Schizophrenia is one of the most debilitating mental disorders and is aggravated by the lack of efficacious treatment. Although its etiology is unclear, epidemiological studies indicate that infection and inflammation during development induces behavioral, morphological, neurochemical, and cognitive impairments, increasing the risk of developing schizophrenia. The inflammatory hypothesis of schizophrenia is also supported by clinical studies demonstrating systemic inflammation and microglia activation in schizophrenic patients. Although elucidating the mechanism that induces this inflammatory profile remains a challenge, mounting evidence suggests that neuroimmune interactions may provide therapeutic advantages to control inflammation and hence schizophrenia. Recent studies have indicated that vagus nerve stimulation controls both peripheral and central inflammation via alpha-7 nicotinic acetylcholine receptor (α7nAChR). Other findings have indicated that vagal stimulation and α7nAChR-agonists can provide therapeutic advantages for neuropsychiatric disorders, such as depression and epilepsy. This review analyzes the latest results regarding: (I) the immune-to-brain pathogenesis of schizophrenia; (II) the regulation of inflammation by the autonomic nervous system in psychiatric disorders; and (III) the role of the vagus nerve and α7nAChR in schizophrenia.

Background: Inflammation is a possible biological mechanism underlying the association between childhood maltreatment and psychosis. Previous investigations on this regard were mainly conducted on chronic schizophrenia and lacked control for confounders. We aim to investigate the role of familial liability, childhood maltreatment and recent stress in determining cytokine abnormalities at the onset of psychosis.Methods: We recruited 114 first-episode psychosis (FEP) patients, 57 unaffected biological siblings of FEP patients, and 251 community-based controls. Plasma cytokines (IL-1β, IL-6, TNF-α, IFN-γ, IL-4, IL-10 and TGF-β) were measured and differences across the groups analysed after adjusting for potential confounders.Results: FEP had a higher pro- and anti-inflammatory cytokine profile (IL-1β, IL-6, TNF-α, IL-10 and TGF-β), which was not observed in unaffected siblings. Siblings presented decreased IL-1β when compared with patients and controls. Childhood maltreatment was associated with higher levels of TGF-β in both patients and siblings when compared with controls. Physical childhood abuse was associated with increased levels of TGF-β in FEP patients but with decreased levels in controls. Other childhood maltreatment subtypes or recent stressors did not affect cytokine levels in any of the groups.Conclusions: Normal or reduced cytokines in siblings represent possibly a protective factor and suggest that the identified inflammatory profile in FEP can be a real pathophysiological component of psychosis. Experience of childhood maltreatment may contribute as long-term immune priming for the TGF-β pathway, and increased levels of this cytokine in both patients and siblings exposed to childhood maltreatment point to a possible biological candidate of familial risk for psychosis.

We investigated GRIN1 and GRIN2B promoter methylation in first-episode schizophrenia patients compared with siblings and controls, testing for correlations between DNA methylation, cognitive performance and clinical variables. Blood-derived DNA from all groups underwent bisulfite conversion and pyrosequencing to determine methylation at CpG sites within the GRIN1 and GRIN2B promoters and results were compared with the measure of global methylation LINE-1. We found hypomethylation among all CpGs analyzed within GRIN2B promoter in patients and greater LINE-1 methylation in patients and siblings. CpG4 was correlated to a measure of intellectual function. Changes in GRIN2B promoter methylation may represent an environmental influence contributing to glutamatergic dysfunction in psychosis and relate to lower cognitive performance in subjects with first-episode schizophrenia.

We estimated the incidence of first-episode psychosis over a 3-year period in a Brazilian catchment area comprising the region's main city, Ribeirão Preto (1 425 306 persons-years at risk), and 25 other municipalities with a total of 1 646 556 persons-years at risk. The incidence rates were estimated and adjusted by gender and age, using the direct standardisation method to the world population as reference. The incidence of psychosis was higher in the younger groups, men, and among Black and minority ethnic Brazilians. Psychosis incidence was lower in Ribeirão Preto (16.69/100 000 person-years at risk; 95% CI 15.68–17.70) compared with the average incidence in the remaining municipalities (21.25/100 000 person-years at risk; 95% CI 20.20–22.31), which have lower population density, suggesting a distinct role for urbanicity in the incidence of first-episode psychosis in low- and middle-income countries.

There is a consensus that the development of premenstrual dysphoric states is related to cyclical change in gonadal hormone secretion during the menstrual cycle. However, results from studies seeking to link symptom severity to luteal phase progesterone concentration have been equivocal. In the present study we evaluated not only the absolute concentrations of progesterone but also the kinetics of the change in progesterone concentration in relation to development of premenstrual symptoms during the last 10days of the luteal phase in a population of 46 healthy young adult Brazilian women aged 18-39 years, mean 26.5±6.7years. In participants who developed symptoms of premenstrual distress, daily saliva progesterone concentration remained stable during most of the mid-late luteal phase, before declining sharply during the last 3days prior to onset of menstruation. In contrast, progesterone concentration in asymptomatic women underwent a gradual decline over the last 8days prior to menstruation. Neither maximum nor minimum concentrations of progesterone in the two groups were related to the appearance or severity of premenstrual symptoms. We propose that individual differences in the kinetics of progesterone secretion and/or metabolism may confer differential susceptibility to the development of premenstrual syndrome.