Toward a dynamic immunopsychiatry.

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.

Low-dose interleukin 2 antidepressant potentiation in unipolar and bipolar depression: Safety, efficacy, and immunological biomarkers.

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.

High unrecognized SARS-CoV-2 exposure of newly admitted and hospitalized psychiatric patients.

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

The future is dynamic: A call for intensive longitudinal data in immunopsychiatry.

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.

Peripheral control of psychiatric disorders: Focus on OCD. Are we there yet?

"We are all in this together" - we often hear this phrase when we want to flag up a problem that is not for a single individual but concerns us all. A similar reflection has been recently made in the field of mental disorders where brain-centric scientists have started to zoom out their brain-focused graphical representations of the mechanisms regulating psychiatric diseases to include other organs or mediators that did not belong historically to the world of neuroscience. The brain itself - that has long been seen as a master in command secluded in its fortress (the blood brain barrier), has now become a collection of Airbnb(s) where all sorts of cells come in and out and sometimes even rearrange the furniture! Under this new framework of reference, mental disorders have become multisystem pathologies where different biological systems - not just the CNS -contribute 'all together' to the development and severity of the disease. In this narrative review article, we will focus on one of the most popular biological systems that has been shown to influence the functioning of the CNS: the immune system. We will specifically highlight the two main features of the immune system and the CNS that we think are important in the context of mental disorders: plasticity and memory.

C-Reactive Protein (CRP): A Potent Inflammation Biomarker in Psychiatric Disorders.

An increasing number of studies have investigated the role of inflammation in psychiatric disorders, by demonstrating how an altered/dysfunctional immunological and inflammatory system may underpin a psychiatric condition. Particularly, several studies specifically investigated the role of a neuroinflammatory biomarker, named C-reactive protein (CRP), in psychiatric disorders. Overall, even though scientific literature so far published still does not appear definitive, CRP is more likely reported to be elevated in several psychiatric disorders, including schizophrenia, mood disorders, anxiety disorders and post-traumatic stress disorder. Moreover, a low-grade inflammation (CRP >3 mg/L) has been more likely observed in a subgroup of patients affected with a more severe psychopathological symptomatology, more treatment resistance and worst clinical mental illness course, strengthening the hypothesis of the need for a different clinical and prognostic characterization based on this concomitant neuroinflammatory predisposition. However, even though further research studies are needed to confirm this preliminary evidence, CRP may represent a potential clinical routine biomarker which could be integrated in the clinical routine practice to better characterize clinical picture and course as well as address clinicians towards a personalized treatment.

A Two-to-Five Year Follow-Up of a Pediatric Acute-Onset Neuropsychiatric Syndrome Cohort.

Little is known about the long-term prognosis of children with pediatric acute-onset neuropsychiatric syndrome (PANS). Out of the 46 eligible patients from the Karolinska PANS cohort, 34 consented to participate in a follow-up (median 3.3 years). Participants underwent a thorough clinical evaluation and were classified according to their clinical course. Resulting groups were compared on clinical characteristics and laboratory test results. We observed significant reductions in clinician-rated PANS symptom severity and improved general function. Two patients were classified as remitted, 20 as relapsing-remitting, and 12 as having a chronic-static/progressive course. The latter group had an earlier onset, greater impairment and received more pharmacological and psychological treatments. Although remission was rare, the majority of children with PANS were significantly improved over the follow-up period but a non-negligible minority of patients displayed a chronic-static/progressive course and required additional treatments. The proposed definitions of flare and clinical course may be useful in future clinical trials.

Inflammation and Depression: A Public Health Perspective.

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.

Measuring clinical outcomes in children with pediatric acute-onset neuropsychiatric syndrome: data from a 2-5 year follow-up study.

BACKGROUND: It is unclear how to best measure the complex symptom presentation of pediatric acute-onset neuropsychiatric syndrome (PANS). METHODS: Well-characterized participants of a 2-5 year follow-up study (n = 34; 56% male) underwent clinical evaluations and completed scales assessing global symptom severity, functional impairment and specific psychiatric symptoms. We explored inter-correlations between the measures and used intraclass correlation coefficients to evaluate the agreement between clinician-, parent- and child ratings of the same constructs. RESULTS: Ratings on symptom-specific measures varied largely between participants. Agreement between informants was excellent on functional scales, fair-to-moderate on global severity scales and mixed on symptom-specific scales. Clinician-rated global and functional measures had stronger inter-correlations with parent- and child-rated functional measures than with symptom-specific measures. CONCLUSIONS: General instruments assessing global severity and functioning are well suited for the assessment and follow-up of PANS, but should be complemented by symptom-specific scales representative of core symptoms.

[Immunopsychiatry and SARS-CoV-2 pandemic: Links and possible consequences]. / Immuno-psychiatrie et pandémie de SARS-CoV-2 : liens et possibles conséquences.

OBJECTIVE: The SARS-CoV-2 (or COVID-19) pandemic has been propagating since December 2019, inducing a drastic increase in the prevalence of anxious and depressive disorders in the general population. Psychological trauma can partly explain these disorders. However, since psychiatric disorders also have an immuno-inflammatory component, the direct effects of the virus on the host's immune system, with a marked inflammatory response, but also the secondary inflammation to these psychosocial stressors, may cause the apparition or the worsening of psychiatric disorders. We describe here the probable immunopsychiatric consequences of the SARS-CoV-2 pandemic, to delineate possible screening actions and care that could be planned. METHOD: Data from previous pandemics, and existing data on the psychopathological consequences of the SARS-CoV-2 pandemic, allowed us to review the possible immunopsychiatric consequences of the SARS-CoV-2 pandemic, on the gestational environment, with the risk of consecutive neurodevelopmental disorders for the fetus on one hand, on the children and adults directly infected being at increased risks of psychiatric disorders on the other hand. RESULTS: As in previous pandemics, the activation of the immune system due to psychological stress and/or to infection during pregnancy, might lead to an increased risk of neurodevelopmental disorders for the fetus (schizophrenia and autism spectrum disorders). Furthermore, in individuals exposed to psychological trauma and/or infected by the virus, the risk of psychiatric disorders, especially mood disorders, is probably increased. CONCLUSION: In this context, preventive measures and specialized care are necessary. Thus, it is important to propose a close follow-up to the individuals who have been infected by the virus, in order to set up the earliest care possible. Likewise, in pregnant women, screening of mood disorders during the pregnancy or the postpartum period must be facilitated. The follow-up of the babies born during the pandemic must be strengthened to screen and care for possible neurodevelopmental disorders.

Do psychiatric patients experience more psychiatric symptoms during COVID-19 pandemic and lockdown? A case-control study with 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.

Longitudinal population subgroups of CRP and risk of depression in the ALSPAC birth cohort.

BACKGROUND: Meta-analyses confirm increased circulating C-reactive protein (CRP) levels in depression. Longitudinal studies have linked one-off measurements of CRP at baseline with increased risk of developing depressive symptoms subsequently at follow-up, but studies with repeat CRP measures from the same individuals are scarce. METHODS: We have examined whether longitudinal patterns of inflammation, based on three CRP measurements from childhood to early-adulthood, are associated with the risk of depression in early-adulthood in the Avon Longitudinal Study of Parents and Children, a prospective birth cohort. RESULTS: Using Gaussian mixture modelling of available CRP data from age 9, 15 and 18 years, we identified four population clusters/sub-groups reflecting different longitudinal patterns of CRP: persistently low (N=463, 29.5%); persistently high (N=371, 24%); decreasing (N=360, 23%); increasing (N=367, 23.5%). The increasing group showed a steep increase in CRP levels between adolescence and early-adulthood. Participants in this group had a higher risk of moderate/severe depression at age 18 years, compared with those with persistently low CRP; adjusted odds ratio (OR)=3.78 (95% Confidence Interval (CI), 1.46-9.81; p=0.006). The odds of moderate/severe depression were also increased for the persistently high CRP group, but this was not statistically significant; OR=2.54 (95% CI, 0.90-7.16). LIMITATIONS: Repeat CRP measures were available for a subset, who may not be representative of all cohort participants. CONCLUSIONS: The results suggest that an increasing pattern of inflammation from adolescence to early-adulthood is associated with risk of depression in early-adulthood.

Prevalence of low-grade inflammation in depression: a systematic review and meta-analysis of CRP levels.

BACKGROUND: Peripheral low-grade inflammation in depression is increasingly seen as a therapeutic target. We aimed to establish the prevalence of low-grade inflammation in depression, using different C-reactive protein (CRP) levels, through a systematic literature review and meta-analysis. METHODS: We searched the PubMed database from its inception to July 2018, and selected studies that assessed depression using a validated tool/scale, and allowed the calculation of the proportion of patients with low-grade inflammation (CRP >3 mg/L) or elevated CRP (>1 mg/L). RESULTS: After quality assessment, 37 studies comprising 13 541 depressed patients and 155 728 controls were included. Based on the meta-analysis of 30 studies, the prevalence of low-grade inflammation (CRP >3 mg/L) in depression was 27% (95% CI 21-34%); this prevalence was not associated with sample source (inpatient, outpatient or population-based), antidepressant treatment, participant age, BMI or ethnicity. Based on the meta-analysis of 17 studies of depression and matched healthy controls, the odds ratio for low-grade inflammation in depression was 1.46 (95% CI 1.22-1.75). The prevalence of elevated CRP (>1 mg/L) in depression was 58% (95% CI 47-69%), and the meta-analytic odds ratio for elevated CRP in depression compared with controls was 1.47 (95% CI 1.18-1.82). CONCLUSIONS: About a quarter of patients with depression show evidence of low-grade inflammation, and over half of patients show mildly elevated CRP levels. There are significant differences in the prevalence of low-grade inflammation between patients and matched healthy controls. These findings suggest that inflammation could be relevant to a large number of patients with depression.

Systemic inflammation and intelligence in early adulthood and subsequent risk of schizophrenia and other non-affective psychoses: a longitudinal cohort and co-relative study.

BACKGROUND: Schizophrenia is associated with impaired neurodevelopment as indexed by lower premorbid IQ. We examined associations between erythrocyte sedimentation rate (ESR), a marker of low-grade systemic inflammation, IQ, and subsequent schizophrenia and other non-affective psychoses (ONAP) to elucidate the role of neurodevelopment and inflammation in the pathogenesis of psychosis. METHODS: Population-based data on ESR and IQ from 638 213 Swedish men assessed during military conscription between 1969 and 1983 were linked to National Hospital Discharge Register for hospitalisation with schizophrenia and ONAP. The associations of ESR with IQ (cross-sectional) and psychoses (longitudinal) were investigated using linear and Cox-regression. The co-relative analysis was used to examine effects of shared familial confounding. We examined mediation and moderation of effect between ESR and IQ on psychosis risk. RESULTS: Baseline IQ was associated with subsequent risk of schizophrenia (adjusted HR per 1-point increase in IQ = 0.961; 95% confidence interval (CI) 0.960-0.963) and ONAP (adjusted HR = 0.973; 95% CI 0.971-0.975). Higher ESR was associated with lower IQ in a dose-response fashion. High ESR was associated with increased risk for schizophrenia (adjusted HR = 1.14; 95% CI 1.01-1.28) and decreased risk for ONAP (adjusted HR = 0.85; 95% CI 0.74-0.96), although these effects were specific to one ESR band (7-10 mm/hr). Familial confounding explained ESR-IQ but not ESR-psychoses associations. IQ partly mediated the ESR-psychosis relationships. CONCLUSIONS: Lower IQ is associated with low-grade systemic inflammation and with an increased risk of schizophrenia and ONAP in adulthood. Low-grade inflammation may influence schizophrenia risk by affecting neurodevelopment. Future studies should explore the differential effects of inflammation on different types of psychosis.

Longitudinal association between inflammatory markers and specific symptoms of depression in a prospective birth cohort.

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 (ß = 0.059, SE = 0.024, P = 0.013) and psychological (ß = 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.

Childhood inflammatory markers and intelligence as predictors of subsequent persistent depressive symptoms: a longitudinal cohort study.

BACKGROUND: To identify developmental sub-groups of depressive symptoms during the second decade of life, a critical period of brain development, using data from a prospective birth cohort. To test whether childhood intelligence and inflammatory markers are associated with subsequent persistent depressive symptoms. METHODS: IQ, a proxy for neurodevelopment, was measured at age 8 years. Interleukin 6 (IL-6) and C-reactive protein, typical inflammatory markers, were measured at age 9 years. Depressive symptoms were measured six times between 10 and 19 years using the short mood and feelings questionnaire (SMFQ), which were coded as binary variable and then used in latent class analysis to identify developmental sub-groups of depressive symptoms. RESULTS: Longitudinal SMFQ data from 9156 participants yielded three distinct population sub-groups of depressive symptoms: no symptoms (81.2%); adolescent-onset symptoms (13.2%); persistent symptoms (5.6%). Lower IQ and higher IL-6 levels in childhood were independently associated with subsequent persistent depressive symptoms in a linear, dose-response fashion, but not with adolescent-onset symptoms. Compared with the group with no symptoms the adjusted odds ratio for persistent depressive symptoms per s.d. increase in IQ was 0.80 (95% CI, 0.68-0.95); that for IL-6 was 1.20 (95% CI, 1.03-1.39). Evidence for an association with IL-6 remained after controlling for initial severity of depressive symptoms at 10 years. There was no evidence that IL-6 moderated or mediated the IQ-persistent depressive symptom relationship. CONCLUSIONS: The results indicate potentially important roles for two distinct biological processes, neurodevelopment and inflammation, in the aetiology of persistent depressive symptoms in young people.

The blood-brain interface: a culture change.

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.

Effectiveness of depression interventions for people living with HIV in Sub-Saharan Africa: A systematic review & meta-analysis of psychological & immunological outcomes.

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.

Association between a functional interleukin 6 receptor genetic variant and risk of depression and psychosis in a population-based birth cohort.

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.

Association between cytokines and psychiatric symptoms in chronic fatigue syndrome and healthy controls.

PURPOSE: The reports regarding the status of the immune system in patients with chronic fatigue syndrome/myalgic encephalopathy (CFS/ME) have been inconclusive. We approached this question by comparing a strictly defined group of CFS/ME outpatients to healthy control individuals, and thereafter studied cytokines in subgroups with various psychiatric symptoms. MATERIALS AND METHODS: Twenty patients diagnosed with CFS/ME according to the Fukuda criteria and 20 age- and sex-matched healthy controls were enrolled in the study. Plasma was analysed by ELISA for levels of the cytokines TNF-α, IL-4, IL-6 and IL-10. Participants also answered questionnaires regarding health in general, and psychiatric symptoms in detail. RESULTS: Increased plasma levels of TNF-α in CFS/ME patients almost reached significance compared to healthy controls (p = .056). When studying the CFS/ME and control groups separately, there was a significant correlation between TNF-α and The Hospital Anxiety and Depression Scale (HADS) depressive symptoms in controls only, not in the CFS/ME group. A correlation between IL-10 and psychoticism was found in both groups, whereas the correlation for somatisation was seen only in the CFS/ME group. When looking at the total population, there was a significant correlation between TNF-α and both the HADS depressive symptoms and the SCL-90-R cluster somatisation. Also, there was a significant association between IL-10 and the SCL-90-R cluster somatisation when analyzing the cohort (patients and controls together). CONCLUSIONS: These findings indicate that immune activity in CFS/ME patients deviates from that of healthy controls, which implies potential pathogenic mechanisms and possible therapeutic approaches to CFS/ME. More comprehensive studies should be carried out on defined CFS/ME subgroups.