2.2. Gene Expression and Genetic Predisposition

Several functional allelic variants and single-nucleotide polymorphisms (SNPs) of genes encoding immune and inflammatory molecules have been associated with MDD, including those encoding expression of inflammatory cytokines, major histocompatibility complex proteins, B and T cells, and inflammatory mediators like cyclo-oxygenase2 [5, 41-44]. In PTSD, results from a genome-wide association study (GWAS) indicated that polymorphisms for genes involved in inflammatory pathways were enriched in women with PTSD [45]. Furthermore, in patients from a high risk urban setting with a history of trauma, those who carried a CRP genotype (rs1130864) that is associated with elevated CRP concentrations had higher rates of PTSD and reported higher severity of symptoms of being overly alert and losing interest in activities [46]. As alluded to in the introduction, such findings have engendered speculation as to whether alleles that promote enhanced inflammatory cytokine secretion were evolutionarily advantageous and thus conserved [5]. Indeed, heightened inflammatory responses to environmental stimuli may have improved survival by conferring greater protection from bacterial and viral infection [5], and genetic priming to respond to stress and the environment with increased inflammatory and antiviral responses could contribute to the high prevalence of psychiatric disorders comorbid with medical illnesses that are associated with inflammation (e.g. cardiovascular disease, metabolic disorders, and autoimmune disorders) [47-52].

In addition to genetic polymorphisms, increased inflammatory gene expression in circulating immune cells has been found in patients with MDD, PTSD and other psychiatric disorders [53-55], and may predict treatment response in MDD. For instance, a targeted analysis of leukocyte mRNA expression of a subset of genes related to inflammation, glucocorticoid receptor signaling, and neuroplasticity revealed higher baseline mRNA levels of interleukin (IL)-1β, macrophage inhibitory factor (MIF), and TNF in patients with MDD who failed to respond to 8 weeks of treatment with escitalopram or nortriptyline [56]. Interestingly, increased expression of a number of inflammatory markers has been observed in the brains of patients with mood disorders [53, 57].

2.3. Sources of Innate Immune Activation and Inflammation

Factors that may activate the innate immune system and contribute to increased inflammation in psychiatric patients who are otherwise medically stable include psychosocial stress (and particularly early life stress or trauma), sleep disturbance, inflammatory diet and gastrointestinal permeability, obesity and other lifestyle factors such as smoking [13]. Persons with a history of childhood trauma exhibit elevated inflammatory biomarkers and higher rates of depression as adults [58, 59], and a “biological embedding” or imprinting of stress through inflammatory processes in childhood has been proposed [60, 61]. For instance, subjects with MDD and a history of early life stress responded to psychological stress (the Trier Social Stress Test) with exaggerated circulating IL-6 production and increased DNA binding of nuclear factor (NF)-kB in peripheral blood mononuclear cells compared to non-depressed controls [62]. Increased IL-6 production in adolescents with histories of childhood adversity has been shown to precede subsequent development of depression 6 months later [63]. Similarly, peripheral CRP prior to trauma has been shown to be a significant predictor of future development of PTSD after trauma, [64] and inflammatory cytokine production early after trauma was also predictive of the development of PTSD [65]. Together these findings suggest causal relationships between early life stress or trauma, increased inflammation, and development of MDD and/or PTSD.

Considerable evidence now exists supporting mechanisms by which stress activates the inflammatory response [66, 67]. On a cellular level, the immune system can detect danger signals in the absence of a pathogen through the release of danger associated molecular patterns (DAMPs) such as heat shock protein-72, uric acid, and adenosine triphosphate (ATP), through a process termed “sterile inflammation” [66, 68]. These DAMPS are released during psychological stress, and one key mechanism by which they may elicit an immune response is through the NLRP3 inflammasome (Fig. ​11), a multi-protein complex that is involved in the processing of IL-1beta. DAMPs are known to stimulate the inflammasome in the presence of endotoxin to activate caspase-1, which cleaves the immature precursor of interleukin IL-1beta as well as IL-18 into their mature, releasable forms [67, 68]. This release of IL-1beta can then induce the production of other inflammatory cytokines that are produced during stress [67]. Therefore, DAMPS and the NLRP3 inflammasome may serve as a primary link by which stress is translated into damage signals that promote inflammatory activity in patients exposed to chronic psychological stress and trauma.

Sleep disturbance may be another variable that is related to inflammation [69-72]. Sleep deprivation results in increased circulating levels of IL-6, TNF, and CRP when compared to periods of undisturbed sleep [73-75]. Disturbed sleep also increase circulating IL-6, TNF and CRP [73-75], and sleep impairments in psychiatric illnesses such as MDD have been associated with increased inflammation [69-72]. In terms of lifestyle factors, inflammatory diets that promote gut permeability and changes in the microbiota, smoking, and increased body mass index (BMI) all contribute to increased inflammation and may interact with genetics and stress to contribute to behavioral symptoms and poor overall health outcomes in patients with psychiatric illness [13, 76]. For example, obesity from consumption of a high-fat diet in rodents induces changes in the gut microbiota and increases ileal inflammation and permeability [77]. Obesity and high BMI are associated with increased concentrations of IL-6 and other inflammatory markers in humans [78, 79] thought to be the result of macrophage accumulation in adipose tissue, and especially visceral adiposity, which can release cytokines into portal circulation [80-82]. Interestingly, adiposity has been suggested as a link between psychiatric illness, increased inflammatory markers and increased risk of coronary heart disease [83, 84].

4.1. Translational Biochemical and Neuroimaging Studies

Initial evidence that inflammation can affect brain DA originates from neurochemical and behavioral studies in rodents administered acute or sub-chronic IFN-α that measured DA and/or DA metabolites in concert with depressive behaviors and changes in locomotor activity [134, 138-141]. Some studies reported increases [138, 140] while others have reported decreases [134, 139, 141] in brain DA and/or metabolites following acute or sub-chronic IFN-α administration. These discrepancies were likely due to differences in dosing, length of exposure, and most importantly, the fact that species-specific IFN-α was variably used and rodents do not respond to human IFN-α with activation of classic type I IFN receptor signaling [142-144]. Moreover, human IFN-α administered to rodents binds to opioid receptors, which may be responsible for some of the observed changes in brain monoamines [145-147]. Moreover, chronic (6 days to 4 weeks) peripheral administration of both human and species-specific IFN-a administered to rodents has demonstrated only limited ability to reliably induce depressive behaviors (for example see [142, 144, 148-154].

Rhesus monkeys exposed to chronic IFN-α exhibit immune, neuroendocrine and behavioral responses similar to that of cytokine-treated patients, including decreases in psychomotor activity and increases in depressive-like huddling behavior (in ~50% of animals) [3, 155]. Of note, depressive huddling behavior in non-human primates has been previously described following chronic administration of the monoamine-depleting agent reserpine, and DA receptor antagonists and partial agonists [156, 157]. Only animals that displayed depressive behavior following IFN-α administration were found to have significantly lower cerebrospinal fluid (CSF) concentrations of the DA metabolites homovanillic acid (HVA) and 3,4 dihydroxy-phenylacetic acid (DOPAC), which also correlated with decreased locomotor activity [3, 155]. Moreover, chronic IFN-α administration reduced effort-based but not freely available sucrose consumption by the monkeys [133]. Similar to the effects of IFN-α, peripheral administration of IL-1β to rodents has been shown to decrease effortful responding for sucrose reward over freely available chow, in the absence of a decrease in preference for freely available sucrose over chow [135]; an effect which was reversed by lisdexamfetamine [158]. Interestingly, peripheral administration of IL-1beta in mice at 24 hours has been shown to decrease locomotor (wheel running) activity, which was improved by methylphenidate but not modafinil [159]. Furthermore, similar to IL-1beta administration, an overall decrease in responding for food reward has been reported in mice following peripheral administration of lipopolysaccharide (LPS; i.e. endotoxin) with no decrease in reward sensitivity (preference for high value sucrose rewards) [160].

To further explore the effects of inflammatory cytokines on synaptic availability and release of striatal DA that may underlie inflammation effects on motivation and motor function, in vivo microdialysis was conducted on IFN-α-treated monkeys [133]. Results indicated that stimulated DA release was indeed decreased in the striatum after chronic administration of IFN-α (4 weeks), which correlated with reduced effort-based sucrose consumption [133]. These in vivo microdialysis findings of cytokine-induced decreases in striatal DA release were corroborated by translational neuroimaging studies in IFN-α-treated monkeys using [¹¹C]raclopride PET that found decreased DA release in putamen and ventral striatum [133]. Furthermore, IFN-α-induced decreases in striatal DA release were reversed by the DA precursor levodopa (L-DOPA) administered via reverse in vivo microdialysis, indicating that cytokines may reduced DA synthesis and availability [161]. In addition to IFN-α administration, models of peripheral inflammation in rodents have also been shown to decrease DA availability. For example, single injections of septic doses of LPS (5 mg/kg) cause progressive neurodegeneration of the nigrostriatal DArgic system [162, 163]. It should be noted that acute systemic administration of low dose LPS (~100 μg/kg) has been reported to either decrease tissue DA content or increase extracellular DA metabolites in the nucleus accumbens (NAcc) [164, 165]. However, these studies assessed DA and “anhedonic” behavior (sucrose preference or responding for brain stimulation) at 2 to 4 hours post-LPS [164-166], a time point that may be confounded due to febrile effects of LPS and related sickness behaviors [167-169]. These early effects of LPS may also reflect, for instance, acute activation of neuroendocrine peptides and hormones (minutes to hours) which can have stimulatory effects on turnover or release of brain catecholamines [170-173], and which may occur ahead of the more chronic mechanisms by which inflammation is thought to contribute to decreased DA availability (see Section 6 below for detailed discussion). Together, these results from animal studies indicate that a variety of inflammatory stimuli have been consistently found to affect brain DA to lead to relevant behavioral symptoms, and have prompt further investigation into inflammation effects on DA and the basal ganglia in clinical populations.

5.1. Amygdala

The amygdala is a principal brain region involved in fear and anxiety, and it is thought to play a crucial role in the neural circuitry of PTSD [206]. Neuroimaging findings in humans indicate that not only does inflammation increase amygdala activity, but also that increased amygdala responses to stress are associated with increased production of inflammatory cytokines [207-209]. Increased IL-6 and TNF after administration of endotoxin to healthy subjects has been shown to increase amygdala activity in response to socially threatening images, which was associated with enhanced feelings of social disconnection [208]. Administration of typhoid vaccination, which increases IL-6 and induces behavioral changes including cognitive disturbance and fatigue, also increased activation of the amygdala during presentation of congruent and incongruent stimuli [210]. In terms of stress sensitivity and neural pathways involved in the inflammatory response to stress, heightened neural activity in the amygdala in response to a psychosocial laboratory stressor was associated with greater stress-induced increases in IL-6 [209]. Thus, greater amygdala sensitivity to stress may lead to higher inflammatory cytokine production, which may in turn affect amygdala activity to create a feed-forward effect of inflammation on neural circuitry relevant to anxiety and PTSD symptoms.

5.2. Medial Prefrontal Cortex and Subgenual ACC

The medial prefrontal cortex, including the rostral ACC, subgenual ACC (BA 25) and medial frontal gyrus, is extensively connected to the amygdala in primates and thought to be involved in fear extinction and emotional regulation in PTSD [206, 211]. Several studies have reported a relationship between peripheral inflammatory cytokines and activity of medial prefrontal cortical regions, including the subgenual ACC, either in individuals undergoing stress or following administration of cytokine-inducers [207, 212]. Indeed, administration of typhoid vaccination to healthy controls induced mood changes that correlated with enhanced activity within subgenual ACC during an implicit emotional face perception task. Typhoid vaccination also reduced task-related functional connectivity of the subgenual ACC to the amygdala and other medial prefrontal cortical regions, as well as the nucleus accumbens and superior temporal sulcus, which correlated with peripheral blood IL-6 [207]. As mentioned above, heightened neural activity in the amygdala was associated with increased IL-6 responses to a psychosocial laboratory stressor, and functional connectivity analyses also indicated that individuals who showed a heightened inflammatory response to the stressor exhibited stronger coupling between the amygdala and the dorsomedial prefrontal cortex [209]. In a separate study of women undergoing the chronic emotional stress of bereavement, elevations in salivary concentrations of IL-1beta and soluble TNF receptor II have been shown to positively correlate with the degree of ventral prefrontal activation (including subgenual ACC and the orbitofrontal cortex) to a grief-elicitation task [212], suggesting a relationship between stress, inflammation, and medial prefrontal cortical activation that may be relevant for emotional processing in stress and trauma-related disorders.

5.3. Insula

Another region associated with amygdala activity and thought to contribute to emotional distress in anxiety disorders and PTSD is the insula [213, 214]. For instance, increased activation of the anterior insula and amygdala, and decreased connectivity among the anterior insula, amygdala, and ACC, have been observed in women with PTSD from intimate partner violence while matching to fearful or angry versus happy target faces [215]. Given the role of the insula in interoception, it is not surprising that this brain region has also been reported to be activated in response to peripheral inflammatory stimuli [210]. As mentioned above, in addition to activation of the amygdala, administration of typhoid vaccination increased activation of the insula during presentation of congruent and incongruent stimuli [210]. Among females but not males administered endotoxin, increases in IL-6 were associated with increases in neural activity in brain regions including the anterior insula in response to social exclusion during a virtual ball-tossing game [216]. Endotoxin administration has also been shown to increase cerebral glucose metabolism in the insula as measured by PET [217], and to decrease its functional connectivity with cingulate cortex [218]. Therefore, heightened sensitivity of the insula to inflammatory cytokines in the periphery, particularly in the presence of emotional stimuli, may contribute to altered neural circuitry involving the amygdala, medial prefrontal cortex and ACC to precipitate symptoms of fear, anxiety and emotional disturbance.

6.1. Therapies that Block Inflammation

A number of recent studies have begun to test the potential of anti-inflammatory compounds as possible antidepressant therapies. Most studies to date have focused on compounds such as cyclooxygenase (COX) inhibitors or minocycline, which have relatively mild anti-inflammatory effects and numerous “off target” effects that may confound data interpretation [16, 239]. A recent meta-analysis reported anti-depressant effects for anti-inflammatory agents in BD [240], however some of the selected trials used drugs that block oxidative stress, which may have many other sources in addition to inflammation. Recent meta-analyses in MDD also reported mild to moderate effect sizes showing that COX inhibitors may reduce depressive symptoms, yet heterogeneity across studies and mostly small sample sizes complicate results [241, 242]. It should be noted that the majority of studies included in the meta-analyses described above have not selected patients with increased inflammation, nor have they measured peripheral inflammatory markers to establish anti-inflammatory activity of the treatments. Interestingly, a recent study tested the efficacy of infliximab, a highly-selective TNF antagonist, in treatment-resistant MDD (TRD) as a function of peripheral inflammation. Treatment with infliximab was associated with robust decreases in plasma CRP concentrations, as well as a strong anti-depressant effect, but only in patients with elevated CRP at baseline [27]. Moreover, the greatest area of symptom improvement was related to motivation (interest in activities), followed by motor retardation and anxiety [27], which is consistent with the hypothesis that blockade of inflammation may exert anti-depressant properties through reversing inflammation effects on corticostriatal reward and motor as well as anxiety circuitry.

A number of holistic and alternative strategies, such as exercise, weight reduction or diet modification, dietary supplements, yoga, massage, tai chi and meditation, that have been shown to reduce depressive and anxiety symptoms are thought to either directly or indirectly reduce inflammation [243]. Weight loss and exercise have been the most studied of these interventions, both of which have been shown to have antidepressant and anti-anxiety effects [244, 245] and to reduce inflammation over time [246, 247]. Another therapy thought to decrease inflammation is supplementation with omega-3 fatty acids, which has been shown to have antidepressant efficacy, especially for eicosapentaenoic acid (EPA) [248], as verified by meta-analysis [249]. Indeed, treatment with EPA has been shown to prevent depression induced by IFN-α [250], and patients who are vulnerable to the development of this inflammation-induced depression have both higher risk alleles for the phospholipase A2 (PLA2) gene and lower levels of EPA in the blood [251]. In MDD, a recent study demonstrated that patients with high CRP and IL-1ra had a greater antidepressant response to EPA, whereas patients with increased CRP and IL-6 were less responsive to placebo [28]. Interestingly, omega-3 fatty acids have been shown to impact brain structure, function, and pathology in human neuroimaging studies, indicating that they may exert antidepressant efficacy in part through affecting pathways in the brain that are targeted by inflammation [252].

Although little work has been done to examine anti-inflammatory treatments in anxiety disorders, normalization of inflammatory cytokines in patients with remitted PTSD [253] or following response to selective serotonin reuptake inhibitor (SSRI) therapy [254], suggests a close and potentially causal association between inflammation and PTSD symptoms. Behavioral interventions that reduce stress, such as exercise, yoga or meditation, can affect the HPA and SNS axes as well as the immune system [255], and may also serve as potential treatments for PTSD and related comorbidities.

6.2. Monoamine Synthesis, Availability and Receptor Signaling

In addition to effects on DA as described above, inflammation also affects other monoamines such as 5-HT. For example, acute administration of inflammatory cytokines increased 5-HT turnover, as determined by increased 5 hydroxyindoleacetic acid (5-HIAA) or 5HIAA/5-HT ratios, in brain regions such as the cortex and nucleus accumbens [194, 195], and these changes in 5-HT turnover occurred in concert with the appearance of later, more persistent depressive-like behaviors [167, 168]. In patients treated chronically with IFN-a for hepatitis C virus (HCV), CSF concentrations of IL-6 negatively correlated with 5-HIAA concentrations, which in turn negatively correlated with IFN-a-induced depression severity [131]. Lower plasma concentrations of 5-HT and higher circulating TNF at baseline have also been associated with somatic symptoms of depression during IFN-a treatment [256].

One primary mechanism by which inflammation may decrease monoamine and particularly DA availability is by negatively impacting synthesis. Indeed, DA synthesis relies on the conversion of tyrosine to L-DOPA by tyrosine hydroxylase (TH), the rate-limiting enzyme for DA synthesis. A major source of tyrosine is phenylalanine, which is converted to tyrosine by phenylalanine hydroxylase (PAH). Likewise, 5-HT synthesis requires conversion of tryptophan to 5-HT by tryptophan hydroxylase (TPH). All of these enzymes, TH, PAH and TPH, require the enzyme cofactor tetrahydrobiopterin (BH4). Although inflammation and cytokines have been shown to induce GTP-cyclohydrolase I, the enzyme necessary for BH4 synthesis, inflammation may in turn decrease BH4 availability [257]. BH4 is also a cofactor for nitric oxide synthases (NOS). Inflammation-induced increases in inducible NOS (iNOS) activity can usurp available BH4, which results in NOS uncoupling and the generation of reactive oxygen species instead of NO [258, 259]. This increase in oxidative stress can then contribute to oxidative reduction of BH4 itself (which is highly redox-sensitive), leaving even less BH4 available for monoamine synthesis (Fig. ​11) [258]. Indeed, intramuscular injection of rats with IFN-α has been shown to decrease CNS concentrations of BH4 through stimulation of NO, and inhibition of NOS was found to reverse IFN-α’s inhibitory effects on brain concentrations of both BH4 and DA [134]. Of note, IL-6 treatment has also been shown to reduce BH4 content in sympathetic neurons [260].

With relevance to DA availability, concentrations of phenylalanine, tyrosine, BH4 and BH2 can be measured in the peripheral blood and CSF, and the BH4/BH2 and phenylalanine/tyrosine ratios have been proposed as indicators of BH4 availability and PAH activity, and may serve as indirect biomarkers of DA synthetic capacity [257, 261-264]. For example, a number of patient populations with increased inflammation, including patients with trauma, sepsis, cancer, and HIV, have been found to exhibit increased peripheral blood concentrations of phenylalanine [257]. Evidence of reduced BH4 activity has also been observed in IFN-α-treated patients [265, 266]. For example, IFN-α administration was associated with increased peripheral blood phenylalanine/tyrosine ratio, which in turn correlated with decreased CSF DA and its major metabolite HVA [265], but not CSF 5-HT or its metabolites. Increased cerebrospinal fluid (CSF) IL-6 was also correlated with decreased BH4 in CSF of IFN-α-treated patients, and the phenylalanine/tyrosine ratio significantly correlated with IFN-α-induced depressive symptoms [265]. These findings are consistent with decreased DA metabolites in the CSF of both IFN-α-treated patients and monkeys [3, 155], and with the complete reversal of IFN-α-induced decreases in DA by L-DOPA administered via reverse in vivo microdialysis in monkeys [267]. Of note, during L-DOPA administration, no changes were found in the DOPAC/DA ratio, which increases when DA is not properly packaged in synaptic vesicles and is subsequently metabolized via monoamine oxidase [268].

Considering the strong evidence presented above indicating that inflammation can inhibit key components of monoamine and DA synthesis, pharmacologic strategies that increase DA may effectively treat inflammation-related symptoms of anhedonia, fatigue and psychomotor slowing. For instance, a number of compounds are available than can boost BH4 availability or activity, which may facility the capacity of PAH and TH to synthesize DA and TPH to synthesis 5-HT. These include administration of BH4 itself [269], which is currently approved in a synthetic form to treat phenylketonuria [270-272], and folic acid or S-adenosyl-methionine (SAMe), which have a role in the synthesis and/or regeneration of BH4 [3, 273, 274]. Although effects of BH4 administration on behavioral symptoms have not been reported outside of case reports [275, 276], folic acid (in the form of L-methylfolate) and SAMe have demonstrated efficacy as adjuvants in depression trials [277-281]. Administration of L-methylfolate (marketed as Deplin and Zervalx) to patients with MDD has been shown to augment the efficacy of standard antidepressant therapy in two studies [278, 279], however mixed results were reported in two parallel-sequential trials with only one trial finding efficacy over placebo [280]. Treatment with SAMe adjunctive to SSRIs led to significantly higher rates of remission and 50% or greater decreases in depressive symptoms compared with placebo [277]. Interestingly, post-hoc analysis of the two parallel-sequential adjuvant trials of L-methylfolate in patients with MDD [280] considered inflammatory markers. It was found in one study that BMI >30 as well as concentrations of CRP, TNF, IL-8, and leptin, alone or in combination with each other or with IL-6, predicted greater symptom improvement [281]. Therefore, strategies to augment BH4 activity exhibit potential for restoring monoamine availability and treating symptoms of depression in patients with increased inflammation.

In addition to compounds that may increase DA availability, adenosine (A2A) receptor antagonists, which are thought to facilitate activation of DA D2 receptors, are efficacious in reversing decreased effort-based sucrose consumption after DA depletion with tetrabenazine (a vesicular monoamine transporter inhibitor) and after peripheral administration of IL-1β in rats [135, 282-285]. The DA receptor agonist, pramipexole, has been shown to block endotoxin-induced degeneration of nigrostriatal DA cells [286], and has also demonstrated efficacy in unipolar MDD and BD patients with TRD [287-290].

6.3. Monoamine Reuptake

Attention has been paid to the effects of cytokines and inflammatory signaling pathways on monoamine reuptake pumps, and particularly the 5-HT transporter (5-HTT) [291-294]. Both in vitro and in vivo data have established that stimulation of p38 mitogen-activated protein kinase (MAPK), a major signaling pathway activated by IFN-α and other cytokines, can increase the expression and function of the 5-HTT, leading to increased 5-HT reuptake [292-294]. MAPK pathways have also been found to influence the DA transporter (DAT). For example, DAT-expressing cells transfected with a constitutively activate MAPK kinase (MEK) show increased DA reuptake (Vmax), whereas treatment of rat striatal synaptosomes with MEK inhibitors was associated with decreased DA reuptake in a concentration and time-dependent manner [291]. Furthermore, subjects with neuropsychiatric disturbances as a result of HIV infection and subsequent neuroinflammation are thought to have increased expression of DAT [295, 296]. Therefore, reduced DA turnover secondary to inflammatory cytokines may be mediated, in part, by increased DAT expression or function. However, no change in DAT binding, as measured by PET with 18F-labeled FECNT, was observed in monkeys exposed to chronic IFN-α [133]. However, increased plasma TNF significantly correlated with higher 5-HTT binding determined by [123I]-beta-CIT SPECT imaging in healthy adult women [297].

In terms of treatment implications, relationships exist between high levels of inflammation and resistance to standard antidepressant therapy with SSRIs, particularly in MDD [26, 56, 298, 299]. Non-responsiveness of inflammation-related symptoms to standard SSRI therapies has been exemplified in patients receiving IFN-α and those experiencing cancer-related behavioral symptoms that are associated with increased inflammation. Indeed, SSRIs have been found to alleviate cancer-related or IFN-α-induced anxiety and some depressive symptoms, but not those of fatigue or psychomotor retardation [126, 300, 301]. Moreover symptoms of anhedonia and motor slowing in psychiatric patients are difficult to treat even in SSRI responders [233-236], suggesting that other neurotransmitter systems, such as DA, may be involved in SSRI-resistant, inflammation-related symptoms [302].

Although classical stimulant medications that increase DA release and/or block DA reuptake increase motivation in rodent models [283, 303], they have demonstrated only limited efficacy in chronically treating fatigue and other DA-related symptoms in trials for patients with cancer and other medical illnesses that are associated with inflammation [304-313]. Since stimulants act to increase DA release and block DAT function to increase synaptic levels of available DA, these drugs may not provide long-term efficacy in the context of inflammation during medical illness. However, new evidence indicates that in MDD patients with high inflammation (as measured by CRP) exhibit a greater antidepressant response to SSRIs used in combination with the DAT blocker bupropion compared to SSRI monotherapy [314]. Interestingly, the use of the DAT blocker methylphenidate in patients with traumatic brain injury has also been found to improve cognitive symptoms as well as those of PTSD [315], which is consistent with findings that the combination of methylphenidate and desipramine improved behavioral symptoms in an animal model of PTSD [316].

6.4. Glutamate Neurotransmission

Another mechanism by which cytokines may influence reward, motor and threat-related circuitry is through effects on glutamate neurotransmission. For example, inflammation is known to stimulate production of indoleamine 2,3 dioxygenase (IDO) and kynurenine pathway metabolites produced in the periphery or CNS, which can then exert downstream effects on neurotransmitters in the brain such as glutamate (Fig. ​11) [317, 318], and have been shown to play a role in TRD and suicide [319]. Immune-mediated activation of IDO catabolizes tryptophan, the primary amino-acid precursor of serotonin, to kynurenine. Kynurenine is further catabolized in the CNS into the neuroactive metabolites kynurenic acid (KA) (in astrocytes) and quinolinic acid (QUIN) (in microglia), both of which have been found to be increased in the plasma and CSF of IFN-α-treated patients [127, 320-322]. Of note, CSF QUIN significantly correlated with depressive symptoms during IFN-α administration, as measured by MADRS [321]. In addition to increasing oxidative stress [323, 324], the neurotoxic metabolite QUIN can also directly activate the n-methyl-d-aspartate (NMDA) receptor to induce the release of glutamate to lead excitotoxicity in the brain [320, 325, 326], thus further increasing inflammation and its potential effects on the monoamine systems as described above [327, 328]. In contrast to QUIN, KA reduces glutamate release, and has been shown to be an antagonist of NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors [329]. DA release is in part under glutamatergic control, and thereby KA may exert downstream effects on DA [320]. Indeed, intra-striatal administration of KA to rodents leads to marked reductions in extracellular dopamine concentrations, as determined by in vivo microdialysis [330].

Finally, cytokines and inflammation have been shown to increase glutamate by effects on microglia and astrocytes. A rich literature has shown that cytokines can decrease the astrocytic expression of glutamate transporters, and increase release of glutamate from astrocytes and activated microglia in vitro [317, 331-333]. Of note, glutamate released from glia may have preferential access to extrasynaptic NMDA receptors, which lead to decreased production of trophic factors including brain-derived neurotrophic factor [334, 335]. Given the sensitivity of DA neurons to oxidative stress and excitotoxicity, inflammation effects on glutamate may contribute to decreased striatal DA availability and eventual neurodegeneration [336, 337].

Inhibition of the IDO pathway or glutamate may be an important target in reversing the impact of inflammation in the brain. The IDO antagonist, 1-methyl tryptophan (1-MT) has been shown to abrogate the impact of LPS, as well as an attenuated form of Mycobacterium bovis, on depressive-like behavior [338, 339]. Given that the neurotoxic effects of QUIN may be mediated by excessive glutamate excitotoxicity [320, 325, 326], glutamate antagonists may be useful in preventing excitotoxic and oxidative effects and even protecting sensitive DA neurons. Indeed, metabotropic glutamate receptor antagonists that modulate glutamate transmission in the basal ganglia have been successful in reducing DA cell loss in an animal model of PD [340]. Antagonism of the NMDA receptor with memantine in monkeys infected with simian immunodeficiency virus (SIV) also reversed loss of DA in the striatum [341] that occurs during SIV and HIV infection secondary to immune cell activation in the basal ganglia [342, 343], in association with increased brain derived neurotrophic factor (BDNF). Interestingly, inflammation-induced release of glutamate from glia cells may preferentially activate extrasynaptic NMDA receptors, which has been shown to decrease BDNF [334]. Administration of the NMDA antagonist ketamine has potent antidepressant effects in depressed patients who are resistant to standard therapies and who often exhibit increased inflammation [26, 344, 345]. Interestingly, a recent study in treatment resistant depression found that patients who were most responsive to ketamine were those with the highest concentrations of serum IL-6 [346]. Therefore, blockade of kynurenine pathways or modulation of glutamate neurotransmission may confer protection against inflammation and/or IDO-mediated effects to improve behavioral symptoms in patients with mood or anxiety-related disorders with increased inflammation.

Declared none.