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Depression during and after pregnancy affects up to 20% of pregnant women, but the biological underpinnings remain incompletely understood. As pregnancy progresses, the immune system changes to facilitate fetal development, leading to distinct fluctuations in the production of pro-inflammatory factors and neuroactive tryptophan metabolites throughout the peripartum period. Therefore, it is possible that depression in pregnancy could constitute a specific type of inflammation-induced depression. Both inflammatory factors and kynurenine metabolites impact neuroinflammation and glutamatergic neurotransmission and can therefore affect mood and behavior. To determine whether cytokines and kynurenine metabolites can predict the development of depression in pregnancy, we analyzed blood samples and clinical symptoms in 114 women during each trimester and the postpartum. We analyzed plasma IL-1 β , IL-2, -6, -8, -10, TNF, kynurenine, tryptophan, serotonin, kynurenic- quinolinic- and picolinic acids and used mixed-effects models to assess the association between biomarkers and depression severity. IL-1 β and IL-6 levels associated positively with severity of depressive symptoms across pregnancy and the postpartum, and that the odds of experiencing significant depressive symptoms increased by >30% per median absolute deviation for both IL-1 β and IL-6 (both P  = 0.01). A combination of cytokines and kynurenine metabolites in the 2nd trimester had a >99% probability of accurately predicting 3rd trimester depression, with an ROC AUC > 0.8. Altogether, our work shows that cytokines and tryptophan metabolites can predict depression during pregnancy and could be useful as clinical markers of risk. Moreover, inflammation and kynurenine pathway enzymes should be considered possible therapeutic targets in peripartum depression.

Neuroinflammatory processes are increasingly believed to participate in the pathophysiology of a number of major psychiatric diseases, including depression. Immune activation stimulates the conversion of the amino acid tryptophan to kynurenine, leading to the formation of neuroactive metabolites, such as quinolinic acid and kynurenic acid. These compounds affect glutamatergic neurotransmission, which plays a prominent role in depressive pathology. Increased tryptophan degradation along the kynurenine pathway (KP) has been proposed to contribute to disease etiology. We used postmortem brain tissue from the ventrolateral prefrontal cortex (VLPFC) to assess tissue levels of tryptophan and KP metabolites, the expression of several KP enzymes and a series of cytokines as well as tissue pathology, including microglial activation. Tissue samples came from nonpsychiatric controls (n = 36) and individuals with depressive disorder not otherwise specified (DD-NOS, n = 45) who died of natural causes, homicide, accident, or suicide. We found a reduction in the enzymatic conversion of tryptophan to kynurenine, determined using the kynurenine:tryptophan ratio, and reduced messenger RNA expression of the enzymes indoleamine-2,3-dioxygenase 1 and 2 and tryptophan-2,3-dioxygenase in depressed individuals irrespective of the cause of death. These findings correlated with reductions in the expression of several cytokines, including interferon-γ and tumour necrosis factor-α. Notably, quinolinic acid levels were also lower in depressed individuals than controls. Information on the use of antidepressants and other psychotropic medications was insufficient for statistical comparisons. Contrary to expectations, the present results indicate that depression, in the absence of medical illness or an overt inflammatory process, is associated with compromised, rather than increased, KP metabolism in the VLPFC.

Compared to microbiomes on other skin sites, the bacterial microbiome of the human hand has been found to have greater variability across time. To increase understanding regarding the longitudinal transfer of the hand microbiome to objects in the built environment, and vice versa, 22 participants provided skin microbiome samples from their dominant hands, as well as from frequently and infrequently touched objects in their office environments. Additional longitudinal samples from home environments were obtained from a subset of 11 participants. We observed stability of the microbiomes of both the hand and built environments within the office and home settings; however, differences in the microbial communities were detected across the two built environments. Occupants’ frequency of touching an object correlated to that object having a higher relative abundance of human microbes, yet the percent of shared microbes was variable by participants. Finally, objects that were horizontal surfaces in the built environment had higher microbial diversity as compared to objects and the occupants’ hands. This study adds to the existing knowledge of microbiomes of the built environment, enables more detailed studies of indoor microbial transfer, and contributes to future models and building interventions to reduce negative outcomes and improve health and well-being.

Polycystic ovarian syndrome (PCOS) is a genetically complex disorder that involves the interplay of multiple genes and environmental factors. It is characterized by anovulation and irregular menses and is associated with type 2 diabetes. Neuroendocrine pathways and ovarian and adrenal dysfunctions are possibly implicated in the disorder pathogenesis. The melatonin system plays a role in PCOS. Melatonin receptors are expressed on the surface of ovarian granulosa cells, and variations in the melatonin receptor genes have been associated with increased risk of PCOS in both familial and sporadic cases. We have recently reported the association of variants in MTNR1A and MTNR1B genes with familial type 2 diabetes. In this study, we aimed to investigate whether MTNR1A and MTNR1B contribute to PCOS risk in peninsular families. In 212 Italian families phenotyped for PCOS, we amplified by microarray 14 variants in the MTNR1A gene and 6 variants in the MTNR1B gene and tested them for linkage and linkage disequilibrium with PCOS. We detected 4 variants in the MTNR1A gene and 2 variants in the MTNR1B gene significantly linked and/or in linkage disequilibrium with the risk of PCOS ( P  < 0.05). All variants are novel and have not been reported before with PCOS or any of its related phenotypes, except for 3 variants previously reported by us to confer risk for type 2 diabetes and 1 variant for type 2 diabetes-depression comorbidity. These findings implicate novel melatonin receptor genes’ variants in the risk of PCOS with potential functional roles.

A seasonal suicide peak in spring is highly replicated, but its specific cause is unknown. We reviewed the literature on suicide risk factors which can be associated with seasonal variation of suicide rates, assessing published articles from 1979 to 2011. Such risk factors include environmental determinants, including physical, chemical, and biological factors. We also summarized the influence of potential demographic and clinical characteristics such as age, gender, month of birth, socioeconomic status, methods of prior suicide attempt, and comorbid psychiatric and medical diseases. Comprehensive evaluation of risk factors which could be linked to the seasonal variation in suicide is important, not only to identify the major driving force for the seasonality of suicide, but also could lead to better suicide prevention in general.

Major depressive disorder (MDD) increases the risk of type 2 diabetes (T2D) by 60% in untreated patients, and hypercortisolism is common in MDD as well as in some patients with T2D. Patients with MDD, despite hypercortisolism, show inappropriately normal levels of corticotropin-releasing hormone (CRH) and plasma adrenocorticotropin (ACTH) in the cerebrospinal fluid, which might implicate impaired negative feedback. Also, a positive feedback loop of the CRH–norepinephrine (NE)–CRH system may be involved in the hypercortisolism of MDD and T2D. Dysfunctional CRH receptor 1 (CRHR1) and CRH receptor 2 (CRHR2), both of which are involved in glucose regulation, may explain hypercortisolism in MDD and T2D, at least in a subgroup of patients. CRHR1 increases glucose-stimulated insulin secretion. Dysfunctional CRHR1 variants can cause hypercortisolism, leading to serotonin dysfunction and depression, which can contribute to hyperglycemia, insulin resistance, and increased visceral fat, all of which are characteristics of T2D. CRHR2 is implicated in glucose homeostasis through the regulation of insulin secretion and gastrointestinal functions, and it stimulates insulin sensitivity at the muscular level. A few studies show a correlation of the CRHR2 gene with depressive disorders. Based on our own research, we have found a linkage and association (i.e., linkage disequilibrium [LD]) of the genes CRHR1 and CRHR2 with MDD and T2D in families with T2D. The correlation of CRHR1 and CRHR2 with MDD appears stronger than that with T2D, and per our hypothesis, MDD may precede the onset of T2D. According to the findings of our analysis, CRHR1 and CRHR2 variants could modify the response to prolonged chronic stress and contribute to high levels of cortisol, increasing the risk of developing MDD, T2D, and the comorbidity MDD-T2D. We report here the potential links of the CRH system, NE, and their roles in MDD and T2D.

The microbiome of the built environment (MoBE) is a relatively new area of study. While some knowledge has been gained regarding impacts of the MoBE on the human microbiome and disease vulnerability, there is little knowledge of the impacts of the MoBE on mental health. Depending on the specific microbial species involved, the transfer of microorganisms from the built environment to occupant’s cutaneous or mucosal membranes has the potential to increase or disrupt immunoregulation and/or exaggerate or suppress inflammation. Preclinical evidence highlighting the influence of the microbiota on systemic inflammation supports the assertion that microorganisms, including those originating from the built environment, have the potential to either increase or decrease the risk of inflammation-induced psychiatric conditions and their symptom severity. With advanced understanding of both the ecology of the built environment, and its influence on the human microbiome, it may be possible to develop bioinformed strategies for management of the built environment to promote mental health. Here we present a brief summary of microbiome research in both areas and highlight two interdependencies including the following: (1) effects of the MoBE on the human microbiome and (2) potential opportunities for manipulation of the MoBE in order to improve mental health. In addition, we propose future research directions including strategies for assessment of changes in the microbiome of common areas of built environments shared by multiple human occupants, and associated cohort-level changes in the mental health of those who spend time in the buildings. Overall, our understanding of the fields of both the MoBE and influence of host-associated microorganisms on mental health are advancing at a rapid pace and, if linked, could offer considerable benefit to health and wellness.

Our team's discovery of the link between chronic \"latent\" infection with Toxoplasma gondii (Nicolle et Manceaux, 1908) and suicidal behaviour, and our subsequent cross-diagnostic confirmatory work and mechanistic extensions, evolved from our neuroimmunology studies on affective and behavioural dysregulation exacerbated by allergic sensitisation and allergen exposure. Another root was studying behavioural changes and cytokine gene expression in the brain of rodents sensitised and exposed to aeroallergens. We \"piggy-backed\" our project funded to study coupling between aeroallergen sensitisation and exposure in patients with recurrent mood disorders, by measuring Toxoplasma gondii (T. gondii) antibodies in existing samples, and found associations between IgG serointensity and past suicide attempts. Successively, we then reported significant associations between T. gondii seropositivity and/or serointensity and suicidal behaviour in patients with schizophrenia in Germany, recent attempters in Sweden, and longitudinally in a cohort of Danish mothers. In the Danish mothers the exposure to T. gondii preceded self-directed harm and violent suicide attempts; the association was stronger with higher serointensity strata demonstrating a dose-effect. Furthermore, we identified links between T. gondii IgG and suicide endophenotypes of aggression and impulsivity in both individuals with no history of mental illness, and in patients with Intermittent Explosive Disorder (IED). We also found associations between T. gondii and risk factors of suicidal behaviour such as hopelessness and anhedonia in the Amish, depressive symptoms in pregnant women and women Veterans, frailty in older adults, and cognitive deficits in patients with bipolar disorder. Recently, we reported positive associations between T. gondii IgG serointensity with suicidal ideation, impulsivity, depression scores, and daytime dysfunction due to sleep problems in US Veterans who previously attempted suicide. Toxoplasma gondii emerged rather unexpectedly and then took over a considerable proportion of our neuroimmune research portfolio. It satisfied both intellectual appetites, and brought celebrations of discovery, with three systematic reviews and meta-analyses published to date, and a substantial majority of primary articles confirming our initial observations. Toxoplasma gondii also brought considerable frustrations, such as initial grant application setbacks, inability to completely demonstrate causality and, so far, prophylactic and therapeutic impotence for mental health applications in general. While we do not have, as of today, effective and safe treatments for chronic toxoplasmosis with demonstrated mental health benefits in immunocompetent hosts, there are reasons to be optimistic regarding future discoveries. These may include vaccines, novel medications using in silico exploration with biological confirmation, trials of reactivation prevention, as well as identification and targeting of mediating mechanisms. Yet the most justified reasons for optimism are the potential to apply machine learning (ML) and artificial intelligence (AI) methodologies to big data with a focus on interaction and causal inference. These novel approaches, utilising ML-weighted models that emulate randomised trials in electronic medical records, have the potential to reveal not only if T. gondii elevates risk and to what extent, but also for whom specifically, under which demographic, clinical and physiological circumstances, and what factors, or combinations thereof, might mitigate this risk.

Our team's discovery of the link between chronic \"latent\" infection with Toxoplasma gondii (Nicolle et Manceaux, 1908) and suicidal behaviour, and our subsequent cross-diagnostic confirmatory work and mechanistic extensions, evolved from our neuroimmunology studies on affective and behavioural dysregulation exacerbated by allergic sensitisation and allergen exposure. Another root was studying behavioural changes and cytokine gene expression in the brain of rodents sensitised and exposed to aeroallergens. We \"piggy-backed\" our project funded to study coupling between aeroallergen sensitisation and exposure in patients with recurrent mood disorders, by measuring Toxoplasma gondii (T. gondii) antibodies in existing samples, and found associations between IgG serointensity and past suicide attempts. Successively, we then reported significant associations between T. gondii seropositivity and/or serointensity and suicidal behaviour in patients with schizophrenia in Germany, recent attempters in Sweden, and longitudinally in a cohort of Danish mothers. In the Danish mothers the exposure to T. gondii preceded self-directed harm and violent suicide attempts; the association was stronger with higher serointensity strata demonstrating a dose-effect. Furthermore, we identified links between T. gondii IgG and suicide endophenotypes of aggression and impulsivity in both individuals with no history of mental illness, and in patients with Intermittent Explosive Disorder (IED). We also found associations between T. gondii and risk factors of suicidal behaviour such as hopelessness and anhedonia in the Amish, depressive symptoms in pregnant women and women Veterans, frailty in older adults, and cognitive deficits in patients with bipolar disorder. Recently, we reported positive associations between T. gondii IgG serointensity with suicidal ideation, impulsivity, depression scores, and daytime dysfunction due to sleep problems in US Veterans who previously attempted suicide. Toxoplasma gondii emerged rather unexpectedly and then took over a considerable proportion of our neuroimmune research portfolio. It satisfied both intellectual appetites, and brought celebrations of discovery, with three systematic reviews and meta-analyses published to date, and a substantial majority of primary articles confirming our initial observations. Toxoplasma gondii also brought considerable frustrations, such as initial grant application setbacks, inability to completely demonstrate causality and, so far, prophylactic and therapeutic impotence for mental health applications in general. While we do not have, as of today, effective and safe treatments for chronic toxoplasmosis with demonstrated mental health benefits in immunocompetent hosts, there are reasons to be optimistic regarding future discoveries. These may include vaccines, novel medications using in silico exploration with biological confirmation, trials of reactivation prevention, as well as identification and targeting of mediating mechanisms. Yet the most justified reasons for optimism are the potential to apply machine learning (ML) and artificial intelligence (AI) methodologies to big data with a focus on interaction and causal inference. These novel approaches, utilising ML-weighted models that emulate randomised trials in electronic medical records, have the potential to reveal not only if T. gondii elevates risk and to what extent, but also for whom specifically, under which demographic, clinical and physiological circumstances, and what factors, or combinations thereof, might mitigate this risk.Our team's discovery of the link between chronic \"latent\" infection with Toxoplasma gondii (Nicolle et Manceaux, 1908) and suicidal behaviour, and our subsequent cross-diagnostic confirmatory work and mechanistic extensions, evolved from our neuroimmunology studies on affective and behavioural dysregulation exacerbated by allergic sensitisation and allergen exposure. Another root was studying behavioural changes and cytokine gene expression in the brain of rodents sensitised and exposed to aeroallergens. We \"piggy-backed\" our project funded to study coupling between aeroallergen sensitisation and exposure in patients with recurrent mood disorders, by measuring Toxoplasma gondii (T. gondii) antibodies in existing samples, and found associations between IgG serointensity and past suicide attempts. Successively, we then reported significant associations between T. gondii seropositivity and/or serointensity and suicidal behaviour in patients with schizophrenia in Germany, recent attempters in Sweden, and longitudinally in a cohort of Danish mothers. In the Danish mothers the exposure to T. gondii preceded self-directed harm and violent suicide attempts; the association was stronger with higher serointensity strata demonstrating a dose-effect. Furthermore, we identified links between T. gondii IgG and suicide endophenotypes of aggression and impulsivity in both individuals with no history of mental illness, and in patients with Intermittent Explosive Disorder (IED). We also found associations between T. gondii and risk factors of suicidal behaviour such as hopelessness and anhedonia in the Amish, depressive symptoms in pregnant women and women Veterans, frailty in older adults, and cognitive deficits in patients with bipolar disorder. Recently, we reported positive associations between T. gondii IgG serointensity with suicidal ideation, impulsivity, depression scores, and daytime dysfunction due to sleep problems in US Veterans who previously attempted suicide. Toxoplasma gondii emerged rather unexpectedly and then took over a considerable proportion of our neuroimmune research portfolio. It satisfied both intellectual appetites, and brought celebrations of discovery, with three systematic reviews and meta-analyses published to date, and a substantial majority of primary articles confirming our initial observations. Toxoplasma gondii also brought considerable frustrations, such as initial grant application setbacks, inability to completely demonstrate causality and, so far, prophylactic and therapeutic impotence for mental health applications in general. While we do not have, as of today, effective and safe treatments for chronic toxoplasmosis with demonstrated mental health benefits in immunocompetent hosts, there are reasons to be optimistic regarding future discoveries. These may include vaccines, novel medications using in silico exploration with biological confirmation, trials of reactivation prevention, as well as identification and targeting of mediating mechanisms. Yet the most justified reasons for optimism are the potential to apply machine learning (ML) and artificial intelligence (AI) methodologies to big data with a focus on interaction and causal inference. These novel approaches, utilising ML-weighted models that emulate randomised trials in electronic medical records, have the potential to reveal not only if T. gondii elevates risk and to what extent, but also for whom specifically, under which demographic, clinical and physiological circumstances, and what factors, or combinations thereof, might mitigate this risk.