Comparison of early risk factors between healthy siblings and subjects with schizophrenia and bipolar disorder.

Introduction: The following work aims to compare the types and magnitude of risk events in patients with Schizophrenia and Bipolar Disorder and each of those groups with of a group of healthy siblings, exploring differences and similarities of the two psychotic disorders. Methods: Retrospective interviews were conducted with 20 families to investigate maternal and obstetric health, social support and the presence of early trauma for the affected family members and healthy siblings. Mothers were interviewed with the Prenatal Psychosocial Profile and each family participant was assessed with the Early Trauma Inventory, Screening Questionnaire of the Genomic Psychiatry Cohort and the Diagnostic Interview for Psychosis and Affective Disorders. Results: Obstetric and gestational history, pregnancy weight changes and early trauma were associated with offspring's mental illness, including statistically significant findings for complications of pregnancy, pregnancy weight changes, general trauma, physical punishment and emotional abuse. Conclusion: These findings highlight the different risk factor exposures that occur within a family, which may increase the risk for severe mental illness.

The schizophrenia syndrome, circa 2024: What we know and how that informs its nature.

With new data about different aspects of schizophrenia being continually generated, it becomes necessary to periodically revisit exactly what we know. Along with a need to review what we currently know about schizophrenia, there is an equal imperative to evaluate the construct itself. With these objectives, we undertook an iterative, multi-phase process involving fifty international experts in the field, with each step building on learnings from the prior one. This review assembles currently established findings about schizophrenia (construct, etiology, pathophysiology, clinical expression, treatment) and posits what they reveal about its nature. Schizophrenia is a heritable, complex, multi-dimensional syndrome with varying degrees of psychotic, negative, cognitive, mood, and motor manifestations. The illness exhibits a remitting and relapsing course, with varying degrees of recovery among affected individuals with most experiencing significant social and functional impairment. Genetic risk factors likely include thousands of common genetic variants that each have a small impact on an individual's risk and a plethora of rare gene variants that have a larger individual impact on risk. Their biological effects are concentrated in the brain and many of the same variants also increase the risk of other psychiatric disorders such as bipolar disorder, autism, and other neurodevelopmental conditions. Environmental risk factors include but are not limited to urban residence in childhood, migration, older paternal age at birth, cannabis use, childhood trauma, antenatal maternal infection, and perinatal hypoxia. Structural, functional, and neurochemical brain alterations implicate multiple regions and functional circuits. Dopamine D-2 receptor antagonists and partial agonists improve psychotic symptoms and reduce risk of relapse. Certain psychological and psychosocial interventions are beneficial. Early intervention can reduce treatment delay and improve outcomes. Schizophrenia is increasingly considered to be a heterogeneous syndrome and not a singular disease entity. There is no necessary or sufficient etiology, pathology, set of clinical features, or treatment that fully circumscribes this syndrome. A single, common pathophysiological pathway appears unlikely. The boundaries of schizophrenia remain fuzzy, suggesting the absence of a categorical fit and need to reconceptualize it as a broader, multi-dimensional and/or spectrum construct.

Gut and oral microbiome modulate molecular and clinical markers of schizophrenia-related symptoms: A transdiagnostic, multilevel pilot study.

Although increasing evidence links microbial dysbiosis with the risk for psychiatric symptoms through the microbiome-gut-brain axis (MGBA), the specific mechanisms remain poorly characterized. In a diagnostically heterogeneous group of treated psychiatric cases and nonpsychiatric controls, we characterized the gut and oral microbiome, plasma cytokines, and hippocampal inflammatory processes via proton magnetic resonance spectroscopic imaging (1H-MRSI). Using a transdiagnostic approach, these data were examined in association with schizophrenia-related symptoms measured by the Positive and Negative Syndrome Scale (PANSS). Psychiatric cases had significantly greater heterogeneity of gut alpha diversity and an enrichment of pathogenic taxa, like Veillonella and Prevotella, in the oral microbiome, which was an accurate classifier of phenotype. Cases exhibited significantly greater positive, negative, and general PANSS scores that uniquely correlated with bacterial taxa. Strong, positive correlations of bacterial taxa were also found with cytokines and hippocampal gliosis, dysmyelination, and excitatory neurotransmission. This pilot study supports the hypothesis that the MGBA influences psychiatric symptomatology in a transdiagnostic manner. The relative importance of the oral microbiome in peripheral and hippocampal inflammatory pathways was highlighted, suggesting opportunities for probiotics and oral health to diagnose and treat psychiatric conditions.

Review of Major Social Determinants of Health in Schizophrenia-Spectrum Psychotic Disorders: III. Biology.

BACKGROUND: Social determinants of health (SDoHs) are nonmedical factors that significantly impact health and longevity. We found no published reviews on the biology of SDoHs in schizophrenia-spectrum psychotic disorders (SSPD). STUDY DESIGN: We present an overview of pathophysiological mechanisms and neurobiological processes plausibly involved in the effects of major SDoHs on clinical outcomes in SSPD. STUDY RESULTS: This review of the biology of SDoHs focuses on early-life adversities, poverty, social disconnection, discrimination including racism, migration, disadvantaged neighborhoods, and food insecurity. These factors interact with psychological and biological factors to increase the risk and worsen the course and prognosis of schizophrenia. Published studies on the topic are limited by cross-sectional design, variable clinical and biomarker assessments, heterogeneous methods, and a lack of control for confounding variables. Drawing on preclinical and clinical studies, we propose a biological framework to consider the likely pathogenesis. Putative systemic pathophysiological processes include epigenetics, allostatic load, accelerated aging with inflammation (inflammaging), and the microbiome. These processes affect neural structures, brain function, neurochemistry, and neuroplasticity, impacting the development of psychosis, quality of life, cognitive impairment, physical comorbidities, and premature mortality. Our model provides a framework for research that could lead to developing specific strategies for prevention and treatment of the risk factors and biological processes, thereby improving the quality of life and increasing the longevity of people with SSPD. CONCLUSIONS: Biology of SDoHs in SSPD is an exciting area of research that points to innovative multidisciplinary team science for improving the course and prognosis of these serious psychiatric disorders.

Baroreflex sensitivity is associated with markers of hippocampal gliosis and dysmyelination in patients with psychosis.

PURPOSE: Hippocampal dysfunction plays a key role in the pathology of psychosis. Given hippocampal sensitivity to changes in cerebral perfusion, decreased baroreflex function could contribute to psychosis pathogenesis. This study had two aims: (1) To compare baroreflex sensitivity in participants with psychosis to two control groups: participants with a nonpsychotic affective disorder and participants with no history of psychiatric disease; (2) to examine the relationship between hippocampal neurometabolites and baroreflex sensitivities in these three groups. We hypothesized that baroreflex sensitivity would be reduced and correlated with hippocampal neurometabolite levels in participants with psychosis, but not in the control groups. METHODS: We assessed baroreflex sensitivity during the Valsalva maneuver separated into vagal and adrenergic components. Metabolite concentrations for cellular processes were quantitated in the entire multivoxel hippocampus using H1-MR spectroscopic (MRS) imaging and were compared with baroreflex sensitivities in the three groups. RESULTS: Vagal baroreflex sensitivity (BRS-V) was reduced in a significantly larger proportion of participants with psychosis compared with patients with nonpsychotic affective disorders, whereas participants with psychosis had increased adrenergic baroreflex sensitivity (BRS-A) compared with participants with no history of psychiatric disease. Only in psychotic cases were baroreflex sensitivities associated with hippocampal metabolite concentrations. Specifically, BRS-V was inversely correlated with myo-inositol, a marker of gliosis, and BRS-A was positively correlated with energy dependent dysmyelination (choline, creatine) and excitatory activity (GLX). CONCLUSIONS: Abnormal baroreflex sensitivity is common in participants with psychosis and is associated with MRS markers of hippocampal pathology. Future longitudinal studies are needed to examine causality.

The kids are not alright: A preliminary report of Post-COVID syndrome in university students.

OBJECTIVE: To investigate the prevalence and features of protracted COVID-19 symptoms in non-hospitalized university students who experienced mild-to-moderate acute illness. PARTICIPANTS: COVID-19 positive participants with symptoms ≥ 28 days (N = 22), herein referred to as post-COVID syndrome, were compared to those who fully recovered (N = 21) and those never diagnosed with the disease (N = 58). METHODS: Students completed online study to earn research credit for class. RESULTS: 51% of COVID-19 positive participants were classified with post-COVID syndrome. During acute illness, those with post-COVID syndrome experienced more chest pain, fatigue, fever, olfactory impairment, headaches, and diarrhea compared to fully recovered participants. They also reported more current exercise intolerance, dyspnea, chest pain, olfactory impairment, lymphadenopathy, gustatory impairment, and appetite loss than students who never contracted COVID-19. CONCLUSIONS: Our results contradict the perception that this yet to be defined post-COVID syndrome predominantly affects middle-aged adults. Student health centers should closely monitor those who contract COVID-19 for lingering effects.

A sister's search for the seeds of psychosis.

Dr. Dolores Malaspina sought a better way to understand the origins of psychosis than a schizophrenogenic mother, as her family had been informed upon her sisters illness. She moved her attention from environmental biology and zoology, to medical science and assembled knowledge on the multilevel components purported to underpin severe mental illness. Her studies cross levels to consider connections among exposures and genetic etiologies, intrinsic homeostatic mechanisms, stimuli perception and clinical illness features. Original contributions include associating later paternal age with increasing risk for schizophrenia in offspring and proposing that de novo mutations with shorter cell cycles explained the association, showing increased resting hippocampal blood flow in psychosis and that it was associated with inflammation, and that autonomic nervous system dysfunction was related to hippocampal inflammation, plausibly reflecting vascular abnormalities. She has been a professor of psychiatry in medical schools at Columbia University, New York University and at Mount Sinai in New York, USA.

Patient-reported exposures and outcomes link the gut-brain axis and inflammatory pathways to specific symptoms of severe mental illness.

We developed a "gut-brain-axis questionnaire" (GBAQ) to obtain standardized person-specific "review of systems" data for microbiome-gut-brain-axis studies. Individual items were compared to PANSS symptom measures using dimensional, transdiagnostic and traditional categorical approaches. METHOD: Forty psychotic participants, independent of diagnoses, and 42 without psychosis (18 nonpsychotic affective disorders, 24 healthy controls) completed the GBAQ and underwent research diagnostic and symptom assessments. The PANSS scales and its dysphoric mood, autistic preoccupation and activation factors were computed. RESULTS: Transdiagnostic analyses robustly linked psychosis severity to constipation (p<.001), and Negative (p=.045) and General Psychopathology scores (p=.016) with bowel hypomotility. Activation factor scores predicted numbers of psychiatric (p=.009) and medical conditions (p=.003), BMI (p=.003), skin (p<.001) and other conditions. Categorical analyses comparing psychotic, nonpsychotic and control groups revealed behavioral differences: cigarette smoking (p=.013), alcohol use (p=.007), diet (p's <.05), exercise (p<.001). All subjects accurately self-reported their diagnosis. CONCLUSIONS: The GBAQ is a promising tool. Transdiagnostic analyses associated psychotic symptoms to gut hypomotility, indicative of low gut vagal tone, consistent with reduced cardiovagal activity in psychosis. Activation, similar to delirium symptoms, predicted medical comorbidity and systemic inflammatory conditions. Group level comparisons only showed behavioral differences. Underpinnings of psychiatric disorders may include reduced gut vagal function, producing psychosis, and systemic inflammation, impacting risks for psychotic and nonpsychotic conditions.

Early trauma and schizophrenia onset: preliminary results of an outpatient cohort in Brazil.

OBJECTIVES: To assess the prevalence of early trauma in individuals with onset of schizophrenia (SZ) at early (≤ 18 years) and adult (> 18 years) ages (EOP and AOP, respectively) and explore relationships between the onset of disease and clinical variables including traumatic events and psychotic and mood symptoms. METHODS: Subjects with SZ (n = 71) and EOP and AOP were compared for history of psychological trauma, sexual abuse, and physical punishment using the Early Trauma Inventory Self Report - Short Form (ETISR-SF). They were also compared for history of comorbidities and affective disorders using the Diagnostic Interview for Psychosis and Affective Disorders, the Positive and Negative Syndrome Scale, the Liebowitz Social Anxiety Scale, and the Calgary Depression Scale for Schizophrenia. Coefficients were calculated for correlations between scale results and disease duration. RESULTS: Early trauma was significantly associated with an early onset psychotic episode (r = -0.315, p < 0.01). General trauma and depressive symptoms in adulthood were also associated (r = 0.442, p < 0.01), as were social anxiety symptoms and early trauma (r = 0.319, p < 0.01). Total ETISR-SF scores and the physical abuse item were significantly higher in EOP than in AOP. In the hierarchical regression, PANSS scores were best predicted by a model including the duration of disease and age of first psychotic episode (R = 0.303). CONCLUSIONS: Our results support the hypothesis that early trauma, including physical abuse, may play a relevant role in schizophrenia symptoms, such as an earlier psychotic occurrence, as well as features of other psychiatric disorders, such as greater severity of social anxiety and depression.

An integrative study of the microbiome gut-brain-axis and hippocampal inflammation in psychosis: Persistent effects from mode of birth.

The mechanism producing psychosis appears to include hippocampal inflammation, which could be associated with the microbiome-gut-brain-axis (MGBS). To test this hypothesis we are conducting a multidisciplinary study, herein described. The procedures are illustrated with testing of a single subject and group level information on the impact of C-section birth are presented. METHOD: Study subjects undergo research diagnostic interviews and symptom assessments to be categorized into one of 3 study groups: psychosis, nonpsychotic affective disorder or healthy control. Hippocampal volume and metabolite concentrations are assessed using 3-dimensional, multi-voxel H1 Magnetic Resonance Imaging (MRSI) encompassing all gray matter in the entire hippocampal volume. Rich self-report information is obtained with the PROMIS interview, which was developed by the NIH Commons for research in chronic conditions. Early trauma is assessed and cognition is quantitated using the MATRICS. The method also includes the most comprehensive autonomic nervous system (ANS) battery used to date in psychiatric research. Stool and oral samples are obtained for microbiome assessments and cytokines and other substances are measured in blood samples. RESULTS: Group level preliminary data shows that C-section birth is associated with higher concentrations of GLX, a glutamate related hippocampal neurotransmitter in psychotic cases, worse symptoms in affective disorder cases and smaller hippocampal volume in controls. CONCLUSION: Mode of birth appears to have persistent influences through adulthood. The methodology described for this study will define pathways through which the MGBA may influence the risk for psychiatric disorders.

Prenatal ambient temperature and risk for schizophrenia.

OBJECTIVE: We conducted a systematic review of the published literature to test the hypothesis that maternal exposure to extremes of ambient temperatures during pregnancy is associated with the risk for psychiatric disorders or congenital malformations in offspring, both of which are indicative of perturbations of fetal neurodevelopment. METHOD: This study was conducted in accordance with the recommendations outlined in the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting proposal. Electronic databases (Ovid MEDLINE, Ovid Embase, Ovid PsycINFO, Ovid Global Health, Web of Science, and Cochrane Library) were searched. Four independent reviewers selected studies with the following criteria: (1) prenatal maternal ambient temperature exposure; (2) outcome of offspring psychiatric disorder or congenital defects; (3) empirical study; (4) full-length article, no conference presentations or abstracts. RESULTS: Twenty-two studies met criteria and one was added from a reference list (n = 23). Of these, schizophrenia (n = 5), anorexia nervosa (n = 3) and congenital cardiovascular malformations (n = 6) studies were the most common. Each of these categories showed some evidence of association with an early pregnancy maternal ambient heat exposure effect, with other evidence for a late pregnancy cold effect. CONCLUSION: Some evidence supports a role for early pregnancy maternal exposure to extreme ambient heat in the development of psychiatric disorders, but large-scale, prospective cohort data on individual births is essential. Optimal studies will be conducted in seasonally variable climates, accounting for actual maternal residence over the pregnancy and at parturition, local environmental temperature records, and appropriate covariates, similar to studies identified by this systematic review for congenital malformations.

Early trauma and schizophrenia onset: preliminary results of an outpatient cohort in Brazil

Abstract Objectives To assess the prevalence of early trauma in individuals with onset of schizophrenia (SZ) at early (≤ 18 years) and adult (> 18 years) ages (EOP and AOP, respectively) and explore relationships between the onset of disease and clinical variables including traumatic events and psychotic and mood symptoms. Methods Subjects with SZ (n = 71) and EOP and AOP were compared for history of psychological trauma, sexual abuse, and physical punishment using the Early Trauma Inventory Self Report - Short Form (ETISR-SF). They were also compared for history of comorbidities and affective disorders using the Diagnostic Interview for Psychosis and Affective Disorders, the Positive and Negative Syndrome Scale, the Liebowitz Social Anxiety Scale, and the Calgary Depression Scale for Schizophrenia. Coefficients were calculated for correlations between scale results and disease duration. Results Early trauma was significantly associated with an early onset psychotic episode (r = -0.315, p < 0.01). General trauma and depressive symptoms in adulthood were also associated (r = 0.442, p < 0.01), as were social anxiety symptoms and early trauma (r = 0.319, p < 0.01). Total ETISR-SF scores and the physical abuse item were significantly higher in EOP than in AOP. In the hierarchical regression, PANSS scores were best predicted by a model including the duration of disease and age of first psychotic episode (R = 0.303). Conclusions Our results support the hypothesis that early trauma, including physical abuse, may play a relevant role in schizophrenia symptoms, such as an earlier psychotic occurrence, as well as features of other psychiatric disorders, such as greater severity of social anxiety and depression.

Viral Inactivation Impacts Microbiome Estimates in a Tissue-Specific Manner.

The global emergence of novel pathogenic viruses presents an important challenge for research, as high biosafety levels are required to process samples. While inactivation of infectious agents facilitates the use of less stringent safety conditions, its effect on other biological entities of interest present in the sample is generally unknown. Here, we analyzed the effect of five inactivation methods (heat, ethanol, formaldehyde, psoralen, and TRIzol) on microbiome composition and diversity in samples collected from four different body sites (gut, nasal, oral, and skin) and compared them against untreated samples from the same tissues. We performed 16S rRNA gene sequencing and estimated abundance and diversity of bacterial taxa present in all samples. Nasal and skin samples were the most affected by inactivation, with ethanol and TRIzol inducing the largest changes in composition, and heat, formaldehyde, TRIzol, and psoralen inducing the largest changes in diversity. Oral and stool microbiomes were more robust to inactivation, with no significant changes in diversity and only moderate changes in composition. Firmicutes was the taxonomic group least affected by inactivation, while Bacteroidetes had a notable enrichment in nasal samples and moderate enrichment in fecal and oral samples. Actinobacteria were more notably depleted in fecal and skin samples, and Proteobacteria exhibited a more variable behavior depending on sample type and inactivation method. Overall, our results demonstrate that inactivation methods can alter the microbiome in a tissue-specific manner and that careful consideration should be given to the choice of method based on the sample type under study. IMPORTANCE Understanding how viral infections impact and are modulated by the microbiome is an important problem in basic research but is also of high clinical relevance under the current pandemic. To facilitate the study of interactions between microbial communities and pathogenic viruses under safe conditions, the infectious agent is generally inactivated prior to processing samples. The effect of this inactivation process in the microbiome is, however, unknown. Further, it is unclear whether biases introduced by inactivation methods are dependent on the sample type under study. Estimating the magnitude and nature of the changes induced by different methods in samples collected from various body sites thus provides important information for current and future studies that require inactivation of pathogenic agents.

Prognostic value of polygenic risk scores for adults with psychosis.

Polygenic risk scores (PRS) summarize genetic liability to a disease at the individual level, and the aim is to use them as biomarkers of disease and poor outcomes in real-world clinical practice. To date, few studies have assessed the prognostic value of PRS relative to standards of care. Schizophrenia (SCZ), the archetypal psychotic illness, is an ideal test case for this because the predictive power of the SCZ PRS exceeds that of most other common diseases. Here, we analyzed clinical and genetic data from two multi-ethnic cohorts totaling 8,541 adults with SCZ and related psychotic disorders, to assess whether the SCZ PRS improves the prediction of poor outcomes relative to clinical features captured in a standard psychiatric interview. For all outcomes investigated, the SCZ PRS did not improve the performance of predictive models, an observation that was generally robust to divergent case ascertainment strategies and the ancestral background of the study participants.

Impairments in odour detection and hedonic ratings of unpleasant smells in asymptomatic university students as SARS-Cov-2 emerged locally.

Sudden olfactory loss in the absence of concurrent nasal congestion is now a well-recognized symptom of COVID-19. We examined olfaction using standardized objective tests of odour detection, identification and hedonics collected from asymptomatic university students before and as SARS-CoV-2 emerged locally. Olfactory performance of students who were tested when the virus is known to be endemic (n = 22) was compared to students tested in the month prior to viral circulation (n = 25), a normative sample assessed during the previous 4 years (n = 272) and those tested in prior years during the same time period. Analyses showed significantly reduced odour detection for the virus exposed cohort compared to students tested before (t = 2.60; P = .01; d = 0.77; CI 0.17, 1.36) and to the normative sample (D = 0.38; P = .005). Odour identification scores were similar, but the exposed cohort rated odours as less unpleasant (P < .001, CLES = 0.77). Hyposmia increased 4.4-fold for students tested 2 weeks before school closure (N = 22) and increased 13.6-fold for students tested in the final week (N = 11). While the unavailability of COVID-19 testing is a limitation, this naturalistic study demonstrates week-by-week increase in hyposmia in asymptomatic students as a virus was circulating on campus, consistent with increasing airborne viral loads. The specific hedonic deficit in unpleasantness appraisal suggests a deficit in the TAAR olfactory receptor class, which conveys the social salience of odours. Assessment of odour detection and hedonic ratings may aid in early detection of SARS-CoV-2 exposure in asymptomatic and pre-symptomatic persons.

Childbirth Pain and Post-Partum Depression: Does Labor Epidural Analgesia Decrease This Risk?

Post-partum depression (PPD) is a common complication of pregnancy worldwide with a prevalence as high as 15% in some countries. Pain has been identified as a risk factor for major depression; however, the relationship between labor-related pain and PPD is less understood. This article sought out to examine the relationship between pain and PPD, examining whether there is a correlation that reducing pain through epidural analgesia can lower the risk for PPD. A PubMed database search was performed using the keywords "post-partum depression" and "labor epidural". Multiple articles including 2 meta-analyses were evaluated for the association between post-partum depression and epidural analgesia for labor. Although there is evidence supporting labor epidural analgesia reducing PPD, many studies including the meta-analyses did not uphold the hypothesis. More well-designed studies on this topic need to be investigated in order to substantiate the current evidence in the literature.