© CelPress Neuron Review The Bidirectional Relationship of Depression and Inflammation: Double Trouble Eléonore Beurel,':* Marisa Toups,” and Charles B. Nemeroff® “Department of Psychiatry and Behavioral Sciences, Miler School of Medicine, University of Miami, Miami, FL 93196, USA "Department of Biochemistry and Molecuiar Biology, Mile School ot Medicine, Universty of Miami, Miami, FL 33136, USA Department of Psychiatry, Mulva Cini for Neurosciences, University of Texas Dell Meckcal School, Austin, TX 78712, USA *Comespondence: cnomeroft@austin utexas.edu hitps/idoL.org/0.1016/, neuron 2020.06.002 Depression represents the number one cause of disability worldwide and is often fatal. Inflammatory pro- cesses have been implicated in the pathophysiology of depression. Itis now well established that dysregu- lation of both the innate and adaptive immune systems occur in depressed patients and hinder favorable prognosis, including antidepressant responses. In this review, we describe how the immune system regu- lates mood and the potential causes of the dysregulated inflammatory responses in depressed patients. However, the proportion of never-treated major depressive disorder (MDD) patients who exhibitinflammation remains to be clarified, as the heterogeneity in inflammation findings may stem in part from examining MDD patients with varied interventions. Inflammation is likely a critical disease modifier, promoting susceptibility to depression. Controlling inflammation might provide an overall therapeutic benefit, regardless of whether it is secondary to early life trauma, a more acute stress response, microbiome alterations, a genetic diathesis, ora combination of these and other factors. ‘Major Depressive Disorder (MDD) ‘Mood disorders are the most common ofthe severe psychiatric illnesses. Episodes of major depression occur in both unipolar depression (in which mood varies between euthymia and depressed) and bipolar disorder (mood has. pathological “highs,” termed lypomania and mania, as well as euthymia land depression). Major depressive episodes are defined in DSM-5 by a constellation of signs and symptoms (OSM-5, 2013), Patients with major depression exhibit alterations in a va- riety of critical functions including sleep, appetite, psychomotor activity, cognition, and, of course, mood. Lifetime prevalence of major depression inthe United States is 2196 of women and 119%~13% of men (Beimaker and Agam, 2008; Kessler et al. 2003). tis the major cause of suicide, now in the top 10 cases of death in the United States, with almost {50,000 reported suicides per year (Mann et al, 2005). Indeed, major depression is associated with a significant reduction in lifespan, in part due to suicide and the remainder due to the marked increase in vulnerability to major medical disorders, Including cardiovascular disease and stroke, autoimmune dis- ease, diabetes, and cancer (Benros et al, 2013; Windle and Windle, 2013; Bortolato eta, 2017). Not only are depressed pa- tients more vulnerable to these and other disorders, but their treatment outcomes for these medical disorders are poorer (a- ton, 2011). The morbidity and mortality associated with major depression renders it the number one cause of disability world- wide and exerts an extraordinary economic burden on society Interms of lost productivity (Bloor etal, 20) Fisk factors for depression include family history of depres- sion (approximately 35% ofthe skis herecitary), early ifeabuse and neglect, as well as female sex and recent ife stressors. Med- icalilness also increases the risk of depression, with particularly 284 Neuron 107, July 22, 2020 © 2020 Elsevier Inc. high rates associated with metabolic (e.g., cardiovascular dis- ‘ease) and autoimmune disorders. Treatment of depression includes three major modalities: (1) antidepressants and other medications that augment antide- pressant action, (2) evidence-based psychotherapy such as ‘cognitve-behavior therapy (CBT) and inter-personal psycho- therapy (PT, and (8) somatic non-pharmacological treatments including electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (FTMS), and vagus nerve stimulation (VNS) (Gartlehner etal, 2017), Monotherapy with ether an antidepres ‘sant or evidence-based psychotherapy results in the virtual absence of any depressive symptoms and return to the premor- bid state, termed remission, in approximately 50% of previously Untreated depressed patients (Ouniop et al, 2017) and in 28% in ‘a more heterogeneous mix of “real-world” patients in an effec- tiveness study (Trivedi et a, 2006), At the current time, there ‘reno clinically useful predictors of response ina given individual to one antidepressant versus another (Zeier et al. 2018) in spite (of claims to the contrary (Greden eta, 2019}. Such biomarkers are of great interest, as ongoing depression is associated with increasing treatment resistance and increased risk forsubstance abuse and suicide. Depressed patients with increases in infiam= matory markers may represent a relatively treatment-rsistant population. In this regard, itis of interest to note that patients ‘ith autoimmune disorders have inordinately high prevalence rates of depression. This is discussed in further detall in subse- ‘quent sections. Peripheral and Central Immunity Mammals are protected by the immune system from infectious agents and many types of insults that cause inury. Immunity in volves (1) recognition of infection or damage, (2) immuneNeuron Review functions to contain the infection/damage, (8) regulation limiting the magnitude and duration ofthe immune response that can it- self be damaging to tissues, and (4) memory to enhance the future response to the same infectious agent or damage if re- encountered (Murphiy, 2012). Inflammation or inflammatory response are the result of the activation of the immune system that often manifests as a localized reaction resulting from irita- ‘ion, injury, oF infections; are associated with warmth, redness, swelling and pain, and sometimes fever; and are necessary 10 eliminate the insult. Many types of immune cells and mecha- nisms are in place to maintain homeostasis, but dysregulation oftheir actions often contributes to diseases, with increasing ev- idence that this occurs in psychiatric disorders, including depression (Murphy, 2012) ‘The immune system je classically divided into innate and adaptive arms, though these two act cooperatively to ensure proper immune actions. The innate Immune system Is the fst ling of defense, because innate immune myeloid cells e.g, mac- rophages/monocytes, dendritic cells) and Iymphoid cells (2.0. natural killer [NK]) constantly patrol the circulation to provide rapid responses. Receptors on these cells are activated when they encounter damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs); DAMPS. {also called alarmins) arehost molecules that signal cellular dam- age c.g, Heat shock proteins), whereas PAMPS are present on infectious pathogens (Gong etl, 2020) After activation, macro- phages and denditic cells produce cytokines (interleukins and/ oF chemokines), which recruit other immune cells to the site of infection or insult. As part of the inflammatory activity, dendritic Cells initiate the adaptive immune response by presenting anti- {gens to cels of the adaptive immune system and are therefore also called antigen-presenting cells (APCs). ‘The adaptive immune system, composed of lymphocytes (T ‘and 8 cells), is slower to respond, as it often raquires recrut- ‘ment, activation, and differentiation of the lymphocytes to exert effector functions. A key characteristic of adaptive immune cells, is their capacity to clonally express a large repertoire of antigen specific receptors, T cell receptors (TCR), and B cel receptors: (BCR), which are produced by site-specific somatic recombina- tion (Smith-Garvin et al, 2009). Each lymphocyte expresses one Unique antigen receptor variant. This confers an antigen speci- ficity to the adaptive immune system, which does not exist in the innate immune system, highlighting the specialization of the adaptive immune system in contrast to the innate immune system that respond to a wide variety of DAMPs and PAMPs. Until lymphocytes are activated by "their" antigen, they are considered naive and inactive cells. Upon antigen recognition, they are activated and undergo clonal differentiation to become fully functional effector ymphacytes. B cells clonally protferate and differentiate into plasma cals, which produce antigen-spe- cific antibodies. Activated T cells can become one of three brod ‘types of effector T cells: cytotoxic, helper, and regulatory. Thus, cytotoxic T cals (CDB" coll kil infected cals. T elper (Th) cols influence the behavior and activity of other immune cells, and regulatory T cells (Tregs) suppress the activity of other lympho- {es that control or imit immune responses to prevent autoim- munity. Some activated B and T cells diferentiate into memory Cells, which can mount a rapid immune response if the same an- © CelPress tigen is encountered again by diferentiating into specific effector cells (Murphy, 2012) Microglia—The CNS Immune System ‘Te bran possesses specialized immune cells called microgta that eomprse 5%-10% of total brain cells and cary out macro- pPhage-tke and other specialized functions (Kim and de Vets, 2005). Microgia are maintained by self-renewal with minimal Contibution trom immune eels outside of the CNS, and their ‘main funetions ace to maintain GNS homeostasis and to provide rapid responses to damage or infection. Microgia exhibit a broad spectrum of activation states upon receiving various tim- Ul. Recent findings have shown that microglia are important for ssyhaptic modulation (@.., synapse pruning and neurogenesis) and are activated in many neurodegenerative and neuropsyeh- atric diseases, where they contribute o pathology by prometing neuroinflammaton (Yimiya et a, 2015). The heterogeneity of microglia suggests that microglia subsets have distinct roles in thebrain (Masuda ct al.2018),but amore complete understand ing of the complex roles of microglia is necessary to provide further insights in understanding ther olin brain funtion and pathology. Interfaces between CNS and Peripheral Immunity Thereis a role for non- microglial cells in CNS immunity wth three ‘other types of CNS macrophages: perivascular, meningeal, and choroid plexus macrophages (for review, see Li and Barres, 2016) as well as lymphoid cells (Beurel and Lowell, 2018). These ‘macrophages are localized at the interface of the parenchyma ‘and blood vessels. Under physiological conditions, peripheral Immune cells do not enter the brain parenchyma, though some are present in cerebrospinal fluid (CSF) and the meninges (Wi son etal, 2010), However, in certain conditions, macrophages, ‘and T cells, can eross the blood-brain barrier (BBB) and enter the brain parenchyma, generally producing damage (Wilson et al, 2010). The BBB is composed of specialized endothelial Celis liked by tigt junctions, limiting the entry of immune cells, various blood constituents, and pathogens. Indeed, the BBB prevents >88% of antibodies and small molecules from entering the parenchyma, while assuring the efflux of other molecules. Various hypotheses have been proposed to explain how peripi- ral immune cells may cross the BBB under pathological condi- tions (for review, see Qusman and Kubes, 2012; Ransohotf and Engetharsit, 2012). In conditions that weaken the BBB or in re- gions where the BBB is more permissive, such as the citcumven- tricular organs. and choroid plexus, immune cells infitrate the brain parenchyma via diapedesis. Because the choroid plexus has a secretory epithelium that produces CSF, it also allows, the passage of iymphocytes to access and provide Immune sur- vellance of the CSF (for review, see Ransohoft and Engelhardt, 2012). In physiological circumstances, few immune cells are pre- sent in the CSF, but a higher percentage of memory or CNS an= tigen experienced CD4” T cells are found in the CSF compared to the circulation (Ransohoff and Engelhardt, 2012) Activated T calls gain access tothe brain by extravasation into the tissue, by upregulating many adhesion molecules and integ- Fins, allowing them toll and adhere tothe vessel walls. Upregu- lation of very late antigen-4 (VLA-4) or lymphocyte function- Neuron 107, July 22, 2020 235© CelPress associated-t (LFA-1) on T cells promotes the binding to vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion ‘molecuie-1 (ICAM-1) present on endothelial cells, and infitration to the parenchyma. Furthermore, the gradient of chemokines produced by the choroid plexus (¢.9., COL9, CCL20) also at- tracts T coll subsets to the brain, which has particularly been demonstrated in studies of autoimmune diseases (Oukka and ‘etteli, 2078; Rebold et al, 2009). Finally, immune ces are pre- Sentin the meninges, and the role of meningeal immune cells has been mainly studied inthe context of vial, bacterial, or parasitic infections (for review, see Forrester et a, 2018). The recent (re) discovery of the lymphatic system within the meninges of the brain has revealed another pathway for immune cells to reach the meninges (Sandon et al, 2019). Indeed, the lymphatic sys- tem is ertical for the drainage of immune calls and soluble fac- tors from the CNS into the deep cervical lymph nodes (Louveau {etal 2015).Ithasalso been proposed thatthe lymphatic vessels ‘maintain anergy of CNS-reactive T cells within the meningeal ‘spaces promoting T cell tolerance, whereas infections may trigger CNS-reactive T calls to attack the CNS. The immune response within the CNS isnot always detrimental, such as after CNS injury when the immune response limits secondary degen- eration (for review, see Louveau et al, 2017) Similarly, although pathogenic T cells have been associated with autoimmune dis eases and neuropsychiatric and neurodegenerative disease, not all T cells are detrimental to brain function. For example, ‘Tells support cognition under physiological conditions (Kipris, 2016). Clearly, the immune system in the CNS functions in a Unique way compared to peripheral tissues. Cytokine Production and Regulation Cytokines are small proteins that affect cel functions and inter- actions and can have either pro-inflammatory or anti-iflamma- tory effects. There are many families of cytokines that provide specialized functions. Cytokines are predominantly produced by immune cells, including microglia in the CNS, but other CNS cells such as neurons and astrocytes also produce cyto- kines. Immune activity including cytokine production is infu fenced by a myriad of factors, including but not limited to ge- netics, and previous exposures to pathogens (MacGiliay and ollmann, 2014). The most studied cytokines in the context of ppsychoneuroimmunology are interleukin (IL}-6, tumor necrosis, factor (TNF), IL-1, and interferons (IFNs) on the inflammatory side and IL-10 on the resolving side, Table 1 summarizes the cy- tokines and related molecules studied in the context of depres- sion and lists their main functions. Inthe brain, cytokines produced by microglia and other CNS. Celis are crucial positive modulators of several CNS functions, such as maintenance of neuroplastcty (Steliwagen and Mal- fenka, 2006; Yirmiya and Goshen, 2011). However, excess or prolonged inflammatory cytokine activity perturbs muttiple neuronal functions, including impairment of neurotransmitter signaling, disruption of the synthesis, reuptake, and release of ‘neurotransmitters (Deverman and Patterson, 2009; Eimer and Modlister, 2012; Stephan et al, 2012). This, in tum, affects eurocircuit function, including that implicated in mood and Cognition (Dantzor et al., 2008; Figure 1). The effects of cyto- kines on the dopaminergic system have been recently reviewed 286 Neuron 107, July 22,2020 Neuron Review (Treadway et al,, 2019; Felger and Treadway, 2017; Capuron «tal, 2012). Relevant mechanisms that may increase cytokine activity inthe brain to pathological levels include psychological ‘and physical stressors. Nevertheless, it remains unclear how the same cytokine exhibit opposite effects on neuronal function depending on the context. It has been proposed that the ‘source and the combination of cytokines dictate the effects ‘of cytokines on brain function. The field of neuroinflammation has been focusing on central cytokines, whereas peripheral cy: tokines certainly contribute to behavioral effects, as suggested by findings showing that blocking peripheral cytokines is suff- cient to tighten the BBB and that blocking BBB disruption is ‘sufficient to exhibit antidepressant actions (Cheng et al., 2018; Menard et a, 2017). There are several well-documented pathways by which peripheral cytokines reach the brain, simi- larly to the immune cells: (1) through “leaky” regions of the BBB, such as the circumventicular organs, or through dis- ‘ease-induced disruptions of the BBB (Quan and Banks, 2007; Vitkovic et l., 2000), (2) through a neural route via afferent nerve fiber cytokine receptors that relay the signal to the brain parenchyma (Watkins et al, 1995) and (8) through the infitra- tion of immune cells that produce cytokines after being at- tracted by a chemokine gradient to the meninges or brain pa- renchyma (Lewitus et a, 2008) Gytokines are one of the most studied components of the im- mune system in depression (for review, Dantzer et al, 2008; Miller and Raison, 2016; Raison et al, 2006), but litle is known ‘about the source and the contribution of eytokines in MDD and their mechanisms of action in the bean Immune Findings in Depression ‘Over the past two decades, there has been growing evidence that MDD is associated with a systemic immune activation, ‘comprising abnormally in inflammatory markers, immune call rhumbers, and antibody titers (Gibney and Drexhage, 2013; Miller, 2014; Figure 2. Immune Activation Aberrant Cytokine Production It is now well established in multiple meta-analyses (Dowlati ct al, 2010; Howren et al, 2009; Liu et al, 2012b; Kohler et al, 2017) that proinftammatory cytokines and acute phase proteins ‘are increased in MDD patients, with a fairly unanimous ‘consensus of increases in IL-6, TNF, and C-reactive protein {(CRP)in the blood of MDD patients compared to heaithy controls, (Maes etal, 2009; Miler etal, 2009; Stewart etal, 2009). With the advances in the measurement of cytokines by multiplexing (Papakosias etal, 2013), many other eytokines are now evalu- ated (Kiraly otal, 2017; Syed et al, 2018). A relatively recent meta-analysis of 82 studies including 3,212 MDD patients and 2,798 healthy controls reveals increased levels of IL-6, TNF, IL 40, siL-2, C-C motif igand (CCL}2, I-13, 1L-18, L-12, IL-1RA, ‘and soluble TNF receptor (STNFF|2 in MDD patients, whereas the level of interferon-y (FN-y) is reduced (KDler et al, 2017). ‘Gene expression upregulation of inflammatory pathways have ‘also been reported in peripheral blood mononuclear cells (PBMCs) of depressed patients. Similarly to the protein data, the expression of I-18, IF6, inf, macrophage migration ihistingNeuron © CelPress Hl Table 1, Gytokines and Their Peripheral immune Functions and Blood Levels in MDD Patients Compared to Healthy Control Subjects yokes Function ‘olen MOD Feterences coz tracts to ee of iteration: Toa (TR2> Thi), monooytes, varies Kahioe et a, 2077 Dbasopis, immature dante cals, NK eas Leighton et al, 2018 cous tracts to ste of intamenation: T cals (Tht > Th2), monoeytes/ 1 ‘Syed eta, 2018; macrophages. NK cals, basophils, immature dendrite cel, Leighton ot al, 2018 eosinophils, fbrobasts,noutrophis, astrocytes, osteoclasts cous targets Teeks Tht > Th}, NK cells, monocytesimacrophages, 4 ‘Syed tal, 2018; bbasopil, immature danitc calls, eosinophils, B cols Leighton ot al, 2018 cous targets T cell (memory cell> Tel, Tht > Tha}, NK els, eosinophils, 1 ‘Syed t a, 2018 neutrophils immature denditic cls, monocyles/macrophages cou recruits ecsinophis, impicatedin alergic response 1 Leighton ot at, 2018 xcs release from platelets, attracts neutrophils, froblasts, ad 1 Leighton ot al, 2018 ‘monocytes, arrests monooyies onthe endothotum, important in \woun healing and in promoting coagulation and atherogenesis oxo released from platelets, attracts neutrophil, angionenic, st 1 Leighton ot a, 2018 Chemokine to ave at he ste of iy oxou10 targets NK cls, Bel, actvated Tes (Th >The}, endothe ces HI ‘Syed ot a, 2018 G-csF stimulates nautroptl dovslopment and difrentiaton 1 aly ta, 2017; ‘Syed et a, 2018) e-osF Promotes granulocyte maturation and prolferation, manocyte 1 ‘aly ta, 2017 evelopment Fr induces macrophage activation, increased expression of MHC vares Kotler et al, 2017 molecules and anign processing components, Immunoglobulin ‘ass switching, suppresses Th? calls ap induces fever, Tcl activation, macrophage activation vares Kotler et al, 2017 NARA antagonizes Lt function varies Kher ot al, 2017 we Promotes T cel proferation t Kotier et al, 2017 a induces 8 cel activation, IgE switch, and ferentiation toward 4 Kotler ot al, 2017 Tr2cale us Promotes eosinophil growth, cifoantaion 1 otro al, 2017 Le Induces T and B cel growth and difeentition, acite phase 1 Kotler et al, 2017 production, fover 7 Induces growth of preB-cols and preT-ools 1 ‘Syed ot a, 2018 8 /cx0L8 ‘targets neutrophils, basophis, CD8 cel subsets, endothe cols varies Koi et al, 2017; Leighton ot a, 2018 Le Induces mast cell acti, stimulates Th cats 1 Syed ot a, 2018 10 Potent suppressant of macrophage functions, ant-nlmmatory 1 Kotler et al, 2017 ne activates NK cel, induces CDs T cal ferentiation nto Tht 1 Kohir ot al, 2017 Ike calla hts Induces B cel growth anc aitterentatin, intibits macrophage 1 Kotler et al, 2017 Intammatory cytokine production and Tht ces, nduces aeray/ asthma nas IL-2 ke cytokine, stulates growth of intestinal epithelium, T cells 1 ‘Syed ot a, 2018 and NK cals, enhances memory GD8 T col survival nvm Pro-inlamatory induces cytokine production by eitheka, 1 Kotler ot al, 2017 endothe, astrocytes, and fiboblasts 118 Induces IFN-y production by T cells and NK cels, promotes Tht 1 Kotler ot al, 2017 Ineieton SIL-2recepter —_incraased in autoimmune ssase t Koheroa, 2017 SL-6receptor promotes IL-6 signal no change oti et al, 2017 ‘Tors antintammatory po change Kotler al, 2017 STWR activated by TNF 1 Kotler et al, 2017 NF romotes inflammation, endothelial activation 1 Kober et al, 2017 Neuron 107, July 22, 2020, 237factor (mi, and lfny genes are increased in PBMCs of MDD pa- tients compared to healthy controls, whereas [4 mRNA level is decreased (Hepgu! et al. 2013). Overal, there isa large hetero- ‘geneity in the data, which depends on the cytokine component studied, ands atleast partly due to the absence of consideration ofthe clinical course and the illness duration, and the effects of potential confounding factors such as comorbidity, medications, fasting status, smoking, assay methodology, or body massindex (BM) among others. ‘Are All MDD Patients Exhibiting Increased Cytokine Production? [Not all MDD patients exhibit increased inflammation. Increased Inflammatory markers have been associated with alypical symptoms of depression (Lamers et al, 2018), and with suicidal MDD (Biack and Miller, 2015), which contrasts with a recent study of measurement of cytokines in never-treated relatively homogeneous MDD patients, for which cytokine levels are elevated in the majority (Syed et al, 2018). This suggests that prior exposure to various regimens of antidepressants might fect the cytokine production in some MDD patients. Although ‘most studies of cytokines in MDD include patients free of anti- opressant, these patients have been previously exposed to antidepressants (Dow/ali et al, 2010). Therefore, even though the study of Syed et al. reported a relatively small sample size of MOD patients, with an overrepresentation of females land high absolute levets of measured cytokines compared to many other studies, this type of study might provide benefit In understanding the impact of immune dysreguiation in MOD independent of prior exposure to antidepressants. It is also plausible that different inflammatory profiles are associated with different subtypes of depression (Dunjc-Kostic et al, 2013; Kaestner et al, 2008; Karlovié et al, 2012). Thus, non- ‘melancholic patients exhibit proinflammatory states, whereas ‘melancholic patients, in contrast, exhibit reduced proiniamma- tory cytokine production (for review, see Kronfol, 2002; Rother ‘mundt et al, 2001a; Rothermundt et al., 20016). in addition, ‘TNF has been associated with atypical features and chronicity, 288 Neuron 107, July 22,2020 Neuron Review Figure 1. Symptoms of Depression ‘Associated with Different immunelogical Changes Monoamine newrotarsnters have been eso tad with vaous symptoms of depression a= de- [ctod naach oval Some symptoms are cepandent ‘or muipie nowetansmitrs, such as psyehomo= tor retrdaton that reqdated by serotonin, Gopamine, ntepnephing, and glutamate. Each ‘ox repesenatha cern immenelogca changes (oa, cytokines, mmaune cl, and oer) S550 Std wih each symptom, while IL-6 might represent a “state indica tor for acute exacerbation” in melancholic patients (Dunjc-Kostic et al, 2019), Furthermore, higher levels of IL-6 pre- dicted over time the chronicity of depres- sion, a8 well as higher severity of depres- sion at follow-up (Lamers et al, 2019) CGRP and TNF have also been associated with greater symptom severity in MDD (Hiaapakoski et al., 2015). This ig consistent with the findings that low-grade inflammation is associated with treatment-resistant depression {Chamberlain et al, 2019; Strawbridge et al, 2018) and poor {treatment response to antidepressants (Uhr et al, 20°4; Vo ‘gelzangs et al, 2074), which will be discussed later in this re- view. Although there is merit in subcategerizing MDD to fit the different cytokine profiles, the subcalegorization should take into account all the disease modifiers to avoid bias in ‘our understanding of the immune response in MDD. 1s Inflammation Unique to MDD? Itis important tonote that aberrant blood levels of cytokines have been reported in other psychiavic disorders, such as bipolar dis- ‘order and schizophrenia, raising the possibilty of common un- 4 depressive episodes, were found in a Danish popula~ tion-based prospective study including 976,998 individuals of whom 142,169 had an history of depression between 1995 and 2012 (Andersson et al, 2016). The interpretation of the study should be, however, taken with caution as socioeconomic status was not controlled for but could account for the differences ‘observed. There is also evidence that various vial and bacterial infections e.g, gastroenterts-related virus, influenza virus, her- pes virus, Epstein-Barr virus, cytomegalovirus, and Borna dis- ease virus) are associated with depressive symptoms and are known to induce the production of cytokines (Yirmiya et al, 2015), suggesting a bidirectional communication between cyto- kines and mood. All these studies suggest that immune re- sponses in MDD patients are altered ina way that MDD patients, are more prone to infections, whichis consistent with the obser- vation of immunosuppression in MDD patients. This also rein- {forces the idea that, although there is an increased production of eytokines in MDD, other parts of the immune response such a the adaptive immune system might participate in increased susceptiblity to infections that in tum might impact the long- term immune characteristics. ‘Autoimmune Diseases and MDD ‘The epidemiological link between psychiatric and autoimmune diseases has been observed for almost a century (Nissen, 11936). Thus, there isan inereased risk of developing subsequent autoimmune diseases (heumatold arthritis, multiple sclerosis, inflammatory bowel disease, systemic lupus erythematosus) in depressed patients (Andersson et al, 2015; Dickens et al, 2002; Euesden et al, 2017; Kurina et al., 2001; Patten et al, 2017), Reciprocally, patients with autoimmune diseases have some of the highest rates of comorbid depression. Thus, for ‘example, MDD is less common early in multiple sclerosis than ints later stages Feinstein eta, 1992) and more prevalent in re- lapsing-remitting than progressive multiple sclerosis (Zabad et al, 2005) and might correlate with relapses (Moore et al, 2012). Gytokines and T cells have been proposed to contribute tooth muttiple sclerosis and depression pathologies (Feinstein ct al, 2014). Th17 cells in particular have attracted attention as they are pathogenic in many autoimmune diseases, and anti- IL-17A therapy induces remission of depression in 40% of pso- riasis patients experiencing moderately severe depression (Gri ‘iths etal, 2017), whereas blocking the downstream effects of L- © CelPress 7A by blocking its receptor using ant-IL-17RA therapy has. been associated with increased suicidality risk and psychiatric disorders in psoriasis patients (Lebwohi tal. 2018), suggesting that Th17 cells could be a potential therapeutic target in popula- tions of MDD patients with autoimmune diseases with elevated levels of Th17 cals, Other Co-morbidities Associated with MDD and Linked {0 Inflammation It has been estimated that more than half of MDD patients have associated comorbidities, and more than a third of MDD patients exhibit drug and alcohol dependence (Fasin et al, 2078; Kessler et al, 1996), which are often associated with microglia inflammation (He and Crews, 2008). Depression also increases disease rate progression and death in cancer Gortolato ot al, 2017), cardiovascular diseases (Rudisch ‘and Nemeroff, 2003), diabetes, renal diseases (Hedayati ft al, 2009), and obesity (Hasler ot al, 2004), all diseases ‘associated with increased inflammation. In the case of dia- betes, anti-diabetic drugs such as the thiazolidinediones of pioglitazone, which are peroxisome proliferators activated re- ceptor (PPAR) agonists, increase insulin sensitivity and normalize glycemia, affecting also cytokine production (Nan- Jan et al., 2018), have been shown to improve depressive symptoms in diabetic patients (Moulton et al., 2018) or as add-on or monotherapy in MDD or bipolar patients (Cole ft al, 2017). However, this was not confirmed in a recent study with bipolar depressed patients (Aftab et al., 2019). A. large cohort study found that newly diagnosed type 2 diabetic patients treated for a year with glucagon-peptide-t agonists and dipeptidy! peptidase-IV inhibitors therapy, which increase insulin secretion, exhibited a reduction in depression symp~ toms, which was correlated with reduced CRP levels, sug- gesting that reduction of inflammation might provide an anti- depressant effect (Moulton ot al, 2016). It remains, however, to be determined whether, the observed antidepressant effect resulted from improvement of the diabetic pathology, and if MDD patients without diabetes would benefit from such agents, The same precautious can be applied to other co-morbidities associated with inflammation and depression Peripheral versus Central Inflammation Besides systemic inflammation, many studies are now focusing ‘on CNS inflammation. In MDD patients, central immune dysre- ulation, also called neuroinlammation, has been analyzed at the level of cytokines in CSF or post-mortem tissue, and at the level ofthe cells involved in the immune response (e.g. mi crogiia, astrocytes, or infitrating immune cells) using both post- ‘mortem tissue and positron emission tomography (PET) imag- ing. Indeed, expression level of the translocator protein (TSPO), analyzed by PET scans using TSPO ligands, is low in the healthy brain and is upregulated locally during neuropatho- logical conditions, and has been therefore used to measure neuroinflammation (Ruprecht ot al, 2010). I is, however, Important to note that the expression of TSPO initially thought to represent microglia activation, has been recently proposed to also measure local myeloid cell proliferation, or monocytes infitration (Owen et al, 2017). Using the ['"FIFEPPA TSPO. "Neuron 107, July 22, 2020, 241© CelPress ligand, elevations of TSPO volume in prefrontal cortex, insula, and anterior cingulate cortex that correlated with depression severity (Setiawan et a, 2015) and duration (Setiawan et al 2018) have been reported, whereas no correlation was found with other ligands (Hennestad et al, 2019). A recent study found that the serum level of products synthetized by activated microglia and actively removed from the brain (eg., TNF and prostaglandin E2), normalized to peripheral CRP level predicts ‘TSPO volume in depressed patients, reinforcing the role of gio- isin depression (Attwalls et al, 2019), Microglal activation is also found in the hippocampus of multiple sclerosis patients ‘and correlates with depressive symptomatology (Colesant ft al, 2014), Increased Tolike receptor (TLR)S and TLA4 ‘MRNA in post-mortem tissue also correlate with increased mi- Crogiial activation, ag TLRS and TLR4, which recognize DAMPS and PAMPS, are critical in the induction of cytokine production (Pandey etal, 2014), Cytokine concentrations are also elevated in post-mortem brain tissue (Shelton et al, 2011), Furthermore, a recent meta-analysis suggests increased microglial activity is. ‘associated with increased IL-6, IL-8, and TNF levels ia CSF and brain parenchyma of MOD patients (Wang and Miller, 2078) and reduced astrocytes and oligodendrocytes numbers in MDD pa- tients (Enache et al., 2019). It has been speculated that the reduction of the astrocytic population is associated with a ‘more permeable BBB, allowing the recruitment and infitration Cf monocytes to the brain parenchyma (Enacie et al, 2019). Itis important to note that suicidal patients exhibit increased recruitment of monocytes (Torres-Piatas et al, 2014), as well, as increased microglial priming and activation (Steiner et al. 2008), whether or not they exhibit psychiatric symptoms. Mi Crogiial activation has also been reported in illness-associated depression. Indeed, many of the bacterial and viral infections: we discussed previously associated with depression, induce ‘microglia activation (Rock etal, 2004). Similarly, immune chal- lenges in humans (eg, endotoxin LPS] or Salmanela typhi ad ‘ministrtions) are known to activate miraglia and induce depressive symptoms; the severty of the symptoms directly Correlates with high blood levels of proinflammatory cytokines (Grigoleit et al, 2011; Harison et al., 2008; Reichenberg ft al, 2007). Consistent with this, neuroinflammation induced by microglia has been thought to be responsible for the high prevalence of depression in HIV-infected patients (De! Guerra ft al, 2019; Kaul et al, 2001). However, data also suggest that microglia are suppressed during depression, as, for example, results of PET studies demonstrating reductions in gla cells, but not neurons, inthe subgenual anterior cingulate (Cotter et a, 2001a, 2001; Ongiret al, 1998) or in many brain regions (Hannestad et al, 2013) of depressed patients compared to healthy controls. This might explain some of the discordant resulls found with NSAIDs on depressive symptoms. (discussed later in the review). Indeed, cyclooxygenase-t (COX-1) inhibitors, are associated with increased depressive ‘symptoms (as oppased to COX-? inhibitors that are antidepres- sant), and COX-1 is predominantly active in microglia, whereas (COX-2 is active in neurons and astrocytes (Chol etal, 2009) re- Inforcing the notion that suppression of certain microglial actv- ity is associated with depressive symptoms, With the recent findings on the various phenotypes of microglia in heathy brain, ‘242 Neuron 107, July 22,2020 Neuron Review itis plausible that certain populations of microglia have benefi- ial roles, whereas. others, in contrast, are detrimental in ‘depression. Loss of beneficial microglia or enrichment of detr- mental microglia may enhance depression, but such a hypoth- ‘esis will nee further testing experimentally Effects of Antidepressants on Inflammation “The role of inflammation in treatment response is of paramount importance. There are two major questions that have been ad ‘dressed. The frst is whether successiul treatment of depres- Sion is associated with a reduction in inflammation. The second is whether antiinflammatory treatments are effective antide- pressants, especially in depressed patients with evidence of increased inflammation. Although no currently approved treat- ments for depression ware developed withthe intent of modu- lating the immune response, there is evidence that conven tional antidepressants have ‘an ant-inflammatory effect and that response may depend partially on immune phenotype. ‘The largest meta-analysis of 45 studies representing 1.517 MDD patients revealed that antidepressant treatment sigrifi- cantly decreases peripheral levels of IL-6, TNF, IL-10, and ‘COL2, but these are not associated with treatment response (Ghler et al, 2018). Reduction of IL-6 by antidepressants hhas been reported in. various meta-analyses. (Hannestad ct al, 2011; Hiles et al, 2012; Strawbridge et al, 2015; Wang et al, 2018; Wiedlocha eta, 2018), although they are very het- ‘erogeneous. Sources of heterogeneity include baseline infiam- mation, BMI, smoking, methodology or standardization, type of depression (melancholic versus atypical depressior), and class ‘of antidepressants. These factors ware not always taken into account due to lack of data availabilty. For example, the selec tive serotonin reuptake inhibitors (SSRs) reduce IL-1p, IL-6, ‘and TNF (Wang et al, 2019), CBT also exhibits antinflamma- tory actions in responders (Syed et al, 2018). In other studies, in contrast, antidepressants such as serotonin and norepineph- fine reuptake inhibitors (SNRs) induce IL-6 and TNF production (Hannestad et al, 2011; Wamer-Schmidt et al., 2011; Pietz ct al, 2009). Treatment with ECT also induces transient eleva- tion of plasma proinflammatory cytokine levels (Hestad et al., 2003; Lehtimaki et al, 2008), and increases the numbers of monocytes, NK cells and granulocytes. In rodents, ECT has been associated with microglial activation (iWennstim et al 2008). Altogether, these findings suggest that the effects of an- tidepressants on cytokines remain unciear, though its gener- ally thought that antidepressants shift the balance toward an antiinflammatory response (Kuibera et al, 2001b; Lanquillon ct al, 2000; Maes et al, 1999; Suzewska et al, 1997). Conversely, proinflammatory cytokine levels, especialy TNF, have been shown to be elevated in trealment-resistant ‘depressed patients, suggesting a negative correlation between treatment response and proinflammatory cytokine levels (Ku bra et al, 2001b; Lanquilon etal, 2000) n contrast, elevated levels ofIL-17/ at baseline is associated with greater reduction (of depression severity after treatment with two antidepressants in combination therapy, buproprion-SSRI, (Jha et al, 2017), ‘whereas higher CRP levels at basaline were reported to predict better treatment outcomes with either an SSRI or SNAI (Uher et al, 2014),Neuron Review Immunosuppression ove ‘\ Impact of Anti-inflammatory Approaches on MDD ‘Symptoms. There is a comparatively larger body of Iterature examining depression response following treatment that modulates the im- mune system. Patients with inflammatory inasses, especially autoimmune diseases, treated with immune suppressive drugs. often experience improvement in depression symptoms. Trials in this area have focused on two drug classes, non-steroidal antiinflammatory drugs (NSAIDs), and cytokine inhibitors. Most ofthe studies have used NSAIDs as add-ons to conven tional antidepressants, though data also exist on monotherapy with NSAIDs. & recent meta-analysis comprised of 96 random ized controlled trials (RCTs) including data trom 10,000 patients ‘ound that both monotherapy and add-on NSAID therapy, cyto kine-inhibitor monotherapy, statin add-on therapy, glucocort- cod add-on therapy, and minocyciine (microglia inhibitor) add- fn and monotherapy possess antidepressant efficacy (Kohler Forsberg et al., 2019). However, previous studies concluded thatthe efficacy of NSAIDs on depressive symptoms negligible (Eyre et al, 2015), possibly due tothe inclusion of studies using aspirin that has. no effect on depression. Cytokine inhibitor monotherapies are promising as 4 out of 6 antiinflammatory ‘drugs ameliorate depression (Kappelmann otal, 2018; Kohler~ Forsberg etl, 2019). However, itis important to note that these studies were conducted in patients with comorbid inflammatory diseases (e.g., psoriasis, reumatoid artrts), which may have a distinct pathophysiology. Furthermore, TNF inhibitors such as, etanercept (Tyring et al, 2013; Tyring et al, 2006), adalimumab (Loftus et al, 2008; Menter et al, 2010), IL-4Rta antagonists (Simpson et al, 2015) or IL-12/1L-23 antagonists (Langley fet al, 2010), antiiL-17A antibody (beekizumab [Grifihs otal, 2017 or ant-L-6 antibody (Sirukumab [Sun et al, 2017) have. all been shown to be more efficacious than placebo in the treat- ment of MDD symptoms. In non-randomized and/or non-pla- ccebo controlled tals that targeted TNF or IL-6, simiar effects hhave been observed (Kappelmann et al, 2018), indicating an improvement of depressive symptoms with cytokine inhibitor treatments. Infiximab, a TNF-neutralzing antibody, only benefits ‘2 sub-population of ‘veatment-resistant MDD patients with elevated levels of inflammation (CRP >5 mg/L) (Wiler and Rei- 2) immonosuppression “antbosies ) Tolerance © CelPress Figure 3. Diagram of Potential Immune Response Dysregulations In MDD Patients Sess induces tha reduction of alarmins. mole ‘Sues tat gue the prodicton of proianany ‘tones by inate mune cals Dut romctos ‘oprossve-ihe behaviors recent. Ganetealy Imada suscepti), a story of fection and Shtommune diseases so can pine the mune System's tespense to ates, tough both the Irate and adaptive inane aystars Infection and auiommune diseases, or example, may act on T faper cells and affect tonne proaucton and antibody producten. The pronarmatory cf tins ar oun o promt dopression, whereas. Ine ole of anriamnstry cytes ass a fntinlaneatory eytoines Induce co mun SSpprossion or lola, are whether tho PPO thaleme-prutary-acenal aie (HPA) andor the Ssympathetenarvous sytom (SNS) axis ae mpl ‘ated ths prenomens paren ‘on, 2015; Raison et a, 201) or patients with a history of child hood trauma (Vcintyre et a, 2019). Ina recent multisite study, infiximab did not significantly reduce depressive-symptoms in bipolar depressed patients (Mcintyre et al., 2019). All these antiinflammatory treatments show relatively good safety pro- files, without major side effects noted, but caution should be taken as the trials were of short duration (Kohler Forsbera et al, 2019). Overall, these findings suggest that cytokine inhib- itor approaches provide benefit in depressed patients with ‘prominent inflammation, butitremains to be determined whether the improvement is due, atleast in part, to their effects on so- ‘matic diseases, Although all hase drugs aim at reducing infla- ‘mation, they all target different mechanisms involved in the inflammatory process. NSAIDs inhibit COX-2, whichis involved in the induction of inflammation. Cytokine inhibitors selectively Inhibit eytokinas, Glucocorticoids act upon a myriad of targets. ‘Statins decrease CRP levels and inhibit lymphocytes. In contrast, drugs targeting circulating monocytes to prevent their Infltrtion in the brain, such as the C-C chemokine receptor (CCRY2 inhibitor (pioglitazone) have no effect on depressive symptoms (Dean et al, 2017; Rasgon et al, 2016; Sepanjnia ct al, 2012) Anti-inflammatory drug adjunctive treatment of an- tidepressants seems also to improve efficacy of the antidepres- sant, and teatmentesistant depressed patients may also benefit from ant-inflammatory drugs (Raison et al, 2019) Mesenchymal stem cell therapy, which has been studied fairy extensively in rodent models of a variety of neuroinfiammatory Conditions (Regi et al, 2019) and in humans, produces a ppan-inhibtion of inflammation after intravenous administration Characterized by long-lasting (>6 months) reductions in TNF and CAP (Tompkins etal, 2017). There is currently an ongoing INiK-funded clinical tial in patients with comorbid MDD and alcohol-use disorder. Overall, there is a large body of evidence that immune re- sponses are dysregulated in MDD patients (Figure 3), Most of these findings have been replicated and expanded in rodent ‘and non-human primate models to identity the mechanisms of ‘action and the cause of the dysregulated immune responses in Corder to develop new treatments targeting the immune system that may benefit MDD patients, Neuron 107, July 22, 2020, 243© CelPress Figure 4. Multiple Mechanisms May Contribute to the Dysregulation of Cytokines in MDD Immune ost prodicton of cytkine regulated by mutiple mechaname, inciuding antlanmatony actors by glicocotiols, ard vagus. neve ahve, and proifarmatory actons luerced bythe mica compo Sten and stess-nduced DAMPS invoking both te lflammasome and the INF pathways. Ach, actjichalns, ATP, adenosine tiphospato; DAMP. angerassocited mclecuar pattem; GR, alucecorsco receptor: GSK, ‘Gyoo9e synthase Kase: HMGB!, ihr mobi gum bang poten IK teres, Fon, ruclea fact happa 8; TLR, Toke recep, TOF, transforming growth actor: TNF, mor nero factor Possible Molecular Basis of Inflammation in MDD ‘As discussed in the previous section, there are likely several “sources” of immune dysfunction that contribute to the patho- {genesis of depression: infection, microbiome atterations, medi- cal illness, stress, and other factors (Figure 4), HPA Axis and SNS From Stress to Inflammation. The HPA axis and the sympa- thetic nervous system (SNS) are activated in response 10 Various types of stress and are known to be immunoregulatory (lor review, see Sternberg, 2006). The HPA axis consists of hy- pothalamic corticotropin-releasing hormone (CRH) and argh rine vasopressin (AVP), which release adrenocortcotropic, hormone (ACTH) from the anterior pituitary gland, which, in turn, releases cortisol (corticosterone in rodents) from the ad- renal cortex, whereas the SNS promotes the secretion of cat- fecholamines, norepinephrine, and epinephrine, from the adre- ‘nal medulla and sympathetic nerve endings. Both cortisol and. catecholamines regulate inflammation, acting as immunosup- pressants, inhibiting leukocyte trafficking and activation, as well as inflammatory cytokine production (lor review, see Dhabhar, 2009). Some subsets of T cells even undergo apoptosis upon receiving a glucocorticoid signal (Pariante and Lightman, 2008). ‘These relationships are aso bidirectional in that inflammatory cytokines also activate the HPA axis and the SNS, similarly to What occurs in infection and injury (for review, see Kenney and Ganta, 2014). Depression is often associated with hypercortiso- emia and glucocorticoid resistance (Raison and Miler, 200%) ‘Stress, particulary in early life, including maternal stress during the intrauterine period, affects glucocorticoid sensitivity via epigenetic mechanisms, tuming down the sensitivity ofthe im- ‘mune system to cortisol (for review, see Wadhwa etal, 2011), 244 Neuron 107, July 22,2020 Neuron Review ‘These changes in the communication between the HPA axis ‘and immune system lead to increased rates of inflammatory ‘and metabolic diseases in survivors of childhood abuse and neglect, as well as increased depression (Hom et l., 2008). ‘The autonomic nervous system is also altered in depression, with increased sympathetic activty (Murphy, 1991) and lower parasympathetic tone. The parasympathetic nervous system has also been implicated in immune function. Sickness behavior, ‘2 physiological and behavioral response associated with increased immune response activity, i, in part, madiated by the vagus nerve, through immune cells (¢.,, macrophages and ‘dendritic cals) present in the perineural sheath (Danizer, 2003) that relay the signals from proinflammatory cytokines (IL-6, TINE, IL-1) to the brain (Dantzer et al, 2008). Stimulation of the vagus nerve through cholinergic signaling, in contrast, exerts ant-inflammatory properties, reducing proinflammatory cyto- kine production TLR4-Mediated Inflammation It has become clear that immune activity in the brain itself is important. Thus, braininduced immune activation has been partialyiluminated by the discovery of alarmins produced in the brain in response to stress that trigger toll-ke receptor athway-dependent cytokine production. Toll-like receptors are & major class of receptors that detect DAMPs and PAMPs, ‘and are critical for the innate immune response. Although the prototypic pathway involving lipopolysaccharide (LPS)-induced sickness behavior has pointed toward the role of TLA4 in regulating cylokine-dependent induction of depressivestke behavior, the finding that TLR4 knockout mice are resistant to depressiverike behavior (Cheng et al., 2018) confirmed its importance. Upon ligand recognition, TLR4 activates glycogen ‘synthase kinase-3 (GSK3) that activates NF-xB to promote proinflammatory cytokine production (Martin eta, 2005). How= ‘ever, only recently have some adaitionaligands responsible for the activation of TLRG in depressive-tke behaviors bean discov- ‘ered. These include the alarmins: high-mobilty group box 1 pro- twin (HMGB!), adenosine triphosphate (ATP), or Myeloid-related protein 8/14 (Mrp8/14, also called S100AB/S) (C0 etal, 2013; ‘Cheng et al, 2018; Gong et al, 2018; Wang et al, 2018; Wu ct al, 2016). Psychological stressors increase TLR4-induced inflammation Joe t al., 2017), TLR4 activation promotes upre- ‘Qulation ofits own expression, and TLR4 mRNA and proteinhave been found elevated in both the periphery and CNS of MDD pa- tients (Hung etal, 2014), Furthermore, TLR4 levels are restored after successful treatment of MDD, confirming a role for TL in MDD patients (Raison and Miller, 2017), Inflammasome Activation ofthe TLR4 pathway is also associated with activation (ofthe inflammasome pathway (Fieshner etal, 2017), though tis, not required. The inflammasome pathways part ofthe innateim- mune response and is responsible forthe production of IL-1, ‘and IL-18 (for review, see Guo et al, 2015). Nod-ike receptor (NLR), caspase-1, and apoptosis-associated speck-lke protein containing C-terminal caspase recruitment domain (ASC)-1 ‘comprise the inffammasome complex. Once activated, pro-IL> 1p and pro-lL-18 are cleaved by caspase-1 to produce active IL-1) and IL-18, NLP induces CNS inflammation and increases susceptibility to depressive-ke behaviors, andNeuron Review NLRPS- and caspase-t-deficient mice are resilient to depres- sive-lke behaviors (Alcocer-Gémez et al, 2014; Iwata et al, 2016; Wong et al., 2016). In contrast, inflammasome activation 's prevented by antidepressants (Alcocer-Gémez et al, 2017) In addition, expression of NLRP3 and caspase-1 in circulating immune cols of MDD patients is increased, suggesting that MDD patients have an activated NLAPS inflammasome, which Correlated with increased blood IL-1Band L-18 (lcocer-Gémez_ etal, 2014; Syed etal, 2016). Interestingly, caspase- cleavage of glucocorticoid receptors induces glucocorticoid resistance in leukemia cells Paugh ot al, 2018), and glucocorticoid resistance: has been associated with MDD (Faison and Miler, 2003), sug- gesting a potential pathway whereby glucocorticoid resistance might originate. 1D0/Kynurenine Pathway Stress has also bean shown to induce the indoleamine 2,3-diox- yaenase (DOVkynurenine pathway through cytokine produc- ‘ion, IDO is responsible forthe fist step of tryptophan catabo- lism. it reduces tryptophan levels so less. tryptophan is, avaiable for the synthesis of serotonin, which is important because serotonin depletion has been hypothesized to promote depression, IDO Is activated in macrophages, dendiitic cals, endothelial co's, and brain glial cells comprising microglia (Dant- 2er, 2009) by signaling from proinflammatory cytokines, such a. L-1B, TNF, and IFN-y, as well as psychological stress or gluco- Corticoids (Kiank eta, 2010) and IDO is inhibited by anti-inflam- matory cytokines (Cerverka etal, 2017). IFN-a-induced depres- sion development and severity in hepatiticC patients is directly associated with an increase in CSF and peripheral tryptophan metabolism through the kynurenine pathway (Capuron et al, 2002,2008; Raison et al.,2010). When tryptophan is catabolized, intermediates collectively known as kynurenines are produced (Cervenka.et al, 2017). Consistent with this, in rodents, adrinis- tration of L-kynurenine induced depressive-ike behaviors, whereas LPS-induced depressive-tike behaviors are blocked by.an ID competitive inhibitor (0'Connor et al, 2008a, 2009). ‘BBB Disruption Itis only recently that researchers are starting to tease apart the Contribution of peripheral and central inflammation in depression with the discovery of the disruption of the BBB in depressive- ike behaviors allowing peripheral signals toreach the brain, reinforc- ing the importance ofthe findings in MDD patients ofa dysregu- lated peripheral immune response. A compromised BBB was described ~40 years ago in MDD patients (Nikiasson and Agren, +1984) but only recently in mice exhibiting depressive-Ike behav- lors, independently of the stressor (Cheng st al, 2078; Menard ot al, 2017). Both IL-6 and TNF have been shown to increase BBB permeabilty, and blocking IL-6 or TNF actions decreases: stress-induced BBB opening (Cheng et al, 2018; Menard etal, 2017). Furthermore, closing ofthe BBB, using the sphingo- sine-1 phosphate receptor inhibitor, fingolmod, is sufficient to rescue learned helplessness in mice (Cheng et al, 2018). One. question remaining regarding the opening ofthe BEB after stress is the biological consequence forthe brain, and whether immune Cells infitrating the brain take advantage of this mechanism. It has been shown that both T calls and monocytes infitrate the brain after stress. Thus, Th17 cells are able to accumulate in ‘the hippocampus and prefrontal cortex of mice exhibiting © CelPress depressive-Ike behavior and Tht? cells are sufficient to promote depressive-tke behaviors (Beurel et al, 2013; Beurel et al, 2018). Whether these brain Th17 cells are required to induce doprassive-ke behavior remains to be determined. Simiary, Peripheral monocytes infiltrate the brain and promote anxiety- like behaviors (Mickim et al, 2018; Wohleb et al, 2013, 2014) ‘These findings provide new avenues to identity potential relevant peripheral biomarkers associated with MDD and selective tar- (els) to induce antidepressant effects. Microbiome ‘The dysregulated peripheral immune response in MDD patients ‘might also result from changes atthe microbiome level, The mi- ‘robiome has increasingly been implicated in shaping the im- ‘mune response and brain functions (gut-brain axis) (for review, ‘see Foster a al, 2017). Recent evidence indicates the presence (of microbiome alterations in depressed patients (Rogers et al, 2016), which therefore might contribute to dysregulated inlam- ‘matory responses. MDD patients exhibit significant changes in the relative abundance of Fimicutes, Actinobacteria, and Bac- {ercidetes compared to heathy individuals (Zheng et al., 2016; forreview, see Cheung eta, 2079). Arecent study with two large Ccohorts of Europeans reported that patients with depression are deficient n several species of gut bacteria (Coprococcus and Di- alister) (Valles-Colomer et al., 2019). Coprococcus in particular has been associated with activity of the dopamine pathway, \which is affected in depressed patients, and also leads to the production of butyrate, an antiinflammatory signal, yet, depressed patients are inflamed. In addition, Coprococcus is positively associated with measures of quality of le (Valles- Colomer et al, 2018), A recent meta-analysis of 10 studies re- pported that the findings were inconsistent atthe phylum level, whereas at the family level, Veiloneliacese, Prevoteliaceae, and Sutterellaceae were less abundant and Actinomycetacese ‘more abundant in MDD patients than healthy contro's (Sanaa, ‘tal, 2020), At the genus level, Coprococcus, Faecalibacterium, Ruminococcus, Bifidobacterium, and Escherichia were reduced In MOD patients compared to healthy controls (Sanada et al. 2020), Nevertheless, it remains to be determined how microbial ‘compounds produced in the gut influence mood. in mice, the se of germ-free mice has allowed the study ofthe role ofthe mi- Crobiome in cognition and mood (Cruz-Pereiraet al, 2020), Simi- larly, antibiotic treatments alter multiple behaviors of mice, sug- gesting that bacteria influence neurobehavioral outcomes (Desbonnet etal, 2015; Hao etal, 2013; Hoban etal, 2016; Ma- lid et a, 2016; O'Mahony eta, 2014; Wang etal, 2017) Also, the development of fecal transfer approaches has opened new pathways to understand microbiome alteration effects on behav lors (Zheng ota, 2016). In addition, there is evidence forthe role of probiotics in regulating betaviors, although the efficacy of probiotics in humans remains questionable (Suez otal, 2019) Nonetheless, meta-analysis of 6 studies using probiotics in MDD patients shows a positive effect ofthe probiotics in combi ration with antidepressant treatments (Sanaa etal, 2020). Pro- biotics act by a variaty of mechanisms of action, which include (1) increasing the biosynthesis of GABA, which may be reduced InMDD patients (Dhakal et al, 2012), @ downregulating the HPA. ‘axis, which is offen overactive in MOD patients (Ait-Belgnaoui tl, 2014), and (8) upregulating the production of tryptophan Neuron 107, July 22, 2020, 245© CelPress Neuron Review ‘Table 2. Open Research Questions: Questions 1. Does dyaregulaton ofthe immune stem contibute to MDD patholoay? iter What are the important immune systom components that contribute to MOD? these act independenty orin synergy to peomete MDD? |s central or periphoral immune system dysregulation mediating the effects? What are the CNS systems that are stored bythe immune system dysregulation that promote MOD? ‘re there dtforent immune syst altoratons that promote MDD in fren indvduals, or ro specific changos common to many MDD pationts? 2. What causes immune system dysregulation Inked to MOD? ‘To what extant do gone infuences determine these immune system charactersios? Does stress (and ist acute or chronic) contribute to immune dysregulation inked fo MOD? How does the environment modulate the Immune system dysreguation inked to MDD? (Do repeated episodes of depression cause long-lasting changes inimmune characteristics? Does the microbiome contribute to immune system dysregulation in MOD? 3. Can treating immune system dysregulation facta recovery rom MDD andlor promete esiionce to MDD onset? ‘What are the immune system targets that are effective interventions for MDD? Can controting the tess response normalize immune systom characteristics? 's controling peripheral immune system characteristics suet to counteract MDD or does the contra mune syeten ned tobe targeted? ‘Dp non-invasive interventions (herapy,nuttlon, exercise} normalize immune system alterations associated with MOD? ‘Are microbiome intervention that alte he immune system elective in MOO? ‘and theretore serotonin availabilty (Desbonnet et al., 2008). As derstanding of how signals trom the environment (such as forthe studies ofthe role of inflammatory markersin depression ‘there are limitations in the studies of the microbiome in MDD pa tients, comprising the small size of most studies, the fact that the different populations inthe studies have cifferent ages, and age affects the microbiota composition (Chen et al,, 2020), the absence of consideration of the diet, or ofthe effects of the an- tidepressant treatment, the regional variations (most studies are from Asia}, and the methodology to sequence the microbiome, hich might affect the results. In a more cortvolled environment, Where a large population of psychiatric inpatients (comprising '~74% MOD patients with or without other comorbidities) remain in the hospital for an ~50 days, where det was controlled for as patients received the same meals, remission was associated with an increased richness of the microbiome (Madan et al, 2020), Altogether, this suggests thatthe microbiota remains an Interesting avenue to understand the dysregulation of the = ‘mune system in depression. Although these mechanisms appear disjointed, they have the common theme of regulating the cytokine production, which ‘seems central to MDD symptomatology. Future Directions ‘Although substantial progress fas been made in understand- ing immune system dysregulation in depression, many ques- tions remain (Table 2). Thus, clinical studies have provided ‘mixed resuits conceming the potential efficacy of anti-iflam- ‘matory agents in depression. Whether this is the result of a oor understanding of the immune system defect, the pres- tence of comorbidity that complicates the clinical picture or a narrow focus on targeting a single cytokine to improve mood. symptoms remains to be determined, We also lack a clear un- 246 Neuron 107, July 22,2020 ‘childhood malteatment or stress in adulthood) intiate changes in neuroinflammation, oF peripheral inflammation, ‘and whether one precedes the other. For example, although rodent studies suggest DAMP production is important in iit- ating the immune response to stress, leading to the production (of cytokines, we do not yet understand how stress causes DAMP production and where the production is initiated or how its regulated. Similarly, factors that may determine the magnitude ofthe immune response, whether it includes down- ‘stream effector pathways such as kynurenine metabolism andor excess of neuroinflammation are stil unanswered and vill have @ major impact on the field From a clinical perspective, itis also poorly understood ‘whether therole ofthe immune system in depression sf clinical importance in most patients or only in a subset of cases (igure 5). For example, an immune index analogous to the poly- ‘genic risk factor score in genomics, may moreeffecively classify the immune state in depressed patients compared with the use ‘ofa single marker such as CRP. Such an index or signature might help define composite criteria for clinical trials addressing the contribution of the immune system to MDD pathogenesis. ‘Such eriteia may also include imaging approaches to assess inflammation both peripherally and centrally, which are currently lacking, and/or algorithms taking into account mutiple cyto~ kines, immune cell subset prevalence or function, and micro- biota species to predict the probability of developing MDD, orre- ‘sponding to particular treatment modalities or drugs (Figo 5). [New paths have been taken to target inflammation to obtain antidepressant effects, such as mesenchymal stem cell therapy, ‘hich has been proposed to induce a global ant-inlammatory response and putative antidepressant effects, which areNeuron Review cot enayse OK peputevon s Merobiome sly population 4 Understanding the role of one contibutor to Inmammation essocisted wth MDD st one time point in varios populations currently being tested in clinical trials. In addition, treatment of ‘microbiota alterations might also help improve responses to an- ‘depressant therapy similarly to exercise, providing among other, antiinflammatory actions, There continues to be much in- terest in future treatment approaches using existing or novel pharmacotherapies to control inflammation and promote or potentiate antidepressant responses. A successful immuno- ‘therapy must improve MDD symptoms without excess immuno suppression, which can occur with multiple cytokine inhibition therapy. Thus, disease modifier therapy such as modulation of the gut microbiota via diet or probiotics regime might help ‘control the unwanted immune responses of MDD in a more piys- iological, and safe manner. However, the contribution of the ‘microbiota to MDD will have to be clacified frst, as wellas the ac- tion of probiotics, for which a great deal of debate has been generated (Suez etal, 2019). Similarly, exercise, which provides: antiinflammatory effects, besides its other known beneficial effects, is also an option to enhance heathy diet habits and an- tidepressant effects in MDD patients. In addition, initiating studies to determine whether non-pharmacological treatments, for depression, including evidence-based psychotherapies, ‘transcranial magnetic stimulation, or electroconvulsive therapies modulate inflammation and immune function might provide valuable new insights, Due to the major contribution of early lfe trauma in the development and maintenance of chronic inflammation in adults, earl intervention after trauma, especially in childhood, might prevent inflammation-associated depres- sion. Consistent with this idea, determining whether methods toreverse the consequences of trauma, for example, via epige~ netic mechanisms, prevent the inflammatory response and associated depression, might also open new therapeutic Finally, and of considerable importance, isan important funda- ‘mental philosophical diference that has plagued this field. We are refering to some who simply believe that peripheral mea~ sures of immune dysfunction or inflammation are, at best, epiphenomena and are in no way related to the pathophysiology of depression. They dismiss the evidence of increased inflamma tory markers in depressed patients and of CNS effects of induced inflammation as interesting, but certainly not causal. ‘This in spite of overwhelming evidence that increases in periph- era inflammation produces in humans and laboratory animals CNS changes as assessed by brain imaging, neurochemistry, © CelPress Figure 6. Where the Feld Is Going Historcaly many studies of wemunclogeal tts tat may act MOD focused on a sngle compo rst sth as geet varies, cytokines, imme {at types of actons, and the merabiome camper Stion” Wh techrelogisl advances. that nave recerty booome avalabe, or ae under deveop- Irene enon Bat ressroters wl be ae 10 ‘opty a more wgrated approach to arlyze ue ‘le paramere each dil syjct oot {are completo and trated picture of gone, Iierobil, and mmunoiogica factors tat nuns the oneet, course, and eaten response of MOD patente ‘and behavioral changes, and moreover they minimize the now well-documented pathways reviewed above by which inflamma- tory cytokines can indeed act upon the CNS. Believing that the only evidence worth considering are measures of increased inflammation in the brain, which, although documented in some CNS studies and PET studies, are relatively meager at the current time might be reductionist and lead to missed thera- peutic opportunity. In spite of a myriad of examples of peripheral ‘mechanisms affecting psychiatric state, e.g., hypothyroidism {and hypoglycaemia, to name only two, the argument continues. to plague the field. As more research is conducted, the role of inflammation and cognate immune function dysregulation in depression will Become clea. [ACKNOWLEDGMENTS Werk in he author's labs s supported bythe NH (MeTO46S6, ME 1445, 1Mi17293, MT T8526, A023), DECLARATION OF INTERESTS. C.BN’'s franca clocuresare as fotows: corel forthe st tr yrs for Xtle, Takeda, Tato Pharmacaica In, Sgnant Health, Samoan Phamaosutos Ines Jarsten Research & Development LLC. Magetm, Ino. Nawior Phamacautio Ine, Sunovin, TC MSO, Ine, nt Calle ‘Thora, Ie, EMA Wolras, Gerson Lota Group (GL), rd oad Phamaceuteds; a socinader in Nhe, Caan, Seale Gences, ADD, (OPKO Heath, Ine, Arar, 8 Gon Holdings, nc, Corcpt Therapetos Phamacautcas Company TC MSO, ne, Trends in Parma. Developmen LU and EWA Wires onthe slot advisory board ofthe Arorea Foundation or Sueide Prevertion AFSP), Gran ata Bahar esearch Four ‘ation (BBFF), Wao, ily Dzordors Associaton of Amore (ADAA, Sky tral, Cigna Healy, Lawes nate for Bain Research (ABM, In land a member ofthe ard of Dractos of AFSP. Gratude Americ, ADAA, land Xa Sman, nc. CBN. aloo reports income sources or equty of 510.000 cr mor in American Poychiat Publting, Nha, Skgrant Heath, (CME Ouittrs,biva-Celuar Therapies, In, Magstin, and ENA Wetbes patents tr matiod and devs for tanedermal daivaty of itm (US 5375,90081; method of assessng atiéepossant rug thorey via wanepor Inhbten of mancumine nurovaramiters by exo astay US 14802762) 1nd compounds, compostions, matt of syed, and methods of Weat- ‘mont (CAF Receptor Bing Uae (US 8.551, 996 82, REFERENCES ‘Adar, 78. Wharton, CM. ites Land Misch T. 008). Te association ‘ween ental neath and site nfscicusliness among aatonl sample ot ‘a: to 24-year college stunts. J. Am, Cl. Health 6, 657-053 Neuron 107, July 22, 2020, 247© CelPress ‘Ader, and Cohen, N. (1975), Behavoraly condoned immunosuporesion, Poyehosom Med. 37, 353-54, ‘Mab, A. Kemp, DE, Ganeoy, $1, Schinagle, M., Conroy C., Srownigg ‘DrArcangeo, N, Golo, Neads,N, Sorano, MB, et (2010, Deb” bing, pacebo-contelod al cf plogiazene for bipolar depression SI itech: isons 245, 057-968, ‘AtBelgnaou, A. Colom, A. Bears, V., Ramaho,L, Mart, A. Carer C., oudeau.€, Thcodorau Vand Tomkins, T2014) Probie pe Alcocer-Gémer, E66 Migu, M, Casas Baquero, N, Niner Vasco, J Sanchez-Acazar, J A, Freea-Rodigue, A, and Corda, MD. (20) [NLR ifarmacome i atvated n moneruckar blood col Fem patos lth major dopressvo doordor. Ban Baha nun, $5, 111117. ‘oocar-Gémex,E., Casas-Barque,N, Villans, MLR, Remar: Gulona, SL, Cotaais Lozano, D., Gulen Since Akszar JR, Novo Pando, “IM, ana Cordero, MLD (2017) Aviepeensots indice aulopagy depen ‘ent ALPS ammaseme nhbiton in Major depressive disorder Pharr or Ree 21, 40-138, ‘evo, O, Rue, Zwanager, PK, L, Bane, BT, Ao V. Scheu, ‘ae Aen, (6019), Sct Defeat Modus T Helper Cal Perconages in’Sess Suscoptne and Restrt Mice. tJ Mo Se-20, 20. ‘Andersson, NW. Gustalson, LN. Othe, N, Taha, F, Col, SW, Munk ‘lovgensen,P. and Goodwin, RD. 2015). Depression athe ak of auton imu dena nana eects, peeping say ‘desson, NW. Goode, RD, Okkel N, Gustafsson LIN, Taha F,.Cl6, ‘Sv, ana Munk-lorgense, P2016). Depression arth ik of sovorerc tions rospacte anaes on anabonwide representative sao Fd ED ‘ami 46, 131-199. ‘Asn, G.M. and Mller, AH. (1980. Phenamenolegy and ilogy of doprs- ‘on potent mechan or neurcmaduaton of nun. Depressive Di ‘rans and lnmanty (amercan Pycac Pres), 1-28 ‘tals, S. Setawan,E, Wison, AA. Fusjan, PM. Miler, Xu, Hutton, Coosa M1, Kh, 5 Vaedov Nea (2019), Repleatnapresietve arom “Sonia of grant arsocstor pron ration vlurse mean Ne pajehopharmacology 45, 25-031. ‘amos. J, Mond, Vand Parants, CM. (2017. Gonetic Gntutions of Inflammation to Depression Neuopsychopnarmaccloy 42, 81-30. ‘Saunas, 0. Atay, Clute. Para, CM, and Monde V. (2076) (Ghichood vaurna ad adutod ifarmatir: a melranayes of peripheral Creactv pein itetolin6 aed tumour recrocsfacor Mol Peyohty Siroa2608. {Beech FD, Lowther, Lata Jl, Mason, PN, Taylor, MM Unio. Lin A ee, 2 Maloney Mucaicharan, A, oa 2010) eased pati- ‘al blood sxpression of acon vansoot cain ganesn bso deoress.on, Sipour bso 12.813-824 Solar, RM. and Agar, . 2008). Major depressive corde N Engh J Mod, 358, 55-68. Benos, ME, Wate BL, Norden, M., Ostergard, 60. Eaton, WM, Krogh J, and Mertonson, PB. (2013). Autcierune cases ae severe = fection a ak factrs for mood eorr:anaonwige study, JAMA yeh thy 70, 812-800. ‘our, and Lowi JA. (2018, THY7 cots in depression, Bran Bay = euro, E, Harngton, LE. and Jope, F.S. 2013) ilammatoryT helper 17 ‘sls proioe aoprestion ike bhavir mice al Paya 72, 628-690, euro, Lowel, A. and Jope, RS. 2018}. itn characterises ot hi pocampal pathogenic Ty ean a mouse moda of dopression Bane Fav-tmmun, 73, 180-104. ‘Black, nd Miter, 8.2015) Meta-Analysis of kines and Odeon In Sunt: Distinguishing Sucidal Vers Nonsucidal Paton il Py. hat 7820-57. 248 Neuron 107, July 22,2020, Bloom, DE, Cater ET, Jané- Lops E Abahams-Gessel, Bloom, LR, Fatma, 5, Feu AS. Gaztano, T, Mowal, M, Pandya A” Pret, K> Rosenberg, L, Seigmen, B, Stein, A, aed Mersin, ©, (201%). Th Gabel Eoanom Burden of Novcommruniatie Diseases (Wert Boonie Forum Border, Jobson, E.. Evans, LM. Seon A, Bere, Ne Silvan, PF ‘0 Kel MLC. 2019). No Suppor for HitorealGandceia Gane or Canc ‘Sate Gone-by- eran Hypotheces for Rajor Depression Aeros Me Urge Samples. Amd. Psych 176, 376-37. Borat, 8, Myphants, TN, Vabona, 5. Pere, G., Maes, M, Mors, . Kebers, hehe, CA Femandes, 6.8, Subs, @, tal 2017). Depression Incancor The mary Bbehavera pathways vg tumor progression. Can or Treat Rey 2, 58-70, Balin, C., Hopgu Agua, E and Parante, CM. 2013) Th le fim ‘mune genes inthe assocaton between depression andammation reve ‘trove lnc studies Bran Bahay un. $7, 3-47. (030, %, Ui LP, Wang, QW, ©. Hu, HL Zhang, M. Fang, Yang, U8. Keng, WC, et (203) Asreeyo-donved ATP ecules pres ‘Soko behaviors. Nat Mod. 18, 772777. ‘Capuron, Ravaud, A, Neveu, PI, Mer, AM, Maes M, and Data, (G0ba,,hesocation betwesn decredaed sen typos conoentetons {2a depressive symptoms in cancer pales undorgang cytokine tery, Mol Peyhaty 7, 108-473. ‘Gapurn,L, Newauter,G., Musselman, D.L, Lawson, DM. Nemerf, 8. Fochs,D, and Miler AH. 003) .trtororn-ipha-nducedchangos ryote ‘han meiapolon,rlaonshp lo depression and paroxetine Westen. Be, Povey 84, 008-014. ‘Capuron, L, Pagron., 6, Drake, DF, Wootwine, 8. Spivey, JAR, Crowe, FJ, Volaw, JR, Goodtran, MM, and Mile. A, (2012. Doparineraic ‘roche of ride basal gangia responsi Yo Redon reward dng Intereron fa adminetation. Aryan, Payer 9, 1044-1083. Convert |, Aguila, LZ. and Russ (2017). Kynuranins: Tryptophan’ ‘metaboesn exec nfisnaton, and mental hea. Science 857, 87. Chamberain SF. Cavanagh, J, 9 Boe, P. Mendel V, Jones, DNC. Dre: vote, MC, Cowen, P), Hariso NA Poon, Parart, GM, and Bu ‘more, ET. 2010) Treamartrestartdoprssion and perphral Ceactve ‘rote Br. J. Psyhiy 214, 11-1. ‘Chapman, OP. While, CL. Flt, V, Dube, S.A, Edwards, Vand ‘Ana, RF. (2008), Adverse chichood exporances and tho rk of depressive ‘ordersn acuthood Aleck. Deer, 82, 217°225, ‘Chon, tan, Chen P., Ouyang, Xu, ., Zang, Zand Sin ¥. 2011. Emerpng tendency towards automune prcese i major depressive pa tint anovelnaight rom Thi? ost aychisy Ros. 1294-290. (Chon, Ho, , Far, Wang, B. Ba S.J, Xe, J, Zhou, Cana W. ‘sndXo,P B02 Ago specie atirenal chang on pt scrbita comp ‘sion i patents wah majr deprossive Georder. Age (Abany NY) 12 Brenan. cheng, ¥. Pardo M, Armin, RS, Marinas A, Moutsine, H., Zagur, slope PS, sr eur © 2018. Stest-indiced neurarnation ‘ted 'by GSI dependent TLR signaling at promtes suscepbity 10 \Sepreshonine behave Brain Sha. nas 9, 207-222, ‘Chong, Dees, S, Marinaz. A, Worthen, FJ, Jope, RS. and Bara, E (2018) Tha ceupis load bran barter itegry to marian prolonged ‘Sepressvtke behavior nmi. Bran Bahay. rein. 69, 556-567. (Ghoung, $6, Gotten, AF, Unlemane, AC Mee, Jo, Rr JM, ae ‘Subsat,M2019, Syatamatie Rovow ol Guthiterobs anaajrDepres™ ‘son. Font Poyehiay 10,34 (Chol. Ai, and Bosal (209), The dict les of yctooyganase- ‘and 2 n nourinfarenato pleas er tarslaonalresearoh Tends Phamacol'So 30, 17183 Coso, A, Vs, TM, Was-Bass,C Bitke, End Grasso, {G014, Chichoed! malratmens and nlarsmatory marr systems re ‘ow Acta Psychiatr, Scand, 729, 120-192.Neuron Review Colasant A, Guo, Q, Matar N Gannet ., Onaga M, Newbould RD. (tear O” Riso, S. Thomas,G. Netwlas, R etal 2013). Ino Assess” trent of Brain Whe Hater iaimation Multiple Sera with (TOF Colo, Fe, de Lamina, Rota. S Haze, F Hardy, P, Vrs; Cy ovo 8, and Combo (2017, Pegitazone coudinucererission maj Sepresson a met-onayse, Nowropnyenatr is Treat 13, 0-16. Cotter, Mackay D, Landa 5. Kerwin snd verl | 20013). Reduced ‘jt cot erat a rewonal sit nthe aero cngio corto mor Aeprossve order: Arch Gen Payhity 58, 545-553. Cotter, Patt, CM. and Evra, LP_ 20018). Gia cel aboemates n traorpyctisie orders the evidence an nplcatone. Bran ie, Bul 6, saoone, Crawler, B., Crag, 2, Manco G., Wit, L. Sth, A, Spal Sen J anon € Wood: A, Yaghootar, Hi tal ajor Depressi Dao Work” ing Grp ot he aycnatie Goreme Consortium 2018) DNA metystion rd iflarematon marker profes assocatod wi & Mistery of depression. Him: Wet Govet 27, 2840-2850, Cruess, B.., Daugis, SD, Peito, LM. Have, TT, Gets, Dubé, 8, Cary Mand evane, DL 2005, Assocation realli major depres wit need ature acy among Hv-seropostive women. Am I Payehiatry 162, 2125-2190. (Pera, Rea, Nolan, Y.M.. O'Leary, 0-F Dinan... ae Cyan, “LF (2020). Beoresser's Unholy Ty: Dysregulted Stress, mut, an ine Merobeme, Annu Row Psychol 740-78. Dantes, F200) Cyne, sekness nehave, and depen. neue A egy Gin. Nort Am 29, 247-208, Dantzsr,R.. O'Connor, J. Freund, G.G, Johnson, RM. and Ketoy, KW. (2008 Frm ntarmaion seks and pressor: wh te rere tem subjugate the bral Nat ev. Newose 9, 1-56, Darko, OF, Lucas, AM, Gil, JC, Rise, S.C, olsen, 5. Hamburge RN, Sverman, Mand Janowsky, OS. (988). Collar mnt and the fypathaleme-ptutary an m mar fective dearer a prema ste Poyehaty Fos 25, 1-8. Davam, Mi, Goharou, Ahmad Vasmehan, A, Ghanen, A, Kesh tar M. Deshi, Land Atastzar MRL O16) Elevated Wand TOPS Seam Lavels:APosive Conelaton between -hapa 7 Cell elatad Pros famratory Resporeas wih Mor Depresive Dicord, Basic Cin, Neuse, risreie. oan, OM. Kanchanatawan, 6. Aston, ML, Mohebl. M, Np, CH. Mass, Mi Bar, Sughonchuwamn, A. Tangwongsta. Singh, AB, et al (2617 Aaknctve mnceyeinetesiment for aor depressive cscrder: A foo! ot canes ti Aust NZJ Payehaty S,a20-840 Del Guerra, FB, Fonseca, JL, Fgueredo, VM. Zi. and Korot, Cc. 2019) Human mmunodeicency vis associated depression cont ‘ere of rmuno-eilammatry, monoamnergje, neuedogoneratve, sd Nu roophic pattways. J. Newowra. 19, 31427. Denburg, $0, Carte, LM, Long, AA. and Deburg, JA (1968), Neuro jena conltes of sium ‘ymphocyotonc antibodies in system pus eeybematosus. ai Sehau. mun 2 722-234. Dosconnat,L, Garett. Cato, G, lonenstock J, nd Dinan TG 2008) "The protic Bacteria: An assessment of potental artaepees Sant proper the at Payer Pes 49, 164-174 Desbonnat L. Clarke, G, Tein, A, O'Suvan, 0, spi, F, Money, RD, Cater BD, Dinan i-G, and Gran, JF G15) Gut meres depo” ton irom early adolescence mice: plcations for bran and behaviour ‘ra Behav. Immun 4, 965-773. Dvorman, 8. and Paterson, PH (200), Cytokines and CNS development ‘Dhaba, 2008) A assay may Kee te pthogens away: The Hot orfight sess response an the augmentation of immune fureon neg. emp. Bo 49, 215-238. © CelPress Dhaka R. Bap VK, and Bask, KH. (2012, Producton of gba Aino bay acd) by microorganisms: revi raz Microb 48, 1250-1241, Dickons,C., McGowan, L, Clark Caer, D, and Creed F202) Depression invtwomated arti sjtoraticreviw ote Morar wit et anales. Poychosom. Med. 6f 82°00 Downg, Lv, Mariner Maza, ©, Wedevoe, IL, and Cows, ML (2008) Fela of pression. ature urcten- ahd imlecton ale coronary ‘try bypnesn wemon Eur. Carona. Nore 7, 52-58. Dowlat,¥. Hermann... Swardoger, W Liu H., Sham, L. Rim, EX. anc Lanett iL 2010, A metaranalsts of ctokines im majr dros. i Payer 67, 4-457. Danie Kote, B. Wave, M, Radon, LV, Peron, NLD. Panto, M. DDamarewe, A, Paonanove ST vanovc, A, Naot, Tan asove- Gs eM. @OIS, Molanchote ard atypal rajor Gopresion-connecion be- {ween etokines, peychopahotogy aed taste. Prog. Newenoychophar- rmacot Bok Poyeaty 4. 1-8, ‘anlop 8. Keley. ME, Aponte var, V, Metako-Crows,. Kinks Fh, 4c. Nera, Cs. Craghoed WE, and Mayborg, HS: PREDICT ‘eam 017. Elects of Paint Preferences on Outcomes in the Peto ct emsion nDepresson toda and Combed Treatments (PREDICT) Stuay A J Payehiaty 174, 516586. Dyorskova tl 1860 7 and 8 ymphocytes in psychotic patos. Paycho- pammacotogy (Ber) 67, 245-268, Ener, 8M, and MeAlier, AK: (2012), Major hitocampatbity complex ‘1 procs In bran development ad plestly. Trends Newosch 5, ‘vain M, Tapas, T. Sapp. Mononen N. Ritoharu E Jokela, M Putc-Raback, Lg, 7, Walgenborper, Mt Hakuiren Cota (2015). Aei= tod meuno-itamnaiory patways ar associated win longstanding Gepressve symptoms: Evidence om chant snatyaes inthe etn Fs Stay Poy Ros. 71, 120-125 nach, D, Pant, C M, and Mendel, V. 2019), Marker of cota inftam- ‘maton inmajorcopessive disorder A ystoraticrovew ancmeta analysis ‘Sluaes examinng ceetrospnal has, poston emeion tmegramy and Post mort rain eave. Bran Bahay. ern BY, 24-40. Eueaden, J, Danese, A. Lew, CM. an Maughan B. (2017), Abisrectons Felatonshin between depression and te autem disorders - Now bet Spoctvee tam the. National Chis Dovelopmant Study. PLAS ONE 2, 0170018. Eye. HA. At. T. Proctor S. Rastano, Sand Baune, 8.7. 2018). Acres Favow ofthe efcacy of no atria ilannatery hugs depression. Prog: Newopsycrephamans. Bi Paychaty 87, 11-18 Feinstein, A du Bouly, Gand Ron, M.A. (1892), Psychotcraesin mute ‘sores A cial and magnetic resonance maging sd. Bri: PySty 161, 600-588. Fenstan, A. Magahaes, 8. Picard, JF. Audet. 8. and Moore C (20) ‘a ink between mufipio sles snd depression’ Nat. Row. Nou 1, Folger, J. an Treadway, MT. 2017). aration Elects on Motivation Sand Motor het Role of Dopamine. Newropsyehopharnacslogy 2, Bean, Fencka, TB. Kesahera, TM, Bars, P.O, Vira, MM, Bitencout, V.C, Hyaino, J. Andrade, AM, Litres, U.C., Andrade, AF, and Bento, CA Bt bape kn cei an ens ae Foruciis, SM. Olvo'a, J. Mhmura, AL. Ponta. Caralho, OR. Seugey EO, PAA, an Za, M. 2008) Aas ofa, bot, andi (Garecton of I-AA pahmorpnisms natal Neuro Festiner M. Frank M, a Me, SF 2017, Danger Signs narra ‘Somes: Stas Evoked Str iniammatonin Mood Deoders, Nesropsyeh rarracology 42, 96-45. Neuron 107, July 22, 2020, 249