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Background: Immune activation or high levels of stress may lead to increased metabo-lism of tryptophan during pregnancy. Porphyromonas gingivalis (Pg), the “keystone” periodontal pathogen, induces immune and indoleamine 2,3-dioxygenase (IDO) activation. Thus, we hypothe-sized that larger gestational decreases in tryptophan and elevations in neopterin and kynurenine would occur in pregnant women with elevated IgG antibodies to Pg capsular (K) serotypes. Methods: Venous blood of 52 Hispanic pregnant women with a mean age (SD) of 31.8 (5.9) years was sampled once per trimester of pregnancy (V1, V2, V3), and plasma was obtained and stored. ELISAs were used to measure Pg capsular (K) serotype IgG serointensity (V1 only) and neopterin levels (V1-V3). Tryptophan and kynurenine (V1-V3) were measured with high-performance liquid chromatography. The participants having IgG serointensity for any of the seven Pg K serotypes in the highest quartile were defined as the “High PgK_IgG” group and those having IgG serointensity for all K serotypes in the lowest three quartiles were defined as the “Low PgK_IgG” group. Statis-tics included multivariable linear and nonparametric methods. Results: Significant decreases in plasma tryptophan levels and increases in neopterin during gesta-tion were found in “High PgK_IgG” women but not in “Low PgK_IgG” women. Kynurenine changes were not significantly different between the two groups. Conclusions: If replicated in larger studies and further characterized clinically, radiologically, and microbiologically, our results may potentially lead to novel interventional targets, as well as the de-velopment of more complete prognostic and predictive interactive biomarkers for adverse obstetri-cal outcomes and peripartum depression, and their prevention.

Background Efficacious treatments for winter seasonal affective disorder (SAD) include light therapy (LT) and cognitive-behavioral therapy (CBT-SAD); however, baseline characteristics may differentially predict treatment outcomes. This study investigated body mass index (BMI) and atypical balance (the proportion of atypical depression symptoms), as predictors of depression remission. Methods The parent study randomized 177 adults diagnosed with Major Depression, Recurrent with Seasonal Pattern to 6-weeks of CBT-SAD (n = 88) or LT (n = 89) and followed participants one and two winters later. At baseline, BMI was measured and atypical balance was derived using the Structured Interview Guide for the Hamilton Rating Scale for Depression–Seasonal Affective Disorder Version (SIGH-SAD) as 8-item atypical subscale score/total SIGH-SAD score × 100. Depression remission was defined using standard SIGH-SAD cutpoints. Hierarchical logistic regressions tested the main effects of treatment modality, BMI, and atypical balance and their interactive effects on depression remission at post-treatment and follow-ups. Results The BMI × treatment and atypical balance × treatment interactions significantly predicted depression remission at second winter follow-up. The probability of remission was higher in CBT-SAD than LT at BMI ≤ 26.1 and atypical balance ≤ 40.3%. This predictive relationship survived when adjusting atypical balance for BMI, but not vice-versa. Limitations Participants were predominantly White and older. BMI does not account for muscle mass or fat distribution. Conclusions BMI and atypical balance prescriptively predicted higher likelihood of depression remission two winters following CBT-SAD but not LT. This work informs clinical decision-making and precision medicine efforts.

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-1β, 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-1β 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-1β 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.

The corticotropin-releasing hormone receptor 2 (

Background Major Depressive Disorder (MDD) and Type 2 Diabetes (T2D) are heterogeneous polygenic and complex disorders and are often comorbid. This shared comorbidity can be partially explained by several genetic, environmental, and hormonal factors such as hypercortisolism in MDD and a subset of patients with T2D. CRH receptor-1 (CRHR1) dysfunction may explain the MDD- and T2D-hypercortisolism, at least in a subgroup of patients. CRHR1-variants predisposing to impaired CRHR1 dosage and/or function may lead to hypercortisolism (substrate for serotonin dysfunction and MDD), as well as hyperglycemia, insulin resistance, and increased visceral fat, all T2D-traits. We hypothesize that CRHR1-variants may impair the stress and cortisol response, conferringincreased risk for MDD, T2D, and MDD-T2D comorbidity. Methods Using 212 Italian families with T2D, enriched T2D-familial history, and MDD, we amplified and tested 158 CRHR1 SNPs by two-point parametric analysis for linkage and linkage-disequilibrium (LD), using the models dominant (D) and recessive (R), with complete (1) and incomplete (2) penetrance (Pseudomarker). Results We detected linkage to and/or LD with MDD: for 93 SNPs (D1), 57 SNPs (D2), 91 SNPs (R1), and 14 (R2); and T2D for 15 SNPs (D1), 18 SNPs (D2), twelve SNPs (R1) and ten SNPs (R2), for a total of 122 SNPs. Specific LD-blocks’ underlined each disorder without overlap. Of note, three independent SNPs were comorbid forMDD and T2D. All risk SNPs are intronic, except for one synonymous, one splice site, one missense, and one 3'UTR. In-silicoanalysis detected functional gene and tridimensional protein changes in a risk-SNP. Conclusion We are the first to report CRHR1 in linkage and LD with MDD and T2D in T2D-families. CRHR1contribution to MDD appears stronger thanthe contribution to T2D and may thus antecede its onset . Genetically impaired stress and cortisol response may lead to comorbid MDD-T2D, likely a molecular-clinical entity in a subset of families. Our findings should be replicated in families from other ethnic groups. Presentation: No date and time listed

Background This study is a confirmatory efficacy trial of two treatments for winter seasonal affective disorder (SAD): SAD-tailored group cognitive-behavioral therapy (CBT-SAD) and light therapy (LT). In our previous efficacy trial, post-treatment outcomes for CBT-SAD and LT were very similar, but CBT-SAD was associated with fewer depression recurrences two winters later than LT (27.3% in CBT-SAD vs. 45.6% in LT). CBT-SAD engaged and altered a specific mechanism of action, seasonal beliefs, which mediated CBT-SAD’s acute antidepressant effects and CBT-SAD’s enduring benefit over LT. Seasonal beliefs are theoretically distinct from LT’s assumed target and mechanism: correction of circadian phase. This study applies the experimental therapeutics approach to determine how each treatment works when it is effective and to identify the best candidates for each. Biomarkers of LT’s target and effect include circadian phase angle difference and the post-illumination pupil response. Biomarkers of CBT-SAD’s target and effect include decreased pupillary and sustained frontal gamma-band EEG responses to seasonal words, which are hypothesized as biomarkers of seasonal beliefs, reflecting less engagement with seasonal stimuli following CBT-SAD. In addition to determining change mechanisms, this study tests the efficacy of a “switch” decision rule upon recurrence to inform clinical decision-making in practice. Methods Adults with SAD (target N = 160) will be randomzied to 6-weeks of CBT-SAD or LT in winter 1; followed in winter 2; and, if a depression recurrence occurs, offered cross-over into the alternate treatment (i.e., switch from LT➔CBT-SAD or CBT-SAD➔LT). All subjects will be followed in winter 3. Biomarker assessments occur at pre-, mid-, and post-treatment in winter 1, at winter 2 follow-up (and again at mid-/post-treatment for those crossed-over), and at winter 3 follow-up. Primary efficacy analyses will test superiority of CBT-SAD over LT on depression recurrence status (the primary outcome). Mediation analyses will use parallel process latent growth curve modeling. Discussion Consistent with the National Institute of Mental Health’s priorities for demonstrating target engagement at the level of Research Domain Criteria-relevant biomarkers, this work aims to confirm the targets and mechanisms of LT and CBT-SAD to maximize the impact of future dissemination efforts. Trial registration ClinicalTrials.gov identifier: NCT03691792. Registered on October 2, 2018.

Purpose of Review This review focuses on recent advances in our understanding of the interactions between psychological stress, the immune system, and periodontitis, including the dynamic role of host stress responses in altering immune function, altering the oral microbiome and biofilm formation, and promoting local and systemic disease progression. Recent Findings Within the context of periodontal health and disease, stress leads to an impairment of effective antimicrobial defense, shifts in oral microbiome profiles toward more pathogenic gene expression and taxa composition, increased translocation, and biofilm formation. The link between stress and periodontitis is multiform and includes hypothalamic–pituitary–adrenal (HPA) axis and catecholamine activation, production of immune mediators of inflammation and, clinically, syndromes of depression, bipolar disorder, anxiety disorders, and sleep-wake disorders. Summary Psychological stress appears to be an important modifiable risk factor for the development and progression of periodontitis and other periodontal diseases.

Increasing evidence incriminates low-grade inflammation in cardiovascular, metabolic diseases, and neuropsychiatric clinical conditions, all important causes of morbidity and mortality. One of the upstream and modifiable precipitants and perpetrators of inflammation is chronic periodontitis, a polymicrobial infection with Porphyromonas gingivalis (P. gingivalis) playing a central role in the disease pathogenesis. We review the association between P. gingivalis and cardiovascular, metabolic, and neuropsychiatric illness, and the molecular mechanisms potentially implicated in immune upregulation as well as downregulation induced by the pathogen. In addition to inflammation, translocation of the pathogens to the coronary and peripheral arteries, including brain vasculature, and gut and liver vasculature has important pathophysiological consequences. Distant effects via translocation rely on virulence factors of P. gingivalis such as gingipains, on its synergistic interactions with other pathogens, and on its capability to manipulate the immune system via several mechanisms, including its capacity to induce production of immune-downregulating micro-RNAs. Possible targets for intervention and drug development to manage distal consequences of infection with P. gingivalis are also reviewed.

Introduction: Previous research has suggested that the Amish may experience a relatively high prevalence of Parkinson’s disease (PD) and/or parkinsonian motor signs. Methods: In a large sample from the Amish community in Lancaster County, Pennsylvania, age ≥18 years, we assessed the prevalence of self-reported PD diagnosis. For those without self-reported PD diagnosis, we assessed the frequency of PD-related motor symptoms using a 9-item questionnaire that was designed by the PD Epidemiology Research Group. Lastly, we queried study participants for the presence of 2 nonmotor symptoms that have been commonly linked to PD: bowel movement frequency and daytime sleepiness. Results: Among 2,025 subjects who answered the PD questionnaire, 430 were older than 60 years. Of 430 participants ≥60 years, 5 (1.2%) reported a PD diagnosis. Of those without a PD diagnosis, 10.5% reported ≥1 and 1.2% ≥ 4 motor symptoms for the 9-item PD screening questionnaire. Of the 3,789 subjects who answered the question about bowel movement frequency, 0.7% reported ≤3 bowel movements per week. Among 1,710 subjects who answered the question about daytime sleepiness, 8.1% of the participants reported “always” sleepy during the day. Discussion: These data neither support a markedly higher PD prevalence in the older Lancaster Amish nor do they show dramatically higher motor and/or selected nonmotor symptoms than the general population. Future studies that employ more rigorous procedures for case identification and PD-specific preclinical symptoms/tests are needed to determine the potential differences and similarities among different Amish populations and between Amish and non-Amish populations.

The prevalence of anxiety, mood and trauma- and stress-related disorders are on the rise; however, efforts to develop new and effective treatment strategies have had limited success. To identify novel therapeutic targets, a comprehensive understanding of the disease etiology is needed, especially in the context of the holobiont, i.e., the superorganism consisting of a human and its microbiotas. Much emphasis has been placed on the role of the gut microbiota in the development, exacerbation, and persistence of psychiatric disorders; however, data for the oral microbiota are limited. The oral cavity houses the second most diverse microbial community in the body, with over 700 bacterial species that colonize the soft and hard tissues. Periodontal diseases encompass a group of infectious and inflammatory diseases that affect the periodontium. Among them, periodontitis is defined as a chronic, multi-bacterial infection that elicits low-grade systemic inflammation via the release of pro-inflammatory cytokines, as well as local invasion and long-distance translocation of periodontal pathogens. Periodontitis can also induce or exacerbate other chronic systemic inflammatory diseases such as atherosclerosis and diabetes and can lead to adverse pregnancy outcomes. Recently, periodontal pathogens have been implicated in the etiology and pathophysiology of neuropsychiatric disorders (such as depression and schizophrenia), especially as dysregulation of the immune system also plays an integral role in the etiology and pathophysiology of these disorders. This review will discuss the role of the oral microbiota associated with periodontal diseases in anxiety, mood and trauma- and stress-related disorders. Epidemiological data of periodontal diseases in individuals with these disorders will be presented, followed by a discussion of the microbiological and immunological links between the oral microbiota and the central nervous system. Pre-clinical and clinical findings on the oral microbiota related to periodontal diseases in anxiety, mood and trauma- and stress-related phenotypes will be reviewed, followed by a discussion on the bi-directionality of the oral-brain axis. Lastly, we will focus on the oral microbiota associated with periodontal diseases as a target for future therapeutic interventions to alleviate symptoms of these debilitating psychiatric disorders.

Objective Psychiatric hospitalizations and emergency department (ED) visits are costly, stigmatizing, and often ineffective. Given the immune and kynurenine activation in bipolar disorder (BD) and schizophrenia, as well as the immune-modulatory effects of statins, we aimed to compare the relative risk (RRs) of psychiatric hospitalizations and ED visits between individuals prescribed lipophilic vs. hydrophilic statins vs. no statins. We hypothesized (a) reduced rates of hospitalization and ER utilization with statins versus no statins and (b) differences in outcomes between statins, as lipophilia increases the capability to penetrate the blood–brain barrier with potentially beneficial neuroimmune, antioxidant, neuroprotective, neurotrophic, and endothelial stabilizing effects, and, in contrast, potentially detrimental decreases in brain cholesterol concentrations leading to serotoninergic dysfunction, changes in membrane lipid composition, thus affecting ion channels and receptors. Methods We used VA service utilization data from October 1, 2010 to September 30, 2015. The RRs for psychiatric hospitalization and ED visits, were estimated using robust Poisson regression analyses. The number of individuals analyzed was 683,129. Results Individuals with schizophrenia and BD who received prescriptions for either lipophilic or hydrophilic statins had a lower RR of psychiatric hospitalization or ED visits relative to nonstatin controls. Hydrophilic statins were significantly associated with lower RRs of psychiatric hospitalization but not of ED visits, compared to lipophilic statins. Conclusion The reduction in psychiatric hospitalizations in statin users (vs. nonusers) should be interpreted cautiously, as it carries a high risk of confounding by indication. While the lower RR of psychiatric hospitalizations in hydrophilic statins relative to the lipophilic statins is relatively bias free, the finding bears replication in a specifically designed study. If replicated, important clinical implications for personalizing statin treatment in patients with mental illness, investigating add-on statins for improved therapeutic control, and mechanistic exploration for identifying new treatment targets are natural next steps.

The gut microbiome is impacted by environmental exposures and has been implicated in many physical and mental health conditions, including anxiety disorders, affective disorders, and trauma- and stressor-related disorders such as posttraumatic stress disorder (PTSD). United States (US) military Veterans are a unique population in that their military-related exposures can have consequences for both physical and mental health, but the gut microbiome of this population has been understudied. In this publication, we describe exposures, health conditions, and medication use of Veterans in the US Veteran Microbiome Project (US-VMP) and examine the associations between these characteristics and the gut microbiota. This cohort included 331 US Veterans seeking healthcare with the Veterans Health Administration who were 83% male with an average (±SD) age of 47.6 ​± ​13.4 years. The cohort displayed a high prevalence of PTSD (49.8%) and history of traumatic brain injuries (76.1%), and high current use of prescription medications (74.9%) to treat various acute and chronic conditions. We observed significant associations between the gut microbiota composition and gastroenteritis, peripheral vascular disease (PVD), bipolar disorders, symptoms of severe depression based on the Beck Depression Inventory, stimulant and opioid use disorders, beta-blockers, serotonin and norepinephrine reuptake inhibitor antidepressants, diabetes medications, and proton pump inhibitors. Many of the Veteran characteristics examined were associated with altered relative abundances of specific taxa. We found that PVD and cardiovascular disease were associated with lower microbiota diversity in the gut (i.e., α-diversity), while supplemental vitamin use was associated with higher α-diversity. Our study contributes novel insights as to whether the unique exposures of Veterans in this cohort correlate with gut microbiota characteristics and, in line with previous findings with other population-level studies of the microbiome, confirms associations between numerous health conditions and medications with the gut microbiome., Highlights • Mental health disorders/symptoms were associated with gut microbiome composition. • Several medication classes were associated with gut microbiome characteristics. • Military deployments were associated with decreased abundance of Bifidobacterium. • Most military-related exposures were not related to microbiome characteristics.

United States military Veterans from recent conflicts are experiencing symptoms related to posttraumatic stress disorder (PTSD). Many Veterans are resistant to conventional health and mental health interventions (e.g., medication, psychotherapy). Alternative treatment approaches are needed. An underlying feature of PTSD is exaggerated inflammation, both peripherally and in the central nervous system. This inflammation is thought to play an important role in the vulnerability to, aggravation of, and persistence of PTSD symptoms. Therefore, an innovative intervention strategy would be the use of immunoregulatory/anti-inflammatory probiotics to reduce inflammation. Here we describe the rationale, design, and methods of a randomized placebo-controlled trial (RCT) ofThis is a Phase IIa trial of LGG for United States military Veterans with PTSD, using a longitudinal, double-blind, randomized placebo-controlled design. The primary outcome measure is plasma concentration of high-sensitivity C-reactive protein.Despite the fact that symptoms associated with PTSD can be disabling, individuals living with this trauma-related disorder have limited options in terms of evidence-based interventions. Recent research efforts aimed at highlighting the biological mechanisms of PTSD suggest that increased inflammation and altered autonomic nervous system activity may be treatment targets, and that immunoregulatory probiotics, such as LGG, have the potential to decrease trauma-induced inflammatory responses, as well as associated symptoms. This manuscript describes the best powered human subjects Phase IIa trial, to date, of a probiotic intervention for those living with PTSD.

Immune activation or high levels of stress may lead to increased metabolism of tryptophan during pregnancy. Porphyromonas gingivalis (Pg), the "keystone" periodontal pathogen, induces immune and indoleamine 2,3-dioxygenase (IDO) activation. Thus, we hypothesized that larger gestational decreases in tryptophan and elevations in neopterin and kynurenine would occur in pregnant women with elevated IgG antibodies to Pg capsular (K) serotypes.Venous blood of 52 Hispanic pregnant women with a mean age (SD) of 31.8 (5.9) years was sampled once per trimester of pregnancy (V1, V2, V3), and plasma was obtained and stored. ELISAs were used to measure Pg capsular (K) serotype IgG serointensity (V1 only) and neopterin levels (V1-V3). Tryptophan and kynurenine (V1-V3) were measured with high-performance liquid chromatography. The participants having IgG serointensity for any of the seven Pg K serotypes in the highest quartile were defined as the "High PgK_IgG" group and those having IgG serointensity for all K serotypes in the lowest three quartiles were defined as the "Low PgK_IgG" group. Statistics included multivariable linear and nonparametric methods.Significant decreases in plasma tryptophan levels and increases in neopterin during gestation were found in "High PgK_IgG" women but not in "Low PgK_IgG" women. Kynurenine changes were not significantly different between the two groups.If replicated in larger studies and further characterized clinically, radiologically, and microbiologically, our results may potentially lead to novel interventional targets, as well as the development of more complete prognostic and predictive interactive biomarkers for adverse obstetrical outcomes and peripartum depression, and their prevention.

Purpose of Review We present biological and psychological factors implicated in psychiatric manifestations of SARS-CoV-2, as well as its neuroinvasive capability and immune pathophysiology. Recent Findings Preexisting mental illness leads to worse clinical outcomes in COVID-19. The presence of the virus was reported in the cerebrospinal fluid (CSF) and brain tissue post-mortem. Most common psychiatric manifestations include delirium, mood disorders, anxiety disorders, and posttraumatic stress disorder. “Long-COVID” non-syndromal presentations include “brain-fogginess,” autonomic instability, fatigue, and insomnia. Summary SARS-CoV-2 infection can trigger prior vulnerabilities based on the priming of microglia and other cells, induced or perpetuated by aging and mental and physical illnesses. COVID-19 could further induce priming of neuroimmunological substrates leading to exacerbated immune response and autoimmunity targeting structures in the central nervous system (CNS), in response to minor immune activating environmental exposures, including stress, minor infections, allergens, pollutants, and traumatic brain injury.

Within the general literature on infections and suicidal behavior, studies onToxoplasma gondii(T. gondii) occupy a central position. This is related to the parasite's neurotropism, high prevalence of chronic infection, as well as specific and non-specific behavioral alterations in rodents that lead to increased risk taking, which are recapitulated in humans byT. gondii'sassociations with suicidal behavior, as well as trait impulsivity and aggression, mental illness and traffic accidents. This paper is a detailed review of the associations betweenT. gondiiserology and suicidal behavior, a field of study that started 15 years ago with our publication of associations betweenT. gondiiIgG serology and suicidal behavior in persons with mood disorders. This “legacy” article presents, chronologically, our primary studies in individuals with mood disorders and schizophrenia in Germany, recent attempters in Sweden, and in a large cohort of mothers in Denmark. Then, it reviews findings from all three meta-analyses published to date, confirming our reported associations and overall consistent in effect size [ranging between 39 and 57% elevation of odds of suicide attempt inT. gondiiimmunoglobulin (IgG) positives]. Finally, the article introduces certain links betweenT. gondiiand biomarkers previously associated with suicidal behavior (kynurenines, phenylalanine/tyrosine), intermediate phenotypes of suicidal behavior (impulsivity, aggression) and state-dependent suicide risk factors (hopelessness/dysphoria, sleep impairment). In sum, an abundance of evidence supports a positive link between suicide attempts (but not suicidal ideation) andT. gondiiIgG (but not IgM) seropositivity and serointensity. Trait impulsivity and aggression, endophenotypes of suicidal behavior have also been positively associated withT. gondiiseropositivity in both the psychiatrically healthy as well as in patients with Intermittent Explosive Disorder. Yet, causality has not been demonstrated. Thus, randomized interventional studies are necessary to advance causal inferences and, if causality is confirmed, to provide hope that an etiological treatment for a distinct subgroup of individuals at an increased risk for suicide could emerge.

Global urbanization, combined with evidence of increased prevalence of mental illness in urban environments, highlights a need to investigate potential connections between the built environment and mental health. Previous research has shown that the built environment may impact occupant mental health through its effects on connection to nature, personal control and indoor air quality. Contact with the natural environment has physiological and psychological benefits; consequently, reduced contact or exposure leads to negative mental health outcomes. The control an occupant has in the built environment can alter the mental health of individuals through direct pathways, such as prevention of exposures to environmental stressors and indirect pathways, such as social connections to others. Indoor air quality is connected to the mental health of built environment occupants, as particulate matter, malodorous irritants and toxins have all been shown to alter mental well-being. Opportunities for architects and engineers to optimize building designs that improve occupant mental health include planned urban greenspace, personalized temperature control and building ventilation. To understand optimization targets, interdisciplinary research utilizing controlled experiments are needed to confirm causality and improve our current understanding of mechanisms underlying the association between the built environment and mental health.

STUDY OBJECTIVES: We hypothesized that sleep duration in the Amish would be longer than in non-Amish. METHODS: Sleep duration was obtained by questionnaire administered to Amish individuals (n = 3,418) and from the 2015–2016 National Health and Nutrition Examination Survey (NHANES; n = 1,912). Self-reported sleep duration was calculated as the difference in usual times that the participants went to bed at night and woke up in the morning. RESULTS: In Amish (43.7 ± 16.7 years) and NHANES (50.0 ± 20.6 years), women had a longer sleep duration than men (P < .0001 in both groups) and sleep was significantly longer in those aged 18–29 years and ≥ 70 years, compared to those aged 30–69 years. Seasonal-adjusted sleep duration was shorter in Amish than that in NHANES (7.8 minutes shorter, age- and sex-adjusted P < .0001). However, Amish were less likely to report sleeping fewer than 7 hours per night (15.4% in Amish versus 20.5% in NHANES, P < .0001). Amish went to bed 80.4 minutes earlier than NHANES and arose 87.6 minutes earlier (age-, sex-, and season-adjusted P < .0001 for both). In the Amish, sleep duration was longer in clerks than in farmers (P < .0001) and was significantly correlated among household members (.15 < r < .62, P < .001), although there was no evidence that this trait was heritable (h(2) approximately 0) after adjustment for household. CONCLUSIONS: The lower frequency of short sleepers in the Amish may contribute to the relatively lower risks of cardiometabolic diseases observed in this population. CITATION: Zhang M, Ryan KA, Wickwire E, Postolache TT, Xu H, Daue M, Snitker S, Pollin TI, Shuldiner AR, Mitchell BD. Self-reported sleep duration and pattern in old order amish and non-amish adults. J Clin Sleep Med. 2019;15(9):1321–1328.

Research has yet to provide a comprehensive understanding of the genetic basis of bipolar disorder (BP). In genetic studies, defining the phenotype by diagnosis may miss risk-allele carriers without BP. The authors aimed to test whether quantitatively detected subclinical symptoms of bipolarity identifies a heritable trait that infers risk for BP. The Quantitative Bipolarity Scale (QBS) was administered to 310 Old Order Amish or Mennonite individuals from multigenerational pedigrees; 110 individuals had psychiatric diagnoses (20 BP, 61 major depressive disorders (MDD), 3 psychotic disorders, 26 other psychiatric disorders). Familial aggregation of QBS was calculated using the variance components method to derive heritability and shared household effects. The QBS score was significantly higher in BP subjects (31.5 ± 3.6) compared to MDD (16.7 ± 2.0), other psychiatric diagnoses (7.0 ± 1.9), and no psychiatric diagnosis (6.0 ± 0.65) (all p 2 = 0.46 ± 0.15, p p = 0.073). When subjects with psychiatric illness were removed, the QBS heritability was similar (h2 = 0.59 ± 0.18, p

Most people spend the majority of their lives indoors. Research over the last thirty years has focused on investigating the mechanisms through which specific elements of the built environment, such as indoor air quality, influence the physical health of occupants. However, similar effort has not been expended in regard to mental health, a significant public health concern. One in five Americans has been diagnosed with a mental health disorder in the past year, and, in the United States, the number of suicide deaths are similar to the number of deaths due to breast cancer. Increases in mental health disorders in Western societies may be due, in part, to increased systemic inflammation, secondary to decreased exposures to a diverse microbial environment (i.e., the hygiene hypothesis, “Old Friends” hypothesis, “missing microbes” hypothesis, or biodiversity hypothesis), as well as increased environmental exposures that lead to chronic low-grade inflammation. In this review, we provide an assessment that integrates historical research across disciplines. We offer ten questions that highlight the importance of current lessons learned regarding the built environment and mental health, including a potential role for the microbiome of the built environment to influence mental health. Suggested areas for future investigation are also highlighted.

Given the increasing rate of death by suicide in the United States, it is imperative to examine specific risk factors and to identify possible etiologies of suicidal behavior in at-risk clinical subpopulations. There is accumulating evidence to support an elevated risk of death by suicide in individuals with a history of traumatic brain injury (TBI). In this review article, after defining terms used in suicidology, we discuss the associations of TBI with death by suicide, suicide attempt, and suicidal ideation. A model for repetitive TBIs, leading to chronic traumatic encephalopathy, is also discussed as a neuroinflammatory process, with discussion about its possible link with suicide. The review concludes with an overview of interventions to prevent suicidal behavior.

Background Suicide risk assessments are often challenging for clinicians, and therefore, biological markers are warranted as guiding tools in these assessments. Suicidal patients display increased cytokine levels in peripheral blood, although the composite inflammatory profile in the subjects is still unknown. It is also not yet established whether certain inflammatory changes are specific to suicidal subjects. To address this, we measured 45 immunobiological factors in peripheral blood and identified the biological profiles associated with cross-diagnostic suicide risk and depression, respectively. Methods Sixty-six women with mood and anxiety disorders underwent computerized adaptive testing for mental health, assessing depression and suicide risk. Weighted correlation network analysis was used to uncover system level associations between suicide risk, depression, and the immunobiological factors in plasma. Secondary regression models were used to establish the sensitivity of the results to potential confounders, including age, body mass index (BMI), treatment and symptoms of depression and anxiety. Results The biological profile of patients assessed to be at increased suicide risk differed from that associated with depression. At the system level, a biological cluster containing increased levels of interleukin-6, lymphocytes, monocytes, white blood cell count and polymorphonuclear leukocyte count significantly impacted suicide risk, with the latter two inferring the strongest influence. The cytokine interleukin-8 was independently and negatively associated with increased suicide risk. The results remained after adjusting for confounders. Limitations This study is cross-sectional and not designed to prove causality. Discussion A unique immunobiological profile was linked to increased suicide risk. The profile was different from that observed in patients with depressive symptoms, and indicates that granulocyte mediated biological mechanisms could be activated in patients at risk for suicide.

Background: Evidence links Toxoplasma gondii (T. gondii), a neurotropic parasite, with schizophrenia, mood disorders and suicidal behavior, all of which are associated and exacerbated by disrupted sleep. Moreover, low-grade immune activation and dopaminergic overstimulation, which are consequences of T. gondii infection, could alter sleep patterns and duration. Methods: Sleep data on 833 Amish participants [mean age (SD) = 44.28 (16.99) years; 59.06% women] were obtained via self-reported questionnaires that assessed sleep problems, duration and timing. T. gondii IgG was measured with ELISA. Data were analyzed using multivariable logistic regressions and linear mixed models, with adjustment for age, sex and family structure. Results: T. gondii seropositives reported less sleep problems (p < 0.005) and less daytime problems due to poor sleep (p < 0.005). Higher T. gondii titers were associated with longer sleep duration (p < 0.05), earlier bedtime (p < 0.005) and earlier mid-sleep time (p < 0.05). Conclusions: It seems unlikely that sleep mediates the previously reported associations between T. gondii and mental illness. Future longitudinal studies with objective measures are necessary to replicate our findings.

The corticotropin-releasing hormone receptor 2 (CRHR2) gene encodes CRHR2, contributing to the hypothalamic–pituitary–adrenal stress response and to hyperglycemia and insulin resistance. CRHR2−/− mice are hypersensitive to stress, and the CRHR2 locus has been linked to type 2 diabetes and depression. While CRHR2 variants confer risk for mood disorders, MDD, and type 2 diabetes, they have not been investigated in familial T2D and MDD. In 212 Italian families with type 2 diabetes and depression, we tested 17 CRHR2 single nucleotide polymorphisms (SNPs), using two-point parametric-linkage and linkage-disequilibrium (i.e., association) analysis (models: dominant-complete-penetrance-D1, dominant-incomplete-penetrance-D2, recessive-complete-penetrance-R1, recessive-incomplete-penetrance-R2). We detected novel linkage/linkage-disequilibrium/association to/with depression (3 SNPs/D1, 2 SNPs/D2, 3 SNPs/R1, 3 SNPs/R2) and type 2 diabetes (3 SNPs/D1, 2 SNPs/D2, 2 SNPs/R1, 1 SNP/R2). All detected risk variants are novel. Two depression-risk variants within one linkage-disequilibrium block replicate each other. Two independent novel SNPs were comorbid while the most significant conferred either depression- or type 2 diabetes-risk. Although the families were primarily ascertained for type 2 diabetes, depression-risk variants showed higher significance than type 2 diabetes-risk variants, implying CRHR2 has a stronger role in depression-risk than type 2 diabetes-risk. In silico analysis predicted variants’ dysfunction. CRHR2 is for the first time linked to/in linkage-disequilibrium/association with depression-type 2 diabetes comorbidity and may underlie the shared genetic pathogenesis via pleiotropy.

The melanocortin receptors are G-protein-coupled receptors, which are essential components of the hypothalamic–pituitary–adrenal axis, and they mediate the actions of melanocortins (melanocyte-stimulating hormones: α-MSH, β-MSH, and γ-MSH) as well as the adrenocorticotropin hormone (ACTH) in skin pigmentation, adrenal steroidogenesis, and stress response. Three melanocortin receptor genes (MC1R, MC2R, and MC5R) contribute to the risk of major depressive disorder (MDD), and one melanocortin receptor gene (MC4R) contributes to the risk of type 2 diabetes (T2D). MDD increases T2D risk in drug-naïve patients; thus, MDD and T2D commonly coexist. The five melanocortin receptor genes might confer risk for both disorders. However, they have never been investigated jointly to evaluate their potential contributing roles in the MDD-T2D comorbidity, specifically within families. In 212 Italian families with T2D and MDD, we tested 11 single nucleotide polymorphisms (SNPs) in the MC1R gene, 9 SNPs in MC2R, 3 SNPs in MC3R, 4 SNPs in MC4R, and 2 SNPs in MC5R. The testing used 2-point parametric linkage and linkage disequilibrium (LD) (i.e., association) analysis with four models (dominant with complete penetrance (D1), dominant with incomplete penetrance (D2), recessive with complete penetrance (R1), and recessive with incomplete penetrance (R2)). We detected significant (p ≤ 0.05) linkage and/or LD (i.e., association) to/with MDD for one SNP in MC2R (rs111734014) and one SNP in MC5R (rs2236700), and to/with T2D for three SNPs in MC1R (rs1805007 and rs201192930, and rs2228479), one SNP in MC2R (rs104894660), two SNPs in MC3R (rs3746619 and rs3827103), and one SNP in MC4R genes (Chr18-60372302). The linkage/LD/association was significant across different linkage patterns and different modes of inheritance. All reported variants are novel in MDD and T2D. This is the first study to report risk variants in MC1R, MC2R, and MC3R genes in T2D. MC2R and MC5R genes are replicated in MDD, with one novel variant each. Within our dataset, only the MC2R gene appears to confer risk for both MDD and T2D, albeit with different risk variants. To further clarity the role of the melanocortin receptor genes in MDD-T2D, these findings should be sought among other ethnicities as well.

Background: Toxoplasma gondii (T. gondii) has been associated with acute food-borne illness, chronic low-grade inflammation, neuropsychiatric conditions and reactivation of chronic latent infection in immunocompetent hosts. Primary infection with T. gondii in pregnant women can lead to congenital toxoplasmosis. In addition to well-known oral tissue-cyst or oocyst ingestion, we hypothesized that the very high prevalence of T. gondii in certain populations exposed to agricultural dust could be, in part, a consequence of airborne infection with oocysts. Methods: We collected environmental dust samples from an area with a reportedly high T. gondii seroprevalence in the Old Order Amish population, in Lancaster, Pennsylvania. Samples included: a) air filters from air-conditioning units; b) swabs of settled dust; and c) vacuum filters containing airborne field dust. Pools of the swabs and shredded sub-samples of the air filters were fed to pigs, with inoculation into mice of heart tissue from seroconverted pigs. We also investigated the presence of T. gondii DNA using PCR amplification. Results: Only one pig seroconverted. However, bioassay of pig heart tissue further inoculated into mice showed no evidence of T. gondii infection. Consistently, no evidence of T. gondii DNA was revealed in any sample. Conclusions: No evidence of airborne transmission was found in the environmental samples that were examined.

OBJECTIVE: Fatty acids (FAs) are involved in the functioning of biological systems previously associated with suicidal behavior (e.g., monoamine signaling and the immune system). We sought to determine (1) whether observed FA levels in a sample of military suicide decedents and living matched controls were consistent with latent classes having distinctive FA profiles and (2) whether those latent classes were associated with suicide and mental health diagnoses. METHODS: Serum samples from eight hundred U.S. military suicide decedents who died between 2002 and 2008 and eight hundred demographically matched living controls were selected at random from a large military serum repository and assayed for 22 different FAs. A latent class cluster analysis was performed using values of 6 FAs previously individually associated with suicide. Once the latent classes were identified, they were compared in terms of suicide decedent proportion, demographic variables, estimated FA enzyme activity, diagnoses, and mental health care usage. RESULTS: A six latent class solution best characterized the dataset. Suicide decedents were less likely to belong to two of the classes and more likely to belong to three of the classes. The low decedent classes differed from the high decedent classes on nine FAs and on estimated indices of activity for three FA enzymes: 14:0, 24:0, 18:1 n-9, 24:1 n-9, 22:5 n-3, 22:6 n-3, 20:2 n-6, 20:4 n-6, 22:5 n-6, elongation of very long chain fatty acids protein 1 (ELOVL1), ELOVL6, and Δ9 desaturase. The latent classes’ FA profiles were consistent with biological abnormalities previously associated with suicidal behavior. CONCLUSIONS: Our study suggests the utility of methods that simultaneously examine multiple FAs when trying to understand their relationship with suicide and psychiatric illness.

Dietary patterns influence gut microbiota composition. To date, there has not been an assessment of diet and gut microbiota in Veterans, who have a history of unique environmental exposures, including military deployment, that may influence associations between diet and gut microbiota. Our aim was to characterise Veteran habitual dietary intake and quality, and to evaluate correlations between diet and gut microbiota. We administered Food Frequency Questionnaires (FFQs) and collected stool samples from 330 Veterans. FFQ data were used to generate Healthy Eating Indices (HEI) of dietary quality. Exploratory factor analysis was used to identify two dietary patterns we defined as “Western” and “Prudent.” Stool samples underwent 16S rRNA gene sequencing, and the resulting data were used to evaluate associations with dietary variables/indices. Analyses included linear regression of α-diversity, constrained analysis of principal coordinates of β-diversity, and multivariate association with linear models and Analysis of Composition of Microbiomes analyses of dietary factors and phylum- and genus-level taxa. There were no significant associations between dietary patterns or factors and α- or β-diversity. At the phylum level, increasing HEI scores were inversely associated with relative abundance of Actinobacteria, and added sugar was inversely associated with abundance of Verrucomicrobia. Veterans largely consumed a Western-style diet, characterised by poor adherence to nutritional guidelines.