The Role of Innate and Adaptive Immune System in the Pathogenesis of Schizophrenia.

Schizophrenia is one of the most severely debilitating mental disorders that affects 1.1% of the world's population. The exact cause of the disease is not known, but genetics, environmental factors (such as infectious agents, season and region of birth, exposure to viruses, low birth weight, advanced paternal age, and tobacco), and immune system dysfunction can all contribute to the development of schizophrenia. Recently, the role of the immune system in schizophrenia has received much attention. Both acquired and innate immune systems are involved in the pathogenesis of schizophrenia and facilitate the disease's progression. Almost all cells of the immune system including microglia, B cells, and T cells play an important role in the blood-brain barrier damage, inflammation, and in the progression of this disease. In schizophrenia, the integrity of the blood-brain barrier is reduced and then the immune cells are recruited into the endothelium following an increase in the expression of cell adhesion molecules. The entry of immune cells and cytokines leads to inflammation and antibody production in the brain. Accordingly, the results of this study strengthen the hypothesis that the innate and acquired immune systems are involved in the pathogenesis of schizophrenia.

Urbanization and psychosis: an update of recent evidence.

PURPOSE OF REVIEW: Urbanization, a complex global phenomenon, has a significant bearing on schizophrenia/psychosis burden through various socioeconomic and environmental factors. This review focuses on recent evidence (2019-2023) linking urbanization, schizophrenia, and the role of green space. RECENT FINDINGS: This review analyzed 43 articles that examined the correlation between urban birth or upbringing, urban living (urbanicity), and various schizophrenia/psychosis-related outcomes such as incidence, psychotic experiences, etc. The studies showed differing results across geographical locations. Socioeconomic factors like area deprivation, migrant status (ethnic density) and social fragmentation were independently associated with the risk of schizophrenia/psychosis irrespective of urbanicity. More recently, environmental factors such as green space reduction and air pollution have been explored in urban living conditions and were positively associated with an increased risk of schizophrenia/psychosis. SUMMARY: There is a need for further investigation in low and middle-income countries. The impact of urbanization-related factors and green space on the risk of schizophrenia/psychosis calls for appropriate governmental commitments toward structured and healthy urban planning.

Understanding the Causal Pathway of Social Determinants of Psychosis: The Role of Social Functioning, Relevance of Animal Models, and Implications for Treatment.

There is mounting evidence that the social determinants of psychosis operate via a long and circuitous route. Here, we comment on the striking findings from a recent study by Ku et al., that area-level social environmental factors yield social disability and increased risk for schizophrenia through intervening variables and over a long time course. We discuss the relevance of animal models of social isolation to understand how environmental factors interrelate with individual-level mechanisms. We also discuss treatment implications, including the search for novel psychopharmacological treatments for reduced social motivation, and the need for a comprehensive prediction and prevention model.

Global environmental risk factors of schizophrenia: a study protocol for systematic review and meta-analysis of cohort studies.

INTRODUCTION: Schizophrenia is a chronic, complex and severe psychiatric disorder affecting millions of people every year and inflicting different costs to the individual, family and community. A growing body of evidence has introduced several genetic and environmental factors and their interactions as aetiological factors of schizophrenia. The goal of this systematic review and meta-analysis is to present an updated representation of the global environmental risk factors of schizophrenia. METHOD AND ANALYSIS: This protocol is developed and reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guideline. We will systematically search the databases such as PubMed, Scopus, Web of Science, PsycINFO and Embase until 30 September 2022. We include Cohort studies that have reported one or more risk factors of schizophrenia. We will also search Google Scholar search engine and references lists of included articles. Extracting the relevant data and assessing the quality of the included studies will be independently performed by different authors of our team. The risk of bias for the included studies will be evaluated using Newcastle-Ottawa Scale. Subgroup analysis, meta-regression or sensitivity analysis will be our solution to deal with heterogeneity between studies. We will use a funnel diagram as well as Begg and Egger tests to check for possible publication bias. ETHICS AND DISSEMINATION: Ethical approval is not required because there will be no primary data collection or human involvement. The results of this study will be published in an international peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42022359327.

Long-term outcomes of deep brain stimulation for treatment-resistant schizophrenia: Exploring potential targets.

BACKGROUND: Schizophrenia is a complex and disabling disorder. Around 30% of patients have treatment-resistant schizophrenia (TRS). OBJECTIVE: This study summarizes the outcomes after three years follow-up of the first series of patients with TRS treated with deep brain stimulation (DBS) and discuss surgical, clinical and imaging analysis. METHODS: Eight patients with TRS treated with DBS in the nucleus accumbens (NAcc) or the subgenual cingulate gyrus (SCG) were included. Symptoms were rated with the PANSS scale and normalized using the illness density index (IDI). A reduction in IDI-PANSS of ≥25% compared to baseline was the criterion of good response. The volume of activated tissue was calculated to perform a connectomic analysis for each patient. An estimation of the tracts and cortical areas modulated was generated. RESULTS: Five women and three men were analyzed. After 3 years' follow-up, positive symptoms improved in 50% of the SCG group and 75% of the NAcc group (p = 0.06), and general symptoms improved in 25% and 50% respectively (p = 0.06). The SCG group showed activation of the cingulate bundle and modulation of orbitofrontal and frontomesial regions; in contrast, the NAcc group showed activation of the ventral tegmental area projections pathway and modulation of regions associated with the "default mode network" (precuneus) and Brodmann areas 19 and 20. CONCLUSIONS: These results showed a trend toward improvement for positive and general symptoms in patients with TRS treated with DBS. The connectomic analysis will help us understand the interaction of this treatment with the disease to pursue future trial designs.

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.

A consideration of the increased risk of schizophrenia due to prenatal maternal stress, and the possible role of microglia.

Schizophrenia is caused by interaction of a combination of genetic and environmental factors. Of the latter, prenatal exposure to maternal stress is reportedly associated with elevated disease risk. The main orchestrators of inflammatory processes within the brain are microglia, and aberrant microglial activation/function has been proposed to contribute to the aetiology of schizophrenia. Here, we evaluate the epidemiological and preclinical evidence connecting prenatal stress to schizophrenia risk, and consider the possible mediating role of microglia in the prenatal stress-schizophrenia relationship. Epidemiological findings are rather consistent in supporting the association, albeit they are mitigated by effects of sex and gestational timing, while the evidence for microglial activation is more variable. Rodent models of prenatal stress generally report lasting effects on offspring neurobiology. However, many uncertainties remain as to the mechanisms underlying the influence of maternal stress on the developing foetal brain. Future studies should aim to characterise the exact processes mediating this aspect of schizophrenia risk, as well as focussing on how prenatal stress may interact with other risk factors.

Impact of Early-Life Factors on Risk for Schizophrenia and Bipolar Disorder.

BACKGROUND AND HYPOTHESIS: Schizophrenia (SCZ) and bipolar disorder (BD) have shared genetic risk and clinical symptoms, yet the extent to which environmental risk factors are shared is not well known. We aimed to examine the associations of early-life environmental exposures with the risk of SCZ and BD. STUDY DESIGN: We conducted a Swedish register-based nested case-control study using 4184 SCZ and 18 681 BD cases diagnosed 1988-2013, individually matched to 5 population-based controls by birth year, sex and birthplace. Conditional logistic regression was used to evaluate the risk of SCZ and BD by seasonality, severe prenatal infections, and perinatal factors. STUDY RESULTS: Seasonality had similar patterns of risk for both disorders: Higher risk for births November-December; lower risk April-June. Experiencing any perinatal factor was associated with a significantly higher risk of SCZ (incidence rate ratio [IRR] 1.19, 95%CI 1.11-1.63) and to a lesser extent BD (IRR 1.08, 95%CI 1.05-1.12). Prenatal infections were only associated with a greater risk of SCZ (IRR 1.30, 95%CI 1.04-1.63). In the mutually adjusted model, only perinatal factors were associated with outcomes. Several perinatal factors were associated with both disorders, but estimates were significantly higher for SCZ for low birth weight, low APGAR, and high parity. Congenital malformations were only associated with risk of SCZ, and jaundice with BD. CONCLUSIONS: Adverse perinatal factors and winter birth were the risk factors for both disorders, while severe prenatal infections were only risk a factor for SCZ. Early-life exposures were associated with a higher risk of both disorders, but may play a larger role in the development of SCZ than BD.

Efficacy and safety of adjunctive therapy with fingolimod in patients with schizophrenia: A randomized, double-blind, placebo-controlled clinical trial.

OBJECTIVES: Studies have suggested that fingolimod, a sphingosine-1-phosphate receptor modulator, exerts neuroprotective and anti-inflammatory effects. Although fingolimod is approved for the treatment of relapsing-remitting multiple sclerosis, limited studies have investigated its effects in patients with schizophrenia. This study investigated the efficacy and safety of fingolimod adjuvant to risperidone in schizophrenia treatment. METHODS: This eight-week, randomized, double-blinded, placebo-controlled trial included 80 (clinical trials registry code: IRCT20090117001556N137) patients with chronic schizophrenia. Participants were assigned to two equal arms and received risperidone plus either fingolimod (0.5 mg/day) or a matched placebo. The positive and negative symptom scale (PANSS) was used to measure and compare the effectiveness of treatment strategies at baseline and weeks 2, 4, 6, and 8. Treatment side effects were also compared. RESULTS: Seventy participants completed the trial (35 in each arm). The baseline characteristics of the groups were comparable (P-value > 0.05). There were significant time-treatment interaction effects on negative symptoms (P-value = 0.003), general symptoms (P-value = 0.037), and the PANSS total score (P-value = 0.035), suggesting greater improvement in symptoms following the fingolimod adjuvant therapy. In contrast, the longitudinal changes in positive and depressive symptoms were similar between the groups (P-values > 0.05). Regarding the safety of treatments, there were no differences in extrapyramidal symptoms [assessed by the extrapyramidal symptom rating scale (ESRS)] or frequency of other complications between the fingolimod and the placebo groups (P-values > 0.05). CONCLUSIONS: This study indicated that fingolimod is a safe and effective adjuvant agent for schizophrenia treatment. However, further clinical trials are required to suggest extensive clinical application.

Low status, humiliation, dopamine and risk of schizophrenia.

The social defeat hypothesis of schizophrenia, which proposes that the chronic experience of outsider status or subordinate position leads to increased striatal dopamine activity and thereby to increased risk, has been criticized. The aims of this paper are to improve the definition of defeat and to integrate the social defeat hypothesis with the neurodevelopmental hypothesis. Marmot advanced the idea that low status is pathogenic in that it is associated with a lack of social participation and a lack of autonomy. Given the similarity with outsider status and subordinate position, we re-define social defeat as low status. From this new perspective it is also likely that pre-schizophrenic impairments (of neurodevelopmental origin or not) are pathogenic in that they contribute to low status. The effect of low status may be enhanced by repeated exposure to humiliation, but few studies have measured this variable. Since most individuals exposed to low status do not develop schizophrenia, we propose that this risk factor increases the risk of disorder in the presence of a poor homeostatic control of dopamine neurons in midbrain and dorsal striatum. This is consistent with studies of healthy subjects which report a negative association between low socio-economic status and dopamine D2/D3 receptor availability in the dorsal striatum. In this new version of the social defeat hypothesis we propose that the combination of low status, repeated humiliation and poor homeostatic control of dopamine neurons in midbrain and dorsal striatum leads to increased striatal dopamine activity and thereby to an increased risk of schizophrenia.

Systematic review and meta-analysis: Season of birth and schizophrenia risk.

OBJECTIVE: Winter birth has been hypothesized to be associated with increased schizophrenia risk for nearly a century. Major hypotheses regarding the potential etiological risk factors for schizophrenia such as vitamin D deficiency and virus exposure in utero are predicated based on the observation that risk of schizophrenia is higher in children born in winter months. METHODS: We conducted a systematic review and meta-analysis to examine the association between season and month of birth and risk of schizophrenia. We further investigated this relationship stratified by hemisphere. RESULTS: Forty-three studies spanning 30 countries and territories and 440,039 individuals with schizophrenia were included in this meta-analysis. Winter births were associated with a small but statistically significant increased risk of schizophrenia (OR 1.05, 95 % CI 1.03-1.07, p < 0.0001) and summer births were associated with a small but statistically significant decreased risk of schizophrenia (OR 0.96, 95 % CI 0.94-0.98, p = 0.0001). Stratified subgroup analysis demonstrated no significant difference between hemispheres in the risk of schizophrenia for either winter or summer births. CONCLUSIONS: Analysis using birth month data demonstrated a clear seasonal trend towards increased risk of schizophrenia being associated with winter birth months and decreased risk of schizophrenia in summer-to-fall months in the Northern but not Southern Hemisphere. These data suggest a small-but-substantial increased risk of schizophrenia in winter birth month. Further research needs to examine potential etiologic causes for this association.

Study protocol of the Berlin Research Initiative for Diagnostics, Genetics and Environmental Factors in Schizophrenia (BRIDGE-S).

BACKGROUND: Large-scale collaborative efforts in the field of psychiatric genetics have made substantial progress in unraveling the biological architecture of schizophrenia (SCZ). Although both genetic and environmental factors are known to play a role in schizophrenia etiology our mechanistic understanding of how they shape risk, resilience and disease trajectories remains limited. METHODS: Here, we present the study protocol of the Berlin Research Initiative for Diagnostics, Genetic and Environmental Factors of Schizophrenia (BRIDGE-S), which aims to collect a densely phenotyped genetic cohort of 1,000 schizophrenia cases and 1,000 controls. The study's main objectives are to build a resource for i) promoting genetic discoveries and ii) genotype-phenotype associations to infer specific disease subtypes, and iii) exploring gene-environment interactions using polyrisk models. All subjects provide a biological sample for genotyping and complete a core questionnaire capturing a variety of environmental exposures, demographic, psychological and health data. Approximately 50% of individuals in the sample will further undergo a comprehensive clinical and neurocognitive assessment. DISCUSSION: With BRIDGE-S we created a valuable database to study genomic and environmental contributions to schizophrenia risk, onset, and outcomes. Results of the BRIDGE-S study could yield insights into the etiological mechanisms of schizophrenia that could ultimately inform risk prediction, and early intervention and treatment strategies.

Levetiracetam Attenuates Adolescent Stress-induced Behavioral and Electrophysiological Changes Associated With Schizophrenia in Adult Rats.

BACKGROUND AND HYPOTHESIS: Stress during adolescence is a major risk factor for schizophrenia. We have found previously in rats that adolescent stress caused, in adulthood, behavioral changes and enhanced ventral tegmental area (VTA) dopamine system activity, which were associated with dysregulation of the excitatory-inhibitory (E/I) balance in the ventral hippocampus (vHip). Levetiracetam, an anticonvulsant drug, regulates the release of neurotransmitters, including glutamate, via SV2A inhibition. It also modulates parvalbumin interneuron activity via Kv3.1 channels. Therefore, levetiracetam could ameliorate deficits in the E/I balance. We tested whether levetiracetam attenuate the adolescent stress-induced behavioral changes, vHip hyperactivity, and enhanced VTA dopamine system activity in adult rats. STUDY DESIGN: Male Sprague-Dawley rats were subjected to a combination of daily footshock (postnatal day [PD] 31-40), and three 1 h-restraint stress sessions (at PD31, 32, and 40). In adulthood (PD62), animals were tested for anxiety responses (elevated plus-maze and light-dark box), social interaction, and cognitive function (novel object recognition test). The activity of vHip pyramidal neurons and VTA dopamine neurons was also recorded. STUDY RESULTS: Adolescent stress produced anxiety-like responses and impaired sociability and cognitive function. Levetiracetam (10 mg/kg) reversed these changes. Levetiracetam also reversed the increased VTA dopamine neuron population activity and the enhanced firing rate of vHip pyramidal neurons induced by adolescent stress. CONCLUSIONS: These findings suggest that levetiracetam attenuates the adverse outcomes associated with schizophrenia caused by stress during adolescence.

Risk of autism spectrum disorder in offspring with parental schizophrenia: a systematic review and meta-analysis.

BACKGROUND: The effect of parental schizophrenia on the risk of Autism Spectrum Disorders (ASD) in offspring has been evaluated in previous studies. However, to our knowledge, no systematic review and meta-analysis have assessed this association. In this study, we aimed to evaluate the risk of ASD in offspring with parental schizophrenia. METHODS: The electronic databases EMBASE, PubMed, and Scopus were systematically searched. We administered the Newcastle Ottawa quality assessment scale (NOS) to assess the quality of all selected studies. Combined effect values, as well as their 95% confidence intervals (CI), were calculated. We evaluated heterogeneity using Q and I2 statistics. The publication bias was evaluated by funnel plot and Egger's regression test. In addition, a leave-one-out sensitivity analysis was performed to assess the robustness of the finding. RESULTS: A total of 12 observational studies (10 cohorts and two case-control) were included. Our study found a high risk of ASD in offspring exposed to parental schizophrenia [RR = 2.38 (CI%95 2.0-2.83)]. Subgroup and sensitivity analysis confirmed the robustness of our main analysis. CONCLUSION: The risk of ASD is considerably higher in offspring with parental schizophrenia. Our findings may suggest a shared pathologic pathway between schizophrenia and ASD.

Development and initial validation of a multivariable predictive Early Adversity Scale for Schizophrenia (EAS-Sz) using register data to quantify environmental risk for adult schizophrenia diagnosis after childhood exposure to adversity.

BACKGROUND: Additional to a child's genetic inheritance, environmental exposures are associated with schizophrenia. Many are broadly described as childhood adversity; modelling the combined impact of these is complex. We aimed to develop and validate a scale on childhood adversity, independent of genetic and other environmental liabilities, for use in schizophrenia risk analysis models, using data from cross-linked electronic health and social services registers. METHOD: A cohort of N = 428 970 Western Australian children born 1980-2001 was partitioned into three samples: scale development sample (N = 171 588), and two scale validation samples (each N = 128 691). Measures of adversity were defined before a child's 10th birthday from five domains: discontinuity in parenting, family functioning, family structure, area-level socioeconomic/demographic environment and family-level sociodemographic status. Using Cox proportional hazards modelling of follow-up time from 10th birthday to schizophrenia diagnosis or censorship, weighted combinations of measures were firstly developed into scales for each domain, then combined into a final global scale. Discrimination and calibration performance were validated using Harrell's C and graphical assessment respectively. RESULTS: A weighted combination of 42 measures of childhood adversity was derived from the development sample. Independent application to identical measures in validation samples produced Harrell's Concordance statistics of 0.656 and 0.624. Average predicted time to diagnosis curves corresponded with 95% CI limits of observed Kaplan-Meier curves in five prognostic categories. CONCLUSIONS: Our Early Adversity Scale for Schizophrenia (EAS-Sz), the first using routinely collected register data, predicts schizophrenia diagnosis above chance, and has potential to help untangle contributions of genetic and environmental liability to schizophrenia risk.

The relative and interactive impact of multiple risk factors in schizophrenia spectrum disorders: a combined register-based and clinical twin study.

BACKGROUND: Research has yielded evidence for genetic and environmental factors influencing the risk of schizophrenia. Numerous environmental factors have been identified; however, the individual effects are small. The additive and interactive effects of multiple risk factors are not well elucidated. Twin pairs discordant for schizophrenia offer a unique opportunity to identify factors that differ between patients and unaffected co-twins, who are perfectly matched for age, sex and genetic background. METHODS: Register data were combined with clinical data for 216 twins including monozygotic (MZ) and dizygotic (DZ) proband pairs (one or both twins having a schizophrenia spectrum diagnosis) and MZ/DZ healthy control (HC) pairs. Logistic regression models were applied to predict (1) illness vulnerability (being a proband v. HC pair) and (2) illness status (being the patient v. unaffected co-twin). Risk factors included: A polygenic risk score (PRS) for schizophrenia, birth complications, birth weight, Apgar scores, paternal age, maternal smoking, season of birth, parental socioeconomic status, urbanicity, childhood trauma, estimated premorbid intelligence and cannabis. RESULTS: The PRS [odds ratio (OR) 1.6 (1.1-2.3)], childhood trauma [OR 4.5 (2.3-8.8)], and regular cannabis use [OR 8.3 (2.1-32.7)] independently predicted illness vulnerability as did an interaction between childhood trauma and cannabis use [OR 0.17 (0.03-0.9)]. Only regular cannabis use predicted having a schizophrenia spectrum diagnosis between patients and unaffected co-twins [OR 3.3 (1.1-10.4)]. CONCLUSION: The findings suggest that several risk factors contribute to increasing schizophrenia spectrum vulnerability. Moreover, cannabis, a potentially completely avoidable environmental risk factor, seems to play a substantial role in schizophrenia pathology.