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Transcriptomic profiles are important indicators for molecular mechanisms and pathways involved in major depressive disorder (MDD) and its different phenotypes, such as immunometabolic depression. We performed whole-transcriptome and pathway analyses on 139 individuals from the observational, case-control, BIOmarkers in DEPression (BIODEP) study, 105 with MDD and 34 controls. We divided MDD participants based on levels of inflammation, as measured by serum high-sensitivity C-reactive protein (CRP), in n = 39 'not inflamed' (CRP < 1 mg/L), n = 31 with 'elevated CRP' (1-3 mg/L), and n = 35 with 'low-grade inflammation' (>3 mg/L). We performed whole-blood RNA sequencing using Illumina NextSeq 550 and statistical analyses with the Deseq2 package for R statistics (RUV-corrected) and subsequent pathway analyses with Ingenuity Pathway Analysis. Immunometabolic pathways were activated in individuals with CRP > 1 mg/L, although surprisingly the CRP 1-3 group showed stronger immune activation than the CRP > 3 group. The main pathways identified in the comparison between CRP < 1 group and controls were cell-cycle-related, which may be protective against immunometabolic abnormalities in this 'non-inflamed' depressed group. We further divided MDD participants based on exposure and response to antidepressants (n = 47 non-responders, n = 37 responders, and n = 22 unmedicated), and identified specific immunomodulatory and neuroprotective pathways in responders (especially vs. non-responders), which could be relevant to treatment response. In further subgroup analyses, we found that the specific transcriptional profile of responders is independent of CRP levels, and that the inhibition of cell-cycle-related pathways in MDD with CRP < 1 mg/L is present only in those who are currently depressed, and not in the responders. The present study demonstrates immunometabolic and cell-cycle-related transcriptomic pathways associated with MDD and different (CRP-based and treatment-based) MDD phenotypes, while shedding light on potential molecular mechanisms that could prevent or facilitate an individual's trajectory toward immunometabolic depression and/or treatment-non-responsive depression. The recognition and integration of these mechanisms will facilitate a precision-medicine approach in MDD., (© 2024. The Author(s).)

Sex hormones have biological effects on inflammation, and these might contribute to the sex-specific features of depression. C-reactive protein (CRP) is the most widely used inflammatory biomarker and consistent evidence shows a significant proportion (20-30 %) of patients with major depressive disorder (MDD) have CRP levels above 3 mg/L, a threshold indicating at least low-grade inflammation. Here, we investigate the interplay between sex hormones and CRP in the cross-sectional, observational Biomarkers in Depression Study. We measured serum high-sensitivity (hs-)CRP, in 64 healthy controls and 178 MDD patients, subdivided into those with hs-CRP below 3 mg/L (low-CRP; 53 males, 72 females) and with hs-CRP above 3 mg/L (high-CRP; 19 males, 34 females). We also measured interleukin-6, testosterone, 17-β-estradiol (E2), progesterone, sex-hormone binding globulin (SHBG), follicle-stimulating and luteinising hormones, and calculated testosterone-to-E2 ratio (T/E2), free androgen and estradiol indexes (FAI, FEI), and testosterone secretion index. In males, high-CRP patients had lower testosterone than controls (p = 0.001), and lower testosterone (p = 0.013), T/E2 (p < 0.001), and higher FEI (p = 0.015) than low-CRP patients. In females, high-CRP patients showed lower SHGB levels than controls (p = 0.033) and low-CRP patients (p = 0.034). The differences in testosterone, T/E2 ratio, and FEI levels in males survived the Benjamini-Hochberg FDR correction. In linear regression analyses, testosterone (β = -1.069 p = 0.033) predicted CRP concentrations (R 2  = 0.252 p = 0.002) in male patients, and SHBG predicted CRP levels (β = -0.628 p = 0.009, R 2  = 0.172 p = 0.003) in female patients. These findings may guide future research investigating interactions between gonadal and immune systems in depression, and the potential of hormonal therapies in MDD with inflammation., Competing Interests: Declaration of competing interest The authors declare that they have no known conflict of interest that could have appeared to influence the work reported in this paper. Dr. Lombardo, Dr. Sforzini, Ms. Worrell, Ms. Kose and Prof. Pariante have received research funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 853966–2, as part of the EU-PEARL project. This Joint Undertaking received support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. Prof. Pariante is also funded by a Senior Investigator award from the National Institute for Health Research (NIHR); the Medical Research Council (grants MR/L014815/1, MR/J002739/1 and MR/N029488/1); the European Commission (EARLYCAUSE grant SC1-BHC-01-2019); the NARSAD; the Psychiatry Research Trust; and the Wellcome Trust (SHAPER, Scaling-up Health-Arts Programme to scale up arts interventions, grant 219,425/Z/19/Z). <10 % of his support in the last 10 years derives from commercial collaborations, including consultation and speakers fees from Boehringer Ingelheim, Eli Lilly, Compass, Eleusis, GH Research, Lundbeck, and Värde Partners. Prof. Mondelli is also funded by MQ: Transforming Mental Health (Grant: MQBF/1 and MQBF/4), by the National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, and the Medical Research Foundation (Grant: MRF-160-0005-ELP-MONDE). Prof. Dazzan has received speaker's fees from Lundbeck and Janssen and is supported by the Medical Research Council (MR/S003444/1). Dr. Nettis has received an honorarium for speaking for Janssen on one occasion., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The biological mechanisms underlying the onset of major depressive disorder (MDD) have predominantly been studied in adult populations from high-income countries, despite the onset of depression typically occurring in adolescence and the majority of the world's adolescents living in low- and middle-income countries (LMIC). Taking advantage of a unique adolescent sample in an LMIC (Brazil), this study aimed to identify biological pathways characterizing the presence and increased risk of depression in adolescence, and sex-specific differences in such biological signatures. We collected blood samples from a risk-stratified cohort of 150 Brazilian adolescents (aged 14-16 years old) comprising 50 adolescents with MDD, 50 adolescents at high risk of developing MDD but without current MDD, and 50 adolescents at low risk of developing MDD and without MDD (25 females and 25 males in each group). We conducted RNA-Seq and pathway analysis on whole blood. Inflammatory-related biological pathways, such as role of hypercytokinemia/hyperchemokinemia in the pathogenesis of influenza (z-score = 3.464, p < 0.001), interferon signaling (z-score = 2.464, p < 0.001), interferon alpha/beta signaling (z-score = 3.873, p < 0.001), and complement signaling (z-score = 2, p = 0.002) were upregulated in adolescents with MDD compared with adolescents without MDD independently from their level of risk. The up-regulation of such inflammation-related pathways was observed in females but not in males. Inflammatory-related pathways involved in the production of cytokines and in interferon and complement signaling were identified as key indicators of adolescent depression, and this effect was present only in females., (© 2024. The Author(s).)

Objective: To present the protocol and methods for the prospective longitudinal assessments-including clinical and digital phenotyping approaches-of the Identifying Depression Early in Adolescence Risk Stratified Cohort (IDEA-RiSCo) study, which comprises Brazilian adolescents stratified at baseline by risk of developing depression or presence of depression., Method: Of 7,720 screened adolescents aged 14 to 16 years, we recruited 150 participants (75 boys, 75 girls) based on a composite risk score: 50 with low risk for developing depression (LR), 50 with high risk for developing depression (HR), and 50 with an active untreated major depressive episode (MDD). Three annual follow-up assessments were conducted, involving clinical measures (parent- and adolescent-reported questionnaires and psychiatrist assessments), active and passive data sensing via smartphones, and neurobiological measures (neuroimaging and biological material samples). Retention rates were 96% (Wave 1), 94% (Wave 2), and 88% (Wave 3), with no significant differences by sex or group ( p > .05). Participants highlighted their familiarity with the research team and assessment process as a motivator for sustained engagement., Discussion: This protocol relied on novel aspects, such as the use of a WhatsApp bot, which is particularly pertinent for low- to-middle-income countries, and the collection of information from diverse sources in a longitudinal design, encompassing clinical data, self-reports, parental reports, Global Positioning System (GPS) data, and ecological momentary assessments. The study engaged adolescents over an extensive period and demonstrated the feasibility of conducting a prospective follow-up study with a risk-enriched cohort of adolescents in a middle-income country, integrating mobile technology with traditional methodologies to enhance longitudinal data collection., (© 2023 The Authors.)

Digital mental health is becoming increasingly common. This includes use of smartphones and wearables to collect data in real time during day-to-day life (remote measurement technologies, RMT). Such data could capture changes relevant to depression for use in objective screening, symptom management and relapse prevention. This approach may be particularly accessible to young people of today as the smartphone generation. However, there is limited research on how such a complex intervention would work in the real world. We conducted a collaborative realist review of RMT for depression in young people. Here we describe how, why, for whom and in what contexts RMT appear to work or not work for depression in young people and make recommendations for future research and practice. Ethical, data protection and methodological issues need to be resolved and standardized; without this, RMT may be currently best used for self-monitoring and feedback to the healthcare professional where possible, to increase emotional self-awareness, enhance the therapeutic relationship and monitor the effectiveness of other interventions., (© 2024. The Author(s).)

In adolescence, parental care is associated with lower depression symptoms whereas parental overprotection is associated with greater depression symptoms, effects which may be mediated by adolescent brain activity and connectivity. The present study examined associations between perceived parenting, brain activity and connectivity, and depression symptoms in adolescents from Brazil, a middle-income country (MIC). Analyses included 100 adolescents who underwent functional magnetic resonance imaging scanning while completing a face matching task. Parental care and overprotection were associated with adolescent depression symptoms in expected directions. We also found that parental care and overprotection were associated with amygdala connectivity with several brain regions; however, amygdala activity was not associated with parenting and neither activity or connectivity mediated the association between parenting and depression symptoms. Results identify how parenting influences brain function and depression symptoms in youth from a MIC., Competing Interests: Declaration of interest V.M. has received in the past research funding from Johnson & Johnson as part of a research program on depression and inflammation, but the research described in this paper is unrelated to this funding.

Background: Associations between inflammatory markers and depression are reported among adults; however, less is known in adolescent depression in particular whether these associations are sex-specific. We aimed to identify inflammatory markers of increased risk and presence of depression in adolescence and their association with severity of depressive symptoms in the entire cohort and separately in boys and girls., Methods: We measured serum cytokines using a Meso Scale Discovery electrochemiluminescence V-PLEX assay in a cohort of 150 adolescents stratified for risk/presence of depression. Risk group and sex-specific differences in inflammatory markers were assessed with 2-way mixed ANOVA, and sex-moderated associations between inflammatory markers and the severity of depressive symptoms were assessed with moderated multiple hierarchical regression analyses., Results: We found a significant interaction between biological sex and the risk group, where boys showed higher interleukin (IL)-2 levels among the depressed group compared with the low-risk group. The severity of depressive symptoms was associated with elevated levels of IL-2 in boys, and of IL-6 in girls. There was a significant moderating effect of sex on the relationship between IL-2 and the severity of depressive symptoms but not for IL-6., Limitations: The cross-sectional design means that we cannot be certain about the direction of the associations., Conclusions: Our findings suggest sex-specific associations between inflammatory markers and the development of adolescent depression, where IL-2 may increase risk for depression and severity of depressive symptoms in boys, but not in girls. However, IL-6 may increase risk for more severe depressive symptoms in girls., Competing Interests: Declaration of competing interest All authors declare that they have no competing interests. Disclosures VM has received research funding from Johnson & Johnson, a pharmaceutical company interested in the development of anti-inflammatory strategies for depression, but the research described in this paper is unrelated to this funding., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Evidence suggests affective disorders such as depression and bipolar disorder are characterised by dysregulated autonomic nervous system (ANS) activity. These findings suggest ANS dysregulation may be involved in the pathogenesis of affective disorders. Different affective states are characterised by different ANS activity patterns (i.e., an increase or decrease in sympathetic or parasympathetic activity). To understand how ANS abnormalities are involved in the development of affective disorders, it is important to understand how affective states correlate with ANS activity before their onset. Using heart rate variability (HRV) as a tool to measure ANS activity, this review aimed to look at associations between affective states and HRV in non-clinical populations (i.e., in those without medical and psychiatric disorders). Searches on PubMed and Google Scholar were completed using the following search terms: heart rate variability, autonomic nervous system, sympathetic nervous system, parasympathetic nervous system, affective state, mood and emotion in all possible combinations. All but one of the studies examined (N = 13), demonstrated significant associations between affect and HRV. Findings suggest negative affect, encompassing both diffused longer-term experiences (i.e., mood) as well as more focused short-term experiences (i.e., emotions), may be associated with a reduction in parasympathetic activity as measured through HRV parameters known to quantify parasympathetic activity (e.g., high frequency (HF)-HRV). HRV measures typically linked to reduction in parasympathetic activity appear to be linked to negative affective states in non-clinical populations. However, given the complex and possibly non-linear relationship between HRV and parasympathetic activity, further studies need to clarify specificity of these findings. Future studies should investigate the potential utility of HRV measures as biomarkers for monitoring changes in affective states and for early detection of onset and relapse of depression in patients with affective disorders., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Compelling evidence demonstrates that some individuals suffering from major depressive disorder (MDD) exhibit increased levels of inflammation. Most studies focus on inflammation-related proteins, such as serum or plasma C-reactive protein (CRP). However, the immune-related modifications associated with MDD may be not entirely captured by CRP alone. Analysing mRNA gene expression levels, we aimed to identify broader molecular immune-related phenotypes of MDD. We examined 168 individuals from the non-interventional, case-control, BIODEP study, 128 with a diagnosis of MDD and 40 healthy controls. Individuals with MDD were further divided according to serum high-sensitivity (hs)CRP levels (n = 59 with CRP <1, n = 33 with CRP 1-3 and n = 36 with CRP >3 mg/L). We isolated RNA from whole blood and performed gene expression analyses using RT-qPCR. We measured the expression of 16 immune-related candidate genes: A2M, AQP4, CCL2, CXCL12, CRP, FKBP5, IL-1-beta, IL-6, ISG15, MIF, GR, P2RX7, SGK1, STAT1, TNF-alpha and USP18. Nine of the 16 candidate genes were differentially expressed in MDD cases vs. controls, with no differences between CRP-based groups. Only CRP mRNA was clearly associated with serum CRP. In contrast, plasma (proteins) IL-6, IL-7, IL-8, IL-10, IL-12/IL-23p40, IL-16, IL-17A, IFN-gamma and TNF-alpha, and neutrophils counts, were all differentially regulated between CRP-based groups (higher in CRP >3 vs. CRP <1 and/or controls), reflecting the gradient of CRP values. Secondary analyses on MDD individuals and controls with CRP values <1 mg/L (usually interpreted as 'no inflammation') confirmed MDD cases still had significantly different mRNA expression of immune-related genes compared with controls. These findings corroborate an immune-related molecular activation in MDD, which appears to be independent of serum CRP levels. Additional biological mechanisms may then be required to translate this mRNA signature into inflammation at protein and cellular levels. Understanding these mechanisms will help to uncover the true immune abnormalities in depression, opening new paths for diagnosis and treatment., (© 2023. The Author(s).)

Background and Aims: We investigated kynurenine pathway (KP) metabolites levels and their association with suicidal ideation in patients with treatment-resistant depression (TRD) and elevated peripheral inflammation. The effect of antidepressant augmentation with minocycline on KP metabolites was tested., Methods: We analysed data from MINocycline in DEPression, a 4-week, randomized, placebo controlled (1:1) trial of minocycline added to antidepressant treatment in 39 TRD patients ( n  = 18 minocycline; n  = 21 placebo) with C-reactive protein (CRP) ⩾1 mg/L. At baseline and at week 4, we collected data on suicidality (Beck Depression Inventory) and blood samples to measure inflammatory markers and KP metabolites. We tested (1) the association of KP metabolites ratios with inflammatory markers and suicidal ideation at baseline and (2) the role of suicidality and treatment (minocycline vs placebo) in affecting KP changes over time., Results: At baseline, kynurenine/tryptophan (KYN/TRP) ratio positively correlated with high-sensitivity CRP (Spearman's ρ = 0.35, p  = 0.02) and IL-10, (ρ = 0.41, p  = 0.009); and tumour necrosis factor was positively correlated with quinolinic acid/3-hydroxykynurenine ratio (ρ = 0.55, p  < 0.001). Moreover, participants with suicidal ideation showed higher levels of KYN/TRP ( U  = 143.000, p  = 0.02) than those without suicidal ideation. There was no significant effect of minocycline on KP metabolites changes from baseline to week 4. However, in the minocycline group, the number of participants with suicidal thoughts decreased from 44.4% (8/18) to 22.2% (4/18)., Conclusion: Increased KP neurotoxic metabolites are associated with elevated peripheral inflammation in depressed individuals, particularly in those with suicidal ideation. Targeting KP in this population could be a potential effective personalized approach. Whether this includes minocycline should be investigated in future larger trials.

Background: There have been significant challenges in understanding functional brain connectivity associated with adolescent depression, including the need for a more comprehensive approach to defining risk, the lack of representation of participants from low- and middle-income countries, and the need for network-based approaches to model connectivity. The current study aimed to address these challenges by examining resting-state functional connectivity of frontolimbic circuitry associated with the risk and presence of depression in adolescents in Brazil., Methods: Adolescents in Brazil ages 14 to 16 years were classified into low-risk, high-risk, and depressed groups using a clinical assessment and composite risk score that integrates 11 sociodemographic risk variables. After excluding participants with excessive head movement, resting-state functional magnetic resonance imaging data of 126 adolescents were analyzed. We compared group differences in frontolimbic network connectivity using region of interest-to-region of interest, graph theory, and seed-based connectivity analyses. Associations between self-reported depressive symptoms and brain connectivity were also explored., Results: Adolescents with depression showed greater dorsal anterior cingulate cortex (ACC) connectivity with the orbitofrontal cortex compared with the 2 risk groups and greater dorsal ACC global efficiency than the low-risk group. Adolescents with depression also showed reduced local efficiency and a lower clustering coefficient of the subgenual ACC compared with the 2 risk groups. The high-risk group also showed a lower subgenual ACC clustering coefficient relative to the low-risk group., Conclusions: These findings highlight altered connectivity and topology of the ACC within frontolimbic circuitry as potential neural correlates and risk factors of developing depression in adolescents in Brazil. This study broadens our understanding of the neural connectivity associated with adolescent depression in a global context., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Aim: Identifying predictors for future onset of depression is crucial to effectively developing preventive interventions. We conducted a systematic review and meta-analysis to identify risk factors for first-onset depression among adolescents and young people., Methods: We searched MEDLINE (Ovid), PsycINFO, Cochrane Database, Web of Science, Lilacs, African Journals Online and Global Health (July 2009 to December 2020) for longitudinal studies assessing risk factors for first-onset depression among adolescents and young people aged 10-25 years. Meta-analyses generated summary odds ratio (OR) estimates., Registration: PROSPERO CRD42018103973., Results: Nineteen studies representing 21 unique populations were included in the meta-analysis. Among studies reporting race/ethnicity, 79% of participants were of White/European descent. Seventeen studies were from high-income countries, with only two from an upper-middle-income country (China). Odds for first-onset depression were significantly greater for girls compared to boys (n = 13; OR = 1.78 [1.78, 2.28], p < 0.001) and for youth with other mental health problems at baseline (n = 4; OR = 3.20 [1.95, 5.23], p < 0.001). There were non-significant associations for negative family environment (n = 8; OR = 1.60 [0.82, 3.10], p = 0.16) and parental depression (n = 3; OR = 2.30 [0.73, 7.24], p = 0.16)., Conclusions: Most longitudinal studies do not report risk factors specifically for first-onset depression. Moreover, predictive data are limited to predominantly White populations in high-income countries. Future research must be more ethnically and geographically representative. Recommendations are provided for consistent and comprehensive reporting of study designs and analyses of risk factors for first-onset depression., (© 2022 The Authors. Early Intervention in Psychiatry published by John Wiley & Sons Australia, Ltd.)

Background: Inflammation is a well-known risk factor for depression. Specifically, patients who do not respond to antidepressant treatment show higher levels of inflammatory biomarkers compared with responders. Thus, several studies have investigated the efficacy of anti-inflammatory add-on treatment in this population. However, major depressive disorder is more prevalent in females than in males, with sex differences present in antidepressant treatment response and in immune system regulation. To explore sex differences in inflammatory profiles and treatment responses, we investigated a cohort of patients with treatment resistant depression (TRD), for which they received an adjunctive, anti-inflammatory treatment with minocycline - the Minocycline in Depression (MINDEP) study., Methods: The MINDEP study is a 4-week double-blind, randomised, placebo-controlled clinical trial (stratified by sex) with 39 TRD participants, which demonstrated the efficacy of minocycline, an antibiotic with anti-inflammatory properties, in TRD patients with major depressive disorder (MDD) and evidence of low-grade inflammation measured with C-reactive protein (CRP) ≥ 3 mg/L. In these secondary analyses, we investigated the differential effects of minocycline in females (N = 22, 10 randomised to minocycline and 12 randomised to placebo) and in males (N = 17, 8 randomised to minocycline and 9 randomised to placebo) on changes in depressive symptoms (Δ- Hamilton Rating Scale for Depression (HAMD)-17), taking also into consideration CRP levels (CRP ≥3 mg/L vs. CRP <3 mg/L). Additionally, we investigated the role of serum IL-6 in predicting treatment response to minocycline, using sex-specific medians of IL-6, in novel exploratory analyses., Results: Sex differences in Δ-HAMD-17 indicate that only females (F = 10.49, p = 0.005), but not males (F = 1.64, p = 0.22), presented an effect of CRP levels on the response to minocycline. Also, we detected sex differences in the relationship between serum CRP and IL-6 levels: CRP was strongly correlated with IL-6 in females (Spearman's ρ = 0.658, P < 0.001) but not in males (ρ = 0.007, p = 0.979). Exploratory analyses found that IL-6 was indeed a better predictor of response than minocycline than CRP, as we found an interaction between study arms and IL-6 groups (above and below the IL-6 sex-specific median) in females (F = 4.435 p = 0.050) and, at trend statistical level, in males (F = 4.258 p = 0.060). Moreover, Δ-HAMD-17 was numerically comparable in the two high-IL-6 group taking minocycline (females, mean 9.20 ± SD 7.80; males, mean 8.80 ± SD 5.97), confirming that high IL-6, differently from high CRP, identified responders to minocycline both in males and females., Conclusion: Our findings highlight the need of sex-specific inflammatory biomarkers in predicting antidepressant response to anti-inflammatories in TRD patients, with the possibility of CRP being a relevant predictor of treatment response only for females, and IL-6 being relevant for both sexes., Competing Interests: CMP, GL, LS, CW, and MK, are members of EU-PEARL project and report grant from European Commission (Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 853966-2). This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. CMP is also funded by a Senior Investigator award from the National Institute for Health Research (NIHR); the Medical Research Council (grants MR/L014815/1, MR/J002739/1 and MR/N029488/1); the European Commission (EARLYCAUSE grant SC1–BHC-01-2019); the NARSAD; the Psychiatry Research Trust; and the Wellcome Trust (SHAPER, Scaling-up Health-Arts Programme to scale up arts interventions, grant 219425/Z/19/Z). Less than 10% of his support in the last 10 years derives from commercial collaborations, including consultation and speakers fees from Boehringer Ingelheim, Eli Lilly, Compass, Eleusis, GH Research, Lundbeck, and Värde Partners. VM is also funded by MQ: Transforming Mental Health (Grant: MQBF/1 and MQBF/4) and the Medical Research Foundation (Grant: MRF-160-0005-ELP-MONDE). PD has received speaker's fees from Lundbeck and Janssen and is supported by the Medical Research Council (MR/S003444/1). AJC has in the last three years received honoraria for educational activities from Janssen; honoraria for consulting from Allergan and Janssen; sponsorship for conference attendance from Janssen; and research grant support from Protexin Probiotics International Ltd., (© 2022 Published by Elsevier Inc.)

Background: Depression and overweight are each associated with abnormal immune system activation. We sought to disentangle the extent to which depressive symptoms and overweight status contributed to increased inflammation and abnormal cortisol levels., Methods: Participants were recruited through the Wellcome Trust NIMA Consortium. The sample of 216 participants consisted of 69 overweight patients with depression; 35 overweight controls; 55 normal-weight patients with depression and 57 normal-weight controls. Peripheral inflammation was measured as high-sensitivity C-Reactive Protein (hsCRP) in serum. Salivary cortisol was collected at multiple points throughout the day to measure cortisol awakening response and diurnal cortisol levels., Results: Overweight patients with depression had significantly higher hsCRP compared with overweight controls ( p = 0.042), normal-weight depressed patients ( p < 0.001) and normal-weight controls ( p < 0.001), after controlling for age and gender. Multivariable logistic regression showed that comorbid depression and overweight significantly increased the risk of clinically elevated hsCRP levels ⩾3 mg/L (OR 2.44, 1.28-3.94). In a separate multivariable logistic regression model, overweight status contributed most to the risk of having hsCRP levels ⩾3 mg/L (OR 1.52, 0.7-2.41), while depression also contributed a significant risk (OR 1.09, 0.27-2). There were no significant differences between groups in cortisol awakening response and diurnal cortisol levels., Conclusion: Comorbid depression and overweight status are associated with increased hsCRP, and the coexistence of these conditions amplified the risk of clinically elevated hsCRP levels. Overweight status contributed most to the risk of clinically elevated hsCRP levels, but depression also contributed to a significant risk. We observed no differences in cortisol levels between groups.

Background: Neuroimaging studies on adolescents at risk for depression have relied on a single risk factor and focused on adolescents in high-income countries. Using a composite risk score, this study aims to examine neural activity and connectivity associated with risk and presence of depression in adolescents in Brazil., Methods: Depression risk was defined with the Identifying Depression Early in Adolescence Risk Score (IDEA-RS), calculated using a prognostic model that included 11 socio-demographic risk factors. Adolescents recruited from schools in Porto Alegre were classified into a low-risk (i.e., low IDEA-RS and no lifetime depression), high-risk (i.e., high IDEA-RS and no lifetime depression), or clinically depressed group (i.e., high IDEA-RS and depression diagnosis). One hundred fifty adolescents underwent a functional MRI scan while completing a reward-related gambling and a threat-related face-matching task. We compared group differences in activity and connectivity of the ventral striatum (VS) and amygdala during the gambling and face-matching tasks, respectively, and group differences in whole-brain neural activity., Results: Although there was no group difference in reward-related VS or threat-related amygdala activity, the depressed group showed elevated VS activity to punishment relative to high-risk adolescents. The whole-brain analysis found reduced reward-related activity in the lateral prefrontal cortex of patients and high-risk adolescents compared with low-risk adolescents. Compared with low-risk adolescents, high-risk and depressed adolescents showed reduced threat-related left amygdala connectivity with thalamus, superior temporal gyrus, inferior parietal gyrus, precentral gyrus, and supplementary motor area., Conclusions: We identified neural correlates associated with risk and presence of depression in a well-characterized sample of adolescents. These findings enhance knowledge of the neurobiological underpinnings of risk and presence of depression in Brazil. Future longitudinal studies are needed to examine whether the observed neural patterns of high-risk adolescents predict the development of depression., (© 2021 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Extensive research suggests a role for the innate immune system in the pathogenesis of depression, but most of the studies are conducted in adult populations, in high-income countries and mainly focus on the study of inflammatory proteins alone, which provides only a limited understanding of the immune pathways involved in the development of depression. The IDEA-FLAME study aims to identify immune phenotypes underlying increased risk of developing depression in adolescence in a middle-income country. To this end, we will perform deep-immunophenotyping of peripheral blood mononuclear cells and RNA genome-wide gene expression analyses in a longitudinal cohort of Brazilian adolescents stratified for depression risk. The project will involve the 3-year follow-up of an already recruited cohort of 150 Brazilian adolescents selected for risk/presence of depression on the basis of a composite risk score we developed using sociodemographic characteristics (50 adolescents with low-risk and 50 with high-risk of developing depression, and 50 adolescents with a current major depressive disorder). We will 1) test whether the risk group classification at baseline is associated with differences in immune cell frequency, phenotype and functional status, 2) test whether baseline immune markers (cytokines and immune cell markers) are associated with severity of depression at 3-year follow-up, and 3) identify changes in gene expression of immune pathways over the 3-year follow-up in adolescents with increased risk and presence of depression. Because of the exploratory nature of the study, the findings would need to be replicated in a separate and larger sample. Ultimately, this research will contribute to elucidating key immune therapeutic targets and inform the development of interventions to prevent onset of depression among adolescents., Competing Interests: Dr Mondelli has received research funding from Johnson & Johnson as part of a research program on depression and inflammation, but the research described in this paper is unrelated to this funding. All other authors declare they have no conflicts of interest to report., (© 2021 The Authors. Published by Elsevier Inc.)

While the role of biological markers in understanding major depressive disorder (MDD) in adults have been studied extensively, less has been done to identify the biomarkers of MDD development and recovery in adolescence. With the majority of mental health disorders starting in adolescence, identifying biomarkers of transition and recovery from MDD early in life is critical for developing effective prevention strategies. Considering most of the child and adolescent populations come from low-and-middle-income countries (LMICs), it is vital to focus on adolescent populations in these settings. With most studies coming from high-income countries (HICs), evidence suggests that elevated morning cortisol levels including cortisol awakening response (CAR), increased peripheral inflammation and brain abnormalities such as cortico-limbic dysregulation or blunted activity in reward related regions in response to positive information are associated with MDD and being at-risk for MDD development in adolescence. We also find that some of the biological mechanisms of recovery from MDD, mainly normalisation in the cortico-limbic dysregulation, are reported following psychological therapy, suggesting shared pathways leading to MDD vulnerability and recovery. Although, only a few studies include adolescent populations. Understanding molecular mechanisms through which psychological interventions are effective, as well as molecular markers of transition to depression in individuals at-risk, are important to inform effective prevention and intervention strategies., Competing Interests: The author declares that there is no conflict of interests., (© 2021 The Author.)

Background: The characterization of adolescents at high risk for developing depression has traditionally relied on the presence or absence of single risk factors. More recently, the use of composite risk scores combining information from multiple variables has gained attention in prognostic research in the field of mental health. We previously developed a sociodemographic composite score to estimate the individual level probability of depression occurrence in adolescence, the Identifying Depression Early in Adolescence Risk Score (IDEA-RS). Objectives: In this report, we present the rationale, methods, and baseline characteristics of the Identifying Depression Early in Adolescence Risk Stratified Cohort (IDEA-RiSCo), a study designed for in-depth examination of multiple neurobiological, psychological, and environmental measures associated with the risk of developing and with the presence of depression in adolescence, with a focus on immune/inflammatory and neuroimaging markers. Methods: Using the IDEA-RS as a tool for risk stratification, we recruited a new sample of adolescents enriched for low (LR) and high (HR) depression risk, as well as a group of adolescents with a currently untreated major depressive episode (MDD). Methods for phenotypic, peripheral biological samples, and neuroimaging assessments are described, as well as baseline clinical characteristics of the IDEA-RiSCo sample. Results: A total of 7,720 adolescents aged 14-16 years were screened in public state schools in Porto Alegre, Brazil. We were able to identify individuals at low and high risk for developing depression in adolescence: in each group, 50 participants (25 boys, 25 girls) were included and successfully completed the detailed phenotypic assessment with ascertainment of risk/MDD status, blood and saliva collections, and magnetic resonance imaging (MRI) scans. Across a variety of measures of psychopathology and exposure to negative events, there was a clear pattern in which either the MDD group or both the HR and the MDD groups exhibited worse indicators in comparison to the LR group. Conclusion: The use of an empirically-derived composite score to stratify risk for developing depression represents a promising strategy to establish a risk-enriched cohort that will contribute to the understanding of the neurobiological correlates of risk and onset of depression in adolescence., Competing Interests: VM has received research funding from Johnson & Johnson, a pharmaceutical company interested in the development of anti-inflammatory strategies for depression, but the research described in this paper is unrelated to this funding. LAR has received grant or research support from, served as a consultant to, and served on the speakers' bureau of Bial, Medice, Novartis/Sandoz, Pfizer, and Shire/Takeda in the last 3 years. The ADHD and Juvenile Bipolar Disorder Outpatient Programs chaired by him have received unrestricted educational and research support from the following pharmaceutical companies: Novartis/Sandoz, and Shire/Takeda. He has received travel grants from Shire/Takeda to take part in the 2018 American Psychiatric Association congress. He also receives authorship royalties from Oxford Press and ArtMed. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kieling, Buchweitz, Caye, Manfro, Pereira, Viduani, Anés, Battel, Benetti, Fisher, Karmacharya, Kohrt, Martini, Petresco, Piccin, Rocha, Rohde, Rohrsetzer, Souza, Velazquez, Walsh, Yoon, Zajkowska, Zonca, Swartz and Mondelli.)

Introduction: Although the aetiology and pathophysiology of depression are multifactorial, to date most studies have examined either biological or environmental mechanisms without looking at the integration of both; with most studies conducted in high-income countries (HICs). Therefore, we conducted a systematic review of worldwide studies investigating the relationship between biological and environmental stress risk factors for major depressive disorder (MDD) in adolescence., Methods: We searched MEDLINE (via Ovid), PsycINFO, Cochrane Database of Systematic Reviews, Web of Science (Core Collection), Lilacs, African Journals Online and Global Health for prospective and cross-sectional studies that examined the association between biological markers and environmental stress risk factors in MDD during adolescence., Findings: Of 11,089 articles identified, 21 were included, with only two from middle-income countries. Increased inflammation, telomere length and brain abnormalities, including blunted reward-related activity, white matter disruptions, and altered volume of limbic brain regions, were associated with increased risk for MDD mainly in the context of early life adversity. There is little evidence suggesting that the neurobiological changes investigated were associated with MDD in the context of recent life stress., Interpretation: The developmental trajectory of depression appears to start with early life adversities and occurs in the context of immune and brain abnormalities. Understanding these biopsychosocial processes will help to improve our ability to detect individuals at risk of developing depression in adolescence. However, generalizability is limited by few studies examining both biological and environmental stress risk factors and a lack of studies on adolescents and young adults in low-and-middle-income countries (LMICs)., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This study aimed to investigate the role of baseline levels of peripheral inflammation when testing the efficacy of antidepressant augmentation with minocycline in patients with treatment-resistant depression. We conducted a 4-week, placebo-controlled, randomised clinical trial of minocycline (200 mg/day) added to antidepressant treatment in 39 patients selected for elevated levels of serum C-reactive protein (CRP ≥ 1 mg/L), n = 18 randomised to minocycline (M) and n = 21 to placebo (P). The main outcome was the change in Hamilton Depression Rating Scale (HAM-D-17) score from baseline to week 4, expressed both as mean and as full or partial response, in the overall sample and after further stratification for baseline CRP≥3 mg/L. Secondary outcomes included changes in other clinical and inflammatory measures. Changes in HAM-D-17 scores and the proportion of partial responders did not differ between study arms. After stratification for CRP levels <3 mg/L (CRP - ) or ≥3 mg/L (CRP + ), CRP + /M patients showed the largest changes in HAM-D-17 scores (mean ± SD = 12.00 ± 6.45) compared with CRP - /M (2.42 ± 3.20, p < 0.001), CRP + /P (3.50 ± 4.34, p = 0.003) and CRP - /P (2.11 ± 3.26, p = 0.006) patients, and the largest proportion (83.3%, p = 0.04) of partial treatment response at week 4. The threshold point for baseline CRP to distinguish responders from non-responders to minocycline was 2.8 mg/L. Responders to minocycline had higher baseline IL-6 concentrations than non-responders (p = 0.03); IFNγ was significantly reduced after treatment with minocycline compared with placebo (p = 0.03). Our data show some evidence of efficacy of add-on treatment with minocycline in MDD patients but only in those with low-grade inflammation defined as CRP ≥3 mg/L.

The endocannabinoid (eCB) system is one of the key players in immunoregulation, and reduced activity of the eCB system has been linked with depressive-like behaviours in animal studies and depression in clinical samples. There is a well-established link between immune activation and depression, such as following the administration of the pro-inflammatory cytokine, interferon-α (IFN-α), used to treat hepatitis C viral (HCV) infection. However, the role of peripheral endocannabinoids (eCBs), anandamide (AEA) and 2-arachidonoylglycerol (2-AG), following immunotherapy with IFN-α and in IFN-α -induced depression, have not been examined yet. In this study, we investigated whether circulating AEA and 2-AG were modified by treatment with IFN-α and whether they were involved in the development of IFN-α-induced depression. We also explored whether circulating eCBs were associated with peripheral cytokines during and after IFN-α treatment. We measured serum concentrations of AEA and 2-AG using High Performance Liquid Chromatography with Tandem Mass Spectrometry, and serum concentrations of cytokines using Meso Scale Discovery electrochemiluminescence V-PLEX assay, in 70 patients with HCV infection and 41 healthy subjects. We assessed HCV patients at baseline, IFN-α-treatment weeks (TW) 4 and 24, end of treatment (END) and at six months follow-up (FU). We assessed depression using M.I.N.I. International Neuropsychiatric Interview. We found a different pattern of change in peripheral AEA and 2-AG during and after IFN-α treatment. Whilst 2-AG increased earlier in immunotherapy (TW4), remained elevated throughout treatment, and reduced at six months follow-up (FU), AEA increased later in treatment (TW24) and remained elevated six months post-treatment. We also found that baseline levels of AEA were lower in HCV patients compared with healthy controls, whereas there were no differences in 2-AG levels. Interestingly, AEA, but not 2-AG, was significantly, negatively correlated with interleukin (IL)-2 and IL-17a at six months follow-up. We did not find any difference in both eCBs between patients with and without IFN-α-induced depression, at any time point. Our findings suggest that AEA and 2-AG are involved in different stages of immunoregulation following IFN-α treatment, where AEA might be involved in chronic inflammation. Lack of association between peripheral eCBs and IFN-α-induced depression suggests that different biological mechanisms may underpin inflammation-induced depression compared with classic "psychiatric" depression, or that any changes in the eCB system in depression may not be captured by peripheral AEA and 2-AG., Competing Interests: Declaration of Competing Interest Dr Forton has received speaker consultancy fees from companies that market drugs to treat hepatitis C, including AbbVie, Gilead, BMS and Janssen. He has received funding for trials from Merck. Dr Kosh Agarwal has received fees from companies that market drugs to treat Hepatitis C, including AbbVie, Gilead, Astellas, Intercept, Janssen, Merck and Achillon, and has received grants from AbbVie, Gileas, BMS and Roche. Prof. Pariante. Dr Mondelli and Dr. Zunszain have received research funding from Johnson & Johnson as part of a program of research on depression and inflammation, and research funding from the Medical Research Council (UK) and the Wellcome Trust for research on depression and inflammation as part of two large consortia that also include Johnson & & Johnson, GSK and Lundbeck. Dr Mondelli is also funded by MQ: Transforming Mental Health (Grant: MQBF1). The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The mRNA expression signatures associated with the 'pro-inflammatory' phenotype of depression, and the differential signatures associated with depression subtypes and the effects of antidepressants, are still unknown. We examined 130 depressed patients (58 treatment-resistant, 36 antidepressant-responsive and 36 currently untreated) and 40 healthy controls from the BIODEP study, and used whole-blood mRNA qPCR to measure the expression of 16 candidate mRNAs, some never measured before: interleukin (IL)-1-beta, IL-6, TNF-alpha, macrophage inhibiting factor (MIF), glucocorticoid receptor (GR), SGK1, FKBP5, the purinergic receptor P2RX7, CCL2, CXCL12, c-reactive protein (CRP), alpha-2-macroglobulin (A2M), acquaporin-4 (AQP4), ISG15, STAT1 and USP-18. All genes but AQP4, ISG15 and USP-18 were differentially regulated. Treatment-resistant and drug-free depressed patients had both increased inflammasome activation (higher P2RX7 and proinflammatory cytokines/chemokines mRNAs expression) and glucocorticoid resistance (lower GR and higher FKBP5 mRNAs expression), while responsive patients had an intermediate phenotype with, additionally, lower CXCL12. Most interestingly, using binomial logistics models we found that a signature of six mRNAs (P2RX7, IL-1-beta, IL-6, TNF-alpha, CXCL12 and GR) distinguished treatment-resistant from responsive patients, even after adjusting for other variables that were different between groups, such as a trait- and state-anxiety, history of childhood maltreatment and serum CRP. Future studies should replicate these findings in larger, longitudinal cohorts, and test whether this mRNA signature can identify patients that are more likely to respond to adjuvant strategies for treatment-resistant depression, including combinations with anti-inflammatory medications.

Childhood trauma is among the most potent contributing risk factors for depression and is associated with poor treatment response. Hypothalamic-pituitary-adrenal (HPA) axis abnormalities have been linked to both childhood trauma and depression, but the underlying mechanisms are poorly understood. The present study aimed to investigate the link between childhood trauma, HPA axis activity and antidepressant response in patients with depression. As part of the Wellcome Trust NIMA consortium, 163 depressed patients and 55 healthy volunteers were included in this study. Adult patients meeting Structured Clinical Interview for Diagnostic and Statistical Manual Version-5 criteria for major depression were categorised into subgroups of treatment responder (n = 42), treatment non-responder (n = 80) and untreated depressed (n = 41) based on current depressive symptom severity measured by the 17-item Hamilton Rating Scale for Depression and exposure to antidepressant medications established by Antidepressant Treatment Response Questionnaire. Childhood Trauma Questionnaire was obtained. Baseline serum C-reactive protein was measured using turbidimetric detection. Salivary cortisol was analyzed at multiple time points during the day using the ELISA technique. Glucocorticoid resistance was defined as the coexistence of hypercortisolemia and inflammation. Our results show that treatment non-responder patients had higher exposure to childhood trauma than responders. No specific HPA axis abnormalities were found in treatment non-responder depressed patients. Untreated depressed showed increased diurnal cortisol levels compared with patients on antidepressant medication, and higher prevalence of glucocorticoid resistance than medicated patients and controls. The severity of childhood trauma was associated with increased diurnal cortisol levels only in individuals with glucocorticoid resistance. Therefore, our findings suggest that the severity of childhood trauma experience contributes to a lack of response to antidepressant treatment. The effects of childhood trauma on increased cortisol levels are specifically evident in patients with glucocorticoid resistance and suggest glucocorticoid resistance as a target for the development of personalized treatment for a subgroup of depressed patients with a history of childhood trauma rather than for all patients with resistance to antidepressant treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Interferon (IFN)-α treatment for hepatitis C virus (HCV) is a well-recognized clinical model for inflammation-induced depression, but the brain cellular mechanisms underlying these effects are still not clear. Previous data reported an alteration in peripheral levels of inflammatory and neuroplasticity markers in the blood of depressed versus non-depressed patients. We investigated the in vitro effect of serum from depressed and non-depressed HCV patients (at baseline, before IFN-α; and after four weeks of IFN-α), on the apoptotic and neurogenic processes in a human hippocampal progenitor cells model. Results show that higher apoptosis during proliferation observed upon treatment of cells with baseline serum, and lower neuronal differentiation observed upon treatment with serum after 4 weeks of IFN-α, were predictive of later development of IFN-α-induced depression (odds ratio = 1.26, p = 0.06, and = 0.80, p = 0.01, respectively). While serum after IFN-α increased neurogenesis compared with baseline serum, a lower increase in neurogenesis was also predictive of later development of depression (odds ratio = 0.86; p = 0.006). Our results provide evidence for the fundamental role of the systemic milieu (captured by serum samples) in the regulation of hippocampal neurogenesis by inflammation, a putative mechanism involved in the development of neuropsychiatric conditions., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Depression is a leading contributor to disability-adjusted life-years because of early onset and chronicity throughout the lifecycle. It is crucial to identify early predictors of depression among adolescents and young people to effectively target prevention. A gap in the literature is a comprehensive systematic review of predictors of depression among adolescents around the globe, especially in low- and middle-income countries LMICs. This review aims to identify evidence for biological, psychological, and contextual risk factors for the development of depression among adolescents and young adults (10-24 years of age) in high-income countries (HICs) and LMICs, ultimately contributing to (a) identification of potential mechanisms underlying depression development, (b) selection of common risk and protective factors as targets for detection, and (c) refinement of risk models that can be evaluated through existing cohorts in HICs and LMICs., Methods: This review will follow the Population, Exposure, Comparison, Outcome (PI(E)CO) model and adheres to the PRISMA-P guidelines. A search strategy was developed by a multidisciplinary research consortium. Seven databases (MEDLINE via Ovid, PsycINFO, Cochrane Database of Systematic Reviews, Web of Science, Lilacs, African Journals Online, Global Health) will be searched to identify articles. Independent raters will screen and retrieve articles for inclusion, conduct quality ratings, and extract data. The Systematic Assessment of Quality in Observational Research adapted for Cultural Psychiatry Epidemiology (SAQOR-CPE) will be used to assess quality of observational studies. We will assess for publication bias using funnel plots and statistical methods. We will use narrative synthesis to present results, addressing the study's objectives following the Cochrane Handbook guidelines. Meta-analyses will be used to report summary statistics for association of risk factors with development of depression., Discussion: This systematic review will summarize evidence-based research that examines the psychological, biological, and contextual factors contributing to the onset of depression in adolescents across the globe. Results will support the development of a model that can be evaluated in existing cohorts around the world., Systematic Review Registration: PROSPERO registration CRD42018103973 .

The role of immune or infective triggers in the pathogenesis of Chronic Fatigue Syndrome (CFS) is not yet fully understood. Barriers to obtaining immune measures at baseline (i.e., before the trigger) in CFS and post-infective fatigue model cohorts have prevented the study of pre-existing immune dysfunction and subsequent immune changes in response to the trigger. This study presents interferon-alpha (IFN-α)-induced persistent fatigue as a model of CFS. IFN-α, which is used in the treatment of chronic Hepatitis C Virus (HCV) infection, induces a persistent fatigue in some individuals, which does not abate post-treatment, that is, once there is no longer immune activation. This model allows for the assessment of patients before and during exposure to the immune trigger, and afterwards when the original trigger is no longer present. Fifty-five patients undergoing IFN-α treatment for chronic HCV were assessed at baseline, during the 6-12 months of IFN-α treatment, and at six-months post-treatment. Measures of fatigue, cytokines and kynurenine pathway metabolites were obtained. Fifty-four CFS patients and 57 healthy volunteers completed the same measures at a one-off assessment, which were compared with post-treatment follow-up measures from the HCV patients. Eighteen patients undergoing IFN-α treatment (33%) were subsequently defined as having 'persistent fatigue' (the proposed model for CFS), if their levels of fatigue were higher six-months post-treatment than at baseline; the other 67% were considered 'resolved fatigue'. Patients who went on to develop persistent fatigue experienced a greater increase in fatigue symptoms over the first four weeks of IFN-α, compared with patients who did not (Δ Treatment Week (TW)-0 vs. TW4; PF: 7.1 ± 1.5 vs. RF: 4.0 ± 0.8, p = 0.046). Moreover, there was a trend towards increased baseline interleukin (IL)-6, and significantly higher baseline IL-10 levels, as well as higher levels of these cytokines in response to IFN-α treatment, alongside concurrent increases in fatigue. Levels increased to more than double those of the other patients by Treatment Week (TW)4 (p =  0.011 for IL-6 and p = 0.001 for IL-10). There was no evidence of an association between persistent fatigue and peripheral inflammation six-months post-treatment, nor did we observe peripheral inflammation in the CFS cohort. While there were changes in kynurenine metabolites in response to IFN-α, there was no association with persistent fatigue. CFS patients had lower levels of the ratio of kynurenine to tryptophan and 3-hydroxykynurenine than controls. Future studies are needed to elucidate the mechanisms behind the initial exaggerated response of the immune system in those who go on to experience persistent fatigue even if the immune trigger is no longer present, and the change from acute to chronic fatigue in the absence of continued peripheral immune activation., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The endocannabinoid (eCB) system, an endogenous lipid signaling system, appears to be dysregulated in depression. The role of endocannabinoids (eCBs) as potent immunomodulators, together with the accumulating support for a chronic low-grade inflammatory profile in depression, suggests a compelling hypothesis for a fundamental impairment in their intercommunication, in depression., Objective: We aim to review previous literature on individual associations between the immune and eCB systems and depression. It will focus on peripheral and central mechanisms of crosstalk between the eCB and immune systems. A potential dysregulation in this crosstalk will be discussed in the context of depression., Results: Investigations largely report a hypoactivity of the eCB system and increased inflammatory markers in individuals with depression. Findings depict a multifaceted communication whereby immunocompetent and eCB-related cells can both influence the suppression and enhancement of the other's activity in both the periphery and central nervous system. A dysregulation of the eCB system, as seen in depression, appears to be associated with central and peripheral concentrations of inflammatory agents implicated in the pathophysiology of this illness., Conclusion: The eCB and immune systems have been individually associated with and implicated in pathogenic mechanisms of depression. Both systems tightly regulate the other's activity. As such, a dysregulation in this crosstalk has potential to influence the onset and maintenance of this neuropsychiatric illness. However, few studies have investigated both systems and depression conjointly. This review highlights the demand to consider joint eCB-immune interactions in the pathoetiology of depression.