Over the last decade, compelling evidence suggests an important link between psychosis and immune system dysfunction, suggesting a mediating role of aberrant immunological processes in genetic and environmental risk for schizophrenia. Of note, inflammation in the context of psychosis is studied as a systemic, chronic, low-grade, and undefined origin phenomenon opposed to the transient nature of inflammatory responses to infections or injuries [51]. Similarities in cytokine alterations are found in schizophrenia, but also bipolar disorder and major depressive disorder during all phases of illness, raising the possibility of common underlying pathways for immune dysfunction [52]. In psychosis, the vast amount of evidence indicates that immune dysregulation of the innate immune response (cytokines and microglia) and components of the adaptive immune response (lymphocyte subsets and anti-neuronal cell surface antibodies) compromise normal neurotransmission and may induce aberrant neurodevelopmental and neurodegenerative processes, which can lead to pathological changes in mood, cognition, and behavior [48]. Moreover, since changes in the levels of individual cytokines have been observed following antipsychotic treatment in acute psychotic exacerbation and FEP, the use of medication has to be considered a potential confounding factor when addressing inflammatory markers in early psychosis [53, 54]. Indeed, while immune dysfunction is evident across all stages of psychosis-spectrum disorders [54], an exacerbated inflammatory cascade characterized by elevated proinflammatory cytokine production has been found as independent of antipsychotic medication and present in both first episode (IL-12, IFN-γ, TNF-α, and sIL-2R) and acutely relapsed phase (IL-1β, IL-6, and TGF-β) of psychotic patients [55], while a recent meta-analysis has reported that proinflammatory cytokines (mainly IFN-γ, IL-6 and IL-12) are significantly elevated in drug naïve FEP populations and associated with presenting negative symptomatology [56]. It is argued that brain morphology is differentially impacted by peripheral cytokines in early psychosis [57], and is further associated with cognitive deficits and symptomatology [58]. Given that genome-wide association studies have demonstrated a significant role of major histocompatibility complex genes in schizophrenia, among other genes [59], gene-expression studies of pro-inflammatory cytokines in brain regions affected in psychosis could provide insight into neuroinflammatory mechanisms that could precipitate neuronal degeneration and decrease neurogenesis, leading to morphological changes increasing liability to psychosis onset [60]. The evidence so far does not support the utility of inflammatory markers in predicting transition to psychosis in high-risk individuals [61] or predicting optimal therapeutic outcomes, as the role of anti-inflammatory agents in the treatment of psychosis remains unclear [54]. Nevertheless, elevated levels of IL-6 are present years prior to the onset of psychosis [62] and have been associated with childhood adversities [63]. It has been postulated that inflammation-mediated pathways may be a common pathway for environmental risk factors, both pre-perinatal exposures, such as maternal infection/ depression [64, 65], and childhood/adult adverse environment, such as childhood trauma, cannabis use, and social exclusion [66], increasing psychosis liability. In line with the above, a two-hit model has been proposed for the role of microglia in the primary immune cells in the central nervous system, and according to this, perinatal stress leads to a primed state of microglia activation, and subsequently later, environmental stress triggers pathological overactivation, leading to excessive synaptic pruning, loss of cortical gray matter, and the emergence of psychotic symptomatology [67], even though the evidence of microglia activation related to brain changes, especially in early stages of psychosis, has been questioned in other research papers [68]. Notably, early programming of the innate immune response as shaped during neurodevelopment may provide insight into broader transdiagnostic importance, and explain the comorbidity between schizophrenia and other major psychiatric and somatic comorbidities, such as coronary heart disease and type 2 diabetes [54].

Disrupted inflammation cascade in psychosis is accompanied by increased oxidative and decreased anti-oxidant cellular stress. It has been proposed that insufficient antioxidant defense leads to higher levels of reactive oxygen species produced by mitochondria dysfunction, causing oxidation of cell macromolecules and, thus, leading to altered cell behavior and brain abnormalities found in patients with psychosis [69]. In detail, increased pro-oxidative status, including impaired antioxidant defense, abnormal serum, plasma, and red blood cell (RBC) oxidative stress parameters, development of redox dysregulation, impaired docosahexaenoic acid levels, and impaired glutathione synthesis have been reported in meta-analytic studies across stages and the broad diagnostic spectrum of psychosis with evidence of independency concerning antipsychotic medication. Moreover, some parameters (total antioxidant status, RBC catalase, and plasma nitrite) are explored as state markers for acute psychosis, while others (RBC superoxide dismutase) as trait markers [70]. In FEP patients, total antioxidant status has been found to be significantly lower than in controls [49], and oxidative markers have been associated with poor clinical, cognitive, and neurobiological outcomes in early-onset FEP patients [71]. The importance of anti-oxidant defense in psychosis onset has been emphasized in a recent systematic review, reporting decreased level of non-enzymatic antioxidants, increased level of lipid peroxides and nitric oxides, and a homeostatic imbalance of purine catabolism, while total decreased antioxidant capacity was significantly associated with cognitive deficits and negative symptoms [72]. In early-onset psychosis, low baseline levels of antioxidants, such as glutathione, have been linked with longitudinal decreases in gray matter volume and cognitive deficits [73], while in young patients with reported childhood trauma, high peripheral oxidation status has been associated with smaller hippocampal volumes and more severe symptom profile than those with a lower oxidation status [74]. Notably, research on the beneficial effects of dietary antioxidants, such as vitamins and Omega-3 PUFAs, has provided mixed results without any proven superiority versus placebo in terms of favorable outcomes in high-risk or recent onset psychosis individuals [75]. Interestingly, the brain-derived neurotrophic factor (BDNF), which regulates the survival and growth of neurons and influences synaptic efficiency and plasticity, seems also to be involved, since peripheral (blood) BDNF levels have been consistently found to be reduced in medicated and drug-naïve patients with schizophrenia [76], and in FEP patients [77]. Nevertheless, small studies with mixed findings of BDNF levels are reported concerning the high-risk state [78, 79], however, its utility for predicting conversion to psychosis or treatment response is yet to be clarified. The studies suggest that genetic polymorphisms of BDNF genes might interact with early life environmental stressors influencing clinical severity, cognitive deficits, and brain structural abnormalities in psychosis spectrum disorders [80]. Overall, it is increasingly evident from clinical studies analyzing patients’ blood and cerebrospinal fluid samples, neuroimaging, and post-mortem brain tissue that aberrant oxidative balance and inflammation processes interact during critical neurodevelopmental periods, shaping brain vulnerability towards psychosis emergence through altered neuromaturation and abnormal aging processes [81]. A diagrammatic representation of oxidation disruption, inflammatory alterations, and resulting neuroanatomical changes is depicted in Fig. (2).

An emerging key player in understanding how stress during critical neurodevelopmental periods increases psychosis vulnerability by shaping contemporary biological conditions associated with low-grade inflammation and oxidative stress is gut dysbiosis. The existing literature indicates that gut microbiota is a complex and individualized ecosystem of microbiomes directly linked with mental health [82]. Although an association between enteropathies and psychiatric disorders has long been recognized, it has been suggested that gut microbes represent direct mediators of psychopathology via bidirectional communication paths between the central nervous system and the gastrointestinal tract [83]. As the microbiome is developed alongside brain development from pregnancy until the first few years after birth, it has been postulated that an imbalance in the gut microbiome during the critical neurodevelopmental phase can influence brain maturation processes, including the establishment of the blood-brain barrier, neurogenesis, maturation of microglia and myelination, by triggering aberrant immune activation and systemic inflammation, thereby leading to symptoms associated with major neuropsychiatric disorders [84]. In later life, the balance between the human microbiome and the development of psychopathology is influenced by several factors, such as diet, exposure to medication, sleep disorders, and external stressors [85]. Environmental stressors, such as adulthood trauma [86] and cannabis exposure [87], have been reported to increase psychosis liability mediated by microbiome alterations. Furthermore, there are consistent findings of altered synthesis and function of the microbiome in chronic schizophrenia [88], first-episode, drug-naïve patients [89], and ultra-high-risk individuals [90], as compared to controls. Diversity in microbiota composition in psychosis has been correlated with altered brain structure and function [91], cognitive dysfunction [92], and symptom severity [93]. It should be noted that current data are insufficient to conclude whether microbiome changes can establish the direction of causality associated with increased risk of psychosis or are simply the result of non-specific factors or treatment/ disease-related factors [94], while the potential therapeutic role of dietary supplements is yet undetermined [95].