in animal studies have focused on DA, some studies have observed changes in the other monoamines, especially serotonin (5-HT). Acutely, monoamines are released in the hypothalamus and other limbic structures to mediate fever and early behavioral changes associated with sickness behavior (Dunn et al. 2005; O’Connor et al. 2009a). Administration of inflammatory cytokines also increase early 5-HT turnover in the cortex and NAcc (Song et al. 1999; De La Garza and Asnis 2003) in association with later, more persistent depressive-like behaviors (O’Connor et al. 2009a; Frenois et al. 2007). Additionally, both chronic administration of cytokines and chronic low-grade inflammation in humans have been shown to increase indoleamine-2,3-dioxygenase (IDO) activity and the metabolisms of tryptophan, the primary amino acid precursor of serotonin, to kynurenine (KYN) in the periphery (Capuron et al. 2003, 2011; Raison et al. 2010b). In patients treated with IFN-α for hepatitis C virus, CSF concentrations of IL-6 negatively correlated with 5-hydroxyindoleacetic acid (5-HIAA) concentrations, which in turn negatively correlated with IFN-α-induced depression severity (Raison et al. 2009). However, in a separate study, increased CSF KYN and QUIN concentrations were observed to correlate with depressive symptoms and with CSF cytokines, yet tryptophan concentrations were not decreased in the CSF despite decreased blood tryptophan concentrations (Raison et al. 2010b). These findings are consistent with recent work in rodents indicating that KYN administration alone was sufficient to induce depressive-like behavior and pharmacological inhibition of IDO with 1-methyl-tryptophan prevented lipopolysaccharide (LPS/endotoxin)-induced depressive-like behavior but did not prevent changes in 5-HT turnover (O’Connor et al. 2009a, b; Salazar et al. 2012). These findings suggest that neuroactive KYN metabolite effects on glutamate signaling are likely responsible for the behavioral changes associated with cytokine-induced IDO activity.

With regard to DA, some studies reported increases (Kumai et al. 2000; Sato et al. 2006), while others have reported decreases (Kamata et al. 2000; Kitagami et al. 2003; Shuto et al. 1997) in brain DA and/or metabolites following acute or sub-chronic IFN-α administration, which has been reviewed elsewhere (Felger and Miller 2012; Felger and Treadway 2017). These discrepancies were likely due to differences in dosing, length of exposure, and, most importantly, the fact that species-specific IFN-α was variably used and rodents do not respond to human IFN-α with activation of classic type I IFN receptor signaling (Loftis et al. 2006a, b; Wang et al. 2008). However, in monkeys chronically administered IFN-α, which causes similar behavioral responses as in humans, stimulated DA release was decreased in the striatum and correlated with reduced effort-based sucrose consumption (Felger et al. 2013a). Furthermore, IFN-α-induced decreases in striatal DA release were reversed by the DA precursor levodopa (l-DOPA) administered via reverse in vivo microdialysis (Felger et al. 2015). These findings were consistent with results from PET imaging with [F18]Fluorodopa in IFN-α-treated patients indicating that cytokines reduce DA synthesis and availability (Felger et al. 2015).

Indeed, inflammation and cytokines may decrease DA (and 5-HT) availability and release by decreasing tetrahydrobiopterin (BH4), an inflammation and oxidative stress-sensitive enzyme cofactor required for conversion of phenylalanine (Phe) to tyrosine (Tyr) by Phe hydroxylase and Tyr to l-DOPA by Tyr hydroxylase (as well as tryptophan to 5-HT) (Neurauter et al. 2008; Cunnington and Channon 2010). We and others have examined biomarkers of the DA synthetic pathway in IFN-α-treated patients, including the plasma Phe/Tyr ratio, which goes up when BH4 is low. We observed increased plasma Phe/Tyr and evidence of reduced cerebrospinal fluid (CSF) BH4 activity in IFN-α-treated patients (Kitagami et al. 2003; Felger et al. 2013b; Zoller et al. 2012), which correlated with decreased CSF DA and its major metabolite homovanillic acid (HVA) and with IFN-α-induced depressive symptoms (Felger et al. 2013b). Similarly, intramuscular injection of rats with IFN-α has been shown to decrease CNS concentrations of BH4 through inflammation-related stimulation of nitric oxide, whereas inhibition of nitric oxide synthase (which usurps BH4 during inflammation) was found to reverse IFN-α’s inhibitory effects on brain concentrations of both BH4 and DA (Kitagami et al. 2003). Moreover, in a study of healthy elderly persons with low-grade inflammation, peripheral blood concentrations of Phe and Tyr and an increased Phe/Tyr ratio were associated with neuropsychiatric symptoms including anhedonia and altered sleep (Capuron et al. 2011).

Finally, attention has been paid to the effects of cytokines and inflammatory signaling pathways on monoamine reuptake mechanisms and particularly the 5-HT transporter (Moron et al. 2003; Zhu et al. 2005, 2006, 2010). Both in vitro and in vivo data have established that stimulation of p38 mitogen-activated protein kinase (MAPK), a primary signaling pathway activated by IFN-α and other cytokines, can increase the expression and function of the serotonin transporter, leading to increased serotonin reuptake (Zhu et al. 2005, 2006, 2010). MAPK pathways have also been found to influence DAT. For example, DAT-expressing cells transfected with constitutively activate MAPK kinase (MEK) show increased DA reuptake (Vmax), whereas treatment of rat striatal synaptosomes with MEK inhibitors decreased DA reuptake in a concentration- and time-dependent manner (Moron et al. 2003). Therefore, reduced synaptic monoamines following chronic exposure to inflammatory cytokines may be mediated, in part, by increased transporter expression or function.

Inflammation Effects on Glutamate

Another mechanism by which cytokines may influence behavior is through stimulation of IDO and downstream KYN pathway metabolites on glutamate neurotransmission in the brain (Dantzer and Walker 2014; Dantzer et al. 2011). Immune-mediated activation of IDO catabolizes tryptophan, the primary amino acid precursor of serotonin, to KYN. KYN is further catabolized into the neuroactive metabolites kynurenic acid (KA) (in astrocytes) and quinolinic acid (QUIN) (in microglia), both of which have been found to be increased in the plasma and CSF of IFN-α-treated patients (Capuron et al. 2003; Raison et al. 2010b; Schwarcz and Pellicciari 2002; Bonaccorso et al. 2002). Of note, CSF QUIN significantly correlated with depressive symptoms during IFN-α administration, as measured by MADRS (Raison et al. 2010b). In addition to increasing oxidative stress (Santamaria et al. 2003; Behan et al. 1999), the neurotoxic metabolite QUIN can also directly activate the n-methyl-d-aspartate (NMDA) receptor to further induce the release of glutamate to lead to excitotoxicity in the brain (Schwarcz and Pellicciari 2002; Tavares et al. 2005). In contrast to QUIN, KA reduces glutamate release and has been shown to be an antagonist of NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (Stone 2000). DA release is in part under glutamatergic control, and thereby KA may exert downstream effects that further decrease DA to contribute to inflammation-induced depressive behavior (Schwarcz and Pellicciari 2002). Indeed, intrastriatal administration of KA to rodents leads to marked reductions in extracellular DA concentrations, as determined by in vivo microdialysis (Wu et al. 2007).

Finally, cytokines and inflammation have been shown to increase glutamate by effects on microglia and astrocytes (Haroon et al. 2017). A rich literature has shown that cytokines can decrease the astrocytic expression of glutamate transporters and increase release of glutamate from astrocytes and activated microglia in vitro (Dantzer and Walker 2014; Tilleux and Hermans 2007; Ida et al. 2008; Takaki et al. 2012). Of note, glutamate released from glia may have preferential access to extrasynaptic NMDA receptors, which lead to decreased production of trophic factors including brain-derived neurotrophic factor (BDNF) (Hardingham et al. 2002; Haydon and Carmignoto 2006). Increased glutamate, as measured by magnetic resonance spectroscopy (MRS), has been observed in patients chronically administered INF-α, which correlated with symptoms of reduced motivation and psychomotor slowing (Haroon et al. 2014, 2015). Likewise, increased glutamate was also observed in MDD patients with increased inflammation that correlated with anhedonia and psychomotor slowing (Haroon et al. 2016).

4 Potential Treatment Targets for Depressed Patients with Increased Inflammation

As described above, the neurobiological effects of inflammation on the brain, particularly via decreased monoamine synthesis and availability or increased reuptake, may circumvent or interfere with standard antidepressant therapies such as SSRIs. Therefore, there is a need to consider new therapies or a combination of treatments that reduce inflammation or that target its sources or consequences on the brain (Fig. 1). Indeed, the preferential effects of inflammation on DA and glutamate in reward and motor circuits and related behaviors indicate that patients with increased inflammation may respond better to DA- and glutamate-relevant therapies (Fig. 1). Reviewed below is current information regarding the clinical and/or translational use of relevant pharmacological strategies to reduce inflammation or its effects on the brain, as well as results from trials in MDD, if available (Table 1). Many potential new therapies exist, and results to date are encouraging; however additional studies using better trial design (i.e., targeting of therapies to patients with high inflammation) are warranted.

Table 1 Pharmacologic targets for blocking inflammation or reversing its effects on the brain and results of trials in MDD that considered antidepressant response in association with increased inflammation
Full size table

4.1 Therapies That Affect the Immune System

Anti-inflammatories

A number of recent studies have begun to test the potential of anti-inflammatory compounds as possible antidepressant therapies (Target 1, Fig. 1). Most studies to date have focused on compounds such as cyclooxygenase (COX)-2 inhibitors that block the production of prostaglandins, which are the primary downstream mediators of the inflammatory response that are increased in the peripheral blood of patients with depression (Lieb et al. 1983). Recent meta-analyses have reported modest effect sizes indicating a benefit of COX-2 inhibitors in reducing symptom severity. However, there was high heterogeneity across studies and mostly small sample sizes (Na et al. 2014; Kohler et al. 2014; Faridhosseini et al. 2014). Of the included studies, only a handful assessed the efficacy of nonsteroidal anti-inflammatories (NSAIDs) compared to placebo, whereas the majority used celecoxib or acetylsalicylic acid (aspirin) as adjuvants to conventional antidepressant therapies. Moreover, these studies did not select patients based on increased inflammation, and only a few measured peripheral inflammatory markers to establish the anti-inflammatory activity of the treatments. It should also be noted that these NSAID therapies convey relatively mild anti-inflammatory activity and numerous “off-target” effects that may confound data interpretation (Miller et al. 2017; Miller and Raison 2015).

More specific therapies inhibiting cytokine activity that are used to treat inflammatory illnesses have shown efficacy for reducing depressive symptoms in medically ill patients or in medically stable persons with MDD (Miller et al. 2017; Kohler et al. 2014). For example, a recent study tested the efficacy of infliximab, a highly selective TNF antagonist, in treatment-resistant patients with MDD as a function of peripheral inflammation. Treatment with infliximab was associated with robust decreases in plasma CRP concentrations, as well as a strong antidepressant effect, but only in patients with elevated CRP at baseline (Raison et al. 2013a). Moreover, the greatest area of symptom improvement was related to motivation (Raison et al. 2013a), which is consistent with the hypothesis that inflammation affects corticostriatal reward circuits as described elsewhere in this chapter. An ongoing clinical trial is examining the efficacy of infliximab in patients with bipolar depression and a CRP >5 mg/L (NCT02363738), and a Phase II trial of an anti-IL-6 mAb (sirukumab) is being run in patients with depression and a CRP >3 mg/L (NCT02473289).

Lastly, strategies aim to stimulate the production of IL-4-producing T cells, which has been accomplished in animal studies by administration of organisms such as helminths or cell therapies such as mesenchymal stem cells (MSCs), both of which have been shown to promote tolerant and anti-inflammatory responses. Helminths have been shown to stimulate IL-4 and regulatory “M2” macrophages in the gut via effects on the microbiome in a mouse model of inflammatory bowel disease (Ramanan et al. 2016). In an emerging field of immunomodulatory treatments involving stem cell therapies, MSCs have been shown to promote the development and differentiation of regulatory T cells and production of immunomodulatory and anti-inflammatory molecules such as TGF-beta, IL-10, and IL-1ra (Shi et al. 2011; Francois et al. 2012). Ongoing trials are testing the efficacy of MSC therapy in inflammatory and autoimmune disorders, and one study is examining the impact of a single infusion of allogeneic human MSCs for patients with treatment-resistant depression and increased inflammation (CRP >3 mg/L) (NCT02675556).

4.2 Compounds That Improve DA Synthesis, Availability, or Signaling

Considering the strong evidence presented above indicating that inflammation can inhibit key components of DA synthesis and availability, pharmacologic strategies that increase DA availability or signaling may effectively treat MDD in patients with high inflammation (Target 2, Fig. 1). Relevant pharmacologic agents include DA agonists, stimulants, bupropion, adenosine A2A receptor antagonists, and drugs that support DA synthesis through stimulation of BH4 activity. Such therapies that increase BH4 include saproterin and folic acid, l-methylfolate, and S-adenosylmethionine (SAMe) (Table 1), many of which help convert inactive BH2 to BH4. Of relevance to low BH4 activity in MDD, low serum folate has been associated with increased risk of depression as well as nonresponse to antidepressant treatment and an increased likelihood of depression relapse (Papakostas et al. 2004). Clinical trials have been conducted using l-methylfolate (marketed as Deplin and Zervalx) and SAMe in depression with mixed results (Papakostas et al. 2012; Sarris et al. 2015). Interestingly, however, a post hoc analysis of two parallel-sequential adjuvant trials of l-methylfolate in patients with MDD (Papakostas et al. 2012) was conducted while considering the influence of inflammatory markers. It was found that BMI >30 as well as increased concentrations of TNF, IL-8, CRP, and leptin over the median, alone or in combination with each other or with IL-6, predicted greater symptom improvement (Shelton et al. 2015). Stratified analyses based on inflammatory biomarkers have not been conducted with SAMe, yet these findings with l-methylfolate support the value of targeting such therapies to MDD patients with high inflammation. Furthermore, whether strategies that augment BH4 restore DA function or improve inflammation-related symptoms of reduced motivation or motor slowing remain to be determined. Replacement of DA with the precursor l-DOPA is known to improve motor function and has also been shown to increase motivation in patients with PD (Czernecki et al. 2002). An ongoing trial will determine whether l-DOPA administration has an antidepressant effect in aged persons with motor slowing (NCT02744391).

Although classical stimulant medications that increase DA release and/or block DA reuptake increase motivation in rodent models (Yohn et al. 2015; Randall et al. 2015), they have demonstrated only limited efficacy in chronically treating fatigue and other DA-related symptoms in trials for patients with cancer and other medical illnesses that are associated with inflammation (Mar Fan et al. 2008; Moraska et al. 2010; Butler et al. 2007; Sugawara et al. 2002; Pucci et al. 2007; Stankoff et al. 2005; Bruera et al. 2013; Ruddy et al. 2014; Escalante et al. 2014; Gong et al. 2014). Since stimulants act to increase DA release and block DAT function to increase synaptic levels of available DA, these drugs may not provide long-term efficacy in the context of inflammation during medical illness. However, new evidence indicates that in MDD patients with high inflammation (as measured by CRP) exhibit a greater antidepressant response to SSRIs used in combination with the DAT blocker bupropion compared to SSRI monotherapy (Jha et al. 2017). Although no data exists in humans, adenosine A2A receptor antagonists (which facilitate DA receptor signaling) reverse the effects of IL-1beta on effort-based sucrose preference (Nunes et al. 2014). Furthermore, DA agonists, such as pramipexole, have demonstrated efficacy in patients with treatment-resistant depression (Cassano et al. 2004; Cusin et al. 2013; Franco-Chaves et al. 2013). Although it is unknown whether this effect is specific to high inflammation in MDD patients, it has been shown to block endotoxin-induced degeneration of nigrostriatal DA cells in rodents (Iravani et al. 2008).

4.3 Therapies That Target Glutamate

Inhibition of glutamate signaling may be an important target in reversing the impact of inflammation in the brain (Target 2, Fig. 1). With regard to preventing activation of the KYN pathway, the IDO antagonist, 1-methyl-tryptophan (1-MT), has been shown to abrogate the impact of LPS, as well as an attenuated form of Mycobacterium bovis, on depressive-like behavior (O’Connor et al. 2009a, b). Given that inflammation can cause neurotoxic effects via increased QUIN and excessive glutamate (Schwarcz and Pellicciari 2002; Tavares et al. 2002, 2005), glutamate receptor antagonists may be useful in preventing excitotoxicity and oxidative stress and may reverse or prevent inflammation-related behavioral change. Indeed, one study in rodents demonstrated that the NMDA antagonist ketamine was able to reverse LPS-induced depressive-like behavior including sucrose preference, a measure of anhedonia (Walker et al. 2013). Ketamine had no effect on LPS-induced inflammation in the brain or CNS activation of IDO or decreases in BDNF expression. Moreover, blockade of AMPA receptors was able to reverse ketamine’s effects on LPS-induced depressive-like behavior, indicating that the effects of ketamine were specific to its impact on glutamate signaling. In humans, administration of the NMDA antagonist ketamine has potent antidepressant effects in MDD patients who are resistant to standard therapies and who often exhibit increased inflammation (aan het Rot et al. 2010; Price et al. 2009; Raison et al. 2013b). Interestingly, a recent study in treatment-resistant depression found that patients who were most responsive to ketamine were those with the highest concentrations of serum IL-6 (Yang et al. 2015). However, another study found that although treatment-resistant depressed patients exhibited increased IL-6 compared to controls, IL-6 and other inflammatory cytokines were not associated with treatment response to ketamine (Kiraly et al. 2017). There are also drugs available or in development that influence glutamate reuptake (e.g., riluzole); however there have been no studies examining their ability to reverse the effects of inflammation in patients with MDD. In sum, future therapies that block KYN pathways or modulate glutamate may confer protection against inflammation and/or IDO-mediated behavioral symptoms in patients with MDD.

4.4 Diet, Supplements, and Alternative Strategies

In terms of modifying the environmental exposures and lifestyle factors that contribute to inflammation in depression (Target 3, Fig. 1), studies have investigated the efficacy of exercise, weight reduction, certain diets, as well as supplements such as omega-3 fatty acids, yoga, massage, tai chi, cognitive behavioral therapy, and meditation to reduce psychiatric symptoms such as depression and anxiety. Many of these interventions have been shown to induce a variety of immune changes including a reduction in inflammation (Bower and Irwin 2016). For example, mindfulness meditation has been shown to increase functional connectivity between the posterior cingulate cortex and the left dorsolateral prefrontal cortex, which in turn was associated with decreases in IL-6 over a 4-month period (Creswell et al. 2016). In addition, both cognitive behavioral therapy and tai chi were associated with reduced levels of CRP, monocyte production of inflammatory cytokines, and inflammatory gene expression in elderly patients with insomnia (Irwin et al. 2015). Both diet and exercise programs have been shown to have antidepressant and antianxiety effects (Schuch et al. 2016; Fabricatore et al. 2011) and to reduce a variety of inflammatory markers in longitudinal studies (Forsythe et al. 2008; Woods et al. 2009). A hatha yoga program was also shown to reduce LPS-induced peripheral blood mononuclear cell production of TNF, IL-6, and IL-1beta as well as fatigue at 3 months in breast cancer survivors (Kiecolt-Glaser et al. 2014). These studies have, however, failed to determine whether changes in inflammation or immune function are required for the efficacy of these interventions (Miller et al. 2017).

The impact of the vast array of dietary supplements including curcumin, resveratrol, and ginger supplementation on the immune system and inflammation has been studied, yet the most common supplements studied in MDD patients involve omega-3 fatty acids. Meta-analyses have shown significant antidepressant efficacy especially for eicosapentaenoic acid (EPA) (Mocking et al. 2016). A recent study demonstrated that patients with a compilation of inflammatory markers including increased CRP and IL-1ra had a greater antidepressant response to EPA, whereas individuals with increased CRP and IL-6 were less responsive to placebo (Rapaport et al. 2016). Although there is some in vitro and in vivo data supporting anti-inflammatory effects of omega-3 fatty acids in humans (Rangel-Huerta et al. 2012), data linking these effects to their impact on behavior including depression is warranted. Therefore, an ongoing trial is currently investigating links between the antidepressant effects of omega-3 fatty acids and anti-inflammatory responses (NCT02553915). Antioxidant supplements such as N-acetyl-d-cysteine have also been included in meta-analyses of the antidepressant efficacy of anti-inflammatory drugs (Rosenblat et al. 2016), even though ability to specifically modulate inflammation has yet to be determined.

5 Summary and Conclusions

This chapter has presented evidence that inflammation is increased in a subset of patients with MDD and that it may play a role in depressive symptoms and influence response to antidepressants in these patients. In addition to observations regarding lack of response to conventional antidepressants in patients with increased peripheral blood markers of inflammation, such as CRP, a vast literature has described the effects that inflammation and cytokines have on neurotransmitters and circuits in the brain. These findings stem largely from over a decade of clinical and translational neuroimaging studies examining the effects of the acute and chronic administration of inflammatory stimuli on the brain. Results have indicated that inflammation affects brain regions relevant to reward, motor activity, and threat sensitivity to lead to symptoms of reduced motivation, motor slowing, and anxiety and these changes are largely driven by effects on monoamines, like DA, and glutamate. These findings are now being translated to better understand the role of inflammation in behavioral symptoms in patients with psychiatric illness and especially MDD.

The current data indicate that novel strategies to block inflammation or reverse its effects on the brain are promising, yet incomplete, and much additional work is needed in the area to move treatment development forward. More informed trials using drugs with known targets and selecting patients based on peripheral inflammation levels using markers such as CRP will contribute to progress in this regard. Another challenge in this area is the ability to image the effects of such treatments on the brain. Although attempts have been made to image local activation of CNS immune cells in these patients, evidence described herein of the functional and neurotransmitter effects of increased inflammation on the brain as measured by fMRI, PET, and MRS have most consistently been associated with increased peripheral inflammatory markers as well as behavior and may be best suited for use in future treatment trials. Coupling measures of target engagement in the brain – for both pharmacological and behavioral intervention studies – with outcome variables based on behaviors that are known to be impacted by inflammation (e.g., motivation, motor activity, or anxiety), will significantly strengthen the interpretation of future results. A number of trials that embrace at least some of these features are under way and may reveal additional information regarding novel therapies for patients with a wide variety of psychiatric disorders and evidence of increased inflammation.