The Bidirectional Relationship of Depression and Inflammation: Double Trouble

Depression represents the number one cause of disability worldwide and is often fatal. Inflammatory processes have been implicated in the pathophysiology of depression. It is now well established that dysregulation 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 regulates 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 exhibit inflammation 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, or a combination of these and other factors. Depression represents the number one cause of disability worldwide and is often fatal. Inflammatory processes have been implicated in the pathophysiology of depression. It is now well established that dysregulation 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 regulates 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 exhibit inflammation 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, or a combination of these and other factors. Mood disorders are the most common of the 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 hypomania and mania, as well as euthymia and depression). Major depressive episodes are defined in DSM-5 by a constellation of signs and symptoms (DSM-5, 2013). Patients with major depression exhibit alterations in a variety of critical functions including sleep, appetite, psychomotor activity, cognition, and, of course, mood. Lifetime prevalence of major depression in the United States is 21% of women and 11%–13% of men (Belmaker and Agam, 2008Belmaker R.H. Agam G. Major depressive disorder.N. Engl. J. Med. 2008; 358: 55-68Crossref PubMed Scopus (1046) Google Scholar, Kessler et al., 2003Kessler R.C. Berglund P. Demler O. Jin R. Koretz D. Merikangas K.R. Rush A.J. Walters E.E. Wang P.S. National Comorbidity Survey ReplicationThe epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R).JAMA. 2003; 289: 3095-3105Crossref PubMed Scopus (5531) Google Scholar). It is 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., 2005Mann J.J. Apter A. Bertolote J. Beautrais A. Currier D. Haas A. Hegerl U. Lonnqvist J. Malone K. Marusic A. et al.Suicide prevention strategies: a systematic review.JAMA. 2005; 294: 2064-2074Crossref PubMed Scopus (1817) Google Scholar). 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 disease, diabetes, and cancer (Benros et al., 2013Benros M.E. Waltoft B.L. Nordentoft M. Ostergaard S.D. Eaton W.W. Krogh J. Mortensen P.B. Autoimmune diseases and severe infections as risk factors for mood disorders: a nationwide study.JAMA Psychiatry. 2013; 70: 812-820Crossref PubMed Scopus (207) Google Scholar, Windle and Windle, 2013Windle M. 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The morbidity and mortality associated with major depression renders it the number one cause of disability worldwide and exerts an extraordinary economic burden on society in terms of lost productivity (Bloom et al., 2011Bloom D.E. Cafiero E.T. Jané-Llopis E. Abrahams-Gessel S. Bloom L.R. Fathima S. Feigl A.B. Gaziano T. Mowafi M. Pandya A. Prettner K. Rosenberg L. Seligman B. Stein A. Weinstein C. The Global Economic Burden of Noncommunicable Diseases. World Economic Forum, 2011Google Scholar). Risk factors for depression include family history of depression (approximately 35% of the risk is hereditary), early life abuse and neglect, as well as female sex and recent life stressors. Medical illness also increases the risk of depression, with particularly high rates associated with metabolic (e.g., cardiovascular disease) and autoimmune disorders. Treatment of depression includes three major modalities: (1) antidepressants and other medications that augment antidepressant action, (2) evidence-based psychotherapy such as cognitive-behavior therapy (CBT) and inter-personal psychotherapy (IPT), and (3) somatic non-pharmacological treatments including electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), and vagus nerve stimulation (VNS) (Gartlehner et al., 2017Gartlehner G. Wagner G. Matyas N. Titscher V. Greimel J. Lux L. Gaynes B.N. Viswanathan M. Patel S. Lohr K.N. Pharmacological and non-pharmacological treatments for major depressive disorder: review of systematic reviews.BMJ Open. 2017; 7: e014912Crossref PubMed Scopus (3) Google Scholar). Monotherapy with either an antidepressant or evidence-based psychotherapy results in the virtual absence of any depressive symptoms and return to the premorbid state, termed remission, in approximately 50% of previously untreated depressed patients (Dunlop et al., 2017Dunlop B.W. Kelley M.E. Aponte-Rivera V. Mletzko-Crowe T. Kinkead B. Ritchie J.C. Nemeroff C.B. Craighead W.E. Mayberg H.S. PReDICT TeamEffects of Patient Preferences on Outcomes in the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) Study.Am. J. Psychiatry. 2017; 174: 546-556Crossref PubMed Scopus (40) Google Scholar) and in 28% in a more heterogeneous mix of “real-world” patients in an effectiveness study (Trivedi et al., 2006Trivedi M.H. Rush A.J. Wisniewski S.R. Nierenberg A.A. Warden D. Ritz L. Norquist G. Howland R.H. Lebowitz B. McGrath P.J. et al.STAR∗D Study TeamEvaluation of outcomes with citalopram for depression using measurement-based care in STAR∗D: implications for clinical practice.Am. J. Psychiatry. 2006; 163: 28-40Crossref PubMed Scopus (2388) Google Scholar). At the current time, there are no clinically useful predictors of response in a given individual to one antidepressant versus another (Zeier et al., 2018Zeier Z. Carpenter L.L. Kalin N.H. Rodriguez C.I. McDonald W.M. Widge A.S. Nemeroff C.B. Clinical Implementation of Pharmacogenetic Decision Support Tools for Antidepressant Drug Prescribing.Am. J. Psychiatry. 2018; 175: 873-886Crossref PubMed Scopus (33) Google Scholar) in spite of claims to the contrary (Greden et al., 2019Greden J.F. Parikh S.V. Rothschild A.J. Thase M.E. Dunlop B.W. DeBattista C. Conway C.R. Forester B.P. Mondimore F.M. Shelton R.C. et al.Impact of pharmacogenomics on clinical outcomes in major depressive disorder in the GUIDED trial: A large, patient- and rater-blinded, randomized, controlled trial.J. Psychiatr. Res. 2019; 111: 59-67Crossref PubMed Scopus (0) Google Scholar). Such biomarkers are of great interest, as ongoing depression is associated with increasing treatment resistance and increased risk for substance abuse and suicide. Depressed patients with increases in inflammatory markers may represent a relatively treatment-resistant population. In this regard, it is of interest to note that patients with autoimmune disorders have inordinately high prevalence rates of depression. This is discussed in further detail in subsequent sections. Mammals are protected by the immune system from infectious agents and many types of insults that cause injury. Immunity involves (1) recognition of infection or damage, (2) immune functions to contain the infection/damage, (3) regulation limiting the magnitude and duration of the immune response that can itself be damaging to tissues, and (4) memory to enhance the future response to the same infectious agent or damage if re-encountered (Murphy, 2012Murphy K. Janeway’s Immunobiology.Eighth Edition. Garland Science, 2012Google Scholar). Inflammation or inflammatory response are the result of the activation of the immune system that often manifests as a localized reaction resulting from irritation, injury, or infections; are associated with warmth, redness, swelling and pain, and sometimes fever; and are necessary to eliminate the insult. Many types of immune cells and mechanisms are in place to maintain homeostasis, but dysregulation of their actions often contributes to diseases, with increasing evidence that this occurs in psychiatric disorders, including depression (Murphy, 2012Murphy K. Janeway’s Immunobiology.Eighth Edition. Garland Science, 2012Google Scholar). The immune system is classically divided into innate and adaptive arms, though these two act cooperatively to ensure proper immune actions. The innate immune system is the first line of defense, because innate immune myeloid cells (e.g., macrophages/monocytes, dendritic cells) and lymphoid cells (e.g., 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) are host molecules that signal cellular damage (e.g., Heat shock proteins), whereas PAMPS are present on infectious pathogens (Gong et al., 2020Gong T. Liu L. Jiang W. Zhou R. DAMP-sensing receptors in sterile inflammation and inflammatory diseases.Nat. Rev. Immunol. 2020; 20: 95-112Crossref PubMed Scopus (21) Google Scholar). After activation, macrophages and dendritic cells produce cytokines (interleukins and/or 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 antigens to cells of the adaptive immune system and are therefore also called antigen-presenting cells (APCs). The adaptive immune system, composed of lymphocytes (T and B cells), is slower to respond, as it often requires recruitment, 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 cell receptors (BCR), which are produced by site-specific somatic recombination (Smith-Garvin et al., 2009Smith-Garvin J.E. Koretzky G.A. Jordan M.S. T cell activation.Annu. Rev. Immunol. 2009; 27: 591-619Crossref PubMed Scopus (1029) Google Scholar). Each lymphocyte expresses one unique antigen receptor variant. This confers an antigen specificity 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 lymphocytes. B cells clonally proliferate and differentiate into plasma cells, which produce antigen-specific antibodies. Activated T cells can become one of three broad types of effector T cells: cytotoxic, helper, and regulatory. Thus, cytotoxic T cells (CD8+ cells) kill infected cells. T helper (Th) cells influence the behavior and activity of other immune cells, and regulatory T cells (Tregs) suppress the activity of other lymphocytes that control or limit immune responses to prevent autoimmunity. Some activated B and T cells differentiate into memory cells, which can mount a rapid immune response if the same antigen is encountered again by differentiating into a large pool of specific effector cells (Murphy, 2012Murphy K. Janeway’s Immunobiology.Eighth Edition. Garland Science, 2012Google Scholar). The brain possesses specialized immune cells called microglia that comprise 5%–10% of total brain cells and carry out macrophage-like and other specialized functions (Kim and de Vellis, 2005Kim S.U. de Vellis J. Microglia in health and disease.J. Neurosci. Res. 2005; 81: 302-313Crossref PubMed Scopus (511) Google Scholar). Microglia are maintained by self-renewal with minimal contribution from immune cells outside of the CNS, and their main functions are to maintain CNS homeostasis and to provide rapid responses to damage or infection. Microglia exhibit a broad spectrum of activation states upon receiving various stimuli. Recent findings have shown that microglia are important for synaptic modulation (e.g., synapse pruning and neurogenesis) and are activated in many neurodegenerative and neuropsychiatric diseases, where they contribute to pathology by promoting neuroinflammation (Yirmiya et al., 2015Yirmiya R. Rimmerman N. Reshef R. Depression as a microglial disease.Trends Neurosci. 2015; 38: 637-658Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar). The heterogeneity of microglia suggests that microglia subsets have distinct roles in the brain (Masuda et al., 2019Masuda T. Sankowski R. Staszewski O. Böttcher C. Amann L. Sagar Scheiwe C. Nessler S. Kunz P. van Loo G. et al.Spatial and temporal heterogeneity of mouse and human microglia at single-cell resolution.Nature. 2019; 566: 388-392Crossref PubMed Scopus (110) Google Scholar), but a more complete understanding of the complex roles of microglia is necessary to provide further insights in understanding their role in brain function and pathology. There is a role for non-microglial cells in CNS immunity with three other types of CNS macrophages: perivascular, meningeal, and choroid plexus macrophages (for review, see Li and Barres, 2018Li Q. Barres B.A. Microglia and macrophages in brain homeostasis and disease.Nat. Rev. Immunol. 2018; 18: 225-242Crossref PubMed Scopus (231) Google Scholar) as well as lymphoid cells (Beurel and Lowell, 2018Beurel E. Lowell J.A. Th17 cells in depression.Brain Behav. Immun. 2018; 69: 28-34Crossref PubMed Scopus (22) Google Scholar). 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 (Wilson et al., 2010Wilson E.H. Weninger W. Hunter C.A. Trafficking of immune cells in the central nervous system.J. Clin. Invest. 2010; 120: 1368-1379Crossref PubMed Scopus (282) Google Scholar). However, in certain conditions, macrophages, and T cells, can cross the blood-brain barrier (BBB) and enter the brain parenchyma, generally producing damage (Wilson et al., 2010Wilson E.H. Weninger W. Hunter C.A. Trafficking of immune cells in the central nervous system.J. Clin. Invest. 2010; 120: 1368-1379Crossref PubMed Scopus (282) Google Scholar). The BBB is composed of specialized endothelial cells linked by tight junctions, limiting the entry of immune cells, various blood constituents, and pathogens. Indeed, the BBB prevents >98% of antibodies and small molecules from entering the parenchyma, while assuring the efflux of other molecules. Various hypotheses have been proposed to explain how peripheral immune cells may cross the BBB under pathological conditions (for review, see Ousman and Kubes, 2012Ousman S.S. Kubes P. Immune surveillance in the central nervous system.Nat. Neurosci. 2012; 15: 1096-1101Crossref PubMed Scopus (195) Google Scholar, Ransohoff and Engelhardt, 2012Ransohoff R.M. Engelhardt B. The anatomical and cellular basis of immune surveillance in the central nervous system.Nat. Rev. Immunol. 2012; 12: 623-635Crossref PubMed Scopus (476) Google Scholar). In conditions that weaken the BBB or in regions where the BBB is more permissive, such as the circumventricular organs and choroid plexus, immune cells infiltrate the brain parenchyma via diapedesis. Because the choroid plexus has a secretory epithelium that produces CSF, it also allows the passage of lymphocytes to access and provide immune surveillance of the CSF (for review, see Ransohoff and Engelhardt, 2012Ransohoff R.M. Engelhardt B. The anatomical and cellular basis of immune surveillance in the central nervous system.Nat. Rev. Immunol. 2012; 12: 623-635Crossref PubMed Scopus (476) Google Scholar). In physiological circumstances, few immune cells are present in the CSF, but a higher percentage of memory or CNS antigen experienced CD4+ T cells are found in the CSF compared to the circulation (Ransohoff and Engelhardt, 2012Ransohoff R.M. Engelhardt B. The anatomical and cellular basis of immune surveillance in the central nervous system.Nat. Rev. Immunol. 2012; 12: 623-635Crossref PubMed Scopus (476) Google Scholar). Activated T cells gain access to the brain by extravasation into the tissue, by upregulating many adhesion molecules and integrins, allowing them to roll and adhere to the vessel walls. Upregulation of very late antigen-4 (VLA-4) or lymphocyte function-associated-1 (LFA-1) on T cells promotes the binding to vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) present on endothelial cells, and infiltration to the parenchyma. Furthermore, the gradient of chemokines produced by the choroid plexus (e.g., CCL9, CCL20) also attracts T cell subsets to the brain, which has particularly been demonstrated in studies of autoimmune diseases (Oukka and Bettelli, 2018Oukka M. Bettelli E. Regulation of lymphocyte trafficking in central nervous system autoimmunity.Curr. Opin. Immunol. 2018; 55: 38-43Crossref PubMed Scopus (0) Google Scholar, Reboldi et al., 2009Reboldi A. Coisne C. Baumjohann D. Benvenuto F. Bottinelli D. Lira S. Uccelli A. Lanzavecchia A. 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Indeed, the lymphatic system is critical for the drainage of immune cells and soluble factors from the CNS into the deep cervical lymph nodes (Louveau et al., 2015Louveau A. Smirnov I. Keyes T.J. Eccles J.D. Rouhani S.J. Peske J.D. Derecki N.C. Castle D. Mandell J.W. Lee K.S. et al.Structural and functional features of central nervous system lymphatic vessels.Nature. 2015; 523: 337-341Crossref PubMed Scopus (1439) Google Scholar). It has also been proposed that the lymphatic vessels maintain anergy of CNS-reactive T cells within the meningeal spaces promoting T cell tolerance, whereas infections may trigger CNS-reactive T cells to attack the CNS. The immune response within the CNS is not always detrimental, such as after CNS injury when the immune response limits secondary degeneration (for review, see Louveau et al., 2017Louveau A. Plog B.A. Antila S. Alitalo K. Nedergaard M. Kipnis J. Understanding the functions and relationships of the glymphatic system and meningeal lymphatics.J. Clin. Invest. 2017; 127: 3210-3219Crossref PubMed Scopus (132) Google Scholar). Similarly, although pathogenic T cells have been associated with autoimmune diseases and neuropsychiatric and neurodegenerative disease, not all T cells are detrimental to brain function. For example, T cells support cognition under physiological conditions (Kipnis, 2016Kipnis J. Multifaceted interactions between adaptive immunity and the central nervous system.Science. 2016; 353: 766-771Crossref PubMed Scopus (110) Google Scholar). Clearly, the immune system in the CNS functions in a unique way compared to peripheral tissues. Cytokines are small proteins that affect cell functions and interactions and can have either pro-inflammatory or anti-inflammatory 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 cytokines. Immune activity including cytokine production is influenced by a myriad of factors, including but not limited to genetics, and previous exposures to pathogens (MacGillivray and Kollmann, 2014MacGillivray D.M. Kollmann T.R. The role of environmental factors in modulating immune responses in early life.Front. Immunol. 2014; 5: 434Crossref PubMed Scopus (0) Google Scholar). The most studied cytokines in the context of psychoneuroimmunology are interleukin (IL)-6, tumor necrosis factor (TNF), IL-1β, and interferons (IFNs) on the inflammatory side and IL-10 on the resolving side. Table 1 summarizes the cytokines and related molecules studied in the context of depression and lists their main functions.Table 1Cytokines and Their Peripheral Immune Functions and Blood Levels in MDD Patients Compared to Healthy Control SubjectsCytokinesFunctionRole in MDDReferencesCCL2attracts to site of inflammation: T cells (Th2 > Th1), monocytes, basophils, immature dendritic cells, NK cellsvariesKöhler et al., 2017Köhler C.A. Freitas T.H. Maes M. de Andrade N.Q. Liu C.S. Fernandes B.S. Stubbs B. Solmi M. Veronese N. Herrmann N. et al.Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies.Acta Psychiatr. Scand. 2017; 135: 373-387Crossref PubMed Scopus (291) Google Scholar; Leighton et al., 2018Leighton S.P. Nerurkar L. Krishnadas R. Johnman C. Graham G.J. Cavanagh J. Chemokines in depression in health and in inflammatory illness: a systematic review and meta-analysis.Molecular Psychiatry. 2018; 23: 48-58Crossref PubMed Scopus (0) Google ScholarCCL3attracts to site of inflammation: T cells (Th1 > Th2), monocytes/macrophages, NK cells, basophils, immature dendritic cells, eosinophils, fibroblasts, neutrophils, astrocytes, osteoclasts↑Syed et al., 2018Syed S.A. Beurel E. Loewenstein D.A. Lowell J.A. Craighead W.E. Dunlop B.W. Mayberg H.S. Dhabhar F. Dietrich W.D. Keane R.W. et al.Defective Inflammatory Pathways in Never-Treated Depressed Patients Are Associated with Poor Treatment Response.Neuron. 2018; 99: 914-924.e3Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar; Leighton et al., 2018Leighton S.P. Nerurkar L. Krishnadas R. Johnman C. Graham G.J. Cavanagh J. Chemokines in depression in health and in inflammatory illness: a systematic review and meta-analysis.Molecular Psychiatry. 2018; 23: 48-58Crossref PubMed Scopus (0) Google ScholarCCL4targets T cells (Th1 > Th2), NK cells, monocytes/macrophages, basophils, immature dendritic cells, eosinophils, B cells↓Syed et al., 2018Syed S.A. Beurel E. Loewenstein D.A. Lowell J.A. Craighead W.E. Dunlop B.W. Mayberg H.S. Dhabhar F. Dietrich W.D. Keane R.W. et al.Defective Inflammatory Pathways in Never-Treated Depressed Patients Are Associated with Poor Treatment Response.Neuron. 2018; 99: 914-924.e3Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar; Leighton et al., 2018Leighton S.P. Nerurkar L. Krishnadas R. Johnman C. Graham G.J. Cavanagh J. Chemokines in depression in health and in inflammatory illness: a systematic review and meta-analysis.Molecular Psychiatry. 2018; 23: 48-58Crossref PubMed Scopus (0) Google ScholarCCL5targets T cell (memory cell > T cell, Th1 > Th2), NK cells, eosinophils, neutrophils, immature dendritic cells, monocytes/macrophages↑Syed et al., 2018Syed S.A. Beurel E. Loewenstein D.A. Lowell J.A. Craighead W.E. Dunlop B.W. Mayberg H.S. Dhabhar F. Dietrich W.D. Keane R.W. et al.Defective Inflammatory Pathways in Never-Treated Depressed Patients Are Associated with Poor Treatment Response.Neuron. 2018; 99: 914-924.e3Abstract Full Text Full Text PDF PubMed Scopus (33) Google ScholarCCL11recruits eosinophils, implicated in allergic response↑Leighton et al., 2018Leighton S.P. Nerurkar L. Krishnadas R. Johnman C. Graham G.J. Cavanagh J. Chemokines in depression in health and in inflammatory illness: a systematic review and meta-analysis.Molecular Psychiatry. 2018; 23: 48-58Crossref PubMed Scopus (0) Google ScholarCXCL4released from platelets, attracts neutrophils, fibroblasts, and monocytes, arrests monocytes on the endothelium, important in wound healing and in promoting coagulation and artherogenesis↑Leighton et al., 2018Leighton S.P. Nerurkar L. Krishnadas R. Johnman C. Graham G.J. Cavanagh J. Chemokines in depression in health and in inflammatory illness: a systematic review and meta-analysis.Molecular Psychiatry. 2018; 23: 48-58Crossref PubMed Scopus (0) Google ScholarCXCL7released from platelets, attracts neutrophils, angionenic, first chemokine to arrive at the site of injury↑Leighton et al., 2018Leighton S.P. Nerurkar L. Krishnadas R. Johnman C. Graham G.J. Cavanagh J. Chemokines in depression in health and in inflammatory illness: a systematic review and meta-analysis.Molecular Psychiatry. 2018; 23: 48-58Crossref PubMed Scopus (0) Google ScholarCXCL10targets NK cells, B cells, activated T cells (Th1 > Th2), endothelial cells↓Syed et al., 2018Syed S.A. Beurel E. Loewenstein D.A. Lowell J.A. Craighead W.E. Dunlop B.W. Mayberg H.S. Dhabhar F. Dietrich W.D. Keane R.W. et al.Defective Inflammatory Pathways in Never-Treated Depressed Patients Are Associated with Poor Treatment Response.Neuron. 2018; 99: 914-924.e3Abstract Full Text Full Text PDF PubMed Scopus (33) Google ScholarG-CSFstimulates neutrophil development and differentiation↑Kiraly et al., 2017Kiraly D.D. Horn S.R. Van Dam N.T. Costi S. Schwartz J. Kim-Schulze S. Patel M. Hodes G.E. Russo S.J. Merad M. et al.Altered peripheral immune profiles in treatment-resistant depression: response to ketamine and prediction of treatment outcome.Transl. Psychiatry. 2017; 7: e1065Crossref PubMed Scopus (57) Google Scholar; Syed et al., 2018Syed S.A. Beurel E. Loewenstein D.A. Lowell J.A. Craighead W.E. Dunlop B.W. Mayberg H.S. Dhabhar F. Dietrich W.D. Keane R.W. et al.Defective Inflammatory Pathways in Never-Treated Depressed Patients Are Associated with Poor Treatment Response.Neuron. 2018; 99: 914-924.e3Abstract Full Text Full Text PDF PubMed Scopus (33) Google ScholarGM-CSFpromotes granulocyte maturation and proliferation, monocyte development↑Kiraly et al., 2017Kiraly D.D. Horn S.R. Van Dam N.T. Costi S. Schwartz J. Kim-Schulze S. Patel M. Hodes G.E. Russo S.J. Merad M. et al.Altered peripheral immune profiles in treatment-resistant depression: response to ketamine and prediction of treatment outcome.Transl. Psychiatry. 2017; 7: e1065Crossref PubMed Scopus (57) Google ScholarIFN-γinduces macrophage activation, increased expression of MHC molecules and antigen processing components, Immunoglobulin class switching, suppresses Th2 cellsvariesKöhler et al., 2017Köhler C.A. Freitas T.H. Maes M. de Andrade N.Q. Liu C.S. Fernandes B.S. Stubbs B. Solmi M. Veronese N. Herrmann N. et al.Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies.Acta Psychiatr. Scand. 2017; 135: 373-387Crossref PubMed Scopus (291) Google ScholarIL-1βinduces fever, T cell activation, macrophage activationvariesKöhler et al., 2017Köhler C.A. Freitas T.H. Maes M. de Andrade N.Q. Liu C.S. Fernandes B.S. Stubbs B. Solmi M. Veronese N. Herrmann N. et al.Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies.Acta Psychiatr. Scand. 2017; 135: 373-387Crossref PubMed Scopus (291) Google ScholarIL-1RAantagonizes IL-1 functionvariesKöhler et al., 2017Köhler C.A. Freitas T.H. Maes M. de Andrade N.Q. Liu C.S. Fernandes B.S. Stubbs B. Solmi M. Veronese N. Herrmann N. e