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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.

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.

Neuroinflammation has been implicated in the pathophysiology of schizophrenia and obsessive-compulsive disorder (OCD) and deviations in brain structure and connectivity are seen in these disorders. Here, we explore the effects of a potent immunomodulatory treatment on neuroimaging. In a pilot study of rituximab treatment in schizophrenia and OCD, a subgroup (n = 13) underwent structural and functional magnetic resonance imaging before and 5 months after treatment, to study longitudinal changes in resting-state functional connectivity (rsFC) and voxel-based morphometry (VBM).A hypothesis-free exploratory whole-brain analysis was performed twice to assess changes in rsFC, using anterior cingulate cortex, anterior insula, posterior insula and nucleus accumbens as seed regions. There were significant interactions (diagnosis x time) in connectivity between right posterior insula and two clusters encompassing basal ganglia and anterior frontal pole, and between left anterior insula and a cluster in basal ganglia, where connectivity decreased in OCD and increased in schizophrenia. The increase of connectivity after rituximab, between left anterior insula and parts of cerebellum and lingual gyrus and between left posterior insula and parts of cerebellum, correlated with improved global psychosocial functioning according to the Personal and Social Performance Scale, especially in schizophrenia. VBM analysis identified two clusters with increased grey matter volumes (GMV) after rituximab, one in right insula overlapping one of the seed regions with significant rsFC changes. This pilot study implies that rituximab may influence both brain structure and connectivity and that GMV changes and rsFC changes are regionally associated.

Background: Immunological mechanisms have been implicated in the development of mental disorders, and interestingly, case reports have suggested that hematopoietic stem cell transplantation (HSCT) can both transmit and cure psychotic disorders by replacing immune progenitor cells. Methods: Using Danish registers, we followed patients who received HSCT from donors with a psychiatric diagnosis or psychotropic medication use. We assessed risk of incident mental disorders or psychotropic medication use compared with recipients with unaffected donors. We identified 464 donor-recipient pairs (51.3% male recipients). All donor-recipient pairs were related. Results: Receiving HSCT from a donor with a psychiatric history was not significantly associated with incident psychiatric diagnoses (hazard rate ratio [HRR] 2.79, 95% CI, 0.83–9.39; p = .098) or incident use of psychotropics (HRR 1.43, 95% CI, 0.91–2.24; p = .118). Subgroup analysis showed an increased risk of antipsychotic use, which remained significant after adjusting for confounders (HRR 4.73, 95% CI, 1.26–17.78; p = .021); however, this was based on a small number of cases. For depression and antidepressant use, data were available to perform a meta-analysis of our and one additional study, which showed no significant difference (HRR 1.24, 95%, CI 0.66–2.35). Conclusions: Receiving HSCT from a donor with a psychiatric history did not affect risk of mental disorders. An increased risk of antipsychotic use was observed only in subgroup analyses; however, the exploratory nature of the study, the limited sample size, and family relationship between donors and recipients do not allow for causal conclusions, and external replication studies are warranted.

BackgroundAlthough characterizing associations between inflammation and depression may prove critical for informing theory, research, and treatment decisions, extant research has been limited by ignoring the possibility that inflammation may be simultaneously associated with depression broadly and with a subset of symptoms. This lack of direct comparison has hampered attempts to understand inflammatory phenotypes of depression and critically fails to consider that inflammation might be uniquely associated with both depression broadly and individual symptoms.MethodsWe used moderated nonlinear factor analysis in 5 NHANES (National Health and Nutrition Examination Survey) cohorts (N = 27,730, 51% female, mean age = 46 years).ResultsC-reactive protein (CRP) is simultaneously associated with latent depression, appetite, and fatigue. Specifically, CRP was associated with latent depression in all 5 samples (rs: 0.044-0.089; ps: < .001-.002) and was associated with both appetite (significant rs: 0.031-0.049, significant ps: .001-.007) and fatigue (significant rs: 0.030-0.054, significant ps: < .001-.029) in 4 samples. These results were largely robust to covariates.ConclusionsMethodologically, these models indicate that the Patient Health Questionnaire-9 is scalar noninvariant as a function of CRP (i.e., identical Patient Health Questionnaire-9 scores may represent different constructs in those with high vs. low CRP levels). Therefore, mean comparisons of depression total scores and CRP might be misleading without accounting for symptom-specific associations. Conceptually, these findings indicate that studies investigating inflammatory phenotypes of depression should examine how inflammation is simultaneously related both to depression broadly and to specific symptoms, and whether these relations function via different mechanisms. This has the potential to yield new theoretical insights and may lead to the development of novel therapies for reducing inflammation-related symptoms of depression.

• 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]

The term “affective immunology” has recently been used to denote a field focused on the interplay between affective processes (including mood states, specific emotions, and regulatory processes) and various aspects of immune function. The overarching goals of this commentary are a) to provide historical underpinnings of this field with a focus on the profound impact of the work of Janice Kiecolt-Glaser, who is further honored in this special issue, b) to review important off-shoots of her legacy work in this domain, and c) to highlight important future directions for the field. Kiecolt-Glaser's work laid much of the foundation for affective immunology, with groundbreaking research related to depression, hostility and dyadic interactions, loneliness, and other affective patterns, often in the context of holistic models, novel experimental designs, and interventions. Her former mentees (and many of their mentees) have carried on her legacy in these domains, in ways that continue to advance appreciation of how affective processes relate to immune function. There are numerous remaining questions for the field to pursue, including better understanding of the role of emotion regulation, emotional reactivity and recovery, restorative processes, affective variability, and developmental and dynamic social processes. Such work will require greater use of longitudinal and within-person approaches and/or examination of processes in daily life, as well as models that account for interactive and reciprocal processes and which integrate behavior, social context, sociocultural factors, individual differences, and other aspects of health. As more work in these domains continues, building on Kiecolt-Glaser's rich legacy, we move toward the emergence of affective immunology as an important subfield in the domain of psychoneuroimmunology, one which will offer more nuanced understanding of the role of affective processes in immune health.

• 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]

(1) Background: philosophical views are important to enable a general and multi-systemic view of the potential understanding of autoimmunity in psychiatric disease that is not solely reflected by an immunological viewpoint. (2) Methods: we reviewed current theories of autoimmunity. (3) Results: we propose a novel area view integrating the "self/non-self" and "continuity" model into the expression of varied forms of autoimmunity in psychiatric disease, ranging from protective to harmful autoimmunity consequences framed into micro-systems (nerve cells) and macro-systems (neuronal networks), termed the "multi-systemic dynamic continuum model". (4) Conclusions: autoimmunity's dynamic spectrum is delineated here as something that probably functions as a whole entity to maintain, first of all, human homeostasis in behavior affecting cells or neuronal networks differently, and secondly to prevent psychiatric disease. [ABSTRACT FROM AUTHOR]

Immunological mechanisms, both alone and in combination, are associated with a broad range of psychiatric disorders encompassing autoimmune, autoinflammatory disorders but also genetic, metabolic, or other immunological disorders. Early treatment improves the outcome for autoimmune disorders, but early diagnosis is more difficult when isolated psychiatric symptoms are manifestations of autoimmunity. Treatment of these cases must encompass integrated models of disease, as both systemic autoimmunity and psychological processes influence mental health. Several challenges need to be overcome to efficiently merge psychiatric and somatic disease paradigms and medical care ranging from language and conceptual barriers to organizational barriers. Since 2015, the Immunopsychiatry team at Uppsala University has developed a collaborative multidisciplinary approach to improve and integrate care for patients with moderate to severe psychiatric disorders. Based on this experience, we have outlined the obstacles to be overcome in taking steps forward to achieve the long-term goal of understanding and early detection and identification of treatable immunological conditions within the psychiatric patient population; the described framework of evaluations and work-flow may serve as a model for other centers.

“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.

In a subset of patients with mental disorders, such as depression, low-grade inflammation and altered immune marker concentrations are observed. However, these immune alterations are often assessed by only one data type and small marker panels. Here, we used a transdiagnostic approach and combined data from two cohorts to define subgroups of depression symptoms across the diagnostic spectrum through a large-scale multi-omics clustering approach in 237 individuals. The method incorporated age, body mass index (BMI), 43 plasma immune markers and RNA-seq data from peripheral mononuclear blood cells (PBMCs). Our initial clustering revealed four clusters, including two immune-related depression symptom clusters characterized by elevated BMI, higher depression severity and elevated levels of immune markers such as interleukin-1 receptor antagonist (IL-1RA), C-reactive protein (CRP) and C-C motif chemokine 2 (CCL2 or MCP-1). In contrast, the RNA-seq data mostly differentiated a cluster with low depression severity, enriched in brain related gene sets. This cluster was also distinguished by electrocardiography data, while structural imaging data revealed differences in ventricle volumes across the clusters. Incorporating predicted cell type proportions into the clustering resulted in three clusters, with one showing elevated immune marker concentrations. The cell type proportion and genes related to cell types were most pronounced in an intermediate depression symptoms cluster, suggesting that RNA-seq and immune markers measure different aspects of immune dysregulation. Lastly, we found a dysregulation of the SERPINF1/VEGF-A pathway that was specific to dendritic cells by integrating immune marker and RNA-seq data. This shows the advantages of combining different data modalities and highlights possible markers for further stratification research of depression symptoms., Competing Interests: Declaration of Competing Interest VIS has provided consulting and advisory services for Roche and Sony. VIS is co-founder of Biomentric UG (entrepreneurial company [with limited liability]), holds equity in and provides consulting and advisory services for Biomentric UG. The other authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Neuroinflammation has been implicated in the pathophysiology of schizophrenia and obsessive-compulsive disorder (OCD) and deviations in brain structure and connectivity are seen in these disorders. Here, we explore the effects of a potent immunomodulatory treatment on neuroimaging. In a pilot study of rituximab treatment in schizophrenia and OCD, a subgroup (n = 13) underwent structural and functional magnetic resonance imaging before and 5 months after treatment, to study longitudinal changes in resting-state functional connectivity (rsFC) and voxel-based morphometry (VBM). A hypothesis-free exploratory whole-brain analysis was performed twice to assess changes in rsFC, using anterior cingulate cortex, anterior insula, posterior insula and nucleus accumbens as seed regions. There were significant interactions (diagnosis x time) in connectivity between right posterior insula and two clusters encompassing basal ganglia and anterior frontal pole, and between left anterior insula and a cluster in basal ganglia, where connectivity decreased in OCD and increased in schizophrenia. The increase of connectivity after rituximab, between left anterior insula and parts of cerebellum and lingual gyrus and between left posterior insula and parts of cerebellum, correlated with improved global psychosocial functioning according to the Personal and Social Performance Scale, especially in schizophrenia. VBM analysis identified two clusters with increased grey matter volumes (GMV) after rituximab, one in right insula overlapping one of the seed regions with significant rsFC changes. This pilot study implies that rituximab may influence both brain structure and connectivity and that GMV changes and rsFC changes are regionally associated., Competing Interests: None of the authors have any interests to declare., (© 2024 The Authors.)

Abstract 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.

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]

Background : Anti-neural autoantibody-associated psychiatric disease is a novel field in immunopsychiatry that has been attracting attention thanks to its potentially positive therapeutic outcome and distinct prognosis compared with non-organic psychiatric disease. This review aims to describe recent novel technological developments for improving diagnostics in the field of autoantibody-related psychiatric disease. Methods: We screened for relevant articles in PubMed for this narrative article. We focused on research methods such as neuroimaging, immune cells and inflammation markers, and molecular biomarkers in human biofluids like serum and cerebrospinal fluid and plasma proteomics. Results: We introduce several novel methods for investigating autoinflammation with the aim of optimizing therapies for autoantibody-associated psychiatric disease. We describe measuring the translocator protein 18kDa in activated microglia via positron emission tomography imaging, brain volumetric assessment, flow cell cytometry of cerebrospinal fluid and blood, and blood biological probes as well as psychopathological cues to help us gain insights into diagnosing inflammation and brain damage better in psychiatric patients presenting a suspected autoimmune etiology. Conclusion: Our short methodological review provides an overview of recent developments in the field of autoantibody-related immunopsychiatry. More research is needed to prove their usefulness in diagnosing and treating autoantibody-associated psychiatric disease and its subtypes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Anti-neural autoantibody-associated psychiatric disease is a novel field in immunopsychiatry that has been attracting attention thanks to its potentially positive therapeutic outcome and distinct prognosis compared with non-organic psychiatric disease. This review aims to describe recent novel technological developments for improving diagnostics in the field of autoantibody-related psychiatric disease.MethodsWe screened for relevant articles in PubMed for this narrative article. We focused on research methods such as neuroimaging, immune cells and inflammation markers, and molecular biomarkers in human biofluids like serum and cerebrospinal fluid and plasma proteomics.ResultsWe introduce several novel methods for investigating autoinflammation with the aim of optimizing therapies for autoantibody-associated psychiatric disease. We describe measuring the translocator protein 18kDa in activated microglia via positron emission tomography imaging, brain volumetric assessment, flow cell cytometry of cerebrospinal fluid and blood, and blood biological probes as well as psychopathological cues to help us gain insights into diagnosing inflammation and brain damage better in psychiatric patients presenting a suspected autoimmune etiology.ConclusionOur short methodological review provides an overview of recent developments in the field of autoantibody-related immunopsychiatry. More research is needed to prove their usefulness in diagnosing and treating autoantibody-associated psychiatric disease and its subtypes.

Autoimmune encephalitis (AIE) is a group of immune-mediated inflammatory processes of the brain with marked psychiatric features. Although relatively rare, they might offer difficult differential diagnosis with psychiatric conditions, especially catatonia and psychotic syndromes. Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is the most common AIE, presenting with psychiatric syndromes in 90% of cases. The associated psychopathology is complex, pleomorphic, and best characterized when there is involvement of a psychiatrist in the assessment. This text will review the main aspects of AIE to psychiatrists and/or neuropsychiatrists. Immune system dysfunction has been implicated in the pathophysiology of psychiatric symptoms and disorders. The use of diagnostic criteria for possible AIE, especially when specific antibodies of AIE are not available, allows early diagnosis and prompt treatment which are associated with better clinical outcomes. The study of the psychiatric aspects of AIE can broaden our knowledge of the underlying mechanisms of various psychiatric manifestations. [ABSTRACT FROM AUTHOR]

N-Methyl-d-Aspartate-receptor (NMDAR) antibody encephalitis is a disease discovered two decades ago. Our knowledge about it has recently deepened dramatically. However, the significance of NMDAR antibodies in psychiatric disease cannot be determined if there are no clear indications of brain inflammation or an autoimmune encephalitis mediated by NMDAR antibodies. Furthermore, the long-term interaction and connection between these two disease entities are unclear. In this paper we aim to elucidate the relationship between these disease entities. We propose two distinct models that explain the on the one hand a condition in which a minor inflammatory state as in psychiatric disease culminates in a severe state of inflammation characterized by NMDAR encephalitis. On the other hand, we postulate a model in which an NMDAR encephalitis might later create favorable conditions for inducing psychiatric disease. These models should be kept in mind for further investigations examining the long-term outcome of NMDAR autoantibody immunity in the brain and its functions.

Background: Immunological mechanisms have been implicated in the development of mental disorders, and interestingly, case reports have suggested that hematopoietic stem cell transplantation (HSCT) can both transmit and cure psychotic disorders by replacing immune progenitor cells., Methods: Using Danish registers, we followed patients who received HSCT from donors with a psychiatric diagnosis or psychotropic medication use. We assessed risk of incident mental disorders or psychotropic medication use compared with recipients with unaffected donors. We identified 464 donor-recipient pairs (51.3% male recipients). All donor-recipient pairs were related., Results: Receiving HSCT from a donor with a psychiatric history was not significantly associated with incident psychiatric diagnoses (hazard rate ratio [HRR] 2.79, 95% CI, 0.83-9.39; p  = .098) or incident use of psychotropics (HRR 1.43, 95% CI, 0.91-2.24; p  = .118). Subgroup analysis showed an increased risk of antipsychotic use, which remained significant after adjusting for confounders (HRR 4.73, 95% CI, 1.26-17.78; p  = .021); however, this was based on a small number of cases. For depression and antidepressant use, data were available to perform a meta-analysis of our and one additional study, which showed no significant difference (HRR 1.24, 95%, CI 0.66-2.35)., Conclusions: Receiving HSCT from a donor with a psychiatric history did not affect risk of mental disorders. An increased risk of antipsychotic use was observed only in subgroup analyses; however, the exploratory nature of the study, the limited sample size, and family relationship between donors and recipients do not allow for causal conclusions, and external replication studies are warranted., (© 2024 The Authors.)

(1) Background: philosophical views are important to enable a general and multi-systemic view of the potential understanding of autoimmunity in psychiatric disease that is not solely reflected by an immunological viewpoint. (2) Methods: we reviewed current theories of autoimmunity. (3) Results: we propose a novel area view integrating the “self/non-self” and “continuity” model into the expression of varied forms of autoimmunity in psychiatric disease, ranging from protective to harmful autoimmunity consequences framed into micro-systems (nerve cells) and macro-systems (neuronal networks), termed the “multi-systemic dynamic continuum model”. (4) Conclusions: autoimmunity’s dynamic spectrum is delineated here as something that probably functions as a whole entity to maintain, first of all, human homeostasis in behavior affecting cells or neuronal networks differently, and secondly to prevent psychiatric disease.

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. [ABSTRACT FROM AUTHOR]

Immunopsychiatry is a subfield of psychoneuroimmunology that integrates immunological and psychopathological processes with promise for improving the classification, identification, and treatment of psychopathology. Using research on the relationship between inflammation and depression as a running example, this mini-review will discuss three areas of work that should be emphasized in future research to maximize the replicability and clinical impact of the field: 1) methodology with respect to planning data collection and statistical analyses with measurement properties and conceptually important sources of variance in mind, 2) characterizing inflammatory phenotypes of psychopathology, and 3) the integration of inflammatory processes into robust, extant psychosocial theoretical frameworks of psychopathology risk. Consistent, parallel growth in all three areas will ensure immunopsychiatry research is replicable, contributes to understanding of how (and for whom) the immune system is associated with psychiatric symptoms, and increases the flexibility and power of personalized treatment planning.

Psychoneuroimmunology, the area of research dedicated to understanding the fundamental interactions between the central nervous system and the immune system, has given rise to the development of Immunopsychiatry, a new discipline which harnesses the immune system to produce beneficial outcomes for mental health problems. Immunopsychiatry has the potential to become a clinically relevant specialty area in psychiatric practice, but has not yet been adopted by the wider mental health community. This paper aims to map out the future trajectory of Immunopsychiatry on its road towards science-to-policy knowledge translation and clinical implementation. Three critical milestones which will need to be reached in order for Immunopsychiatry to fulfil its promise for clinical innovation are discussed: a clear definition of patients who fall within the immunopsychiatric continuum; demonstration of well-defined clinical benefit and incorporation in clinical guidelines; and convergence with other paradigms in biological psychiatry.

When psychosis develops in NMDA receptor (NMDAR) antibody encephalitis, it usually has an acute or subacute onset, and antipsychotic treatment may be ineffective and associated with adverse effects. Serum NMDAR antibodies have been reported in a minority of patients with first-episode psychosis (FEP), but their role in psychosis onset and response to antipsychotic treatment is unclear. Sera from 387 patients with FEP (duration of psychosis <2 years, minimally or never treated with antipsychotics) undergoing initial treatment with amisulpride as part of the OPTiMiSE (Optimization of Treatment and Management of Schizophrenia in Europe) trial (ClinicalTrials.gov number NCT01248195) were tested for NMDAR IgG antibodies using a live cell–based assay. Symptom severity was assessed using the Positive and Negative Syndrome Scale and the Clinical Global Impressions Scale at baseline and again after 4 weeks of treatment with amisulpride. At baseline, 15 patients were seropositive for NMDAR antibodies and 372 were seronegative. The seropositive patients had similar symptom profiles and demographic features to seronegative patients but a shorter duration of psychosis (median 1.5 vs. 4.0 months; p =.031). Eleven seropositive and 284 seronegative patients completed 4 weeks of amisulpride treatment: after treatment, there was no between-groups difference in improvement in Positive and Negative Syndrome Scale scores or in the frequency of adverse medication effects. These data suggest that in FEP, NMDAR antibody seropositivity alone is not an indication for using immunotherapy instead of antipsychotic medications. Further studies are required to establish what proportion of patients with FEP who are NMDAR antibody seropositive have coexisting cerebrospinal fluid inflammatory changes or other paraclinical evidence suggestive of a likely benefit from immunotherapy. [ABSTRACT FROM AUTHOR]

A growing number of studies are pointing out the need for a conceptual shift from a brain-centered to a body-inclusive approach in mental health research. In this perspective, the link between the immune and the nervous system, which are deeply interconnected and continuously interacting, is one of the most important novel theoretical framework to investigate the biological bases of major depressive disorder and, more in general, mental illness. Indeed, depressed patients show high levels of inflammatory markers, administration of pro-inflammatory drugs triggers a depressive symptomatology and antidepressant efficacy is reduced by excessive immune system activation. A number of molecular and cellular mechanisms have been hypothesized to act as a link between the immune and brain function, thus representing potential pharmacologically targetable processes for the development of novel and effective therapeutic strategies. These include the modulation of the kynurenine pathway, the crosstalk between metabolic and inflammatory processes, the imbalance in acquired immune responses, in particular T cell responses, and the interplay between neural plasticity and immune system activation. In the personalized medicine approach, the assessment and regulation of these processes have the potential to lead, respectively, to novel diagnostic approaches for the prediction of treatment outcome according to the patient's immunological profile, and to improved efficacy of antidepressant compounds through immune modulation. [ABSTRACT FROM AUTHOR]

The term "affective immunology" has recently been used to denote a field focused on the interplay between affective processes (including mood states, specific emotions, and regulatory processes) and various aspects of immune function. The overarching goals of this commentary are a) to provide historical underpinnings of this field with a focus on the profound impact of the work of Janice Kiecolt-Glaser, who is further honored in this special issue, b) to review important off-shoots of her legacy work in this domain, and c) to highlight important future directions for the field. Kiecolt-Glaser's work laid much of the foundation for affective immunology, with groundbreaking research related to depression, hostility and dyadic interactions, loneliness, and other affective patterns, often in the context of holistic models, novel experimental designs, and interventions. Her former mentees (and many of their mentees) have carried on her legacy in these domains, in ways that continue to advance appreciation of how affective processes relate to immune function. There are numerous remaining questions for the field to pursue, including better understanding of the role of emotion regulation, emotional reactivity and recovery, restorative processes, affective variability, and developmental and dynamic social processes. Such work will require greater use of longitudinal and within-person approaches and/or examination of processes in daily life, as well as models that account for interactive and reciprocal processes and which integrate behavior, social context, sociocultural factors, individual differences, and other aspects of health. As more work in these domains continues, building on Kiecolt-Glaser's rich legacy, we move toward the emergence of affective immunology as an important subfield in the domain of psychoneuroimmunology, one which will offer more nuanced understanding of the role of affective processes in immune health., Competing Interests: None., (© 2024 The Author.)

This Editorial discusses the missions and scope of the new Gold Open Access journal “Brain, Behavior and Immunity (BBI) – Health” and how it complements the activity of the established BBI journal.

Depression has been associated with increased inflammatory proteins, but changes in circulating immune cells are less well defined. We used multiparametric flow cytometry to count 14 subsets of peripheral blood cells in 206 depression cases and 77 age- and sex-matched controls (N = 283). We used univariate and multivariate analyses to investigate the immunophenotypes associated with depression and depression severity. Depression cases, compared with controls, had significantly increased immune cell counts, especially neutrophils, CD4+ T cells, and monocytes, and increased inflammatory proteins (C-reactive protein and interleukin-6). Within-group analysis of cases demonstrated significant associations between the severity of depressive symptoms and increased myeloid and CD4+ T-cell counts. Depression cases were partitioned into 2 subgroups by forced binary clustering of cell counts: the inflamed depression subgroup (n = 81 out of 206; 39%) had increased monocyte, CD4+, and neutrophil counts; increased C-reactive protein and interleukin-6; and more severe depression than the uninflamed majority of cases. Relaxing the presumption of a binary classification, data-driven analysis identified 4 subgroups of depression cases, 2 of which (n = 38 and n = 100; 67% collectively) were associated with increased inflammatory proteins and more severe depression but differed in terms of myeloid and lymphoid cell counts. Results were robust to potentially confounding effects of age, sex, body mass index, recent infection, and tobacco use. Peripheral immune cell counts were used to distinguish inflamed and uninflamed subgroups of depression and to indicate that there may be mechanistically distinct subgroups of inflamed depression. [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]

Keywords: innate immunity; inflammation; obsessive compulsive disorder; child and adolescent psychiatric disorders; COX-2 inhibitor; immunopsychiatry; prostanoid; non-steroidal anti-inflammatory drug EN innate immunity inflammation obsessive compulsive disorder child and adolescent psychiatric disorders COX-2 inhibitor immunopsychiatry prostanoid non-steroidal anti-inflammatory drug 1 5 5 04/24/20 20200422 NES 200422 Introduction Enzymes of the cyclooxygenase (COX) family catalyze the metabolism of arachidonic acids to prostanoids. Ultimately, longitudinal clinical characterization combined with a broad approach to immune phenotyping - as employed in a recent analysis of microarray data in MDD ([17]) - is likely a higher-yield approach both for biomarker discovery and for improving our understanding of how peripheral inflammation reflects or perpetuates psychiatric symptoms. Diverse Non-Steroidal Anti-Inflammatory Drug Mechanisms of Action: The Specific Drug Matters While all NSAIDS have anti-inflammatory, antipyretic, and analgesic properties attributable to prostaglandin inhibition, they vary with respect to COX selectivity ([27]) and likely with respect to COX-independent mechanisms ([28]-[30]). Innate immunity, inflammation, obsessive compulsive disorder, child and adolescent psychiatric disorders, COX-2 inhibitor, immunopsychiatry, prostanoid, non-steroidal anti-inflammatory drug. [Extracted from the article]

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]

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. [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]

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. [ABSTRACT FROM AUTHOR]

C-reactive protein (CRP) tends to be elevated in individuals with psychiatric disorders. Recent findings have suggested a protective effect of the genetic liability to elevated CRP on schizophrenia risk and a causative effect on depression despite weak genetic correlations, while causal relationships with bipolar disorder were inconclusive. We investigated the shared genetic underpinnings of psychiatric disorders and variation in CRP levels. Genome-wide association studies for CRP (n = 575,531), bipolar disorder (n = 413,466), depression (n = 480,359), and schizophrenia (n = 130,644) were used in causal mixture models to compare CRP with psychiatric disorders based on polygenicity, discoverability, and genome-wide genetic overlap. The conjunctional false discovery rate method was used to identify specific shared genetic loci. Shared variants were mapped to putative causal genes, which were tested for overrepresentation among gene ontology gene-sets. CRP was six to ten times less polygenic (n = 1400 vs 8600–14,500 variants) and had a discoverability one to two orders of magnitude higher than psychiatric disorders. Most CRP-associated variants were overlapping with psychiatric disorders. We identified 401 genetic loci jointly associated with CRP and psychiatric disorders with mixed effect directions. Gene-set enrichment analyses identified predominantly CNS-related gene sets for CRP and each of depression and schizophrenia, and basic cellular processes for CRP and bipolar disorder. In conclusion, CRP has a markedly different genetic architecture to psychiatric disorders, but the majority of CRP associated variants are also implicated in psychiatric disorders. Shared genetic loci implicated CNS-related processes to a greater extent than immune processes, which may have implications for how we conceptualise causal relationships between CRP and psychiatric disorders. • CRP is six to ten times less polygenic than psychiatric disorders. • Four-hundred and one independent genetic loci are shared between CRP and major psychiatric disorders. • Shared loci display mixed effect directions, consistent with minimal genetic correlation. • Implicated gene sets are predominantly related to CNS-related processes and structures. [ABSTRACT FROM AUTHOR]