Inflammation has been involved in the pathophysiology and treatment response of major depressive disorder (MDD). Plasma cytokine profiles of 171 treatment-naive MDD patients (none of the MDD patients received an adequate trial of antidepressants or evidence-based psychotherapy) and 64 healthy controls (HCs) were obtained. MDD patients exhibited elevated concentrations of 18 anti- and proinflammatory markers and decreased concentrations of 6 cytokines. Increased inflammasome protein expression was observed in MDD patients, indicative of an activated inflammatory response. The plasma of MDD patients was immunosuppressive on healthy donor peripheral blood mononuclear cells, inducing reduced activation of monocytes/dendritic cells and B cells and reduced T cell memory. Comparison between 33 non-responders and 71 responders at baseline and 12 weeks revealed that after treatment, anti-inflammatory cytokine levels increase in both groups, whereas 5 proinflammatory cytokine levels were stabilized in responders, but continued to increase in non-responders. MDD patients exhibit remodeling of their inflammatory landscape.

In addition, we found associated with the increased cytokine production an increase in the inflammasome protein levels, pointing toward an upregulation of the cytokine production machinery in MDD patients compared to healthy controls (HCs). Examination of the potential effect of the plasma content of MDD patients on peripheral blood mononuclear cell (PBMC) activation revealed that plasma of MDD patients exhibits immunosuppressive capacity, consistent with previous literature (). Nevertheless, response to antidepressant treatments was not associated with changes in the inflammasome proteins or PBMC activation, suggesting that cytokine concentrations might represent better biomarkers to evaluate the effects of intervention in treatment-naive MDD patients 12 weeks after initiating the treatment.

In the current investigation, we measured 27 cytokines, chemokines, and growth factors in the PReDICT cohort of treatment-naive MDD patients and healthy volunteers. The majority of patients exhibited elevated levels of both proinflammatory and anti-inflammatory cytokines, pointing toward an increased inflammatory response. We also found that independent of treatment type, responders exhibited stabilized levels of proinflammatory cytokines whereas non-responders exhibited continued increases in proinflammatory cytokines. In contrast, anti-inflammatory cytokines remained elevated in both responders and non-responders.

The Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) study was designed to identify predictors of the response to three well-established and effective interventions, escitalopram (10–20 mg/day), duloxetine (30–60 mg/day), and cognitive behavioral therapy (CBT; 16 sessions), among MDD patients who had never previously received an evidence-based treatment for depression (). This unique and relatively homogeneous population of treatment-naive depressed patients represents an ideal paradigm to identify predictors of treatment response and to identify biomarkers by comparing MDD patients to healthy volunteers. The PReDICT study demonstrated that antidepressants and CBT treatment were similarly efficacious with remission rates in the 44%–52% range (). Further, magnetic resonance imaging (MRI) using resting state functional connectivity distinguished between the likelihood of remitting or failing to benefit from CBT or antidepressant treatment in the PReDICT cohort ().

PReDICT Team Effects of Patient Preferences on Outcomes in the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) Study.

Response to antidepressant treatments has been reported to be impaired by proinflammatory cytokines, which may be overcome by co-administering anti-inflammatory drugs (). Although antidepressants are generally thought to shift the balance toward anti-inflammatory response (), the overall net effect of antidepressants on cytokines remains unclear, as antidepressants have also been reported to promote proinflammatory cytokine production (). Nonetheless, high levels of proinflammatory cytokines are often observed in treatment-resistant depression (TRD) patients, suggesting a negative correlation between proinflammatory cytokine levels and treatment response (). Taken together, the data suggest that changing the balance between pro- and anti-inflammatory cytokines may promote antidepressant actions. However, no prior studies have focused on previously untreated patients and, furthermore, there are limited data on multiple inflammatory and anti-inflammatory cytokines.

The role of inflammation in MDD is supported, in part, by the results of a meta-analysis that supported the efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) compared with placebo in the treatment of depression (). It is important to note, however, that although NSAIDs have broad anti-inflammatory actions, they do not block the effects of inflammatory cytokines. Indeed, in the SADHEART study all patients received NSAIDs, but they continued to exhibit an elevation in inflammatory markers (). With the development of novel targeted therapeutics in other inflammatory diseases such as psoriasis and rheumatoid arthritis, FDA-approved monoclonal antibodies and other cytokine inhibitors have been used to block individual cytokines in depressed patients, and they have demonstrated significant antidepressant properties in some patient cohorts (). For example, TNF inhibitors such as adalimumab () or etanercept (), IL-12/IL-23 antagonists (), or IL-4Ra antagonists () have been shown to be more efficacious than placebo in the treatment of MDD symptoms. Similar effects have been observed in non-randomized and/or non-placebo controlled trials that targeted TNF or IL-6 (), indicating an improvement of depressive symptoms with anti-cytokine treatments. Infliximab, a TNF neutralizing antibody, only benefited a sub-population of treatment-resistant MDD patients with elevated levels of inflammation (CRP > 5 mg/L) (). This suggests that anti-cytokine approaches might only provide benefit in depressed patients with prominent inflammation.

The immune system induces the expression of anti-inflammatory cytokines to diminish inflammation. Thus, it is particularly intriguing that the levels of anti-inflammatory cytokines IL-2, IL-4, and IL-10 are also often elevated in depressed patients, raising the question of whether these anti-inflammatory cytokines play a role in the onset or recovery from depression (). As discussed below, elevated anti-inflammatory cytokines may represent responses to antidepressant treatments or compensatory mechanisms related to the duration of depressive episodes; this emphasizes the need for a study with a relatively homogeneous population of patients with a minimal number of depressive episodes and free of antidepressant treatment exposure to interpret changes in the inflammatory system.

Major depressive disorder (MDD) is a widespread and debilitating disorder with a lifetime prevalence rate in the United States of 21% in women and 11% in men (). It is characterized by disturbances in sleep, appetite, concentration, ability to experience pleasure, and psychomotor alterations (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [DSM-5]). It is also associated with a markedly increased risk for suicide and a variety of comorbid medical disorders (stroke, myocardial infarction, diabetes, and others) (). Various approaches ranging from functional brain imaging of patients to animal models of depression have been proposed to discover biomarkers to identify at risk populations and/or to predict individual treatment responses. However, because of the current lack of validated biomarkers and heterogeneity in different MDD patient populations, these approaches, with some exceptions (), have provided only limited advances toward these goals. This current limitation is particularly evident in studies of the role of inflammation in depression (). It is now well established that psychological stress, a prominent risk factor for MDD, induces an inflammatory response, and in multiple meta-analyses, two cytokines, interleukin (IL)-6 and tumor necrosis factor (TNF), are reproducibly elevated in the blood and cerebrospinal fluid (CSF) of depressed patients (). Furthermore, elevation of these proinflammatory cytokines in healthy volunteers is associated with the development of depressive symptoms (), suggesting that investigating proinflammatory cytokines represents a reasonable strategy to identify biomarkers for depression.

However, memory T cells (CD4CD45ROCD69) were significantly lower in responders compared to non-responders ( Table 6 ). Associated with the reduced memory T cells, we found no change in the frequency of cells expressing the activation marker CD69 ( Table 6 ), but reduced expression of CD69 at the cell level, on CD8cells and B cells in responders compared to non-responders ( Table 7 ). In contrast, CD69 expression on Tregs, though significantly lower in responders compared to non-responders, did not survive the Bonferroni correction, suggesting that lower activation of T and B cells might be associated with lower memory.

We conducted exploratory analyses and did not find any difference between responders and non-responders in the activation of the inflammasome pathway ( Table S6 ), or in the proportion of activated CD4, CD8, B cells, and CD11b cells ( Figure S7 ), suggesting that antidepressant treatments might target pathways downstream of cytokines rather than their production.

The pattern of results suggested by these data indicates that antidepressant treatments in general promote anti-inflammatory cytokine production and inhibition of some proinflammatory cytokines ( Table S4 Figures S5 and S6 ).

We conducted a similar repeated-measures MANOVA on anti-inflammatory cytokines (IL-4, IL-5, and IL-10). IL-2 and IL-15 were not included because of significant missing data. There was no Responder × Time effect (Wilks’ lambda F(1,102) = 2.56; p = 0.087), but there was a main effect for Time (Wilks’ lambda [F(1,102) = 12.11; p < 0.001]. There was no Responder effect (Wilks’ lambda F(1,102) = 0.78; p = 0.378). Post-hoc tests on the main effect for time revealed the three cytokines (IL-4, p = 0.001; IL-5, p = 0.002; IL-10, p = 0.027) generally thought to be anti-inflammatory cytokines were elevated in response to antidepressant treatments ( Table 5 Figures 1 A and S5 B). There were only 31 responders and 21 non-responders who had a detectable level of IL-2 and a similar number of participants who had a detectable level of IL-15. The results of ANCOVA analyses revealed an identical main effect as observed on the MANOVA analyses of other anti-inflammatory markers. For IL-2 and IL-15, there was a statistically significant time effect (F(1,47) = 5.97, p = 0.018 and F(1,47) = 6.6, p = 0.013, respectively). No Responder or Responder × Time Interaction effects were observed. Taken together, these results indicate that MDD patients undergoing 12 weeks of treatment have increases in anti-inflammatory markers independent of treatment response.

We tested if antidepressant treatments for 12 weeks altered the inflammatory molecule profile and whether there were differences between responders and non-responders. Due to the modest number of subjects who completed treatment in each arm (33 non-responders and 71 responders), we pooled all the treatments together as there were no differences in the cytokine levels and response outcome among the 3 treatments ( Table S5 ) or on PBMC counts ( Table S7 ). We hypothesized that MDD responders would have reduced proinflammatory cytokine levels compared with MDD non-responders after 12 weeks of treatment. To test this hypothesis, we conducted a 2 × 2 (Responder × Time) multivariate analysis of variance (MANOVA) with IL-6, IL-1β, TNF, IFNγ, and IL-17A serving as outcome measures. No covariates were entered into the model because responders and non-responders did not differ on demographic factors such as age, gender, or BMI ( Table S3 ). We focused on the Responder × Time interaction term because this would reveal any potential differences in patterns of change of proinflammatory cytokines in responders versus non-responders, over time. Following a statistically significant multivariate test of significance, individual univariate analyses were conducted for each proinflammatory cytokine. As predicted, there was a Responder × Time effect (Wilks’ lambda F(1,99) = 5.84; p = 0.017), but there was no main effect for Time (Wilks’ lambda F(1,99) = 0.46; p = 0.5) or Responder (Wilks’ lambda F(1,99) = 0.74; p = 0.392). Univariate analyses on the interaction terms for each proinflammatory cytokines revealed that each of the five proinflammatory cytokines reached statistical significance (IFNγ, p = 0.027; IL-1β, p = 0.026; IL-6, p = 0.041; IL-17A, p = 0.035; TNF, p = 0.017) ( Table 5 Figure S5 A); furthermore, the proinflammatory markers tended to rise in non-responders during treatment while they were relatively lower or stabilized in treatment responders ( Figure 1 B).

Anti-inflammatory cytokines (A) and proinflammatory cytokines (B) were measured in the plasma of responders and non-responders, and the means were presented at baseline and 12 weeks after treatment. Mean ± SD.

Anti-inflammatory Cytokines Increase in Both Responders and Non-responders Whereas Proinflammatory Cytokines Are Stabilized in Responders but Increased in Non-responders

Figure 1 Anti-inflammatory Cytokines Increase in Both Responders and Non-responders Whereas Proinflammatory Cytokines Are Stabilized in Responders but Increased in Non-responders

Taken together, these data suggest that MDD patients experienced a relatively major remodeling of the cytokine landscape, accompanied by an overall immunosuppressive phenotype at the cellular level.

Because plasma from MDD patients exhibited increased levels of both pro- and anti-inflammatory cytokines, we tested the overall effects of the plasma from MDD patients on freshly isolated PBMCs from a healthy volunteer donor. Both pro- and anti-inflammatory cytokines have been shown to modulate PBMC activation (). Compared with plasma from HC subjects, addition of plasma from MDD patients on donor PBMCs led to a lower population of the CD86CD11bcells (p = 0.005) ( Table 4 Figure S4 B) in control PBMCs, indicating a reduced activation of monocytes/dendritic cells, and a reduced proportion of CD69CD19(p = 0.001) cell population ( Table 4 Figure S4 B), indicative of reduced activated B cells. There was no change in the overall populations of CD4(p = 0.292), CD8(p = 0.531), CD19(p = 0.913), and CD11b(p = 0.351) cells from the donor PBMCs exposed to the plasma of MDD patients or HC subjects ( Table S2 A). Furthermore, the percent of activated donor PBMCs exposed to plasma from MDD patients or HC subjects was similar after treatment with lipopolysaccharide (LPS) ( Table S2 B), suggesting that the reduced activation of PBMCs in the presence of the MDD patient’s plasma was not the result of an incapacity of the PBMCs to become activated. The amount of lymphocyte activation marker CD69 expression on CD8cells, Tregs (CD4CD25), and B cells was also significantly reduced after LPS treatment, confirming there was less activation of the donor PBMCs by LPS in the presence of plasma from MDD patients compared to the plasma of HC subjects ( Table S2 C). We also excluded any potential activating effect of the HC plasma on PBMCs, as PBMCs that did not receive any plasma have similar PBMC activation level as PBMCs exposed to plasma from HC subjects ( Table S2 D). We excluded any change in cell viability as the counts and frequency data were similar (data not shown). CD4CD45ROCD69(p < 0.001) memory cells from the healthy donor were also reduced after exposure to MDD patient’s plasma compared to plasma from HC subjects ( Table 4 ), suggesting that plasma of MDD patients exhibits properties that also inhibit cellular memory formation.

Non-parametric Mann-Whitney U test of ranks, mean ± SD, all statistically significant results survived the Bonferroni correction, ∗ p < 0.05. CD69 and CD86 are activation markers of the adaptive and the innate immune systems, respectively. CD4 + CD25 + are T regulatory cells, CD4 + CD45 + CD69 − are memory T cells, and CD4 + CD69 + CD45RO − are effector T cells.

Results here demonstrate that IL-18, caspase-1, and ASC-1 were significantly elevated in MDD patients compared to HC subjects ( Table 3 Figure S3 ), suggesting that the upstream pathway responsible for the production of IL-18 or IL-1β was elevated in MDD patients. However, IL-1β ( Table 2 ) was not significantly different between the MDD and HC groups. These findings substantiate the idea that MDD patients exhibit elevated inflammatory responses.

We also examined whether MDD patients exhibited alterations of the cytokine-producing inflammasome pathway, which can be reliably analyzed in plasma samples. Inflammasomes are intracellular multiprotein complexes that function as sensors of danger-associated molecular patterns (DAMPS) or pathogen-associated molecular patterns (PAMPs), which leads to the activation of proinflammatory caspases and the cleavage and release of proinflammatory cytokines. Inflammasomes generally comprise three proteins: (1) an NLR (nucleotide-binding domain, leucine-rich repeat family member), (2) the adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and (3) the proinflammatory cysteine aspartase, caspase-1 (). The inflammasome regulates caspase-1 activity and, consequently, regulates the activation of the proinflammatory cytokines IL-1β and IL-18 (). To date, there is only one report showing that caspase-1, NLRP3 mRNA expression, and NLRP3 protein levels are increased in PBMCs of MDD patients compared to HC subjects ().

Taken together, these results indicate that MDD patients commonly demonstrated elevated levels of many inflammatory molecules, along with several that had lower levels; this is in contrast to the notion that only a subset of MDD patients experience inflammatory dysregulation (). In addition, both pro- and anti-inflammatory cytokines were increased in MDD patients, suggesting an overall increased inflammatory response in treatment-naive MDD subjects.

Chemokine level elevations in the 171 MDD patients compared to HC subjects were evident in 2 (MIP1α/CCL3 and RANTES/CCL5; 1.7-fold and 6.8-fold of HC levels, respectively) out of 7 measured, and 4 were lower by 66%–17% in the 171 MDD patients (IP10/CXCL10, MCP1/CCL2, IL-8, and MIP1β/CCL4) ( Table 2 Figure S2 A). The 171 MDD patients demonstrated elevated levels on 4 of the 6 measured growth factors, including G-CSF, PDGF, FGF, and IL-7, which were elevated to 1.2- to 11-fold levels of HC subjects ( Table 2 Figure S2 B). It is important to note, however, that there were three chemokines and growth factors that were differentially regulated between the matched and whole-sample analyses. RANTES/CCL5 and FGF were increased in the whole-sample analysis in the MDD patients, but did not change or decrease, respectively, in the matched sample analysis in MDD patients compared to HC subjects. Similarly, GM-CSF did not change in the whole-sample analysis in MDD patients, but significantly decreased in the matched sample analysis in MDD patients when compared to HC subjects. Although IL-6 concentration was increased in both the matched and whole-sample analyses, the fold increase was ∼3-fold lower in the 62 matched MDD patients. This suggests that these factors might be sensitive to age, gender, ethnicity, and BMI variation.

Compared to HC subjects, the 171 MDD patients exhibited elevated levels for six of the seven measured proinflammatory cytokines, including IL-12, TNF, IL-6, IFNγ, IL-9, and IL-17A, with levels that were ∼2- to 13-fold those in HC subjects, and elevations were evident in 66%–100% of the MDD patients ( Table 2 Figure S1 A). Of the 7 potential anti-inflammatory cytokines measured among the 171 MDD patients, 5 were elevated (IL-5, IL-15, IL-10, IL-2, and IL-13) ranging from ∼1.6- to 17-fold levels in HC subjects, and 2 were diminished (IL-1RA and IL-4) by ∼25%. The effects found with the potential anti-inflammatory cytokines occurred in 79%–100% of MDD patients ( Table 2 Figure S1 B).

Due to differences between the HC subjects and the MDD patients, and to adjust for various covariates (age, gender, and race), we performed a 1:1 match HC subjects and MDD patients and excluded any effects of the various covariates on the production of cytokines, chemokines, and growth factors except for RANTES/CCL5, FGF, and GM-CSF ( Figure S1 ). In addition, because there were a number of occasions in which there were heterogeneity of variance, questionable distributional normality, and an unequal N, a non-parametric Mann-Whitney U test of ranks test was also used.GM-CSF did not survive the Bonferroni correction,p ≤ 0.001, mean ± SD. CCL, chemokine ligand; FGF, fibroblast growth factor; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFNγ, interferon-γ; IL, interleukin; CXCL, chemokine (C-X-C motif) ligand; MCP-1, monocyte chemoattractant protein-1; MIP, macrophage inflammatory protein; PDGF, platelet-derived growth factor; RANTES, regulated on activation, normal T cell expressed and secreted; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.

Because the populations of HC subjects and MDD patients were significantly different in demographic characteristics (age, gender, ethnicity, and BMI) that could significantly impact the dependent variables ( Table 1 ), we carefully matched 62 HC subjects with 62 MDD patients on these demographic characteristics to avoid any bias in our conclusions ( Tables S1 A and S1B). Two HC participants could not be effectively matched. This matching strategy resulted in equivalent age, gender, and ethnicity as well as BMI among the HC and MDD matched groups ( Table S1 A). We then compared these results to statistical analysis performed with the full compliment of 64 HC subjects and 171 MDD patients. Because the results were identical for the cytokine data, we present the data for the total sample below.

A total of 171 patients meeting DSM-IV criteria for MDD and 64 HCs were included in the analyses. The sociodemographic and clinical characteristics of the patients are presented in Tables 1 S1 A, and S3 and Figures S3 A and S4 A.

Discussion

In this comprehensive assessment of inflammatory markers in treatment-naive MDD patients, who had never received an adequate trial of antidepressant medication or evidence-based psychotherapy for the treatment of depression, we observed elevated levels of 18 pro- and anti-inflammatory cytokines, chemokines, and growth factors, together with lower levels of 6 cytokines and chemokines compared to HC subjects. These widespread differences indicate that a major remodeling of the inflammatory landscape occurred in MDD patients. Associated with these changes in cytokines was an upregulation of the inflammasome proteins IL-18, caspase-1, and ASC in MDD patients. There was a decrease of the activation and cellular memory of healthy donor PBMCs exposed to plasma of MDD patients compared to the plasma of HC subjects, suggestive of cellular immunosuppressive properties of the plasma of MDD patients. Overall, these findings demonstrated that treatment-naive MDD patients exhibited features of a significant remodeling of their cytokine profiles.

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Miller A.H. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. Although the idea that depressed patients have increased proinflammatory and anti-inflammatory cytokines is now well accepted (), the novelty of the present study is based on the measurement of 27 cytokines in a unique population of treatment-naive MDD patients. Most studies measuring cytokines in MDD patients have only measured a limited number of cytokines per patient. We found that levels of most cytokines (23/27) were different in MDD patients and HC subjects, which contrasts with a recent study that reported that TRD patients have only 5 cytokines differentially expressed compared to HC subjects (). The discrepancy between our study and others’ findings likely originates from the populations of MDD patients studied, and the fact that most previous studies focused on MDD patients that were previously exposed to multiple trials of antidepressant medications. Our population is unique because they are treatment-naive and many were diagnosed for the first time, thereby providing a unique group for interrogation of the role of the inflammatory response in MDD patients. Surprisingly, and in contrast to recent findings proposing that only a subgroup of MDD patients exhibit increased inflammatory markers (), we found that the majority of MDD patients have elevated inflammatory markers above the mean of the HC subjects. Moreover, this increase in the cytokine levels occurred early in the disease: five cytokine (IL-2, IL-10, IL-12, IL-15, and IL-17A), one chemokine (MIP1a/CCL3), and two growth factor (GM-CSF and FGF) levels were elevated in MDD patients within their first episode of the disease compared to MDD patients who experienced several episodes of the disease (data not shown).

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Kelley K.W. From inflammation to sickness and depression: when the immune system subjugates the brain. To test the overall effect of the cytokine profile remodeling on immune cells, we analyzed the activation of healthy donor PBMCs in the presence of plasma of MDD patients or HC subjects. We found that the overall phenotype of plasma from MDD patients was immunosuppressive, as the PBMCs incubated with the plasma of MDD patients were less frequently activated than the PBMCs cultured with plasma of HC subjects. This suggests that MDD patients experience an upregulation of the production of cytokines, whereas the overall effect of MDD plasma on immune cells is immunosupressive. It remains to be explored whether these immunosuppressive properties are due to the cytokine milieu favoring an anti-inflammatory response or other molecules present in the plasma providing immunosuppression. In addition, the fact that both pro- and anti-inflammatory cytokines are elevated in MDD patients but that the overall effect on healthy donor PBMCs is immunosuppressive suggests that the anti-inflammatory response in MDD patients might be failing to terminate the inflammatory responses; this is consistent with the presence of chronic inflammation in MDD patients ().

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Nakayama T. Type II membrane protein CD69 regulates the formation of resting T-helper memory. Although CD69 is considered to be an activation marker of T and B cells, CD69 has ambiguous immunoregulatory functions (). In humans, its expression is associated with an ongoing immune response and tissue damage. Our data are consistent with a proinflammatory role of CD69 in MDD patients, though the role of CD69 in MDD patients will need to be confirmed in PBMCs isolated directly from MDD patients. Cytokines have been shown to modulate CD69 expression (); anti-inflammatory cytokines such as IL-10 reduce CD69 expression (). Reduced levels of CD69 have been shown to be associated with reduced memory T cell formation, which might explain why memory T cells are reduced in the responders compared to non-responders (). Nevertheless, a deeper characterization of the memory immune cells is needed to follow up this finding.

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Raison C.L. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Because MDD patients have a significant remodeling of their immune response, we also analyzed the effect of antidepressant treatments on the immune response, as antidepressants have been shown to modulate both cytokine production () and immune cells (). Because there were no differential effects in proinflammatory or anti-inflammatory cytokines in the different types of depression treatments, we were able to model the profiles of MDD responders versus non-responders over the 12-week treatment period. The current results indicated that anti-inflammatory cytokines were increased in both MDD responders and non-responders, whereas only proinflammatory cytokines were stabilized in responders while they continued to increase in non-responders. This suggests that the antidepressant response may be associated with the ability of anti-inflammatory cytokines to block increasing levels of proinflammatory cytokines (e.g., IL-1β, IL-6, and TNF), while non-responders may have a defect in the response to anti-inflammatory cytokines. However, the mechanism of defective anti-inflammatory response remains to be determined.

+CD11b+ cells, indicative of activated monocytes/dendritic cells, which represent activated cells of the innate immune response that in part regulate the inflammasome pathway ( Guo et al., 2015 Guo H.

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Ting J.P.Y. Inflammasomes: mechanism of action, role in disease, and therapeutics. It is unlikely that the difference in the production of cytokines between responders and non-responders is due to a reduction in the production of cytokines as upstream inflammasome activation is similar between responders and non-responders; thus, it is most likely due to an absence of the response to inflammatory termination signals. Consistent with this conclusion, the percent of CD86CD11bcells, indicative of activated monocytes/dendritic cells, which represent activated cells of the innate immune response that in part regulate the inflammasome pathway (), was similar between non-responders and responders. Furthermore, CD69, which is present on adaptive immune cells, was expressed similarly between non-responders and HC but decreased in responders. Altogether, these findings suggest that the plasma of responders has anti-inflammatory and anti-activation properties that are absent in the non-responder group and are likely mediated by different cell types.

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Paul W.E. Differentiation of effector CD4 T cell populations. +CD25+), known to be anti-inflammatory cells, or CD8 cells or B cells expressing CD69 were reduced in responders compared to non-responders. This suggests that T and B cell activation markers might help to discriminate between patients’ responses to antidepressant treatments, consistent with a recent study of Grosse et al. (2016) Grosse L.

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Bergink V. Circulating cytotoxic T cells and natural killer cells as potential predictors for antidepressant response in melancholic depression. Restoration of T regulatory cell populations after antidepressant therapy. It is interesting to note that antidepressant actions, although likely expected to be different between escitalopram, duloxetine (), and CBT (), have similar effects on the immune response. Better mood outcomes were associated with a healthier immune response. It is possible that a direct central nervous system effect of the antidepressant medication and CBT influences the immune system response, perhaps by modulating HPA axis activity or the production of growth factors (). Because escitalopram and duloxetine are present in plasma, it is also possible that the medications directly affect the PBMCs (). However, because we found no difference between duloxetine, escitalopram, and CBT in the activation levels of CD69, or cytokine levels, it is unlikely that the observed effects are due to a direct effect of the medication on PBMC activation, but rather results from downstream effects of the treatments leading to cytokine changes. In addition, it is possible that the absence of effects on PBMC activation between responders and non-responders at the frequency level is due to the small changes of cytokine concentrations observed between these two groups. The differentiation of T cells, which is known to be regulated by cytokines (), might also be an important component to measure as T cells, even though exhibiting the same level of activation, might differentiate toward pro- or anti-inflammatory subsets. It is particularly interesting that the regulatory T cells (CD4CD25), known to be anti-inflammatory cells, or CD8 cells or B cells expressing CD69 were reduced in responders compared to non-responders. This suggests that T and B cell activation markers might help to discriminate between patients’ responses to antidepressant treatments, consistent with a recent study of

Taken together, the results of this study show a broad effect of depression on the immune system, although unknown confounds may contribute to some of the differences reported here, and that causality was not directly tested. Interestingly, effective treatments for depression modulate the inflammatory response, although these effects might be the results of epiphenomena, e.g., sleeplessness, stress, and weight loss associated with MDD. Effective treatments seem to target both the innate and adaptive immune system.