Association of interleukin-2 and interleukin-10 with the pathophysiology and development of generalized anxiety disorder: a case-control study.

BACKGROUND: Generalized anxiety disorder (GAD) is a devastating mental health condition characterized by constant, uncontrolled worrying. Recent hypotheses indicate that pro-inflammatory cytokines and chemokines are potential contributors to the pathogenesis of GAD. Here, we aimed to assess the role of interleukin-2 (IL-2) and interleukin-10 (IL-10) in the pathophysiology and development of GAD. METHODS: This study recruited 50 GAD patients diagnosed according to the DSM-5 criteria and 38 age-sex-matched healthy controls (HCs). A qualified psychiatrist evaluated all study subjects. The socio-demographic and clinical characteristics of the study population were determined using pre-structured questionnaires or interviews, and cytokine serum levels were estimated using commercially available ELISA kits. RESULTS: We observed reduced serum IL-10 levels in GAD patients compared to HCs (33.69 ± 1.37 pg/ml vs. 44.12 ± 3.16 pg/ml). Also, we observed a significant negative correlation between altered IL-10 levels and GAD-7 scores (r=-0.315, p = 0.039). Moreover, IL-10 serum measurement exhibited good predictive value in receiver operating characteristics (ROC) analysis with an area under the curve (AUC) value of 0.793 (p < 0.001) with 80.65% sensitivity and 62.79% specificity at a cutoff value of 33.93 pg/ml. Conversely, we noticed elevated serum IL-2 levels in GAD patients than in HCs (14.81 ± 2.88 pg/ml vs. 8.08 ± 1.1 pg/ml); however, it failed to maintain any significant association with GAD-7 scores, implying that IL-2 might not be involved in GAD pathogenesis. The lower AUC value (0.640; p > 0.05) exhibited by IL-2 serum measurement in ROC analysis further supported that IL-2 might not be associated with GAD. CONCLUSION: This study provides new insights into the complex interplay between anti-inflammatory cytokines and GAD pathogenesis. Based on the present findings, we can assume that IL-10 but not IL-2 may be associated with the pathophysiology and development of GAD. However, further research with a larger population size and longitudinal design is required to confirm the potential diagnostic efficacy of IL-10.

Population-based cohort study of Toxoplasma gondii P22 antibody positivity correlation with anxiety.

BACKGROUND: Accumulating evidence suggests that latent infection with Toxoplasma gondii (T. gondii) is associated with a variety of neuropsychiatric and behavioral conditions. This research aims to explore the potential correlation between T. gondii antibody positivity and neuropsychiatric disorders through a comprehensive prospective cohort study. METHODS: The cohort study utilized the UK Biobank database to recruit 8814 individuals with no prior diagnosis of neuropsychiatric disorders. Cox proportional hazards models were employed to investigate the associations between T. gondii P22 antibody seropositivity (P22+) and the development of various types of neuropsychiatric disorders. RESULTS: Of the population, 14.65 % tested positive for T. gondii P22 antibody. The presence of T. gondii P22 antibody showed a slight inverse association with epilepsy (HR: 0.28; 95 % CI: 0.10-0.77), while it was positively associated with an increased risk of developing anxiety disorders (HR: 1.38; 95 % CI: 1.04-1.83). LIMITATIONS: The study sample consisted mostly of white British individuals aged 40 to 69 years old. Although we adjusted for potential confounders, there may be other unmeasured and residual confounding factors that could have influenced our reported associations. CONCLUSIONS: The findings suggested an increased risk of anxiety and potential evidence of epilepsy associated with T. gondii P22+. However, our analysis did not reveal an increased risk of several other neuropsychiatric conditions including Alzheimer's disease, dementia, substance abuse disorders, depression, and neurodegenerative disorders, associated with P22 antibody seropositivity.

Childhood trauma and LPS-stimulated inflammation in adulthood: Results from the Netherlands Study of Depression and Anxiety

BACKGROUND: Childhood trauma (CT) is robustly associated with psychiatric disorders including major depressive and anxiety disorders across the life span. The innate immune system may play a role in the relation between CT and stress-related psychopathology. However, whether CT influences the innate production capacity of cytokine levels following ex vivo stimulation by lipopolysaccharide (LPS), is currently unknown. METHODS: Using data from the Netherlands Study of Depression and Anxiety (NESDA, n=1237), we examined whether CT (emotional neglect, emotional, physical, and sexual abuse before the age of 16), assessed by the Childhood Trauma Interview, was associated with levels in supernatants of interferon (IFN)γ, interleukin-2 (IL-2), IL-4, IL-6, IL-8, IL-10, IL-18, monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1α, MIP-1ß, matrix metalloproteinase-2 (MMP-2), TNFα and TNFß after ex vivo stimulation with LPS. Cytokines were analysed individually and cumulatively (overall inflammation index and number of cytokines in high-risk quartile (HRQ)) using linear regression analyses. RESULTS: After adjustment for demographic, lifestyle, and health-related covariates, total CT severity was associated with the overall inflammation index (ß = 0.085, PFDR = 0.011), the number of cytokines in HRQ (ß = 0.063, PFDR = 0.036), and individual markers of IL-2 (ß = 0.067, PFDR = 0.036), IL-6 (ß = 0.091 PFDR = 0.011), IL-8 (ß = 0.085 PFDR = 0.011), IL-10 (ß = 0.094 PFDR = 0.011), MCP-1 (ß = 0.081 PFDR = 0.011), MIP-1α (ß = 0.061 PFDR = 0.047), MIP1-ß (ß = 0.077 PFDR = 0.016), MMP-2 (ß = 0.070 PFDR = 0.027), and TNFß (ß = 0.078 PFDR = 0.016). Associations were strongest for individuals with severe CT, reporting multiple types or higher frequencies of trauma. Half of the findings persisted after adjustment for psychiatric status. The findings were consistent across different CT types. CONCLUSION: Childhood Trauma is associated with increased LPS-stimulated cytokine levels, with evidence for a dose-response relationship. Our results highlight a dysregulated innate immune system capacity in adults with CT, which could contribute to an increased vulnerability for psychopathology and somatic disorders across the lifespan.

Is Anxiety Associated with the Gut Microbiota?

Understanding how the microbiome influences health and disease has emerged as an important area of research across all domains of biomedical and health sciences. An extensive body of work in animal models has established a link between the gut microbiome and anxiety-like behaviour. Foundational work on germ-free mice provided the catalyst for neuroscientists to consider the microbiota-brain axis and brain health. Research manipulating the microbiome, including use of germ-free mice, antibiotics, and probiotics, provide evidence that the microbiota influences stress systems and in particular anxiety-like behaviour. Consideration of anxiety-like behaviour in animal models of metabolic and inflammatory disorders expands the scope of the work and correlates in clinical studies are emerging. This chapter highlights the work done to date in animal studies and reviews the recent clinical literature translating these observations to anxiety disorders.

Effects of anxiety sensitivity, disgust, and intolerance of uncertainty on the COVID stress syndrome: a longitudinal assessment of transdiagnostic constructs and the behavioural immune system.

Excessive fear and worry in response to the COVID-19 pandemic (e.g., COVID stress syndrome) is prevalent and associated with various adverse outcomes. Research from the current and past pandemics supports the association between transdiagnostic constructs-anxiety sensitivity (AS), disgust, and intolerance of uncertainty (IU)-and pandemic-related distress. Recent research suggests a moderating effect of disgust on the relationship of AS-physical concerns and COVID-19-related distress, suggesting that transdiagnostic constructs underlie individual differences in activation of the behavioral immune system (BIS). No previous study has examined the independent and conjoint effects of pre-COVID-19 AS-physical concerns, disgust propensity (DP), disgust sensitivity (DS), and IU in this context; thus, we did so using longitudinal survey data (N = 3,062 Canadian and American adults) with simple and moderated moderations controlling for gender, mental health diagnosis, and COVID-19 diagnosis. Greater AS-physical concerns, DP, and DS predicted more severe COVID stress syndrome assessed one month later. Either DP or DS further amplified the effect of AS-physical concerns on COVID stress syndrome, except danger and contamination fears. IU did not interact with AS-physical concerns and DS or DP. Theoretical and clinical implications pertaining to delivery of cognitive behavioural therapy for pandemic-related distress are discussed.

[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.

Role of interleukin 8 in depression and other psychiatric disorders.

Low grade neuroinflammation has been suggested as one of the underlying mechanisms of many psychiatric diseases as well as cognitive disorders. Interleukin 8 (IL-8), a proinflammatory cytokine produced by many cell types including macrophage and microglia, mainly functions as a neutrophil chemoattractant in the bloodstream. IL-8 is also found in the brain, where it is released from microglia in response to proinflammatory stimuli. In this review, we highlight studies focusing on the role of IL-8 in psychiatric diseases such as major depression, bipolar disorder, schizophrenia, sleep disorder, autism spectrum disorder, anxiety disorders and dementia. Increased peripheral IL-8 levels have been reported in these diseases, particularly in schizophrenic disorder, bipolar disorder, obstructive sleep apnea and autism spectrum disorder. The literature on IL-8 and major depression is inconsistent. IL-8 has been found to be a factor associated with schizophrenic prognosis and therapeutic response, and may affect a wide range of symptomatology. Considering that the exact role of immune alterations is still under research, the success of immune-based therapies in psychiatric diseases is limited for the time being.

Anxiety and depression in COVID-19 survivors: Role of inflammatory and clinical predictors.

Infection-triggered perturbation of the immune system could induce psychopathology, and psychiatric sequelae were observed after previous coronavirus outbreaks. The spreading of the Severe Acute Respiratory Syndrome Coronavirus (COVID-19) pandemic could be associated with psychiatric implications. We investigated the psychopathological impact of COVID-19 in survivors, also considering the effect of clinical and inflammatory predictors. We screened for psychiatric symptoms 402 adults surviving COVID-19 (265 male, mean age 58), at one month follow-up after hospital treatment. A clinical interview and a battery of self-report questionnaires were used to investigate post-traumatic stress disorder (PTSD), depression, anxiety, insomnia, and obsessive-compulsive (OC) symptomatology. We collected sociodemographic information, clinical data, baseline inflammatory markers and follow-up oxygen saturation levels. A significant proportion of patients self-rated in the psychopathological range: 28% for PTSD, 31% for depression, 42% for anxiety, 20% for OC symptoms, and 40% for insomnia. Overall, 56% scored in the pathological range in at least one clinical dimension. Despite significantly lower levels of baseline inflammatory markers, females suffered more for both anxiety and depression. Patients with a positive previous psychiatric diagnosis showed increased scores on most psychopathological measures, with similar baseline inflammation. Baseline systemic immune-inflammation index (SII), which reflects the immune response and systemic inflammation based on peripheral lymphocyte, neutrophil, and platelet counts, positively associated with scores of depression and anxiety at follow-up. PTSD, major depression, and anxiety, are all high-burden non-communicable conditions associated with years of life lived with disability. Considering the alarming impact of COVID-19 infection on mental health, the current insights on inflammation in psychiatry, and the present observation of worse inflammation leading to worse depression, we recommend to assess psychopathology of COVID-19 survivors and to deepen research on inflammatory biomarkers, in order to diagnose and treat emergent psychiatric conditions.

Daytime melatonin levels in saliva are associated with inflammatory markers and anxiety disorders.

BACKGROUND: The bidirectional interaction between melatonin and the immune system has largely gone unexplored in a clinical context and especially in a psychiatric population. This study explored the association between melatonin during the day and inflammatory cytokines in young adult patients seeking psychiatric care. METHODS: Samples and data were collected from 108 young adults (mean age 21, SD = 2) at an outpatient clinic for affective disorders. Daytime saliva melatonin levels were analyzed with enzyme-linked immunosorbent assay (ELISA) in relation to normalized serum expression levels of 72 inflammatory markers in a proximity extension assay (PEA). In a post hoc analysis the markers associated with melatonin were tested in a generalized linear model to see whether there is a relationship to anxiety disorder or depression. RESULTS: After Bonferroni correction for multiple testing, melatonin levels at 11:00 were positively correlated with CD5 (p = 4.2e-4). Melatonin levels after lunch were correlated with CCL2/MCP-1 (p = 4.2e-4), CCL3/MPI-1α (p = 6.5e-4) and VEGF-A (p = 5.3e-6). In the generalized linear model, positive associations were found for the presence of any anxiety disorder with melatonin after lunch (p = 0.046), VEGF-A (p = 0.001) and CCL3/MPI-1α (p = 0.001). CONCLUSION: Daytime saliva levels of melatonin were related to several inflammatory markers in young adults with psychiatric disorders. This observation likely reflects the bidirectional relationship between melatonin production and the immune system. These findings may have relevance for the understanding of psychiatric disorders and other conditions associated with low-grade inflammation.

Decoding rumination: A machine learning approach to a transdiagnostic sample of outpatients with anxiety, mood and psychotic disorders.

OBJECTIVE: To employ machine learning algorithms to examine patterns of rumination from RDoC perspective and to determine which variables predict high levels of maladaptive rumination across a transdiagnostic sample. METHOD: Sample of 200 consecutive, consenting outpatient referrals with clinical diagnoses of schizophrenia, schizoaffective, bipolar, depression, anxiety disorders, obsessive compulsive and post-traumatic stress. Machine learning algorithms used a range of variables including sociodemographics, serum levels of immune markers (IL-6, IL-1ß, IL-10, TNF-α and CCL11) and BDNF, psychiatric symptoms and disorders, history of suicide and hospitalizations, functionality, medication use and comorbidities. RESULTS: The best model (with recursive feature elimination) included the following variables: socioeconomic status, illness severity, worry, generalized anxiety and depressive symptoms, and current diagnosis of panic disorder. Linear support vector machine learning differentiated individuals with high levels of rumination from those ones with low (AUC = 0.83, sensitivity = 75, specificity = 71). CONCLUSIONS: Rumination is known to be associated with poor prognosis in mental health. This study suggests that rumination is a maladaptive coping style associated not only with worry, distress and illness severity, but also with socioeconomic status. Also, rumination demonstrated a specific association with panic disorder.

Stress-induced disturbances along the gut microbiota-immune-brain axis and implications for mental health: Does sex matter?

Women are roughly twice as likely as men to suffer from stress-related disorders, especially major depression and generalized anxiety. Accumulating evidence suggest that microbes inhabiting the gastrointestinal tract (the gut microbiota) interact with the host brain and may play a key role in the pathogenesis of mental illnesses. Here, the possibility that sexually dimorphic alterations along the gut microbiota-immune-brain axis could play a role in promoting this female bias of mood and anxiety disorders will be discussed. This review will also analyze the idea that gut microbes and sex hormones influence each other, and that this reciprocal crosstalk may come to modulate inflammatory players along the gut microbiota-immune-brain axis and influence behavior in a sex-dependent way.

Effects of SSRIs on peripheral inflammatory cytokines in patients with Generalized Anxiety Disorder.

BACKGROUND: Extensive research into psychoneuroimmunology has led to substantial advances in our understanding of the reciprocal interactions between the central nervous system and the immune system in neuropsychiatric disorders. To date, inflammation has been implicated in the pathogenesis of depression and anxiety. The immunomodulating effects of antidepressants on depression have been reported, however, there is no evidence of the similar effects of antidepressants on anxiety. The aim of the study was to investigate the effects of selective serotonin reuptake inhibitors (SSRIs) on peripheral inflammatory cytokines in patients with first episode generalized anxiety disorder (GAD). METHODS: A prospective cohort design was employed: 42 patients with first episode GAD were treated with either escitalopram or sertraline for 12 weeks. Anxiety was measured by the Generalized Anxiety Disorder Scale and the State Trait Anxiety Inventory, serum pro-inflammatory cytokine levels were measured by the enzyme-linked immunosorbent assay (ELISA), and CRP determined by an immunoturbidimetric method before and after SSRIs treatment RESULTS: Baseline levels of anxiety and pro-inflammatory cytokines including IL-1α, IL-6, IL-8, IL-12, IFN-γ, and CRP were significantly reduced after treatment of SSRIs (p < 0.05 in all cases). In addition, the change of anxiety measures co-vary with the change of peripheral cytokine levels (p < 0.05 in all cases). The regression model revealed that log transformed baseline levels of CRP and IL-6 predicted treatment response (p < 0.05 in both cases). CONCLUSIONS: This study is the first to investigate the effects of SSRIs on pro-inflammatory cytokines in patients with first episode GAD. The findings indicate moderate acute anti-inflammatory effects of SSRIs in GAD, and suggest that these anti-inflammatory effects may underlie anxiolytic effects of SSRIs. The study also indicates that serum levels of CRP and IL-6 may predict treatment response. However, data from randomized controlled trials is warranted to confirm these findings.

Persistent central inflammation and region specific cellular activation accompany depression- and anxiety-like behaviours during the resolution phase of experimental colitis.

Depression and anxiety-related psychological symptoms are increasingly recognised as important co-morbidities in patients with inflammatory bowel disease (IBD). Dextran sulfate sodium (DSS) -induced colitis is an animal model of IBD in which afferent activation of the gut-brain axis can be assessed and explored as a source of behavioural change. Exposure of adult male Wistar rats to DSS (5%) in drinking water induced distal colitis. In parallel to local inflammatory responses in the gut wall, increased expression of IL-6 and iNOS was found in the cerebral cortex and an increase in ventricular volume. Immunoreactivity of immediate early gene FosB/ΔFosB activation was measured as an index of cellular activation and was increased in the nucleus accumbens and dorsal raphe nucleus in acutely colitic animals. Following resolution of the acute colitic response, sustained anhedonia in the saccharin preference test, immobility in the forced swim test, reduced burying behaviour in the marble burying test, and mild signs of anxiety in the elevated plus maze and light/dark box were observed. Central increases in iNOS expression persisted during the recovery phase and mapped to reactive microglia, particularly those found in the parenchyma surrounding circumventricular regions. Evidence of associated nitration was also found. Sustained increases in ventricular volume and reduced T2 magnetic resonance relaxometry time in cortical regions were observed during the recovery period. FosB/ΔFosB activation was evident in the dorsal raphe during recovery. Persistent central inflammation and cellular activation may underpin the emergence of symptoms of depression and anxiety in experimental colitis.

Maternal thyroid autoimmunity associated with acute-onset neuropsychiatric disorders and global regression in offspring.

Epidemiological studies, animal models, and case-control studies indicate maternal immune activation may be an important factor involved in disease expression of autism spectrum disorder (ASD), Tourette syndrome, and obsessive-compulsive disorder (OCD). We report eight children (mean age 6y 6mo [range 4-15y]; six males and two females) referred over a 2-year period with at least one of these neurodevelopmental disorders plus a maternal history of thyroid autoimmunity. Seven of eight children presented with an abrupt onset of neuropsychiatric symptoms (OCD [n=6], tics [n=5], and/or psychosis [n=1]), associated with an autistic or global regression. Four children had a pre-existing diagnosis of ASD. Six presentations were preceded by infection, and symptoms followed a relapsing-remitting course in seven children. All children responded to immunomodulatory treatment as indicated by a reduction in psychiatric symptoms, and seven children were also managed with conventional treatment with additional improvement. We propose that maternal autoimmunity can activate fetal microglia or alter transcription of neurodevelopmental vulnerability and/or immune genes in utero, and is an environmental factor that increases the expression and severity of neurodevelopmental problems, and susceptibility to deteriorations after infectious or stress stimuli. WHAT THIS PAPER ADDS: Maternal thyroid autoimmunity may represent a risk factor for neuropsychiatric disorders in offspring. Atypical neuropsychiatric features in these children may be due to maternal immune activation in utero.

AUTOINMUNIDAD MATERNA TIROIDEA ASOCIADA CON TRASTORNOS NEUROPSIQUIÁTRICOS DE INICIO AGUDO Y REGRESIÓN GLOBAL EN LA DESCENDENCIA: Los estudios epidemiológicos, los modelos animales y los estudios de casos y controles indican que la activación inmune materna puede ser un factor importante involucrado en la expresión de la enfermedad del trastorno del espectro autista (TEA), el síndrome de Tourette y el trastorno obsesivo compulsivo (TOC). Informamos ocho niños (edad media 6 años de edad y 6 meses [rango 4-15 años]; 6 varones y 2 mujeres) remitidos durante un período de 2 años con al menos uno de estos trastornos del desarrollo neurológico más un historial materno de autoinmunidad tiroidea. Siete de ocho niños presentaron un inicio brusco de síntomas neuropsiquiátricos (TOC [n = 6], tics [n = 5] y / o psicosis [n = 1]), asociados con una regresión autista o global. Cuatro niños tenían un diagnóstico preexistente de TEA. Seis presentaciones fueron precedidas por infección, y los síntomas siguieron un curso de recaídas y remisiones en siete niños. Todos los niños respondieron al tratamiento inmunomodulador según lo indicado por una reducción en los síntomas psiquiátricos, y siete niños también fueron tratados con tratamiento convencional con una mejora adicional. Proponemos que la autoinmunidad materna puede activar la microglía fetal o alterar la transcripción de la vulnerabilidad del desarrollo neurológico y / o los genes inmunes en el útero, y es un factor ambiental que aumenta la expresión y la gravedad de los problemas del desarrollo neurológico, y la susceptibilidad a deterioros después de estímulos infecciosos o estresantes.

AUTOIMUNIDADE TIREÓIDE MATERNA ASSOCIADA COM DESORDENS NEUROPSIQUIÁTRICAS DE INÍCIO AGUDO E REGRESSÃO GLOBAL NA PROLE: Estudos epidemiológicos, modelos animais, e estudos de caso-controle indicam que a ativação imune materna pode ser um importante fator envolvido na expressão de doenças do transtorno do espectro autista (TEA), síndrome de Tourette, e transtorno obsessivo compulsivo (TOC). Reportamos oito crianças (média de idade 6a 6m [variação 4-15a]; 6 do sexo masculino e 2 do sexo feminino) encaminhadas em um período de 2 anos com pelo menos uma desordem neurodesenvolvimental e história de auto-imunidade tireóide materna. Sete das oito crianças apresentaram início agudo de sintomas neuropsiquiátricos (TOC [n=6], tiques [n=5], e/ou psicose [n=1]), associados com regressão autística ou global. Quatro crianças tinham diagnóstico pré-existente de TEA. Seis apresentações foram precedidas por infecção, e os sintomas seguiram um curso recorrência-remisão em sete crianças. Todas as crianças responderam ao tratamento imunomodulatório, indicado pela redução nos sintomas psiquiátricos, e sete crianças também foram abordadas com tratamento convencional, com melhora adicional. Nós propomos que a autoimunidade maternal pode ativar a microglia fetal ou alterar a transcrição de genes de vulnerabilidade neurodesenvolvimental e/ou imunes, e um fator ambiental pode aumentar a expressão e severidade de problemas neurodesenvolvimentais e suscetibilidade a deterioração após estímulo infeccioso ou estresse.

Repeated social defeat in female mice induces anxiety-like behavior associated with enhanced myelopoiesis and increased monocyte accumulation in the brain.

Anxiety and mood disorders affect both men and women. The majority of experimental models of stress, however, are completed using only male animals. For repeated social defeat (RSD), a rodent model, this is due to the inherent difficulty in eliciting male aggression toward female mice. To address this limitation, a recent study showed that a DREADD-based activation of the ventrolateral subdivision of the ventromedial hypothalamus (VMHvl) was effective in inducing aggressive behavior in male mice towards females in a social defeat paradigm. Therefore, the goal of this study was to determine if this modified version of RSD in females elicited behavioral, physiological, and immune responses similar to those reported in males. Here, we show that female mice subjected to RSD with the male DREADD aggressor developed anxiety-like behavior and social avoidance. These behavioral alterations coincided with enhanced neuronal and microglial activation in threat-appraisal regions of the brain. Moreover, stressed female mice had an enhanced peripheral immune response characterized by increased myelopoiesis, release of myeloid cells into circulation, and monocyte accumulation in the spleen and brain. These results are consistent with previously reported findings that male mice exposed to RSD exhibited increased fear and threat appraisal responses, enhanced myelopoiesis, myeloid cell release and trafficking, and anxiety-like behavior. These findings validate that RSD is a relevant model to study stress responses in female mice.

Antiphospholipid antibodies are associated with positive screening for common mental disorders in women with previous pregnancy loss. The NOHA-PSY observational study.

OBJECTIVES: Case reports describe neuropsychiatric manifestations associated with antiphospholipid antibodies (aPlAbs). In patients sharing the same symptoms fulfilling the antiphospholipid syndrome (APS) clinical criteria, the prevalence of common mental disorders has, however, never been studied. METHODS: We observed women with three consecutive abortions before the 10th week of gestation or one foetal loss at or beyond the 10th week. We compared the prevalence of common psychiatric disorders detected through screening using the Mini International Neuropsychiatric Interview, 10 years after inclusion, in women with APS (n = 506), women negative for aPlAbs but carrying the F5rs6025 or F2rs1799963 thrombogenic polymorphism (n = 269), and women with negative thrombophilia screening results as controls (n = 764). RESULTS: Similar prevalence values were obtained for controls and women bearing one of the two thrombogenic polymorphisms. Women with APS more frequently had mood disorders (relative risk (RR) 1.57 (1.262-1.953), P = .0001) and anxiety (RR 1.645 (1.366-1.979), P < .0001). Within the APS group, lupus anticoagulant (LA) and anti-ß2GP1 IgG, or triple positivity, were strong risk factors for mood disorders. CONCLUSIONS: Women with obstetric APS have a higher risk of positive screening for common mental disorders than women without APS.

Innate immune activation and depressive and anxious symptoms across the peripartum: An exploratory study.

BACKGROUND: There are complex associations between immune function and mental illness, yet studies in the perinatal period focus primarily on individual inflammatory markers and depressive symptoms only, cross-sectionally. We sought to examine associations between both depressive and anxious symptoms and immune activation longitudinally across the peripartum. METHODS: We measured mood (Beck Depression Inventory, BDI-1 A) and anxiety (State-Trait Anxiety Inventory, STATE) and levels of 23 cytokines at 5 points in pregnancy and postpartum in 51 women. Within subject cytokine trajectories over time by depressive and anxious symptom grouping were assessed using linear mixed effects models with random intercept and slope. We also undertook an exploratory cluster analysis based on third trimester cytokine values. RESULTS: Based on categorical BDI scores, IL-6 (p < 0.001), IL-15 (p = 0.047), GCSF (p = 0.003), and CCL3 (p < .001) were significantly different across time, with IL-6 (p < 0.001), IL-15 (p = 0.003), and CCL3 (p < 0.001) higher at the third trimester visit in more depressed subjects. Based on categorical STATE scores, GM-CSF significantly decreased across pregnancy for the less anxious group (p = 0.016), but not for the more anxious, and CCL3 (p = 0.017), CXCL8 (p = 0.011), and IL-6 (p < 0.001) were higher at the third trimester visit for more anxious subjects. In exploratory cluster analysis based on cytokine level, there were no differences in mood or anxiety scores, but significant differences by race/ethnicity and overweight/obesity status. Women with higher pro-inflammatory cytokine values are more likely to be Hispanics (69.2% vs. 21.4%, p = 0.015), but less likely to be African American (23.1% vs. 60.7%, p = 0.015) or overweight/obese (25% vs. 69.2%, p = 0.016) compared to women with lower pro-inflammatory cytokine values. CONCLUSION: We identified a pro-inflammatory burst at the third trimester, indicative of innate immune activation, in women with higher levels of both depressive and anxious symptoms, as well as differences in pro-inflammatory changes across time. We also found significant differences in cytokine levels by race, ethnicity, and overweight/obesity status. These results point the way toward future longitudinal work that considers race/ethnicity, timing, and weight status, and evaluates perinatal mood and anxiety disorders in the context of changing immune functioning across the peripartum.

Latent toxoplasmosis and psychiatric symptoms - A role of tryptophan metabolism?

Toxoplasma gondii (TOX) is a common parasite which infects approximately one third of the human population. In recent years, it has been suggested that latent toxoplasmosis may be a risk factor for the development of mental disorders, particularly schizophrenia and anxiety. With regards to depression the results have been varied. The main objective of this study was to examine subpopulations from the Danish PRISME and GENDEP populations for TOX IgG antibodies. These consisted of: a group with symptoms of anxiety, a group suffering from burnout syndrome, as well as two different subpopulations with depression of differing severity. The secondary objective of this study was to examine whether tryptophan metabolism was altered in TOX-positive subjects within each subpopulation. Our results show that the anxiety and burnout populations were more likely to be TOX IgG seropositive. Furthermore, we find that the moderate-severe but not mild-moderate depressive subpopulation were associated with TOX seropositivety, suggesting a possible role of symptom severity. Additionally, we found that TOX positive subjects in the anxiety and burnout subpopulations had altered tryptophan metabolism. This relationship did not exist in the mild-moderate depressive subpopulation. These results suggest that TOX seropositivity may be related to anxiety, burnout and potentially to severity of depression. We furthermore show that the psychiatric symptoms could be associated with an altered tryptophan metabolism.