Brain Kynurenine and BH4 Pathways: Relevance to the Pathophysiology and Treatment of Inflammation-Driven Depressive Symptoms

Abstract

The prevalence of depressive disorders is growing worldwide, notably due to stagnation in the development of drugs with greater antidepressant efficacy, the continuous large proportion of patients who do not respond to conventional antidepressants, and the increasing rate of chronic medical conditions associated with an increased vulnerability to depressive comorbidities. Accordingly, better knowledge on the pathophysiology of depression and mechanisms underlying depressive comorbidities in chronic medical conditions appears urgently needed, in order to help in the development of targeted therapeutic strategies. In this review, we present evidence pointing to inflammatory processes as key players in the pathophysiology and treatment of depressive symptoms. In particular, we report preclinical and clinical findings showing that inflammation-driven alterations in specific metabolic pathways, namely kynurenine and tetrahydrobiopterin (BH4) pathways, leads to substantial alterations in the metabolism of serotonin, glutamate and dopamine that are likely to contribute to the development of key depressive symptom dimensions. Accordingly, anti-inflammatory interventions targeting kynurenine and BH4 pathways may be effective as novel treatment or as adjuvants of conventional medications rather directed to monoamines, notably when depressive symptomatology and inflammation are comorbid in treated patients. This notion is discussed in the light of recent findings illustrating the tight interactions between known antidepressant drugs and inflammatory processes, as well as their therapeutic implications. Altogether, this review provides valuable findings for moving toward more adapted and personalized therapeutic strategies to treat inflammation-related depressive symptoms.

Introduction

Depression currently represents a global public health concern. Not only its prevalence is steadily increasing worldwide but also it relates to a stronger risk of morbidity and death (World Health Organization, 2017). In addition, despite advances made in the treatment of depression, at least one third of depressed patients fail to respond to conventional medications (Rush et al., 2006). Further contributing to the global burden of depression, most of the chronic diseases whose prevalence is also continuously rising, including metabolic, autoimmune and cardiovascular diseases, are associated with an increased risk of depression (Luppino et al., 2010; Capuron et al., 2017; Zuzarte et al., 2018). The latter impairs the quality of life of affected patients and emerges as a potent contributor of subsequent medical complications (Penninx et al., 2013). Thus, a better knowledge of the pathophysiological bases of depression and identification of new targets relevant for therapeutic advances are still clearly needed.

While different neurobiological systems are likely involved in the pathophysiology of depression, this review will summarize evidence that supports a main role for inflammatory processes. First dedicated to decipher the intricate relationship between the innate immune system and the brain, initial research performed in the field of psychoneuroimmunology started to identify the molecular mechanisms underlying the behavioral and neuropsychiatric consequences of inflammation (for review Dantzer et al., 2008; Capuron and Miller, 2011). Meanwhile, converging clinical studies reported a link between increased circulating levels of inflammatory factors and greater risk of developing mood alterations (Capuron et al., 2002; Evans et al., 2005). Altogether, these findings have fostered still on-going investigations aiming to further identify the neurobiological pathways targeted by cytokines and in turn mediating their neuropsychiatric effects. Moreover, in line with recent data suggesting that elevated basal inflammation, as reported in obesity and metabolic syndrome, may contribute to impair the therapeutic efficiency of conventional antidepressant treatment (Kloiber et al., 2007; Toups et al., 2013), a corollary question arises as to whether inflammatory factors, their signaling pathways and/or neurobiological targets, may represent potential targets for new pharmacological interventions. This review will discuss those issues in the light of recent findings providing a deeper mechanistic understanding of the role of inflammation in the pathophysiology of depression and relevant insights for novel therapies.

The Inflammatory Hypothesis of Depression

Although progressively extended to several mental illnesses, including bipolar disorders, anxiety disorders or schizophrenia (Potvin et al., 2008; Hoge et al., 2009; Barbosa et al., 2013), the notion that inflammation may be involved in the pathophysiology of neuropsychiatric symptoms was particularly studied in the context of depression (Raison et al., 2006; Capuron and Miller, 2011). The first studies strongly supporting this notion report higher circulating levels of inflammatory mediators, including C-reactive protein (CRP), cytokines (particularly interleukin-6, IL-6) and different chemokines, in depressed individuals compared to healthy controls (Dowlati et al., 2010; Leighton et al., 2018). Moreover, longitudinal investigations reveal that higher inflammatory profiles predict the development of depressive symptoms (Valkanova et al., 2013; Smith et al., 2018). To move from correlation to causality, chronic cytokine administration has been shown to induce depression in up to 50% of medically ill patients undergoing cytokine immunotherapy (Musselman et al., 2001; Capuron et al., 2002; Kawase et al., 2016). Similarly, direct administration of cytokines, or cytokine inducers, such as lipopolysaccharide (LPS), to healthy volunteers triggers depressive symptoms (Schedlowski et al., 2014; Engler et al., 2017). Consistent with clinical findings, both acute or chronic immune challenges in rodents induce sustained depressive-like and anxiety-like behaviors (Merali et al., 2003; Frenois et al., 2007; Moreau et al., 2008; Klaus et al., 2016). Conversely, anti-inflammatory compounds reduce these behaviors in animal models of inflammatory diseases (Llorens-Martin et al., 2014; Zaminelli et al., 2014; Norden et al., 2015). Likewise, directly targeting specific inflammatory cytokines decreases mood alterations in both humans and rodents (Tyring et al., 2006; Kekow et al., 2010; Haji et al., 2012; Bayramgürler et al., 2013; Fleming et al., 2015).

Inflammation-induced behavioral changes have been shown to rely on a large communication network allowing inflammatory cytokines [e.g., IL-1β, IL-6, tumor necrosis factor (TNF)-α], which are released peripherally by activated immune cells, to reach the brain through humoral, nervous and chemical pathways and to locally induce production of brain cytokines by activated microglia, the immune cells of the brain. These cytokines in turn influence pathways involved in the regulation of behavior and mood, including neurotransmitter metabolism, neuroendocrine function and neural plasticity (Castanon et al., 2004; Frenois et al., 2007; Dantzer et al., 2008; Capuron and Miller, 2011). These neuroimmune interactions not only coordinate the immune response, but also the development of adaptive behavioral changes collectively referred to as sickness behavior. These changes, which include weakness, listlessness, malaise, anorexia and fatigue, have been shown to be necessary for recovery, by helping the body to actively fight against aggressions. Inflammatory activation is usually transient and controlled by anti-inflammatory mechanisms to warrant time-limitation and reversibility of sickness behavior. Conversely, failure of those control mechanisms that allows development of sustained inflammation has been shown to represent a major leading cause of inflammation-related mood alterations (Dantzer et al., 2008; Capuron and Miller, 2011; Castanon et al., 2014; Capuron and Castanon, 2017). Indeed, if inflammation initially serves a protective function in controlling infection and promoting tissue repair, it can in the long run interfere with brain neurotransmission and cause tissue damages, what ultimately contributes to promote sustained behavioral and mood alterations. Interestingly, compelling clinical studies revealed that patients under cytokine immunotherapy display symptoms spanning multiple dimensions from neurovegetative (e.g., fatigue, decreased tone and motivation) to neuropsychiatric (e.g., depressed mood, anxiety, cognitive alterations) levels (Musselman et al., 2001; Capuron and Miller, 2011; Capuron and Castanon, 2017). Importantly, these symptoms differ in their time-course and responsiveness to prophylactic treatment with classical antidepressant drugs, particularly those targeting serotonin neurotransmission. In particular, neurovegetative symptoms appear early after initiation of cytokine immunotherapy and in a large proportion of patients. On the contrary, neuropsychiatric symptoms progressively develop after several weeks of cytokine administration and only affect 30–50% of patients. These last symptoms can be prevented by antidepressant treatment, in contrast to neurovegetative symptoms that are not, or only minimally, responsive to this intervention (Musselman et al., 2001; Capuron and Miller, 2011). Altogether, these findings suggested the involvement of distinct underlying mechanisms.

Strong support for this assumption came from studies performed in immune-challenged animals in which it is possible to experimentally dissociate sickness behavior, occurring early after the immune stimulation, from protracted depressive-like behaviors (Merali et al., 2003; Frenois et al., 2007; Moreau et al., 2008; Klaus et al., 2016). First attempts to assess the respective underlying neurobiological mechanisms have concentrated on the same preclinical models. In that context, it is worth mentioning that some of the behavioral changes characterizing sickness behavior, particularly motor slowing, could interfere with the measure of depressive-like behaviors when assessed in paradigms based on motor responses. This potential methodological bias has, however, been circumvented by using several reliable and complementary behavioral tests modeling different core symptoms of depression, and by testing mice in these tests only once they have totally recovered from sickness behavior (Frenois et al., 2007; Godbout et al., 2008; O’Connor et al., 2009c). Interestingly, this experimental design in LPS-challenged mice enabled to show a neuroanatomical dissociation between the brain structures that underlie LPS-induced sickness and depressive-like behaviors, respectively (Frenois et al., 2007). It could still be argued that some inconsistencies exist across the literature (see Biesmans et al., 2013) and that a model of acute immune activation with LPS is not necessarily relevant to the clinical situation. Several studies performed in models of chronic inflammation, which can be claimed as more suitable, however, confirmed the presence of sustained depressive-like behaviors while sickness behavior was not anymore detectable nor levels of circulating cytokines elevated (Moreau et al., 2008; O’Connor et al., 2009a,b). Together with clinical studies, all these models turned out to be very useful to progress in the identification of the neurobiological bases of inflammation-related depressive symptoms.

Neurobiological Bases of Inflammation-Related Depressive Symptoms

Mounting clinical and preclinical findings led us and others to propose that the multidimensional inflammation-related symptoms may rely on the ability of inflammatory cytokines to alter important metabolic pathways, namely kynurenine and tetrahydrobiopterin (BH4) pathways, which in turn can impair neurotransmission of monoamines, particularly serotonin, glutamate and dopamine, involved in mood regulation (Dantzer et al., 2008; Capuron and Miller, 2011; Capuron and Castanon, 2017; Haroon et al., 2017).

The Kynurenine Pathway: At the Crossroad Between Inflammation and Mood

The metabolism of the essential amino acid tryptophan produces an array of crucial factors able of regulating key physiological processes linked to behavior and mood, particularly serotonin. Tryptophan metabolism along the kynurenine pathway (KP) accounts for most of the tryptophan that is not used for protein synthesis, and ultimately leads to the production of several neuroactive metabolites, including 3-hydroxykynurenine (3-HK) and quinolinic acid (QA), which are able to stimulate N-methyl-D-aspartate (NMDA) glutamatergic receptors and promote oxidative stress, and kynurenic acid (KA) that rather displays neuroprotective properties (Figure 1) (Schwarcz and Stone, 2017). Since microglia preferentially produce QA, while KA is synthesized by astrocytes, neurotoxicity prevails in conditions of immune activation. Accordingly, increased plasma and/or cerebrospinal fluid QA levels have been reported in a plethora of conditions that encompass inflammatory and neurodegenerative damages, together with an increased prevalence of mood symptoms (Capuron et al., 2011; Bay-Richter et al., 2015; Lovelace et al., 2017; O’Farrell and Harkin, 2017; Schwarcz and Stone, 2017). More importantly, KP activation correlates with both stretch of brain damages and severity of neuropsychiatric symptoms (Capuron et al., 2002; Raison et al., 2010; Savitz et al., 2015a,b). These findings prompted a surge of interest for the involvement of KP enzymes and metabolites in inducing these symptoms, starting by the enzyme indoleamine 2,3-dioxygenase (IDO) that catalyzes the first and rate-limiting step of tryptophan metabolism along the KP (Lestage et al., 2002; Moreau et al., 2005; André et al., 2008). For example, it was shown in mice that inoculation with Bacillus Calmette-Guerin (BCG) chronically increases both peripheral and brain IDO activity, this activation paralleling development of sustained depressive-like behaviors (Moreau et al., 2008; O’Connor et al., 2009a,b). Aged mice (Godbout et al., 2008; Wynne et al., 2010), or mice exhibiting constitutive microglial over-activation (Corona et al., 2013) also display sustained cytokine production after an immune challenge, together with protracted brain IDO expression and depressive-like behavior (Godbout et al., 2008; Wynne et al., 2010; Corona et al., 2013). Similarly, a link between inflammation-related brain IDO activation and depressive-like behavior has been reported in other chronic inflammatory conditions, such as murine models of obesity (André et al., 2014; Dinel et al., 2014). Importantly, direct KP activation within the brain is sufficient to alter emotional behaviors in rodents, particularly when it occurs in key brain areas for behavior and mood, particularly the hippocampus (Henry et al., 2009; Fu et al., 2010; Park et al., 2011; Dobos et al., 2012; Lawson et al., 2013). By using mice with either genetic or systemic inhibition of IDO and submitted to an immune challenge, we and others described the causal role of IDO activation in the induction of depressive-like and anxiety-like behaviors (Godbout et al., 2008; O’Connor et al., 2009a,b,c; Salazar et al., 2012; Corona et al., 2013; Gibney et al., 2013; Xie et al., 2014; Castanon, 2015). This induction can be related to the potential for IDO to negatively impact serotonin synthesis by decreasing bioavailability of tryptophan. However, the fact that immune activation is actually associated with increased serotonin turnover (Godbout et al., 2008; O’Connor et al., 2009c; Gibney et al., 2013; Parrott et al., 2016a), regardless of concomitant IDO activation (O’Connor et al., 2009c), weakens this hypothesis. These findings may rather suggest intervention of other cytokine-induced alterations in serotonin neurotransmission, including modulation of serotonin transporter and receptors (Zhu et al., 2006). Follow-up work is therefore needed to deeply study the consequences of KP activation on the temporal and spatial patterns of serotonin-related processes.

FIGURE 1

An alternative explanation for the involvement of KP activation in inflammation-related mood symptoms is the generation of neurotoxic glutamatergic kynurenine metabolites, as they have been clinically related to the severity of mood alterations (Capuron et al., 2011; Bay-Richter et al., 2015; Haroon et al., 2017; Schwarcz and Stone, 2017). In line with the well-established role of altered neuron integrity and/or function in subtending the clinical outcomes of neurodegenerative diseases, neuronal damages have been also linked to the development of inflammation-induced depressive symptoms (Dantzer and Walker, 2014). This may particularly involve the NMDA receptors, which have recently drawn much attention in the field of depression research (Dantzer and Walker, 2014; Haroon et al., 2017). Supporting further this notion, preclinical studies report that depressive-like behaviors induced by LPS challenge (Parrott et al., 2016a,b) or related to neuropathic pain (Laumet et al., 2017) are associated with skewing of the kynurenine metabolic balance toward production of neurotoxic metabolites, and this in a region-specific manner with the hippocampus being particularly affected. Moreover, systemic administration of kynurenine (O’Connor et al., 2009c; Salazar et al., 2012; Agudelo et al., 2014) or 3-HK (Parrott et al., 2016a,b) dose-dependently impairs emotional behaviors, whereas mice deficient for IDO are protected against NMDA receptor-mediated excitotoxicity (Mazarei et al., 2013). Of note, NMDA receptor blockade abrogates inflammation-induced depressive-like behavior (Walker et al., 2013), along with selective inhibition of downstream KP enzymes, i.e., kynurenine 3-monooxygenase (KMO) or 3-hydroxyanthranilic acid dioxygenase (HAAO) that ultimately synthesize the NMDA receptor agonist QA (Parrott et al., 2016b; Laumet et al., 2017). Interestingly, this especially improves depressive-like behaviors related to clinical behavioral despair (i.e., immobility in the tail suspension test), while being less efficient on behavioral changes rather modeling anhedonia (i.e., sucrose preference) (Parrott et al., 2016b). These results are particularly relevant to help identifying the neurobiological mechanisms that, respectively, underlie the different inflammation-related depressive symptoms. As each behavior/symptom is functionally subtended by preferential activation of selective neuronal pathways in discrete brain regions, such dimensional dissociation may rely on the regional differences of KP activation reported in those experimental studies (Parrott et al., 2016a,b; Laumet et al., 2017). While LPS-induced brain expression of cytokines is largely region-independent, the 3-HK/KA ratio is significantly increased in the hippocampus, but not central amygdala or nucleus accumbens (Parrott et al., 2016a). Consistent with these preclinical findings, post-mortem studies of depressed patients link severe depression with increased microglial QA detection in selective cortical subregions (Steiner et al., 2011). Conversely, a higher neuroprotective index, as reflected by elevated KA/QA ratio, positively correlates with hippocampal volume in clinically depressed but non-medicated patients (Savitz et al., 2015a). Otherwise, the above-mentioned dissociation between KP activation and development of specific depressive symptoms may rather reflect involvement of other metabolic pathways and/or neurotransmission systems (Capuron and Castanon, 2017). This assumption is nicely supported by a recent study showing that inflammation-induced impairment of motivation-driven behaviors is independent from IDO activation since it persists in LPS-treated IDO deficient mice (Vichaya et al., 2018). With regard to inflammation-related motivational deficits, the BH4 pathway that can ultimately impair dopamine neurotransmission appears as a likely candidate (Felger and Treadway, 2017). This is supported by data obtained in mice deficient in BH4, which exhibit dopamine-related behavioral alterations (Choi and Tarazi, 2010). Both alternatives are not necessarily disconnected since KA has been shown to modulate striatal dopaminergic tone, by acting on α7-nicotinic acetylcholine receptors (Wu et al., 2007), while pharmacological activation of these receptors mitigates anhedonia in a mouse model of chronic stress (Zhao et al., 2017). Moreover, clinical data report an inverse association between circulating KA/QA ratio and the degree of anhedonia in depressed patients (Savitz et al., 2015a).

The BH4 Pathway: A Key Player in Neurobiological Modulation of Depressive Symptoms

BH4 is a pivotal cofactor for the optimal functioning of the nitric oxide synthase isoforms (NOS) and three aromatic amino acid hydroxylases: phenylalanine hydroxylase (PAH), tryptophan hydroxylase (trypOH) and tyrosine hydroxylase (TH) (Thöny et al., 2000; Sumi-Ichinose et al., 2001). Accordingly, it is required for the synthesis of dopamine, serotonin and nitric oxide from the essential amino acids tyrosine, tryptophan and arginine, respectively (Sumi-Ichinose et al., 2001). BH4 de novo synthesis involves the sequential activation of three enzymes, the first one, GTP-cyclohydrolase 1 (GCH1) being the rate-limiting step (Thöny et al., 2000) (Figure 2). The activity of this enzyme, which is co-localized with the monoamine-containing cells, has been shown to differ according to the brain area (Sawada et al., 1986; Nagatsu et al., 1995; Dassesse et al., 1997). Inflammatory cytokines, including IL-1β, interferon-γ and TNF-α, are able to induce both GCH1 expression and activity, therefore increasing BH4 synthesis (Shi et al., 2004). At the post-translational level, GCH1 is inhibited by BH4 and stimulated by phenylalanine, through its complex formation with the cyclohydrolase feedback regulatory protein (GFRP) (Neurauter et al., 2008). This process ensures tightly keeping BH4 levels within a physiological range in the body. BH4 is also oxidized to BH2, which can, however, be conversely converted back to BH4 by the dihydrofolate reductase (DHFR) (Harada et al., 1993). In fine, the net cellular bioavailability of BH4 likely results therefore from the balance between its de novo synthesis, its oxidation to BH2, and its regeneration by DHFR.

FIGURE 2

Several clinical conditions have been associated with a defect in the BH4-pathway, mainly linked to alterations affecting the different enzymatic steps. Mutation of GCH1 results in greatly reduced BH4 level, which has been shown to cause neurological diseases, such as dopamine-responsive dystonia (Ichinose et al., 1994; Müller et al., 2002). Mice genetically deficient for BH4 (hph1 model) display decreased dopamine levels and increased depressive-like behaviors (Nasser et al., 2014). Supporting preclinical findings, patients with GCH1 deficiency have been shown to exhibit an increased frequency of psychiatric disorders, including depression and anxiety (Van Hove et al., 2006; Trender-Gerhard et al., 2009). Moreover, we have recently reported that variations in markers of GCH1 activity correlate with neurovegetative symptoms and inflammatory factors in elderly persons (Capuron et al., 2011). Low BH4 levels have also been found in postmortem brains of subjects with a history of severe depression (Blair et al., 1984). Conversely, raised urine and plasma total biopterin levels are measured in depressed patients (Duch et al., 1984; Garbutt et al., 1985; Knapp and Irwin, 1989; Hashimoto et al., 1994; Abou-Saleh et al., 1995), suggesting impaired BH4 metabolism. In addition, reduced GCH1 activity, assessed through the increased phenylalanine/tyrosine ratio, has been reported in depressive patients responding to electroconvulsive therapy (Anderson et al., 1994). This phenylalanine/tyrosine ratio is also used as indicator of BH4 availability and PAH activity and may serve therefore as an indirect biomarker of dopamine and norepinephrine synthesis (Neurauter et al., 2008; Capuron et al., 2011).

In Human, low PTPS activity directs the production of neopterin at the expense of BH4 in conditions of GCH1 stimulation, such as inflammation. Neopterin is therefore considered as a marker of cell-mediated immunity in inflammatory conditions (Murr et al., 2002). Increased phenylalanine levels and phenylalanine/tyrosine ratio is reported in patients suffering from chronic inflammatory conditions, this increase being correlated with neopterin concentrations (Neurauter et al., 2008; Ploder et al., 2008; Zangerle et al., 2010; Murr et al., 2014; Hirayama et al., 2016; Ormstad et al., 2016). It is well known that inflammatory stimulation activates the inducible NOS, which considerably increases the use of BH4 for optimal enzymatic activity, and induces formation of large amounts of oxygen radicals that in turn contribute to the oxidative loss of BH4 (Werner et al., 2003). Both increased use and loss of BH4 driven by a chronic inflammatory state may synergistically act to alter the function of BH4-dependent enzymes and then compromise the biosynthesis of monoamines, which may contribute to development of mood disorders (Neurauter et al., 2008; Felger et al., 2013a,b).

Preclinical studies show changes in brain dopamine and serotonin, and/or respective metabolite levels after an immune stimulation (Kamata et al., 2000; Kumai et al., 2000; Kitagami et al., 2003; Sato et al., 2006). Interestingly, inflammation-induced impairment of dopamine neurotransmission, which may involve induction of oxidative damages, has been proposed as a potential mechanism underlying motivational changes reported in LPS-challenged mice (Vichaya et al., 2018). Clinical studies also reveal some functional alterations of the dopaminergic reward system, in association with impairment in motivation and motor slowing (Capuron et al., 2007; Eisenberger et al., 2010; Capuron et al., 2012). Similar blunting of neural responses to reward has been observed in condition of dietary depletion of amino acid precursors for dopamine synthesis (Bjork et al., 2014). Decreased dopamine synthesis and release have been confirmed using microdialysis in monkeys and mice under inflammatory conditions (Felger and Treadway, 2017 for review). Some evidence also shows that inflammatory cytokines may alter the presynaptic dopamine storage through changes in expression and function of the vesicular monoamine transporter (VMAT2) (Kazumori et al., 2004). Moreover, functional changes of the dopamine reuptake pump, DAT, have been suggested in neuroinflammatory conditions associated to HIV infection or prenatal LPS challenge (Gelman et al., 2006; Tien et al., 2013). Then, a reduced presynaptic vesicular storage and/or altered DAT-reuptake of dopamine could together lead to reduced dopamine turnover in inflammatory conditions.

Based on these data, the BH4 pathway is emerging as an important regulator for a number of symptoms and pathologies associated with over-production of inflammatory mediators. Moreover, as previously mentioned recent data suggest a link between KP and BH4 pathways that could act synergistically upon inflammatory conditions to compromise monoamine synthesis. Thus, increased xanthurenic acid, a metabolite of 3-HK, has been shown to directly lower BH4 biosynthesis by inhibiting sepiapterin reductase (Haruki et al., 2016). Similarly, it has been suggested that a concurrent upregulation of kynurenines and BH2 production may lead to a combined up-regulated activity of NOS (by kynurenines) and decreased availability of BH4, as NOS cofactor (Oxenkrug, 2011). Such a combination results in an uncoupling of NOS and consequently reduced production of NO in favor of “inflammogenic” reactive oxygen species (ROS), which cause further oxidative BH4 loss. Altogether, these data strongly support the role of both kynurenine and BH4 pathways in development of inflammatory-related depressive symptoms.

Therapeutic Implications

One of the major issues when dealing with depressive disorders is the heightened resistance to standard antidepressant therapy (Rush et al., 2006). In that context, the possibility of alternatively and/or concomitantly targeting inflammatory processes to improve clinical outcomes has recently received particular attention (Schmidt et al., 2016; Colpo et al., 2018; Kappelmann et al., 2018; Shariq et al., 2018; Zuzarte et al., 2018). It has been postulated that most classical antidepressants known to primary act on monoamine neurotransmission [i.e., selective serotonin reuptake blockers: SSRIs, tricyclic antidepressants (TCA) acting on norepinephrine reuptake, and antidepressants acting on both serotonin and norepinephrine reuptake: SNRI] may also act on inflammation since they display anti-inflammatory properties both peripherally and within the brain (Lanquillon et al., 2000; Tynan et al., 2012; Strawbridge et al., 2015; Wiêdłocha et al., 2018). Importantly, they not only reduce circulating cytokine levels, but also downstream activation of the KP (Ara and Bano, 2012; Zoga et al., 2014; Reus et al., 2015), ultimately correcting the imbalance between neuroprotective and neurotoxic kynurenine metabolites (Kocki et al., 2012; Eskelund et al., 2017). Hence, sustained SSRI treatment in rodent models of depression reduces QA levels in different brain regions known to be involved in mood regulation (Eskelund et al., 2017). Moreover, variations in the genes coding for IDO and GCH1 have been shown to predict SSRI treatment outcome in depressive patients (Cutler et al., 2012; Kishi et al., 2012), further supporting a role for both pathways in the therapeutic response. Of note, the immune-modulatory impact of antidepressants differs depending on their class, with SSRI and SNRI drugs being mostly anti-inflammatory, while TCAs rather displaying in some studies pro-inflammatory properties (Hamer et al., 2011; Vogelzangs et al., 2012; Nazimek et al., 2016; Chen et al., 2018). Further highlighting the complexity of the relationship between antidepressants and inflammation, a given antidepressant drug can display both pro- or anti-inflammatory properties depending on what immune parameter is assessed (e.g., cytokine release or activation of specific intracellular signaling pathways) (Horowitz et al., 2014). Mounting evidence suggests that treatment resistance might be predicted by elevated inflammation, whether linked to specific gene variants (Baune et al., 2010), activation of selective intracellular pathways (Horowitz et al., 2014) or the presence of chronic inflammatory conditions/diseases (Luppino et al., 2010; Vogelzangs et al., 2012; Hughes and Kumari, 2017). In support of this notion, conditions such as overweight or obesity, which are characterized by a chronic low-grade inflammatory state together with a higher prevalence of depression, have been recently shown to relate to a greater risk of non-response to conventional antidepressants (Kloiber et al., 2007; Toups et al., 2013; Woo et al., 2016; Jantaratnotai et al., 2017). Interestingly, in those conditions, systemic inflammation is associated with both KP activation, as revealed by increased circulating kynurenine levels and expression of the KP enzymes – notably neurotoxic metabolites – in the adipose tissue of obese subjects (Favennec et al., 2015; Alemán et al., 2017), and mood symptoms (Capuron et al., 2008; Daly, 2013). Similar results were obtained in preclinical models of obesity (Dinel et al., 2011, 2014; André et al., 2014; Boitard et al., 2014; Castanon et al., 2015; Almeida-Suhett et al., 2017; de Cossio et al., 2017). Interestingly, weight loss that reduces inflammation and KP activation (Cancello and Clement, 2006; Alemán et al., 2017) correlates with significant mood improvement (mery et al., 2007; Capuron et al., 2011). Beside KP activation, studies reporting increased neopterin levels in obese (Brandacher et al., 2006; Oxenkrug et al., 2011; Mangge et al., 2014) also suggest the potential involvement of BH4 pathway in obesity-related depressive comorbidity, consistent with impairment of dopamine neurotransmission reported in obesity (Sharma and Fulton, 2013; Krishna et al., 2015).

Compelling evidence supports the notion that anti-inflammatory interventions may be effective as novel antidepressants or adjuvants of conventional antidepressants, as long as inflammation and depressive symptoms are comorbid in treated patients (Strawbridge et al., 2015; Kappelmann et al., 2018; Köhler et al., 2016; Schmidt et al., 2016; Jantaratnotai et al., 2017; Jha and Trivedi, 2018) (Table 1). For example, non-steroidal anti-inflammatory drugs (NSAIDs) improve antidepressant treatment outcomes in patients with depressive disorders (Müller et al., 2006; Akhondzadeh et al., 2009). Similarly, NSAIDs administration decreases severity of emotional alterations in several animal models of inflammatory diseases, such as cancer (Norden et al., 2015), Alzheimer’s disease (Llorens-Martin et al., 2014), and Parkinson’s disease (Zaminelli et al., 2014). Significant antidepressant effects of the tetracycline antibiotic minocycline have also been reported in depressed patients compared to placebo (for review Rosenblat and McIntyre, 2018). It is also worth mentioning that natural anti-inflammatory agents, such as ω-3 polyunsaturated fatty acids (PUFAs), have also shown promising results on mood, particularly as add-on therapy with conventional antidepressants (for review Layé et al., 2018). Supporting the link between obesity and depression, this strategy revealed to be particularly effective in depressed patients with low-grade basal inflammation (Rapaport et al., 2016), which is linked to elevated body mass index (BMI). Interestingly, supplementation with ω-3 PUFAs in obese subjects also accentuates weight loss induced by low-calorie diet (Kunesová et al., 2006), weight loss in the context of obesity being associated – as mentioned earlier – with reduced inflammation (Lasselin et al., 2014) and improved depressive symptoms (Emery et al., 2007; Capuron et al., 2011). Current knowledge on the implication of specific inflammatory pathways in driving neuropsychiatric symptoms also offers the potential for targeted anti-inflammatory interventions. Thus, monoclonal antibodies against IL-6, IL-17, and TNF-α display antidepressant effects in chronically inflamed patients with significant depressive symptoms, as well as depressed patients with basal low-grade inflammation (Traki et al., 2014; Gossec et al., 2015; Griffiths et al., 2017; Jha and Trivedi, 2018; Kappelmann et al., 2018). Abundant literature also reports antidepressant effects of anti-TNF-α drugs, such as etanercept or infliximab, in clinical trials (Kekow et al., 2010; Arisoy et al., 2013; Raison et al., 2013; Fleming et al., 2015) and murine models of inflammatory diseases (Haji et al., 2012; Bayramgürler et al., 2013). Of note, targeting TNF-α in treatment-resistant depressed patients was found to improve depressive symptomatology particularly in those with higher baseline inflammation (Raison et al., 2013), which tended to be those with higher BMI. In addition, chronic stress-induced depressive-like behaviors are reduced by TNF-α antagonism through decreased IDO activation (Fu et al., 2016).

The possibility of acting on brain neurobiological targets of inflammation, such as the KP, rather than on inflammation itself has also drawn much attention, particularly since global anti-inflammatory strategies are often accompanied by important side effects. Thus, compelling preclinical studies report that reducing KP activation promotes antidepressant effects (Reus et al., 2015; Remus and Dantzer, 2016; Jeon and Kim, 2017; Lovelace et al., 2017; O’Farrell and Harkin, 2017). First promising on-trial strategies include blockade of KP enzymes, particularly IDO and KMO, which has been shown to display antidepressant-like properties whose efficiency varies, however, depending on what symptom domains were assessed (Toledo-Sherman et al., 2015; Laumet et al., 2017; Lovelace et al., 2017; Tashiro et al., 2017). Instead of directly targeting KP enzymes, other studies have rather investigated the possibility of reducing the peripheral kynurenine transport across the blood–brain barrier, as the majority of brain kynurenine comes from the periphery. This procedure has been indeed shown to prevent production of QA by activated microglia (Carrillo-Mora et al., 2010), as well as LPS-induced depressive-like behavior (Remus and Dantzer, 2016). Alternatively, it may be worthwhile to increase synthesis/availability of KA, the neuroprotective kynurenine metabolite (Vécsei et al., 2013). By counteracting the neurotoxic effect of QA and other NMDA receptor agonists, increasing KA formation has been shown to reduce neuronal damages and associated experimentally-induced seizures (Russi et al., 1992; Silva-Adaya et al., 2011). Similar beneficial effects still need to be confirmed regarding inflammation-related depressive symptoms, but these data are already very encouraging. Lastly, in agreement with the literature that links glutamate with mood disorders and highlights antidepressant effects of NMDA receptor antagonists such as ketamine (see for review Haroon et al., 2017), several interesting studies suggest that targeting glutamate activity or preventing QA from activating NMDA receptors also offer additional therapeutic opportunities (Dantzer and Walker, 2014; Reus et al., 2015). Blocking activation of those receptors, which was already shown to protect against chronic stress-induced depressive-like behavior (Li et al., 2011), are similarly effective regarding LPS-induced behavioral alterations (Walker et al., 2013). Moreover, IDO deficient mice are less sensitive to QA-induced neuronal damages (Mazarei et al., 2013). Further supporting the role of NMDA receptor activation as potential therapeutic targets to improve inflammation-related depressive symptoms, antidepressant treatment was recently shown to reduce both stress-induced activation of the KP and changes of NMDA receptor expression (Martín-Hernández et al., 2018). Similarly, reducing NMDA receptor activation by enhancing brain KYNA levels has been proposed as a promising way of counteracting amyloid beta-related neurodegeneration (Carrillo-Mora et al., 2010).

Even if the potential antidepressant effect of targeting the BH4 pathway, for example with oral BH4 supplementation, has been only poorly studied so far and with inconsistent results (Curtius et al., 1983; Woggon et al., 1984), supplementation with synthetic BH4 is already used to treat patients suffering from phenylketonuria (Blau, 2013). Moreover, an interesting case report shows that administrating a BH4 replacement protein improves depressive symptoms in a patient suffering from major depression (Pan et al., 2011). Preclinical data also highlight the possibility of increasing brain BH4 levels through its peripheral administration (Ohashi et al., 2016), which consequently changes serotonin and dopamine metabolism (Brand et al., 1996), TH protein content (Homma et al., 2013), dopamine levels and neuronal activities in the brain (Koshimura et al., 2000). More studies are necessary to test if such BH4-induced changes in dopamine and norepinephrine neurotransmission might underlie the expected behavioral improvement, particularly regarding depression-related anhedonic symptoms.

Altogether, these findings clearly show that targeting, either directly or indirectly, inflammation and/or neurobiological mediators shown to underlie inflammation-driven depressive symptoms represents promising new therapeutic strategies (Figure 3). These strategies may not only rely on pharmacological approaches using currently available drugs prescribed for their antidepressant properties, but also on the use of still to discover/validate drugs. Regarding the KP, the potential beneficial effects of KP enzyme inhibitors are currently considered in other medical fields, particularly in oncology (see for review Prendergast et al., 2018). Studies carried out in the context of inflammation-driven depressive symptoms should likely benefit therefore from findings reported in other fields. Beside pharmacological approaches, non-pharmacological therapeutic strategies, such as nutritional interventions, may represent a promising alternative associated with reduced risk of complications and economic cost. This particularly includes diet supplementation with natural agents such as ω-3 PUFAs, amino acids or antioxidants, namely compounds known to ultimately protect against inflammation, oxidative stress and/or other neurotoxic insults. Importantly, the opportunity to combine these different therapeutic strategies or rather favor one of them according to the type of depressive symptoms to treat, should broaden the spectrum of action of currently used antidepressant interventions and therefore help improving the management and/or treatment of depressive symptoms associated with inflammation.

FIGURE 3

Conclusion

Given the steadily rising prevalence of depression and inflammation-based chronic diseases, their combined negative impact on the etiology of other severe diseases, and the elevated resistance to conventional antidepressants, a better understanding of the pathophysiological mechanisms of inflammation-driven depressive symptoms is urgently required for the identification of new and efficacious therapeutic strategies. Altogether, findings discussed in the present review show that strategies directed to inflammatory processes might be particularly promising, because of their pivotal role in the pathophysiology of depression and their substantial impact on the metabolism of monoamines involved in the regulation of mood. Despite the important advances made over the last decade, several issues are still at stake, from the identification of the best candidates to be targeted within the inflammatory pathways to the determination of the most suitable protocol of treatment (i.e., anti-inflammatory strategies as treatment or co-treatment with conventional antidepressants). Resolving these issues, which clearly depend on the patient’s individual characteristics, constitutes a crucial challenge for the future, as it should allow personalizing antidepressant prescription, and in turn contributing to the development of a precision medicine in psychiatry.

References

• 1

  Abou-SalehM.AndersonD. N.CollinsJ.HughesK.CattellR. J.HamonC. G.et al (1995). The role of pterins in depression and the effects of antidepressive therapy.Biol. Psychiatry38458–463. 10.1016/0006-3223(94)00323-U

  • CrossRef
  • Google Scholar
  • View reference in article

• 2

  AgudeloL. Z.FemeniaT.OrhanF.Porsmyr-PalmertzM.GoinyM.Martinez-RedondoV.et al (2014). Skeletal muscle PGC-1alpha1 modulates kynurenine metabolism and mediates resilience to stress-induced depression.Cell15933–45. 10.1016/j.cell.2014.07.051

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 3

  AkhondzadehS.JafariS.RaisiF.NasehiA. A.GhoreishiA.SalehiB.et al (2009). Clinical trial of adjunctive celecoxib treatment in patients with major depression: a double blind and placebo controlled trial.Depress. Anxiety26607–611. 10.1002/da.20589

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 4

  AlemánJ. O.IyengarN. M.WalkerJ. M.MilneG. L.Da RosaJ. C.LiangY.et al (2017). Effects of rapid weight loss on systemic and adipose tissue inflammation and metabolism in obese postmenopausal women.J. Endocr. Soc.1625–637. 10.1210/js.2017-00020

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 5

  Almeida-SuhettC. P.GrahamA.ChenY.DeusterP. (2017). Behavioral changes in male mice fed a high-fat diet are associated with IL-1beta expression in specific brain regions.Physiol. Behav.169130–140. 10.1016/j.physbeh.2016.11.016

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 6

  AndersonD. N.WilkinsonA. M.Abou-SalehM. T.BlairJ. A. (1994). Recovery from depression after electroconvulsive therapy is accompanied by evidence of increased tetrahydrobiopterin-dependent hydroxylation.Acta Psychiatr. Scand.9010–13. 10.1111/j.1600-0447.1994.tb01547.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 7

  AndréC.DinelA. L.FerreiraG.LayéS.CastanonN. (2014). Diet-induced obesity progressively alters cognition, anxiety-like behavior and lipopolysaccharide-induced depressive-like behavior: focus on brain indoleamine 2,3-dioxygenase activation.Brain Behav. Immun.4110–21. 10.1016/j.bbi.2014.03.012

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 8

  AndréC.O’ConnorJ. C.KelleyK. W.LestageJ.DantzerR.CastanonN. (2008). Spatio-temporal differences in the profile of murine brain expression of proinflammatory cytokines and indoleamine 2,3-dioxygenase in response to peripheral lipopolysaccharide administration.J. Neuroimmunol.20090–99. 10.1016/j.jneuroim.2008.06.011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 9

  AraI.BanoS. (2012). Citalopram decreases tryptophan 2,3-dioxygenase activity and brain 5-HT turnover in swim stressed rats.Pharmacol. Rep.64558–566. 10.1016/S1734-1140(12)70851-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 10

  ArisoyO.BesC.CifciC.SercanM.SoyM. (2013). The effect of TNF-alpha blockers on psychometric measures in ankylosing spondylitis patients: a preliminary observation.Rheumatol. Int.331855–1864. 10.1007/s00296-013-2671-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 11

  BarbosaI. G.RochaN. P.BauerM. E.de MirandaA. S.HuguetR. B.ReisH. J. (2013). Chemokines in bipolar disorder: trait or state?Eur. Arch. Psychiatry Clin. Neurosci.263159–165. 10.1007/s00406-012-0327-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 12

  BauneB. T.DannlowskiU.DomschkeK.JanssenD. G.JordanM. A.OhrmannP.et al (2010). The interleukin 1 beta (IL1B) gene is associated with failure to achieve remission and impaired emotion processing in major depression.Biol. Psychiatry67543–549. 10.1016/j.biopsych.2009.11.004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 13

  BayramgürlerD.KarsonA.OzerC.UtkanT. (2013). Effects of long-term etanercept treatment on anxiety- and depression-like neurobehaviors in rats.Physiol. Behav.119145–148. 10.1016/j.physbeh.2013.06.010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 14

  Bay-RichterC.LinderholmK. R.LimC. K.SamuelssonM.Träskman-BendzL.GuilleminG. J.et al (2015). A role for inflammatory metabolites as modulators of the glutamate N-methyl-D-aspartate receptor in depression and suicidality.Brain Behav. Immun.43110–117. 10.1016/j.bbi.2014.07.012

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 15

  BiesmansS.MeertT. F.BouwknechtJ. A.ActonP. D.DavoodiN.De HaesP.et al (2013). Systemic immune activation leads to neuroinflammation and sickness behavior in mice.Mediators Inflamm.271359. 10.1155/2013/271359

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 16

  BjorkJ. M.GrantS. J.ChenG.HommerD. W. (2014). Dietary tyrosine/phenylalanine depletion effects on behavioral and brain signatures of human motivational processing.Neuropsychopharmacology39595–604. 10.1038/npp.2013.232

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 17

  BlairJ. A.BarfordP. A.MorarC.PheasantA. E.HamonC. G.WhitburnS. B.et al (1984). Tetrahydrobiopterin metabolism in depression.Lancet2:163. 10.1016/S0140-6736(84)91075-4

  • CrossRef
  • Google Scholar
  • View reference in article

• 18

  BlauN. (2013). Sapropterin dihydrochloride for the treatment of hyperphenylalaninemias.Expert Opin. Drug Metab. Toxicol.91207–1218. 10.1517/17425255.2013.804064

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 19

  BoitardC.CavarocA.SauvantJ.AubertA.CastanonN.LayeS.et al (2014). Impairment of hippocampal-dependent memory induced by juvenile high-fat diet intake is associated with enhanced hippocampal inflammation in rats.Brain Behav. Immun.409–17. 10.1016/j.bbi.2014.03.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 20

  BrandM. P.HylandK.EngleT.SmithI.HealesS. J. (1996). Neurochemical effects following peripheral administration of tetrahydropterin derivatives to the hph-1 mouse.J. Neurochem.661150–1156. 10.1046/j.1471-4159.1996.66031150.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 21

  BrandacherG.WinklerC.AignerF.SchwelbergerH.SchroecksnadelK.MargreiterR.et al (2006). Bariatric surgery cannot prevent tryptophan depletion due to chronic immune activation in morbidly obese patients.Obes. Surg.16541–548. 10.1381/096089206776945066

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 22

  CancelloR.ClementK. (2006). Is obesity an inflammatory illness? Role of low-grade inflammation and macrophage infiltration in human white adipose tissue.BJOG1131141–1147. 10.1111/j.1471-0528.2006.01004.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 23

  CapuronL.CastanonN. (2017). Role of inflammation in the development of neuropsychiatric symptom domains: evidence and mechanisms.Curr. Top. Behav. Neurosci.3131–44. 10.1007/7854_2016_14

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 24

  CapuronL.GumnickJ. F.MusselmanD. L.LawsonD. H.ReemsnyderA.NemeroffC. B.et al (2002). Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions.Neuropsychopharmacology26643–652. 10.1016/S0893-133X(01)00407-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 25

  CapuronL.LasselinJ.CastanonN. (2017). Role of adiposity-driven inflammation in depressive morbidity.Neuropsychopharmacology42115–128. 10.1038/npp.2016.123

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 26

  CapuronL.MillerA. H. (2011). Immune system to brain signaling: neuropsychopharmacological implications.Pharmacol. Ther.130226–238. 10.1016/j.pharmthera.2011.01.014

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 27

  CapuronL.PagnoniG.DemetrashviliM. F.LawsonD. H.FornwaltF. B.WoolwineB.et al (2007). Basal ganglia hypermetabolism and symptoms of fatigue during interferon-alpha therapy.Neuropsychopharmacology322384–2392. 10.1038/sj.npp.1301362

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 28

  CapuronL.PagnoniG.DrakeD. F.WoolwineB. J.SpiveyJ. R.CroweR. J.et al (2012). Dopaminergic mechanisms of reduced basal ganglia responses to hedonic reward during interferon alfa administration.Arch. Gen. Psychiatry691044–1053. 10.1001/archgenpsychiatry.2011.2094

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 29

  CapuronL.SchroecksnadelS.FeartC.AubertA.HigueretD.Barberger-GateauP.et al (2011). Chronic low-grade inflammation in elderly persons is associated with altered tryptophan and tyrosine metabolism: role in neuropsychiatric symptoms.Biol. Psychiatry70175–182. 10.1016/j.biopsych.2010.12.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 30

  CapuronL.SuS.MillerA. H.BremnerJ. D.GoldbergJ.VogtG. J.et al (2008). Depressive symptoms and metabolic syndrome: is inflammation the underlying link?Biol. Psychiatry64896–900. 10.1016/j.biopsych.2008.05.019

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 31

  Carrillo-MoraP.Mendez-CuestaL. A.Perez-De La CruzV.Fortoul-van Der GoesT. I.et al (2010). Protective effect of systemic L-kynurenine and probenecid administration on behavioural and morphological alterations induced by toxic soluble amyloid beta (25-35) in rat hippocampus.Behav. Brain Res.210240–250. 10.1016/j.bbr.2010.02.041

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 32

  CastanonN. (2015). “Animal models to study the role of kynurenine pathway in mood, behavior and cognition,” inTargeting the Broadly Pathogenic Kynurenine Pathway, ed.MittalS. (Berlin: Springer), 323–337. 10.1007/978-3-319-11870-3_25

  • CrossRef
  • Google Scholar
  • View reference in article

• 33

  CastanonN.LasselinJ.CapuronL. (2014). Neuropsychiatric comorbidity in obesity: role of inflammatory processes.Front. Endocrinol.5:74. 10.3389/fendo.2014.00074

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 34

  CastanonN.LuheshiG.LayeS. (2015). Role of neuroinflammation in the emotional and cognitive alterations displayed by animal models of obesity.Front. Neurosci.9:229. 10.3389/fnins.2015.00229

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 35

  CastanonN.MedinaC.MormedeC.DantzerR. (2004). Chronic administration of tianeptine balances lipopolysaccharide-induced expression of cytokines in the spleen and hypothalamus of rats.Psychoneuroendocrinology29778–790. 10.1016/S0306-4530(03)00142-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 36

  ChenC. Y.YehY. W.KuoS. C.LiangC. S.HoP. S.HuangC. C.et al (2018). Differences in immunomodulatory properties between venlafaxine and paroxetine in patients with major depressive disorder.Psychoneuroendocrinology87108–118. 10.1016/j.psyneuen.2017.10.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 37

  ChoiY. K.TaraziF. I. (2010). Alterations in dopamine and glutamate neurotransmission in tetrahydrobiopterin deficient spr-/- mice: relevance to schizophrenia.BMB Rep.43593–598. 10.5483/BMBRep.2010.43.9.593

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 38

  ColpoG. D.LeboyerM.DantzerR.TrivediM. H.TeixeiraA. L. (2018). Immune-based strategies for mood disorders: facts and challenges.Expert Rev. Neurother.18139–152. 10.1080/14737175.2018.1407242

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 39

  CoronaA. W.NordenD. M.SkendelasJ. P.HuangY.O’ConnorJ. C.LawsonM.et al (2013). Indoleamine 2,3-dioxygenase inhibition attenuates lipopolysaccharide induced persistent microglial activation and depressive-like complications in fractalkine receptor (CX(3)CR1)-deficient mice.Brain Behav. Immun.31134–142. 10.1016/j.bbi.2012.08.008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 40

  CurtiusH. C.NiederwieserA.LevineR. A.LovenbergW.WoggonB.AngstJ. (1983). Successful treatment of depression with tetrahydrobiopterin.Lancet1657–658. 10.1016/S0140-6736(83)91837-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 41

  CutlerJ. A.RushA. J.McMahonF. J.LajeG. (2012). Common genetic variation in the indoleamine-2,3-dioxygenase genes and antidepressant treatment outcome in major depressive disorder.J. Psychopharmacol.26360–367. 10.1177/0269881111434622

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 42

  DalyM. (2013). The relationship of C-reactive protein to obesity-related depressive symptoms: a longitudinal study.Obesity21248–250. 10.1002/oby.20051

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 43

  DantzerR.O’ConnorJ. C.FreundG. G.JohnsonR. W.KelleyK. W. (2008). From inflammation to sickness and depression: when the immune system subjugates the brain.Nat. Rev. Neurosci.946–56. 10.1038/nrn2297

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 44

  DantzerR.WalkerA. K. (2014). Is there a role for glutamate-mediated excitotoxicity in inflammation-induced depression?J. Neural Transm.121925–932. 10.1007/s00702-014-1187-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 45

  DassesseD.HemmensB.CuvelierL.RésiboisA. (1997). GTP-cyclohydrolase-I like immunoreactivity in rat brain.Brain Res.777187–201. 10.1016/S0006-8993(97)01111-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 46

  de CossioL. F.FourrierC.SauvantJ.EverardA.CapuronL.CaniP. D.et al (2017). Impact of prebiotics on metabolic and behavioral alterations in a mouse model of metabolic syndrome.Brain Behav. Immun.6433–49. 10.1016/j.bbi.2016.12.022

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 47

  DinelA. L.AndréC.AubertA.FerreiraG.LayeS.CastanonN. (2011). Cognitive and emotional alterations are related to hippocampal inflammation in a mouse model of metabolic syndrome.PLoS One6:e24325. 10.1371/journal.pone.0024325

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 48

  DinelA. L.AndréC.AubertA.FerreiraG.LayeS.CastanonN. (2014). Lipopolysaccharide-induced brain activation of the indoleamine 2,3-dioxygenase and depressive-like behavior are impaired in a mouse model of metabolic syndrome.Psychoneuroendocrinology4048–59. 10.1016/j.psyneuen.2013.10.014

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 49

  DobosN.de VriesE. F.KemaI. P.PatasK.PrinsM.NijholtI. M.et al (2012). The role of indoleamine 2,3-dioxygenase in a mouse model of neuroinflammation-induced depression.J. Alzheimers Dis.28905–915. 10.3233/JAD-2011-111097

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 50

  DowlatiY.HerrmannN.SwardfagerW.LiuH.ShamL.ReimE. K.et al (2010). A meta-analysis of cytokines in major depression.Biol. Psychiatry67446–457. 10.1016/j.biopsych.2009.09.033

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 51

  DuchD. S.WoolfJ. H.NicholC. A.DavidsonJ. R.GarbuttJ. C. (1984). Urinary excretion of biopterin and neopterin in psychiatric disorders.Psychiatry Res.1183–89. 10.1016/0165-1781(84)90090-8

  • CrossRef
  • Google Scholar
  • View reference in article

• 52

  EisenbergerN. I.BerkmanE. T.InagakiT. K.RamesonL. T.MashalN. M.IrwinM. R. (2010). Inflammation-induced anhedonia: endotoxin reduces ventral striatum responses to reward.Biol. Psychiatry68748–754. 10.1016/j.biopsych.2010.06.010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 53

  EmeryC. F.FondowM. D.SchneiderC. M.ChristofiF. L.HuntC.BusbyA. K.et al (2007). Gastric bypass surgery is associated with reduced inflammation and less depression: a preliminary investigation.Obes. Surg.17759–763. 10.1007/s11695-007-9140-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 54

  EnglerH.BrendtP.WischermannJ.WegnerA.RohlingR.SchoembergT.et al (2017). Selective increase of cerebrospinal fluid IL-6 during experimental systemic inflammation in humans: association with depressive symptoms.Mol. Psychiatry221448–1454. 10.1038/mp.2016.264

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 55

  EskelundA.LiY.BudacD. P.MüllerH. K.GulinelloM.SanchezC.et al (2017). Drugs with antidepressant properties affect tryptophan metabolites differently in rodent models with depression-like behavior.J. Neurochem.142118–131. 10.1111/jnc.14043

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 56

  EvansD. L.CharneyD. S.LewisL.GoldenR. N.GormanJ. M.KrishnanK. R.et al (2005). Mood disorders in the medically ill: scientific review and recommendations.Biol. Psychiatry58175–189. 10.1016/j.biopsych.2005.05.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 57

  FavennecM.HennartB.CaiazzoR.LeloireA.YengoL.VerbanckM.et al (2015). The kynurenine pathway is activated in human obesity and shifted toward kynurenine monooxygenase activation.Obesity102066–2074. 10.1002/oby.21199

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 58

  FelgerJ. C.LiL.MarvarP. J.WoolwineB. J.HarrisonD. G.RaisonC. L.et al (2013a). Tyrosine metabolism during interferon-alpha administration: association with fatigue and CSF dopamine concentrations.Brain Behav. Immun.31153–160. 10.1016/j.bbi.2012.10.010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 59

  FelgerJ. C.MunJ.KimmelH. L.NyeJ. A.DrakeD. F.HernandezC. R.et al (2013b). Chronic interferon-α decreases dopamine 2 receptor binding and striatal dopamine release in association with anhedonia-like behavior in nonhuman primates.Neuropsychopharmacology382179–2187. 10.1038/npp.2013.115

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 60

  FelgerJ. C.TreadwayM. T. (2017). Inflammation effects on motivation and motor activity: role of dopamine.Neuropsychopharmacology42216–241. 10.1038/npp.2016.143

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 61

  FlemingP.RoubilleC.RicherV.StarninoT.McCourtC.McFarlaneA.et al (2015). Effect of biologics on depressive symptoms in patients with psoriasis: a systematic review.J. Eur. Acad. Dermatol. Venereol.291063–1070. 10.1111/jdv.12909

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 62

  FrenoisF.MoreauM.O’ConnorJ.LawsonM.MiconC.LestageJ.et al (2007). Lipopolysaccharide induces delayed FosB/DeltaFosB immunostaining within the mouse extended amygdala, hippocampus and hypothalamus, that parallel the expression of depressive-like behavior.Psychoneuroendocrinology32516–531. 10.1016/j.psyneuen.2007.03.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 63

  FuX.ZunichS. M.O’ConnorJ. C.KavelaarsA.DantzerR.KelleyK. W. (2010). Central administration of lipopolysaccharide induces depressive-like behavior in vivo and activates brain indoleamine 2,3 dioxygenase in murine organotypic hippocampal slice cultures.J. Neuroinflammation7:43. 10.1186/1742-2094-7-43

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 64

  FuX. Y.LiH. Y.JiangQ. S.CuiT.JiangX. H.ZhouQ. X.et al (2016). Infliximab ameliorating depression-like behavior through inhibiting the activation of the IDO-HAAO pathway mediated by tumor necrosis factor-alpha in a rat model.Neuroreport27953–959. 10.1097/WNR.0000000000000637

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 65

  GarbuttJ. C.DuchD. S.NicholC. A.WoolfJ. H. (1985). Urinary biopterin and neopterin excretion and pituitary-adrenal activity in psychiatric patients.Psychiatry Res.16181–187. 10.1016/0165-1781(85)90105-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 66

  GelmanB. B.SpencerJ. A.HolzerC. E.IIISoukupV. M. (2006). Abnormal striatal dopaminergic synapses in National NeuroAIDS Tissue Consortium subjects with HIV encephalitis.J. Neuroimmune Pharmacol.1410–420. 10.1007/s11481-006-9030-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 67

  GibneyS. M.FaganE. M.WaldronA. M.O’ByrneJ.ConnorT. J.HarkinA. (2014). Inhibition of stress-induced hepatic tryptophan 2,3-dioxygenase exhibits antidepressant activity in an animal model of depressive behavior.Int. J. Neuropsychopharmacol.17917–928. 10.1017/S1461145713001673

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 68

  GibneyS. M.McGuinnessB.PrendergastC.HarkinA.ConnorT. J. (2013). Poly I:C-induced activation of the immune response is accompanied by depression and anxiety-like behaviours, kynurenine pathway activation and reduced BDNF expression.Brain Behav. Immun.28170–181. 10.1016/j.bbi.2012.11.010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 69

  GodboutJ. P.MoreauM.LestageJ.ChenJ.SparkmanN. L.O’ConnorJ.et al (2008). Aging exacerbates depressive-like behavior in mice in response to activation of the peripheral innate immune system.Neuropsychopharmacology332341–2351. 10.1038/sj.npp.1301649

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 70

  GossecL.SteinbergG.RouanetS.CombeB. (2015). Fatigue in rheumatoid arthritis: quantitative findings on the efficacy of tocilizumab and on factors associated with fatigue. The French multicentre prospective PEPS Study.Clin. Exp. Rheumatol.33664–670.

  • Pubmed Abstract
  • Google Scholar
  • View reference in article

• 71

  GriffithsC. E. M.ThaçiD.GerdesS.ArenbergerP.PulkaG.KingoK.et al (2017). The EGALITY study: a confirmatory, randomized, double-blind study comparing the efficacy, safety and immunogenicity of GP2015, a proposed etanercept biosimilar, vs. the originator product in patients with moderate-to-severe chronic plaque-type psoriasis.Br. J. Dermatol.176928–938. 10.1111/bjd.15152

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 72

  HajiN.MandolesiG.GentileA.SacchettiL.FresegnaD.RossiS.et al (2012). TNF-(-mediated anxiety in a mouse model of multiple sclerosis.Exp. Neurol.237296–303. 10.1016/j.expneurol.2012.07.010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 73

  HamerM.BattyG. D.MarmotM. G.Singh-ManouxA.KivimäkiM. (2011). Anti-depressant medication use and C-reactive protein: results from two population-based studies.Brain Behav. Immun.25168–173. 10.1016/j.bbi.2010.09.013

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 74

  HaradaT.KagamiyamaH.HatakeyamaK. (1993). Feedback regulation mechanisms for the control of GTP cyclohydrolase I activity.Science2601507–1510. 10.1126/science.8502995

  • CrossRef
  • Google Scholar
  • View reference in article

• 75

  HaroonE.MillerA. H.SanacoraG. (2017). Inflammation, glutamate, and glia: a trio of trouble in mood disorders.Neuropsychopharmacology42193–215. 10.1038/npp.2016.199

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 76

  HarukiH.HoviusR.PedersenM. G.JohnssonK. (2016). Tetrahydrobiopterin biosynthesis as a potential target of the kynurenine pathway metabolite xanthurenic acid.J. Biol. Chem.291652–657. 10.1074/jbc.C115.680488

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 77

  HashimotoR.MizutaniM.OhtaT.NakazawaK.NagatsuT. (1994). Changes in plasma tetrahydrobiopterin levels of depressives in depressive and remission phases: reconfirmed by measurement with an internal standard.Neuropsychobiology2957–60. 10.1159/000119064

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 78

  HenryC. J.HuangY.WynneA. M.GodboutJ. P. (2009). Peripheral lipopolysaccharide (LPS) challenge promotes microglial hyperactivity in aged mice that is associated with exaggerated induction of both pro-inflammatory IL-1beta and anti-inflammatory IL-10 cytokines.Brain Behav. Immun.23309–317. 10.1016/j.bbi.2008.09.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 79

  HirayamaM.TsunodaM.YamamotoM.TsudaT.OhnoK. (2016). Serum tyrosine-to-phenylalanine ratio is low in Parkinson’s disease.J. Parkinsons Dis.6423–431. 10.3233/JPD-150736

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 80

  HogeE. A.BrandstetterK.MoshierS.PollackM. H.WongK. K.SimonN. M. (2009). Broad spectrum of cytokine abnormalities in panic disorder and posttraumatic stress disorder.Depress. Anxiety26447–455. 10.1002/da.20564

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 81

  HommaD.KatohS.TokuokaH.IchinoseH. (2013). The role of tetrahydrobiopterin and catecholamines in the developmental regulation of tyrosine hydroxylase level in the brain.J. Neurochem.12670–81. 10.1111/jnc.12287

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 82

  HorowitzM. A.WertzJ.ZhuD.CattaneoA.MusaelyanK.NikkheslatN. (2014). Antidepressant compounds can be both pro- and anti-inflammatory in human hippocampal cells.Int. J. Neuropsychopharmacol.18:yu076. 10.1093/ijnp/pyu076

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 83

  HughesA.KumariM. (2017). Associations of C-reactive protein and psychological distress are modified by antidepressants, supporting an inflammatory depression subtype: Findings from UKHLS.Brain Behav. Immun.6689–93. 10.1016/j.bbi.2017.07.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 84

  IchinoseH.OhyeT.TakahashiE.SekiN.HoriT.SegawaM.et al (1994). Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene.Nat. Genet.8236–242. 10.1038/ng1194-236

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 85

  JantaratnotaiN.MosikanonK.LeeY.McIntyreR. S. (2017). The interface of depression and obesity.Obes. Res. Clin. Pract.111–10. 10.1016/j.orcp.2016.07.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 86

  JeonS. W.KimY. K. (2017). Inflammation-induced depression: Its pathophysiology and therapeutic implications.J. Neuroimmunol.31392–98. 10.1016/j.jneuroim.2017.10.016

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 87

  JhaM. K.TrivediM. H. (2018). Personalized antidepressant selection and pathway to novel treatments: clinical utility of targeting inflammation.Int. J. Mol. Sci.191–15. 10.3390/ijms19010233

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 88

  KamataM.HiguchiH.YoshimotoM.YoshidaK.ShimizuT. (2000). Effect of single intracerebroventricular injection of alpha-interferon on monoamine concentrations in the rat brain.Eur. Neuropsychopharmacol.10129–132. 10.1016/S0924-977X(99)00067-X

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 89

  KappelmannN.LewisG.DantzerR.JonesP. B.KhandakerG. M. (2018). Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions.Mol. Psychiatry23335–343. 10.1038/mp.2016.167

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 90

  KawaseK.KondoK.SaitoT.ShimasakiA.TakahashiA.KamataniY.et al (2016). Risk factors and clinical characteristics of the depressive state induced by pegylated interferon therapy in patients with hepatitis C virus infection: a prospective study.Psychiatry Clin. Neurosci.70489–497. 10.1111/pcn.12424

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 91

  KazumoriH.IshiharaS.RumiM. A.Ortega-CavaC. F.KadowakiY.KinoshitaY. (2004). Transforming growth factor-alpha directly augments histidine decarboxylase and vesicular monoamine transporter 2 production in rat enterochromaffin-like cells.Am. J. Physiol. Gastrointest. Liver Physiol.286G508–G514. 10.1152/ajpgi.00269.2003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 92

  KekowJ.MootsR. J.EmeryP.DurezP.KoenigA.SinghA.et al (2010). Patient-reported outcomes improve with etanercept plus methotrexate in active early rheumatoid arthritis and the improvement is strongly associated with remission: the COMET trial.Ann. Rheum. Dis.69222–225. 10.1136/ard.2008.102509

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 93

  KishiT.IchinoseH.YoshimuraR.FukuoY.KitajimaT.InadaT.et al (2012). GTP cyclohydrolase 1 gene haplotypes as predictors of SSRI response in Japanese patients with major depressive disorder.J. Affect. Disord.142315–322. 10.1016/j.jad.2012.05.004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 94

  KitagamiT.YamadaK.MiuraH.HashimotoR.NabeshimaT.OhtaT. (2003). Mechanism of systemically injected interferon-alpha impeding monoamine biosynthesis in rats: role of nitric oxide as a signal crossing the blood-brain barrier.Brain Res.978104–114. 10.1016/S0006-8993(03)02776-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 95

  KlausF.PaternaJ. C.MarzoratiE.SigristH.GötzeL.SchwendenerS.et al (2016). Differential effects of peripheral and brain tumor necrosis factor on inflammation, sickness, emotional behavior and memory in mice.Brain Behav. Immun.58310–326. 10.1016/j.bbi.2016.08.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 96

  KloiberS.IsingM.ReppermundS.HorstmannS.DoseT.MajerM.et al (2007). Overweight and obesity affect treatment response in major depression.Biol. Psychiatry62321–326. 10.1016/j.biopsych.2006.10.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 97

  KnappS.IrwinM. (1989). Plasma levels of tetrahydrobiopterin and folate in major depression.Biol. Psychiatry26156–162. 10.1016/0006-3223(89)90019-X

  • CrossRef
  • Google Scholar

• 98

  KockiT.WnukS.KlocR.KockiJ.Owe-LarssonB.UrbanskaE. M. (2012). New insight into the antidepressants action: modulation of kynurenine pathway by increasing the kynurenic cid/3-hydroxykynurenine ratio.J. Neural. Transm.119235–243. 10.1007/s00702-011-0668-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 99

  KöhlerO.GasseC.PetersenL.IngstrupK. G.NierenbergA. A.MorsO.et al (2016). The effect of concomitant treatment with SSRIs and statins: a population-based study.Am. J. Psychiatry173807–815. 10.1176/appi.ajp.2016.15040463

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 100

  KoshimuraK.MurakamiY.TanakaJ.KatoY. (2000). The role of 6R-tetrahydrobiopterin in the nervous system.Prog. Neurobiol.61415–438. 10.1016/S0301-0082(99)00059-3

  • CrossRef
  • Google Scholar

• 101

  KrishnaS.KeralapurathM. M.LinZ.WagnerJ. J.de La SerreC. B.HarnD. A.et al (2015). Neurochemical and electrophysiological deficits in the ventral hippocampus and selective behavioral alterations caused by high-fat diet in female C57BL/6 mice.Neuroscience297170–181. 10.1016/j.neuroscience.2015.03.068

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 102

  KumaiT.TateishiT.TanakaM.WatanabeM.ShimizuH.KobayashiS. (2000). Effect of interferon-alpha on tyrosine hydroxylase and catecholamine levels in the brain of rats.Life Sci.67663–669. 10.1016/S0024-3205(00)00660-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 103

  KunesováM.BraunerováR.HlavatıP.TvrzickáE.StankováB.SkrhaJ. (2006). The influence of n-3 polyunsaturated fatty acids and very low calorie diet during a short-term weight reducing regimen on weight loss and serum fatty acid composition in severely obese women.Physiol. Res.5563–72.

  • Pubmed Abstract
  • Google Scholar

• 104

  LanquillonS.KriegJ. C.Bening-Abu-ShachU.VedderH. (2000). Cytokine production and treatment response in major depressive disorder.Neuropsychopharmacology22370–379. 10.1016/S0893-133X(99)00134-7

  • CrossRef
  • Google Scholar

• 105

  LasselinJ.MagneE.BeauC.LedaguenelP.DexpertS.AubertA.et al (2014). Adipose inflammation in obesity: relationship with circulating levels of inflammatory markers and association with surgery-induced weight loss.J. Clin. Endocrinol. Metab.99E53–E61. 10.1210/jc.2013-2673

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 106

  LaumetG.ZhouW.DantzerR.EdralinJ. D.HuoX.BudacD. P.et al (2017). Upregulation of neuronal kynurenine 3-monooxygenase mediates depression-like behavior in a mouse model of neuropathic pain.Brain Behav. Immun.6694–102. 10.1016/j.bbi.2017.07.008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 107

  LawsonM. A.ParrottJ. M.McCuskerR. H.DantzerR.KelleyK. W.O’ConnorJ. C. (2013). Intracerebroventricular administration of lipopolysaccharide induces indoleamine-2,3-dioxygenase-dependent depression-like behaviors.J. Neuroinflammation10:87. 10.1186/1742-2094-10-87

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 108

  LayéS.NadjarA.JoffreC.BazinetR. P. (2018). Anti-inflammatory effects of Omega-3 fatty acids in the brain: physiological mechanisms and relevance to pharmacology.Pharmacol. Rev.7012–38. 10.1124/pr.117.014092

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 109

  LeightonS. P.NerurkarL.KrishnadasR.JohnmanC.GrahamG. J.CavanaghJ. (2018). Chemokines in depression in health and in inflammatory illness: a systematic review and meta-analysis.Mol. Psychiatry2348–58. 10.1038/mp.2017.205

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 110

  LestageJ.VerrierD.PalinK.DantzerR. (2002). The enzyme indoleamine 2,3-dioxygenase is induced in the mouse brain in response to peripheral administration of lipopolysaccharide and superantigen.Brain Behav. Immun.16596–601. 10.1016/S0889-1591(02)00014-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 111

  LiN.LiuR. J.DwyerJ. M.BanasrM.LeeB.SonH.et al (2011). Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure.Biol. Psychiatry69754–761. 10.1016/j.biopsych.2010.12.015

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 112

  Llorens-MartinM.Jurado-ArjonaJ.Fuster-MatanzoA.HernandezF.RabanoA.AvilaJ. (2014). Peripherally triggered and GSK-3beta-driven brain inflammation differentially skew adult hippocampal neurogenesis, behavioral pattern separation and microglial activation in response to ibuprofen.Transl. Psychiatry4:e463. 10.1038/tp.2014.92

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 113

  LovelaceM. D.VarneyB.SundaramG.LennonM. J.LimC. K.JacobsK.et al (2017). Recent evidence for an expanded role of the kynurenine pathway of tryptophan metabolism in neurological diseases.Neuropsychopharmacology112373–388. 10.1016/j.neuropharm.2016.03.024

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 114

  LuppinoF. S.de WitL. M.BouvyP. F.StijnenT.CuijpersP.PenninxB. W.et al (2010). Overweight, obesity, and depression: a systematic review and meta-analysis of longitudinal studies.Arch. Gen. Psychiatry67220–229. 10.1001/archgenpsychiatry.2010.2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 115

  ManggeH.SummersK. L.MeinitzerA.ZelzerS.AlmerG.PrasslR.et al (2014). Obesity-related dysregulation of the tryptophan-kynurenine metabolism: role of age and parameters of the metabolic syndrome.Obesity22195–201. 10.1002/oby.20491

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 116

  Martín-HernándezD.Tendilla-BeltránH.MadrigalJ. L. M.García-BuenoB.LezaJ. C.CasoJ. R. (2018). Chronic mild stress alters kynurenine pathways changing the glutamate neurotransmission in frontal cortex of rats.Mol. Neurobiol.10.1007/s12035-018-1096-7[Epub ahead of print].

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 117

  MazareiG.BudacD. P.LuG.LeeH.MollerT.LeavittB. R. (2013). The absence of indoleamine 2,3-dioxygenase expression protects against NMDA receptor-mediated excitotoxicity in mouse brain.Exp. Neurol.249144–148. 10.1016/j.expneurol.2013.08.007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 118

  MeraliZ.BrennanK.BrauP.AnismanH. (2003). Dissociating anorexia and anhedonia elicited by interleukin-1beta: antidepressant and gender effects on responding for “free chow” and “earned” sucrose intake.Psychopharmacology165413–418. 10.1007/s00213-002-1273-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 119

  MoreauM.AndréC.O’ConnorJ. C.DumichS. A.WoodsJ. A.KelleyK. W.et al (2008). Inoculation of Bacillus Calmette-Guerin to mice induces an acute episode of sickness behavior followed by chronic depressive-like behavior.Brain Behav. Immun.221087–1095. 10.1016/j.bbi.2008.04.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 120

  MoreauM.LestageJ.VerrierD.MormèdeC.KelleyK. W.DantzerR.et al (2005). Bacille Calmette-Guerin inoculation induces chronic activation of peripheral and brain indoleamine 2,3-dioxygenase in mice.J. Infect. Dis.192537–544. 10.1086/431603

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 121

  MüllerN.SchwarzM. J.DehningS.DouheA.CeroveckiA.Goldstein-MullerB.et al (2006). The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine.Mol. Psychiatry11680–684. 10.1038/sj.mp.4001805

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 122

  MüllerU.SteinbergerD.TopkaH. (2002). Mutations of GCH1 in Dopa-responsive dystonia.J. Neural. Transm.109321–328. 10.1007/s007020200026

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 123

  MurrC.GrammerT. B.MeinitzerA.KleberM. E.MärzW.FuchsD. (2014). Immune activation and inflammation in patients with cardiovascular disease are associated with higher phenylalanine to tyrosine ratios: the ludwigshafen risk and cardiovascular health study.J. Amino Acids2014:783730. 10.1155/2014/783730

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 124

  MurrC.WidnerB.WirleitnerB.FuchsD. (2002). Neopterin as a marker for immune system activation.Curr. Drug Metab.3175–187. 10.2174/1389200024605082

  • CrossRef
  • Google Scholar

• 125

  MusselmanD. L.LawsonD. H.GumnickJ. F.ManatungaA. K.PennaS.GoodkinR. S.et al (2001). Paroxetine for the prevention of depression induced by high-dose interferon alfa.N. Engl. J. Med.344961–966. 10.1056/NEJM200103293441303

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 126

  NagatsuI.IchinoseH.SakaiM.TitaniK.SuzukiM.NagatsuT. (1995). Immunocytochemical localization of GTP cyclohydrolase I in the brain, adrenal gland, and liver of mice.J. Neural Transm. Gen. Sect.102175–188. 10.1007/BF01281153

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 127

  NasserA.MøllerL. B.OlesenJ. H.Konradsen RefsgaardL.AndreasenJ. T. (2014). Anxiety- and depression-like phenotype of hph-1 mice deficient in tetrahydrobiopterin.Neurosci. Res.8944–53. 10.1016/j.neures.2014.08.015

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 128

  NazimekK.KozlowskiM.BryniarskiP.StrobelS.BrykA.MyszkaM.et al (2016). Repeatedly administered antidepressant drugs modulate humoral and cellular immune response in mice through action on macrophages.Exp. Biol. Med.2411540–1550. 10.1177/1535370216643769

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 129

  NeurauterG.SchröcksnadelK.Scholl-BürgiS.Sperner-UnterwegerB.SchubertC.LedochowskiM.et al (2008). Chronic immune stimulation correlates with reduced phenylalanine turnover.Curr. Drug Metab.9622–627. 10.2174/138920008785821738

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 130

  NordenD. M.McCarthyD. O.BicerS.DevineR. D.ReiserP. J.GodboutJ. P.et al (2015). Ibuprofen ameliorates fatigue- and depressive-like behavior in tumor-bearing mice.Life Sci.14365–70. 10.1016/j.lfs.2015.10.020

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 131

  O’ConnorJ. C.AndréC.WangY.LawsonM. A.SzegediS. S.LestageJ.et al (2009a). Interferon-gamma and tumor necrosis factor-alpha mediate the upregulation of indoleamine 2,3-dioxygenase and the induction of depressive-like behavior in mice in response to bacillus Calmette-Guerin.J. Neurosci.294200–4209. 10.1523/JNEUROSCI.5032-08.2009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 132

  O’ConnorJ. C.LawsonM. A.AndréC.BrileyE. M.SzegediS. S.LestageJ.et al (2009b). Induction of IDO by bacille Calmette-Guerin is responsible for development of murine depressive-like behavior.J. Immunol.1823202–3212. 10.4049/jimmunol.0802722

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 133

  O’ConnorJ. C.LawsonM. A.AndreC.MoreauM.LestageJ.CastanonN.et al (2009c). Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice.Mol. Psychiatry14511–522. 10.1038/sj.mp.4002148

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 134

  O’FarrellK.HarkinA. (2017). Stress-related regulation of the kynurenine pathway: relevance to neuropsychiatric and degenerative disorders.Neuropharmacology112307–323. 10.1016/j.neuropharm.2015.12.004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 135

  OhashiA.SaekiY.HaradaT.NaitoM.TakahashiT.AizawaS.et al (2016). Tetrahydrobiopterin supplementation: elevation of tissue biopterin levels accompanied by a relative increase in dihydrobiopterin in the blood and the role of probenecid-sensitive uptake in scavenging dihydrobiopterin in the liver and kidney of rats.PLoS One11:e0164305. 10.1371/journal.pone.0164305

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 136

  OrmstadH.VerkerkR.SandvikL. (2016). Serum phenylalanine, tyrosine, and their ratio in acute ischemic stroke: on the trail of a biomarker?J. Mol. Neurosci.58102–108. 10.1007/s12031-015-0659-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 137

  OxenkrugG.TuckerK. L.RequintinaP.SummergradP. (2011). Neopterin, a marker of interferon-gamma-inducible inflammation, correlates with pyridoxal-5’-phosphate, waist circumference, HDL-cholesterol, insulin resistance and mortality risk in adult Boston community dwellers of puerto Rican origin.Am. J. Neuroprot. Neuroregen.348–52. 10.1166/ajnn.2011.1024

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 138

  OxenkrugG. F. (2011). Interferon-gamma-inducible kynurenines/pteridines inflammation cascade: implications for aging and aging-associated psychiatric and medical disorders.J. Neural Transm.11875–85. 10.1007/s00702-010-0475-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 139

  PanL.McKainB. W.Madan-KhetarpalS.McguireM.DilerR. S.PerelJ. M.et al (2011). GTP-cyclohydrolase deficiency responsive to sapropterin and 5-HTP supplementation: relief of treatment-refractory depression and suicidal behaviour.BMJ Case Rep.2011:bcr0320113927. 10.1136/bcr.03.2011.3927

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 140

  ParkS. E.DantzerR.KelleyK. W.McCuskerR. H. (2011). Central administration of insulin-like growth factor-I decreases depressive-like behavior and brain cytokine expression in mice.J. Neuroinflammation8:12. 10.1186/1742-2094-8-12

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 141

  ParrottJ. M.RedusL.O’ConnorJ. C. (2016a). Kynurenine metabolic balance is disrupted in the hippocampus following peripheral lipopolysaccharide challenge.J. Neuroinflammation13:124. 10.1186/s12974-016-0590-y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 142

  ParrottJ. M.RedusL.Santana-CoelhoD.MoralesJ.GaoX.O’ConnorJ. C. (2016b). Neurotoxic kynurenine metabolism is increased in the dorsal hippocampus and drives distinct depressive behaviors during inflammation.Transl. Psychiatry6:e918. 10.1038/tp.2016.200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 143

  PenninxB. W.MilaneschiY.LamersF.VogelzangsN. (2013). Understanding the somatic consequences of depression: biological mechanisms and the role of depression symptom profile.BMC Med.11:129. 10.1186/1741-7015-11-129

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 144

  PloderM.NeurauterG.SpittlerA.SchroecksnadelK.RothE.FuchsD. (2008). Serum phenylalanine in patients post trauma and with sepsis correlate to neopterin concentrations.Amino Acids35303–307. 10.1007/s00726-007-0625-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 145

  PotvinS.StipE.SepehryA. A.GendronA.BahR.KouassiE. (2008). Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review.Biol. Psychiatry63801–808. 10.1016/j.biopsych.2007.09.024

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 146

  PrendergastG. C.MalachowskiW. P.DuHadawayJ. B.MullerA. J. (2018). Discovery of IDO1 inhibitors: from bench to bedside.Cancer Res.776795–6811. 10.1158/0008-5472.CAN-17-2285

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 147

  RaisonC. L.CapuronL.MillerA. H. (2006). Cytokines sing the blues: inflammation and the pathogenesis of depression.Trends Immunol.2724–31. 10.1016/j.it.2005.11.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 148

  RaisonC. L.DantzerR.KelleyK. W.LawsonM. A.WoolwineB. J.VogtG.et al (2010). CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-alpha: relationship to CNS immune responses and depression.Mol. Psychiatry15393–403. 10.1038/mp.2009.116

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 149

  RaisonC. L.RutherfordR. E.WoolwineB. J.ShuoC.SchettlerP.DrakeD. F.et al (2013). A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers.JAMA Psychiatry7031–41. 10.1001/2013.jamapsychiatry.4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 150

  RapaportM. H.NierenbergA. A.SchettlerP. J.KinkeadB.CardoosA.WalkerR.et al (2016). Inflammation as a predictive biomarker for response to omega-3 fatty acids in major depressive disorder: a proof-of-concept study.Mol. Psychiatry2171–79. 10.1038/mp.2015.22

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 151

  RemusJ. L.DantzerR. (2016). Inflammation models of depression in rodents: relevance to psychotropic drug discovery.Int. J. Neuropsychopharmacol.191–13. 10.1093/ijnp/pyw028

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 152

  ReusG. Z.JansenK.TitusS.CarvalhoA. F.GabbayV.QuevedoJ. (2015). Kynurenine pathway dysfunction in the pathophysiology and treatment of depression: evidences from animal and human studies.J. Psychiatr. Res.68316–328. 10.1016/j.jpsychires.2015.05.007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 153

  RosenblatJ. D.McIntyreR. S. (2018). Efficacy and tolerability of minocycline for depression: a systematic review and meta-analysis of clinical trials.J. Affect. Disord.227219–225. 10.1016/j.jad.2017.10.042

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 154

  RushA. J.TrivediM. H.WisniewskiS. R.NierenbergA. A.StewartJ. W.WardenD.et al (2006). Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR^∗D report.Am. J. Psychiatry1631905–1917. 10.1176/ajp.2006.163.11.1905

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 155

  RussiP.AlesianiM.LombardiG.DavolioP.PellicciariR.MoroniF. (1992). Nicotinylalanine increases the formation of kynurenic acid in the brain and antagonizes convulsions.J. Neurochem.592076–2080. 10.1111/j.1471-4159.1992.tb10097.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 156

  SalazarA.Gonzalez-RiveraB. L.RedusL.ParrottJ. M.O’ConnorJ. C. (2012). Indoleamine 2,3-dioxygenase mediates anhedonia and anxiety-like behaviors caused by peripheral lipopolysaccharide immune challenge.Horm. Behav.62202–209. 10.1016/j.yhbeh.2012.03.010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 157

  SatoT.SuzukiE.YokoyamaM.SembaJ.WatanabeS.MiyaokaH. (2006). Chronic intraperitoneal injection of interferon-alpha reduces serotonin levels in various regions of rat brain, but does not change levels of serotonin transporter mRNA, nitrite or nitrate.Psychiatry Clin. Neurosci.60499–506. 10.1111/j.1440-1819.2006.01538.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 158

  SavitzJ.DrevetsW. C.SmithC. M.VictorT. A.WurfelB. E.BellgowanP. S.et al (2015a). Putative neuroprotective and neurotoxic kynurenine pathway metabolites are associated with hippocampal and amygdalar volumes in subjects with major depressive disorder.Neuropsychopharmacology40463–471. 10.1038/npp.2014.194

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 159

  SavitzJ.DrevetsW. C.WurfelB. E.FordB. N.BellgowanP. S.VictorT. A.et al (2015b). Reduction of kynurenic acid to quinolinic acid ratio in both the depressed and remitted phases of major depressive disorder.Brain Behav. Immun.4655–59. 10.1016/j.bbi.2015.02.007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 160

  SawadaM.HorikoshiT.MasadaM.AkinoM.SugimotoT.MatsuuraS.et al (1986). A sensitive assay of GTP cyclohydrolase I activity in rat and human tissues using radioimmunoassay of neopterin.Anal. Biochem.154361–366. 10.1016/0003-2697(86)90537-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 161

  SchedlowskiM.EnglerH.GrigoleitJ. S. (2014). Endotoxin-induced experimental systemic inflammation in humans: a model to disentangle immune-to-brain communication.Brain Behav. Immun.351–8. 10.1016/j.bbi.2013.09.015

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 162

  SchmidtF. M.KirkbyK. C.LichtblauN. (2016). Inflammation and immune regulation as potential drug targets in antidepressant treatment.Curr. Neuropharmacol.14674–687. 10.2174/1570159X14666160115130414

  • CrossRef
  • Google Scholar

• 163

  SchwarczR.StoneT. W. (2017). The kynurenine pathway and the brain: challenges, controversies and promises.Neuropharmacology112237–247. 10.1016/j.neuropharm.2016.08.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 164

  ShariqA. S.BrietzkeE.RosenblatJ. D.BarendraV.PanZ.McIntyreR. S. (2018). Targeting cytokines in reduction of depressive symptoms: a comprehensive review.Prog. Neuropsychopharmacol. Biol. Psychiatry8386–91. 10.1016/j.pnpbp.2018.01.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 165

  SharmaS.FultonS. (2013). Diet-induced obesity promotes depressive-like behaviour that is associated with neural adaptations in brain reward circuitry.Int. J. Obes.37382–389. 10.1038/ijo.2012.48

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 166

  ShiW.MeiningerC. J.HaynesT. E.HatakeyamaK.WuG. (2004). Regulation of tetrahydrobiopterin synthesis and bioavailability in endothelial cells.Cell. Biochem. Biophys.41415–434. 10.1385/CBB:41:3:415

  • CrossRef
  • Google Scholar

• 167

  Silva-AdayaD.Pérez-De La CruzV.Villeda-HernándezJ.Carrillo-MoraP.González-HerreraI. G.et al (2011). Protective effect of L-kynurenine and probenecid on 6-hydroxydopamine-induced striatal toxicity in rats: implications of modulating kynurenate as a protective strategy.Neurotoxicol. Teratol.33303–312. 10.1016/j.ntt.2010.10.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 168

  SmithK. J.AuB.OllisL.SchmitzN. (2018). The association between C-reactive protein, Interleukin-6 and depression among older adults in the community: a systematic review and meta-analysis.Exp. Gerontol.102109–132. 10.1016/j.exger.2017.12.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 169

  SteinerJ.WalterM.GosT.GuilleminG. J.BernsteinH. G.SarnyaiZ.et al (2011). Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: evidence for an immune-modulated glutamatergic neurotransmission?J. Neuroinflammation8:94. 10.1186/1742-2094-8-94

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 170

  StrawbridgeR.ArnoneD.DaneseA.PapadopoulosA.Herane VivesA.CleareA. J. (2015). Inflammation and clinical response to treatment in depression: a meta-analysis.Eur. Neuropsychopharmacol.251532–1543. 10.1016/j.euroneuro.2015.06.007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 171

  Sumi-IchinoseC.UranoF.KurodaR.OhyeT.KojimaM.TazawaM.et al (2001). Catecholamines and serotonin are differently regulated by tetrahydrobiopterin. A study from 6-pyruvoyltetrahydropterin synthase knockout mice.J. Biol. Chem.27641150–41160. 10.1074/jbc.M102237200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 172

  TashiroT.MurakamiY.MouriA.ImamuraY.NabeshimaT.YamamotoY.et al (2017). Kynurenine 3-monooxygenase is implicated in antidepressants-responsive depressive-like behaviors and monoaminergic dysfunctions.Behav. Brain Res.317279–285. 10.1016/j.bbr.2016.09.050

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 173

  ThönyB.AuerbachG.BlauN. (2000). Tetrahydrobiopterin biosynthesis, regeneration and functions.Biochem. J.347(Pt 1), 1–16.

  • Google Scholar

• 174

  TienL. T.KaizakiA.PangY.CaiZ.BhattA. J.FanL. W. (2013). Neonatal exposure to lipopolysaccharide enhances accumulation of (-synuclein aggregation and dopamine transporter protein expression in the substantia nigra in responses to rotenone challenge in later life.Toxicology30896–103. 10.1016/j.tox.2013.03.014

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 175

  Toledo-ShermanL. M.PrimeM. E.MrzljakL.BeconiM. G.BeresfordA.BrookfieldF. A.et al (2015). Development of a series of aryl pyrimidine kynurenine monooxygenase inhibitors as potential therapeutic agents for the treatment of Huntington’s disease.J. Med. Chem.58115911–115983. 10.1021/jm501350y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 176

  ToupsM. S.MyersA. K.WisniewskiS. R.KurianB.MorrisD. W.RushA. J.et al (2013). Relationship between obesity and depression: characteristics and treatment outcomes with antidepressant medication.Psychosom. Med.75863–872. 10.1097/PSY.0000000000000000

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 177

  TrakiL.RostomS.TahiriL.BahiriR.HarzyT.AbouqalR.et al (2014). Responsiveness of the EuroQol EQ-5D and hospital anxiety and depression scale (HADS) in rheumatoid arthritis patients receiving tocilizumab.Clin. Rheumatol.331055–1060. 10.1007/s10067-014-2609-z

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 178

  Trender-GerhardI.SweeneyM. G.SchwingenschuhP.MirP.EdwardsM. J.GerhardA.et al (2009). Autosomal-dominant GTPCH1-deficient DRD: clinical characteristics and long-term outcome of 34 patients.J. Neurol. Neurosurg. Psychiatry80839–845. 10.1136/jnnp.2008.155861

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 179

  TynanR. J.WeidenhoferJ.HinwoodM.CairnsM. J.DayT. A.WalkerF. R. (2012). A comparative examination of the anti-inflammatory effects of SSRI and SNRI antidepressants on LPS stimulated microglia.Brain Behav. Immun.26469–479. 10.1016/j.bbi.2011.12.011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 180

  TyringS.GottliebA.PappK.GordonK.LeonardiC.WangA.et al (2006). Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial.Lancet36729–35. 10.1016/S0140-6736(05)67763-X

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 181

  ValkanovaV.EbmeierK. P.AllanC. L. (2013). CRP, IL-6 and depression: a systematic review and meta-analysis of longitudinal studies.J. Affect. Disord.150736–744. 10.1016/j.jad.2013.06.004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 182

  Van HoveJ. L.SteyaertJ.MatthijsG.LegiusE.TheysP.WeversR.et al (2006). Expanded motor and psychiatric phenotype in autosomal dominant Segawa syndrome due to GTP cyclohydrolase deficiency.J. Neurol. Neurosurg. Psychiatry7718–23. 10.1136/jnnp.2004.051664

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 183

  VécseiL.SzalárdyL.FülöpF.ToldiJ. (2013). Kynurenines in the CNS: recent advances and new questions.Nat. Rev. Drug Discov.1264–82. 10.1038/nrd3793

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 184

  VichayaE. G.LaumetG.ChristianD. L.GrossbergA. J.EstradaD. J.HeijnenC. B.et al (2018). Motivational changes that develop in a mouse model of inflammation-induced depression are independent of indoleamine 2,3 dioxygenase.Neuropsychopharmacology10.1038/s41386-018-0075-z[Epub ahead of print].

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 185

  VogelzangsN.DuivisH. E.BeekmanA. T.KluftC.NeuteboomJ.HoogendijkW.et al (2012). Association of depressive disorders, depression characteristics and antidepressant medication with inflammation.Transl. Psychiatry21:e79. 10.1038/tp.2012.8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 186

  WalkerA. K.BudacD. P.BisulcoS.LeeA. W.SmithR. A.BeendersB.et al (2013). NMDA receptor blockade by ketamine abrogates lipopolysaccharide-induced depressive-like behavior in C57BL/6J mice.Neuropsychopharmacology381609–1616. 10.1038/npp.2013.71

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 187

  WernerE. R.GorrenA. C.HellerR.Werner-FelmayerG.MayerB. (2003). Tetrahydrobiopterin and nitric oxide: mechanistic and pharmacological aspects.Exp. Biol. Med.2281291–1302. 10.1177/153537020322801108

  • CrossRef
  • Google Scholar

• 188

  WiêdłochaM.MarcinowiczP.KrupaR.Janoska-JaździkM.JanusM.DêbowskaW. (2018). Effect of antidepressant treatment on peripheral inflammation markers - A meta-analysis.Prog. Neuropsychopharmacol. Biol. Psychiatry80217–226. 10.1016/j.pnpbp.2017.04.026

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 189

  WoggonB.AngstJ.CurtiusH. C.NiederwieserA. (1984). Unsuccessful treatment of depression with tetrahydrobiopterin.Lancet2:1463. 10.1016/S0140-6736(84)91648-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 190

  WooY. S.SeoH. J.McIntyreR. S.BahkW. M. (2016). Obesity and its potential effects on antidepressant treatment outcomes in patients with depressive disorders: a literature review.Int. J. Mol. Sci.171–20. 10.3390/ijms17010080

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 191

  World Health Organization (2017). Depression and Other Common Mental Disorders: Global Health Estimates.Geneva: World Health Organization.

  • Google Scholar

• 192

  WuH. Q.RassoulpourA.SchwarczR. (2007). Kynurenic acid leads, dopamine follows: a new case of volume transmission in the brain?J. Neural Transm.11433–41. 10.1007/s00702-006-0562-y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 193

  WynneA. M.HenryC. J.HuangY.ClelandA.GodboutJ. P. (2010). Protracted downregulation of CX3CR1 on microglia of aged mice after lipopolysaccharide challenge.Brain Behav. Immun.241190–1201. 10.1016/j.bbi.2010.05.011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 194

  XieW.CaiL.YuY.GaoL.XiaoL.HeQ.et al (2014). Activation of brain indoleamine 2,3-dioxygenase contributes to epilepsy-associated depressive-like behavior in rats with chronic temporal lobe epilepsy.J. Neuroinflammation11:41. 10.1186/1742-2094-11-41

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 195

  ZaminelliT.GradowskiR. W.BassaniT. B.BarbieroJ. K.SantiagoR. M.Maria-FerreiraD.et al (2014). Antidepressant and antioxidative effect of Ibuprofen in the rotenone model of Parkinson’s disease.Neurotox. Res.26351–362. 10.1007/s12640-014-9467-y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 196

  ZangerleR.KurzK.NeurauterG.KitchenM.SarclettiM.FuchsD. (2010). Increased blood phenylalanine to tyrosine ratio in HIV-1 infection and correction following effective antiretroviral therapy.Brain Behav. Immun.24403–408. 10.1016/j.bbi.2009.11.004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 197

  ZhaoX.CaoF.LiuQ.LiX.XuG.LiuG.et al (2017). Behavioral, inflammatory and neurochemical disturbances in LPS and UCMS-induced mouse models of depression.Behav. Brain Res.10.1016/j.bbr.2017.05.064[Epub ahead of print].

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 198

  ZhuC. B.BlakelyR. D.HewlettW. A. (2006). The proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha activate serotonin transporters.Neuropsychopharmacology312121–2131. 10.1038/sj.npp.1301029

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 199

  ZogaM.OulisP.ChatzipanagiotouS.MasdrakisV. G.PliatsikaP.BoufidouF.et al (2014). Indoleamine 2,3-dioxygenase and immune changes under antidepressive treatment in major depression in females.In Vivo28633–638.

  • Pubmed Abstract
  • Google Scholar

• 200

  ZuzarteP.DuongA.FigueiraM. L.VitaliA. C.ScolaG. (2018). Current therapeutic approaches for targeting inflammation in depression and cardiovascular disease.Curr. Drug Metab.10.2174/1389200219666180305143501[Epub ahead of print].

  • Pubmed Abstract
  • CrossRef
  • Google Scholar