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• Immune-inflammatory mechanisms are promising targets for antidepressant pharmacology. • In a randomized controlled trial low-dose IL-2 significantly improved antidepressant response. • IL-2 rapidly expanded the population of Treg, Th2, and Naive CD4+/CD8 + immune cell counts. • Strengthening in the T cell system predicted antidepressant response. Immune-inflammatory mechanisms are promising targets for antidepressant pharmacology. Immune cell abnormalities have been reported in mood disorders showing a partial T cell defect. Following this line of reasoning we defined an antidepressant potentiation treatment with add-on low-dose interleukin 2 (IL-2). IL-2 is a T-cell growth factor which has proven anti-inflammatory efficacy in autoimmune conditions, increasing thymic production of naïve CD4 + T cells, and possibly correcting the partial T cell defect observed in mood disorders. We performed a single-center, randomised, double-blind, placebo-controlled phase II trial evaluating the safety, clinical efficacy and biological responses of low-dose IL-2 in depressed patients with major depressive (MDD) or bipolar disorder (BD). 36 consecutively recruited inpatients at the Mood Disorder Unit were randomised in a 2:1 ratio to receive either aldesleukin (12 MDD and 12 BD) or placebo (6 MDD and 6 BD). Active treatment significantly potentiated antidepressant response to ongoing SSRI/SNRI treatment in both diagnostic groups, and expanded the population of T regulatory, T helper 2, and percentage of Naive CD4+/CD8 + immune cells. Changes in cell frequences were rapidly induced in the first five days of treatment, and predicted the later improvement of depression severity. No serious adverse effect was observed. This is the first randomised control trial (RCT) evidence supporting the hypothesis that treatment to strengthen the T cell system could be a successful way to correct the immuno-inflammatory abnormalities associated with mood disorders, and potentiate antidepressant response. [ABSTRACT FROM AUTHOR]

• Newly admitted and hospitalized psychiatric patients without known history of infection have high SARS-CoV-2 prevalence and antibody titers. • We did not observe differences in SARS-CoV-2 global and antigen-specific titers between patient subgroups. • We found no effect of hospitalization duration on SARS-CoV-2 exposure risk. • Psychiatric patients present with SARS-CoV-2 post-acute immune profile. • Pro-inflammatory cytokine levels could not predict serological status. Patients with pre-existing mental disorders are at higher risk for SARS-CoV-2 infection and adverse outcomes, and severe mental illness, including mood and psychosis spectrum disorders, is associated with increased mortality risk. Despite their increased risk profile, patients with severe mental illness have been understudied during the pandemic, with limited estimates of exposure in inpatient settings. The aim of this study was to describe the SARS-CoV-2 seroprevalence and antibody titers, and pro-inflammatory cytokine concentrations of newly admitted or hospitalized psychiatric inpatients without known history of COVID-19 infection, using robust quantitative multi-antigen assessments, and compare patients' exposure to that of hospital staff. This multi-centric, cross-sectional study compared SARS-CoV-2 seroprevalence and titers of 285 patients (University Psychiatric Centre Duffel [UPCD] N = 194; Assistance-Publique-Hopitaux de Paris [AP-HP] N = 91), and 192 hospital caregivers (UPCD N = 130; AP-HP N = 62) at two large psychiatric care facilities between January 1st and the May 30th 2021. Serum levels of SARS-CoV-2 antibodies against Spike proteins (full length), spike subunit 1 (S1), spike subunit 2 (S2), spike subunit 1 receptor binding domain (S1-RBD) and Nucleocapsid proteins were quantitatively determined using an advanced capillary Western Blot technique. To assess the robustness of the between-group seroprevalence differences, we performed sensitivity analyses with stringent cut-offs for seropositivity. We also assessed peripheral concentrations of IL-6, IL-8 and TNF-a using ELLA assays. Secondary analyses included comparisons of SARS-CoV-2 seroprevalence and titers between patient diagnostic subgroups, and between newly admitted (hospitalization ≤ 7 days) and hospitalized patients (hospitalization > 7 days) and correlations between serological and cytokines. Patients had a significantly higher SARS-CoV-2 seroprevalence (67.85 % [95% CI 62.20–73.02]) than hospital caregivers (27.08% [95% CI 21.29–33.77]), and had significantly higher global SARS-CoV-2 titers (F = 29.40, df = 2, p < 0.0001). Moreover, patients had a 2.51-fold (95% CI 1.95–3.20) higher SARS-CoV-2 exposure risk compared to hospital caregivers (Fisher's exact test, P < 0.0001). No difference was found in SARS-CoV-2 seroprevalence and titers between patient subgroups. Patients could be differentiated most accurately from hospital caregivers by their higher Spike protein titers (OR 136.54 [95% CI 43.08–481.98], P < 0.0001), lower S1 (OR 0.06 [95% CI 0.02–0.15], P < 0.0001) titers and higher IL-6 (OR 3.41 [95% CI 1.73–7.24], P < 0.0001) and TNF-α (OR 34.29 [95% CI 5.00–258.87], P < 0.0001) and lower titers of IL-8 (OR 0.13 [95% CI 0.05–0.30], P < 0.0001). Seropositive patients had significantly higher SARS-COV-2 antibody titers compared to seropositive hospital caregivers (F = 19.53, df = 2, P < 0.0001), while titers were not different in seronegative individuals. Pro-inflammatory cytokine concentrations were not associated with serological status. Our work demonstrated a very high unrecognized exposure to SARS-CoV-2 among newly admitted and hospitalized psychiatric inpatients, which is cause for concern in the context of highly robust evidence of adverse outcomes following COVID-19 in psychiatric patients. Attention should be directed toward monitoring and mitigating exposure to infectious agents within psychiatric hospitals. [ABSTRACT FROM AUTHOR]

• Longitudinal research often features overly long follow-up durations. • Overly long follow-up durations can obscure causal effects. • Identification of optimal time lags is necessary to guide expectations for time-to-improvement in treatment. • More immunopsychiatric studies should collect intensive longitudinal data. The long-term value of immunopsychiatry will be based on its ability to translate basic science into effective clinical interventions. In this article, we discuss a key obstacle to achieving this important translational goal—namely, the preponderance of studies that are cross-sectional, or that have months-to-years long follow-up periods. Immunopsychiatric processes such as stress, inflammation, and depression symptoms are inherently dynamic and fluctuate over hours, days, and weeks. This fact suggests that higher-density data collection with only days between measurements is necessary to capture—with adequate resolution—the actual dynamics of these systems, determine optimal time lags with which to observe associations between variables of interest, and maximize the translational potential of these data. To illustrate these points, we use pilot data from our own intensive longitudinal immunopsychiatric study. We then conclude by making several recommendations for future research. By learning how to better use existing data for dynamically informative studies as well as collecting intensive longitudinal data, we believe immunopsychiatry will be much better positioned to advance our causal understanding of the interplay between the immune system and health. [ABSTRACT FROM AUTHOR]

In this article, we briefly clarify several points regarding immunopsychiatry. In particular, we argue that higher density data and a greater focus on temporal dynamics are both important, and that studies incorporating these features have the potential to greatly advance the field. We also respond to recent comments made on our original article on this topic (Moriarity and Slavich, 2023), including the contention that our perspective on immunopsychiatry is reductionistic. To the contrary, we believe that strong immunopsychiatry studies are highly integrative and include data from multiple major levels of analysis to form a more complete picture of how processes that are relevant for mental health and behavior emerge and dynamically change over time in relation to one another. [ABSTRACT FROM AUTHOR]

• Levels of anxiety, depression, stress and insomnia were higher in psychiatric patients. • Psychiatric patients had more health concerns, impulsivity and suicidal ideation. • More than one-third of psychiatric patients fulfil the diagnostic criteria for PTSD. • Poor physical health was associated with higher levels of anxiety, depression and stress. • The above findings have service and research implications for immunopsychiatry. This study aimed to assess and compare the immediate stress and psychological impact experienced by people with and without psychiatric illnesses during the peak of 2019 coronavirus disease (COVID-19) epidemic with strict lockdown measures. Seventy-six psychiatric patients and 109 healthy control subjects were recruited from Chongqing, China and completed a survey on demographic data, physical symptoms during the past 14 days and a range of psychiatric symptoms using the Impact of Event Scale-Revised (IES-R), Depression, Anxiety and Stress Scale (DASS-21) and Insomnia Severity Index (ISI). IES-R measures PTSD symptoms in survivorship after an event. DASS-21 is based on tripartite model of psychopathology that comprise a general distress construct with distinct characteristics. The mean IES-R, DASS-21 anxiety, depression and stress subscale and ISI scores were higher in psychiatric patients than healthy controls (p < 0.001). Serious worries about their physical health, anger and impulsivity and intense suicidal ideation were significantly higher in psychiatric patients than healthy controls (p < 0.05). More than one-third of psychiatric patients might fulfil the diagnostic criteria post-traumatic stress disorder (PTSD). More than one-quarter of psychiatric patients suffered from moderately severe to severe insomnia. Respondents who reported no change, poor or worse physical health status and had a psychiatric illness were significantly more likely to have higher mean IES-R, DASS depression, anxiety and stress subscale scores and ISI scores (p < 0.05). This study confirms the severity of negative psychological impact on psychiatric patients during the COVID-19 epidemic with strict lockdown measures. Understanding the psychological impact on psychiatric patients during the COVID-19 pandemic has the potential to provide insight into how to develop a new immunopsychiatry service. Further research is required to compare pro-inflammatory cytokines between psychiatric patients and healthy controls during the pandemic. [ABSTRACT FROM AUTHOR]

The multifaceted role of low-grade systemic inflammation in depression and physical illnesses like cardiovascular disease highlights complex interactions between the body, brain and mind. While current research on inflammation and depression has largely focused on exploring possible disease mechanisms and therapeutic potential, we seek to broaden the current discussion by introducing a public health perspective. In this Viewpoint, we propose that inflammation and its contributing sources could represent important targets for public health strategies aimed at improving both mental and physical health. We discuss potential universal, selective and indicated primary prevention strategies for inflammation-related depression. We consider potential approaches to secondary prevention, including scope for anti-inflammatory treatment and CRP testing for guiding treatment allocation and prognosis. Preventive strategies discussed here could also be relevant for other inflammation-mediated mental health conditions. [ABSTRACT FROM AUTHOR]

Highlights • At symptom level, IL-6 is associated with diurnal variation in mood, concentration difficulties, fatigue and sleep disturbances. • These are so-called somatic/neurovegetative symptoms of depression. • At dimension level, IL-6 is associated with both somatic/neurovegetative and psychological symptom dimensions. • Somatic/neurovegetative symptoms could be useful treatment targets and markers of treatment response in clinical trials of anti-inflammatory treatment for depression. Abstract Background Low-grade inflammation is associated with depression, but studies of specific symptoms are relatively scarce. Association between inflammatory markers and specific symptoms may provide insights into potential mechanism of inflammation-related depression. Using longitudinal data, we have tested whether childhood serum interleukin 6 (IL-6) and C-reactive protein (CRP) levels are associated with specific depressive symptoms in early adulthood. Methods In the ALSPAC birth cohort, serum IL-6 and CRP levels were assessed at age 9 years and 19 depressive symptoms were assessed at age 18 years. We used modified Poisson generalised linear regression with robust error variance to estimate the risk ratio (RR) and 95% confidence interval (95% CI) for each depressive symptom. In addition, we used confirmatory factor analysis to create two continuous latent variables representing somatic/neurovegetative and psychological dimension scores. Structural equation modelling was used to test the associations between IL-6 and these dimension scores. Results Based on data from 2731 participants, IL-6 was associated with diurnal mood variation, concentration difficulties, fatigue and sleep disturbances. The adjusted RRs for these symptoms at age 18 years for participants in top, compared with bottom, third of IL-6 at age 9 years were 1.75 (95% CI, 1.13–2.69) for diurnal mood variation, 1.50 (95% CI, 1.11–2.02) for concentration difficulties, 1.31 (95% CI, 1.12–1.54) for fatigue, and 1.24 (95% CI, 1.01–1.52) for sleep disturbances. At dimension level, IL-6 was associated with both somatic/neurovegetative (β = 0.059, SE = 0.024, P = 0.013) and psychological (β = 0.056, SE = 0.023, P = 0.016) scores. Conclusions Inflammation is associated with specific symptoms of depression. Associations with so-called somatic/neurovegetative symptoms of depression such as fatigue, sleep disturbances and diurnal mood variation indicate that these symptoms could be useful treatment targets and markers of treatment response in clinical trials of anti-inflammatory treatment for depression. [ABSTRACT FROM AUTHOR]

Highlights • Pharmacological interventions showed the greatest improvement in depression scores. • Meta-analysis showed non-significant improvements in immune status. • Antidepressants alone might not address ART non-adherence associated with MDD. • A combination of psychological and pharmacological treatment is recommended. Abstract This meta-analytic review evaluated the effectiveness of depression interventions on the psychological and immunological outcomes of people living with HIV in sub-Saharan Africa. 14 studies, yielding 932 participants were eligible. A random-effects models indicated that depression interventions were followed by large reductions in depression scores (effect size = 1.86, 95% CI = 1.71, 2.01, p < 0.01). No significant effect on immune outcome was observed, however there was a trend toward immune improvement of medium effect size (effect size on CD4 count and/or viral suppression = 0.57, 95% CI = −0.06, 1.20, p = 0.08). Pharmacological interventions appeared to have a significantly larger improvement in depression scores than psychological interventions. The greatest improvement in immune status was demonstrated in psychological treatments which incorporated a component to enhance HIV medication adherence, however these results did not reach significance. Small sample sizes and highly heterogeneous analysis necessitate caution in interpretation. The results of this meta-analysis should thus be treated as preliminary evidence and used to encourage further studies of immunopsychiatry in HIV in sub-Saharan Africa. [ABSTRACT FROM AUTHOR]

Objective Interleukin 6 (IL-6) levels are commonly elevated in patients with depression and psychosis and in people who are at risk of developing these disorders. A common, functional variant in the IL6R gene ( IL6R Asp358Ala; rs2228145 A > C) is known to dampen down inflammation by impairing IL6R signaling. We have examined the association of Asp358Ala with diagnosis of depression and psychosis, serum IL-6, CRP levels, and a number of risk factors commonly linked with inflammation, depression or psychosis. We predicted that if IL-6 were related to depression/psychosis risk causally, rather than due to confounding, Asp358Ala would be associated with risk of these disorders, serum IL-6, CRP levels, but not with any of the confounders. Method We used data from the population-based ALSPAC birth cohort. Serum IL-6 and CRP levels were measured at age 9 years. Psychotic disorder, ICD-10 diagnosis of severe depressive episode, and total depression score were assessed at age 18 years. IL6R Asp358Ala was genotyped using the Illumina HumanHap550 quad genome-wide SNP genotyping platform. Risk factors assessed include sex, body mass index, social class, ethnicity, maternal education, birth weight, gestational age, maternal post-natal depression, childhood psychological and behavioral problems, and total IQ score. Results Asp358Ala was associated with decreased risk of severe depression and/or psychosis; adjusted odds ratio for those with CC, compared with AA, genotype was 0.38 (95% CI, 0.15–0.94). The variant was associated with increased serum IL-6 levels ( P  = 5.5 × 10 −22 ) but decreased serum CRP levels ( P  = 3.5 × 10 −5 ), consistent with an anti-inflammatory effect downstream of IL-6. Asp358Ala was not associated with total depression score. Asp358Ala was not associated with any of the other risk factors commonly linked with inflammation, depression or psychosis (all P  > 0.20). Conclusions The findings provide further evidence that the IL-6/IL6R pathways are involved in pathogenesis of severe depression and psychosis, and may be novel therapeutic targets. Previously reported associations between IL-6, depression and psychosis are unlikely to be fully explained by confounding. Based on a small number of cases, findings from the current study need replication in other samples. [ABSTRACT FROM AUTHOR]

The blood-brain interface (BBI) is the subject of a new named series at Brain, Behavior, and Immunity . It is timely to reflect on a number of advances in the field within the last ten years, which may lead to an increased understanding of human behaviour and a wide range of psychiatric and neurological conditions. We cover discoveries made in solute and cell trafficking, endothelial cell and pericyte biology, extracellular matrix and emerging tools, especially those which will enable study of the human BBI. We now recognize the central role of the BBI in a number of immunopsychiatric syndromes, including sickness behaviour, delirium, septic encephalopathy, cognitive side effects of cytokine-based therapies and the frank psychosis observed in neuronal surface antibody syndromes. In addition, we find ourselves interrogating and modulating the brain across the BBI, during diagnostic investigation and treatment of brain disease. The past ten years of BBI research have been exciting but there is more to come. [ABSTRACT FROM AUTHOR]