Neurofilament light-chain (NfL) and 18 kDa translocator protein in early psychosis and its putative high-risk.

Evidence of elevated peripheral Neurofilament light-chain (NfL) as a biomarker of neuronal injury can be utilized to reveal nonspecific axonal damage, which could reflect altered neuroimmune function. To date, only a few studies have investigated NfL as a fluid biomarker in schizophrenia primarily, though none in its putative prodrome (Clinical High-Risk, CHR) or in untreated first-episode psychosis (FEP). Further, it is unknown whether peripheral NfL is associated with 18 kDa translocator protein (TSPO), a validated neuroimmune marker. In this secondary study, we investigated for the first time (1) serum NfL in early stages of psychosis including CHR and FEP as compared to healthy controls, and (2) examined its association with brain TSPO, using [18F]FEPPA positron emission tomography (PET). Further, in the exploratory analyses, we aimed to assess associations between serum NfL and symptom severity in patient group and cognitive impairment in the combined cohort. A large cohort of 84 participants including 27 FEP (24 antipsychotic-naive), 41 CHR (34 antipsychotic-naive) and 16 healthy controls underwent structural brain MRI and [18F]FEPPA PET scan and their blood samples were obtained and assessed for serum NfL concentrations. We found no significant differences in serum NfL levels across clinical groups, controlling for age. We also found no significant association between NfL levels and brain TSPO in the entire cohort. We observed a negative association between serum NfL and negative symptom severity in CHR. Our findings suggest that neither active neuroaxonal deterioration as measured with NfL nor associated neuroimmune activation (TSPO) is clearly identifiable in an early mostly untreated psychosis sample including its putative high-risk.

Interaction between peripheral and central immune markers in clinical high risk for psychosis.

Neuroinflammatory events prior to the diagnosis of schizophrenia may play a role in transition to illness. To date only one in-vivo study has investigated this association between peripheral proinflammatory cytokines and brain markers of inflammation (e.g., mitochondrial 18 kDa translocator protein, TSPO) in schizophrenia, but none in its putative prodrome. In this study, we primarily aimed to (Barron et al., 2017) test study group (clinical high-risk (CHR) and healthy controls) differences in peripheral inflammatory markers and test for any associations with symptom measures, (Hafizi et al., 2017a) investigate the interaction between brain TSPO levels (dorsolateral prefrontal cortex (DLPFC) and hippocampus) and peripheral inflammatory clusters (entire cohort and (CHR) group independently) within a relatively large group of individuals at CHR for psychosis (N = 38) and healthy controls (N = 20). Participants underwent structural brain magnetic resonance imaging (MRI) and TSPO [18F]FEPPA positron emission tomography (PET) scans. Serum samples were assessed for peripheral inflammatory markers (i.e., CRP and interleukins). For exploratory analysis, we aimed to examine cluster differences for symptom measures and identify independent peripheral predictors of brain TSPO expression. Here, we report increased IL-8 levels that are positively correlated with prodromal general symptom severity and showed trend-level association with apathy in CHR. We identified distinct inflammatory clusters characterized by inflammatory markers (IL-1 ß, IL-2, IFN-γ) that were comparable between entire cohort and CHR. TSPO levels did not differ between inflammatory clusters (entire cohort or CHR). Finally, we show that CRP, IL-1 ß, TNF-α, and IFN-γ levels were the independent peripheral predictors of brain TSPO expression. Thus, alterations in brain TSPO expression in response to inflammatory processes are not evident in CHR. Taken together, clustering by inflammatory status is a promising strategy to characterize the interaction between brain TSPO and peripheral markers of inflammation.

Modifiable risk factors of dementia linked to excitation-inhibition imbalance.

Recent evidence identifies 12 potentially modifiable risk factors for dementia to which 40% of dementia cases are attributed. While the recognition of these risk factors has paved the way for the development of new prevention measures, the link between these risk factors and the underlying pathophysiology of dementia is yet not well understood. A growing number of recent clinical and preclinical studies support a role of Excitation-Inhibition (E-I) imbalance in the pathophysiology of dementia. In this review, we aim to propose a conceptual model on the links between the modifiable risk factors and the E-I imbalance in dementia. This model, which aims to address the current gap in the literature, is based on 12 mediating common mechanisms: the hypothalamic-pituitary-adrenal (HPA) axis dysfunction, neuroinflammation, oxidative stress, mitochondrial dysfunction, cerebral hypo-perfusion, blood-brain barrier (BBB) dysfunction, beta-amyloid deposition, elevated homocysteine level, impaired neurogenesis, tau tangles, GABAergic dysfunction, and glutamatergic dysfunction. We believe this model serves as a framework for future studies in this field and facilitates future research on dementia prevention, discovery of new biomarkers, and developing new interventions.

Association of mental disorders and psychotropic medications with bone texture as measured with trabecular bone score.

INTRODUCTION: Mental disorders and psychotropic medications are known to increase the risk of osteoporosis and fractures. However, current evidence is mostly limited to studies that used bone mineral density (BMD), which does not provide information about the texture of bone tissue and can underestimate fracture risk. METHODS: We tested the association between bone texture, as measured with lumbar spine trabecular bone score (TBS), and both diagnosed mental disorders and psychotropic medication use in a large population-based BMD registry from Manitoba, Canada. General linear and logistic regression models were used to test the association of TBS with mental disorders (anxiety, depression, schizophrenia, and alcohol use disorder) and psychotropic medications use (selective serotonin reuptake inhibitors [SSRI], tricyclic antidepressants [TCA], other antidepressants, lithium, non­lithium mood stabilizers, antipsychotics, and benzodiazepines), adjusted for comorbidities and confounding factors. RESULTS: The study population contained 45,716 women (mean age = 64.1, SD = 10.4), which included 21.1 % with diagnoses for mental disorders and 18.7 % using psychotropic medications. We observed significant negative covariate-adjusted effects on TBS from diagnosed alcohol use disorder (3.1 % reduction in TBS, p < 0.001) and exposure to SSRI (0.6 % reduction, p < 0.001), TCA (0.8 % reduction, p < 0.001), other antidepressants (0.8 % reduction, p < 0.001), and lithium (3 % reduction, p < 0.001). Logistic regression revealed that TBS in the lowest (versus highest) tertile was associated with alcohol use disorder (adjusted odds ratio [OR] = 2.87, 95 % confidence interval [CI]: 1.95, 4.21), exposure to SSRI (OR = 1.21; 95 % CI: 1.08, 1.35), TCA (OR = 1.18, 95 % confidence interval [CI]: 1.04, 1.35), other antidepressants (OR = 1.26; 95 % CI: 1.09, 1.45), and lithium (OR = 1.97; 95 % CI: 1.09, 3.57). CONCLUSION: Our results suggest that alcohol use disorder, antidepressants, and lithium are associated with poorer bone texture in women. These findings add to the current literature on the link of bone pathology with mental disorders and psychotropic medications.

Genetically Predicted Brain C4A Expression Is Associated With TSPO and Hippocampal Morphology.

BACKGROUND: Alterations in the immune system, particularly C4A, have been implicated in the pathophysiology of schizophrenia. C4A promotes synapse elimination by microglia in preclinical models; however, it is unknown whether this process is also present in living humans and how it affects brain morphology. METHODS: Participants (N = 111; 33 patients with psychosis, 37 individuals at clinical high risk, and 41 healthy control subjects) underwent a TSPO [18F]FEPPA positron emission tomography scan and a magnetic resonance imaging scan. Brain C4A expression was genetically predicted as a function of the dosage of each of 4 structural elements (C4AL, C4BL, C4AS, C4BS). RESULTS: Higher genetically predicted brain C4A expression was associated with higher brain microglial marker (TSPO) and altered hippocampal morphology, including reduced surface area and medial displacement in the CA1 area. This study is the first to quantify genetically predicted brain C4A expression in individuals at clinical high risk, showing significantly lower C4A in individuals at clinical high risk compared with healthy control subjects. We also showed a robust effect of sex on genetically predicted brain C4A expression and effects of both sex and cannabis use on brain TSPO. CONCLUSIONS: This study shows for the first time complement system (C4A) coupling with a microglial marker (TSPO) and hippocampal morphology in living human brain. These findings pave the way for future research on the interaction between C4A and glial cell function, which has the potential to inform the disease mechanism underlying psychosis and schizophrenia.

Review of Clinical Studies Targeting Inflammatory Pathways for Individuals With Autism.

Immune dysfunction and abnormal immune response may be associated with certain mechanisms underlying autism spectrum disorder (ASD). The early evidence for this link was based on the increased incidence of ASD in children with a history of maternal infection during pregnancy. Observational studies show increased prevalence of immune-related disorders-ranging from atopy, food allergy, viral infections, asthma, primary immunodeficiency, to autoimmune disorders-in individuals with ASD and their families. Evidence of neuroglial activation and focal brain inflammation in individuals with ASD implies that the central nervous system immunity may also be atypical in some individuals with ASD. Also, both peripheral and central inflammatory responses are suggested to be associated with ASD-related behavioral symptoms. Atypical immune responses may be evident in specific ASD subgroups, such as those with significant gastrointestinal symptoms. The present review aimed to evaluate current literature of potential interventions that target inflammatory pathways for individuals with ASD and to summarize whether these interventions were associated with improvement in autism symptoms and adaptation. We found that the current literature on the efficacy of anti-inflammatory interventions in ASD is still limited and large-scale randomized controlled trials are needed to provide robust evidence. We concluded that the role of immune-mediated mechanisms in the emergence of ASD or related challenges may be specific to subsets of individuals (e.g. those with concurrent immunological disorders, developmental regression, or high irritability). These subsets of individuals of ASD might be more likely to benefit from interventions that target immune-mediated mechanisms and with whom next-stage immune-mediated clinical trials could be conducted.

In Vivo Imaging of Translocator Protein in Long-term Cannabis Users.

Importance: Cannabis is the most commonly used illicit drug in the world. Cannabinoids have been shown to modulate immune responses; however, the association of cannabis with neuroimmune function has never been investigated in vivo in the human brain. Objective: To investigate neuroimmune activation or 18-kDa translocator protein (TSPO) levels in long-term cannabis users, and to evaluate the association of brain TSPO levels with behavioral measures and inflammatory blood biomarkers. Design, Setting, and Participants: This cross-sectional study based in Toronto, Ontario, recruited individuals from January 1, 2015, to October 30, 2018. Participants included long-term cannabis users (n = 24) and non-cannabis-using controls (n = 27). Cannabis users were included if they had a positive urine drug screen for only cannabis and if they used cannabis at least 4 times per week for the past 12 months and/or met the criteria for cannabis use disorder. All participants underwent a positron emission tomography scan with [18F]FEPPA, or fluorine F 18-labeled N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide. Main Outcomes and Measures: Total distribution volume was quantified across regions of interest. Stress and anxiety as well as peripheral measures of inflammatory cytokines and C-reactive protein levels were also measured. Results: In total, 24 long-term cannabis users (mean [SD] age, 23.1 [3.8] years; 15 men [63%]) and 27 non-cannabis-using controls (mean [SD] age, 23.6 [4.2] years; 18 women [67%]) were included and completed all study procedures. Compared with the controls, cannabis users had higher [18F]FEPPA total distribution volume (main group effect: F1,48 = 6.5 [P = .01]; ROI effect: F1,200 = 28.4 [P < .001]; Cohen d = 0.6; 23.3% higher), with a more prominent implication for the cannabis use disorder subgroup (n = 15; main group effect: F1,39 = 8.5 [P = .006]; ROI effect: F1,164 = 19.3 [P < .001]; Cohen d = 0.8; 31.5% higher). Greater TSPO levels in the brain were associated with stress and anxiety and with higher circulating C-reactive protein levels in cannabis users. Conclusions and Relevance: The results of this study suggest that TSPO levels in cannabis users, particularly in those with cannabis use disorder, are higher than those in non-cannabis-using controls. The findings emphasize the need for more complementary preclinical systems for a better understanding of the role of cannabinoids and TSPO in neuroimmune signaling.

GABA levels and TSPO expression in people at clinical high risk for psychosis and healthy volunteers: a PET-MRS study.

BACKGROUND: γ-Aminobutyric acidergic (GABAergic) dysfunction and immune activation have been implicated in the pathophysiology of schizophrenia. Preclinical evidence suggests that inflammation-related abnormalities may contribute to GABAergic alterations in the brain, but this has never been investigated in vivo in humans. In this multimodal imaging study, we quantified cerebral GABA plus macromolecule (GABA+) levels in antipsychotic-naive people at clinical high risk for psychosis and in healthy volunteers. We investigated for the first time the association between GABA+ levels and expression of translocator protein 18 kDa (TSPO; a marker of microglial activation) using positron emission tomography (PET). METHODS: Thirty-five people at clinical high risk for psychosis and 18 healthy volunteers underwent 3 T proton magnetic resonance spectroscopy to obtain GABA+ levels in the medial prefrontal cortex (mPFC). A subset (29 people at clinical high risk for psychosis and 15 healthy volunteers) also underwent a high-resolution [18F]FEPPA PET scan to quantify TSPO expression. Each participant was genotyped for the TSPO rs6971 polymorphism. RESULTS: We found that GABA+ levels were significantly associated with TSPO expression in the mPFC (F1,40 = 10.45, p = 0.002). We found no significant differences in GABA+ levels in the mPFC (F1,51 = 0.00, p > 0.99) between people at clinical high risk for psychosis and healthy volunteers. We found no significant correlations between GABA+ levels or residuals of the association with TSPO expression and the severity of prodromal symptoms or cognition. LIMITATIONS: Given the cross-sectional nature of this study, we could determine no cause-and-effect relationships for GABA alterations and TSPO expression. CONCLUSION: Our findings suggest that TSPO expression is negatively associated with GABA+ levels in the prefrontal cortex, independent of disease status.

Preliminary data indicating a connection between stress-induced prefrontal dopamine release and hippocampal TSPO expression in the psychosis spectrum.

Prolonged stress can cause neuronal loss in the hippocampus resulting in disinhibition of glutamatergic neurons proposed to enhance dopaminergic firing in subcortical regions including striatal areas. Supporting this, imaging studies show increased striatal dopamine release in response to psychosocial stress in healthy individuals with low childhood maternal care, individuals at clinical high risk for psychosis (CHR) and patients with schizophrenia. The prefrontal cortex (PFC) is connected to the hippocampus and a key region to control neurochemical responses to stressful stimuli. We recently reported a disrupted PFC dopamine-stress regulation in schizophrenia, which was intact in CHR. Given the available evidence on the link between psychosocial stress, PFC dopamine release and hippocampal immune activation in psychosis, we explored, for the first time in vivo, whether stress-induced PFC dopamine release is associated with hippocampal TSPO expression (a neuroimmune marker) in the psychosis spectrum. We used an overlapping sample of antipsychotic-naïve subjects with CHR (n = 6) and antipsychotic-free schizophrenia patients (n = 9) from our previously published studies, measuring PFC dopamine release induced by a psychosocial stress task with [11C]FLB457 positron emission tomography (PET) and TSPO expression with [18F]FEPPA PET. We observed that participants on the psychosis spectrum with lower stress-induced dopamine release in PFC had significantly higher TSPO expression in hippocampus (ß = -2.39, SE = 0.96, F(1,11) = 6.17, p = 0.030). Additionally, we report a positive association between stress-induced PFC dopamine release, controlled for hippocampal TSPO expression, and Global Assessment of Functioning. This is the first exploration of the relationship between PFC dopamine release and hippocampal TSPO expression in vivo in humans.

Hippocampal glutamate metabolites and glial activation in clinical high risk and first episode psychosis.

Alterations in glutamate neurotransmission have been implicated in the pathophysiology of schizophrenia, as well as in symptom severity and cognitive deficits. The hippocampus, in particular, is a site of key functional and structural abnormalities in schizophrenia. Yet few studies have investigated hippocampal glutamate in antipsychotic-naïve first episode psychosis patients or in individuals at clinical high risk (CHR) of developing psychosis. Using proton magnetic resonance spectroscopy (1H-MRS), we investigated glutamate metabolite levels in the left hippocampus of 25 CHR (19 antipsychotic-naïve), 16 patients with first-episode psychosis (13 antipsychotic-naïve) and 31 healthy volunteers. We also explored associations between hippocampal glutamate metabolites and glial activation, as indexed by [18F]FEPPA positron emission tomography (PET); symptom severity; and cognitive function. Groups differed significantly in glutamate plus glutamine (Glx) levels (F(2, 69) = 6.39, p = 0.003). Post-hoc analysis revealed that CHR had significantly lower Glx levels than both healthy volunteers (p = 0.003) and first-episode psychosis patients (p = 0.050). No associations were found between glutamate metabolites and glial activation. Our findings suggest that glutamate metabolites are altered in CHR.

TSPO expression and brain structure in the psychosis spectrum.

Psychosis is associated with abnormal structural changes in the brain including decreased regional brain volumes and abnormal brain morphology. However, the underlying causes of these structural abnormalities are less understood. The immune system, including microglial activation, has been implicated in the pathophysiology of psychosis. Although previous studies have suggested a connection between peripheral proinflammatory cytokines and structural brain abnormalities in schizophrenia, no in-vivo studies have investigated whether microglial activation is also linked to brain structure alterations previously observed in schizophrenia and its putative prodrome. In this study, we investigated the link between mitochondrial 18 kDa translocator protein (TSPO) and structural brain characteristics (i.e. regional brain volume, cortical thickness, and hippocampal shape) in key brain regions such as dorsolateral prefrontal cortex and hippocampus of a large group of participants (N = 90) including individuals at clinical high risk (CHR) for psychosis, first-episode psychosis (mostly antipsychotic-naïve) patients, and healthy volunteers. The participants underwent structural brain MRI scan and [18F]FEPPA positron emission tomography (PET) targeting TSPO. A significant [18F]FEPPA binding-by-group interaction was observed in morphological measures across the left hippocampus. In first-episode psychosis, we observed associations between [18F]FEPPA VT (total volume of distribution) and outward and inward morphological alterations, respectively, in the dorsal and ventro-medial portions of the left hippocampus. These associations were not significant in CHR or healthy volunteers. There was no association between [18F]FEPPA VT and other structural brain characteristics. Our findings suggest a link between TSPO expression and alterations in hippocampal morphology in first-episode psychosis.

Interaction between TSPO-a neuroimmune marker-and redox status in clinical high risk for psychosis: a PET-MRS study.

Altered neuroimmune response and oxidative stress have both been implicated in the pathophysiology of schizophrenia. While preclinical studies have proposed several pathways regarding potential interactions between oxidative stress and neuroimmune imbalance in the development of psychosis, the molecular mechanisms underlying this interaction are not yet understood. To date, no study has investigated this link in vivo in the human brain. We conducted the first in vivo study linking translocator protein 18 kDa (TSPO) expression and glutathione (a major brain antioxidant and a marker for redox status) in the medial prefrontal cortex (mPFC) of a relatively large sample of participants (N = 48) including 27 antipsychotic-naïve individuals at clinical high risk for psychosis and 21 matched healthy volunteers using high-resolution PET with TSPO radioligand, [18F]FEPPA, and 3T proton magnetic resonance spectroscopy (1H MRS). The omnibus model (including TSPO genotype as covariate) was significant (F(4, 43) = 10.01, p < 0.001), with a significant group interaction (t = -2.10, p = 0.04), suggesting a different relation between [18F]FEPPA VT and glutathione in each clinical group. In healthy volunteers, but not in individuals at clinical high risk for psychosis, we found a significant negative association between glutathione levels and [18F]FEPPA VT (r = -0.60, p = 0.006). We observed no significant group differences with respect to [18F]FEPPA VT or glutathione levels. These findings suggest an abnormal interaction between TSPO expression and redox status in the clinical high risk states for psychosis.

Glutathione, the Major Redox Regulator, in the Prefrontal Cortex of Individuals at Clinical High Risk for Psychosis.

Introduction: Oxidative stress and glutathione dysregulation have been implicated in the etiology of schizophrenia. To date, most in vivo studies have investigated alterations in cerebral glutathione levels in patients in which the disorder is already established; however, whether oxidative stress actually predates the onset of psychosis remains unknown. In the current study, we investigated cerebral glutathione levels of antipsychotic-naïve individuals at clinical high risk for psychosis. As exploratory analyses, we also investigated the associations between cerebral glutathione levels and peripheral glutathione peroxidase activity and clinical and neuropsychological measures. Methods: Glutathione levels were measured in the medial prefrontal cortex of 30 clinical high risk (n=26 antipsychotic naïve) and 26 healthy volunteers using 3T proton magnetic resonance spectroscopy. Each participant was assessed for glutathione peroxidase activity in plasma and genotyped for the glutamate cysteine ligase catalytic subunit polymorphism. Results: No significant differences were observed in glutathione levels between clinical high risk and healthy volunteers in the medial prefrontal cortex (F(1,54)=0.001, P =0.98). There were no significant correlations between cerebral glutathione levels and clinical and neuropsychological measures. Similarly, no significant differences were found in peripheral glutathione peroxidase activity between clinical high risk and healthy volunteers (F(1,37)=0.15, P =0.70). However, in clinical high risk, we observed a significant effect of lifetime history of cannabis use on glutathione peroxidase activity (F(1,23)=7.41, P =0.01). Discussion: The lack of significant differences between antipsychotic naïve clinical high risk and healthy volunteers suggests that alterations in glutathione levels in medial prefrontal cortex are not present in the clinical high risk state.

The effect of SPARK on social and motor skills of children with autism.

BACKGROUND: This study aimed to evaluate the effectiveness of a selected group exercise known as Sports, Play and Active Recreation for Kids (SPARK) on the motor and behavioral skills of children with autism spectrum disorder (ASD) using a quasi-experimental design with repeated measures. METHODS: Twenty-eight children with ASD (age range of 5e12 years) participated in this study. The participants were examined at baseline, pre-test, and post-test using Bruininks-Oseretsky Test of Motor Proficiency (BOTMP), Autism treatment evaluation checklist (ATEC), and Gilliam Autism Rating Scale-second edition (GARS-2). RESULTS: The results showed that the SPARK program significantly improved balance (static and dynamic), bilateral coordination and social interaction (p < 0.05) in children with ASD. CONCLUSION: The results of this study suggest that the SPARK's training can be considered as a therapeutic option not only for motor enhancement but also for improving social skills in children with ASD.

Imaging microglial activation and amyloid burden in amnestic mild cognitive impairment.

Amnestic mild cognitive impairment (aMCI) is defined as a transitional state between normal aging and Alzheimer's disease (AD). Given the replicated finding of increased microglial activation in AD, we sought to investigate whether microglial activation is also elevated in aMCI and whether it is related to amyloid beta (Aß) burden in-vivo . Eleven aMCI participants and 14 healthy volunteers completed positron emission tomography (PET) scans with [18F]-FEPPA and [11C]-PIB. Given the known sensitivity in affinity of second-generation TSPO radioligands, participants were genotyped for the TSPO polymorphism and only high-affinity binders were included. Dynamic [18F]-FEPPA PET images were analyzed using the 2-tissue compartment model with arterial plasma input function. Additionally, a supplementary method, the standardized uptake value ratio (SUVR), was explored. [11C]-PIB PET images were analyzed using the Logan graphical method. aMCI participants had significantly higher [11C]-PIB binding in the cortical regions. No significant differences in [18F]-FEPPA binding were observed between aMCI participants and healthy volunteers. In the aMCI group, [18F]-FEPPA and [11C]-PIB bindings were correlated in the hippocampus. There were no correlations between our PET measures and cognition. Our findings demonstrate that while Aß burden is evident in the aMCI stage, microglial activation may not be present.

Using molecular imaging to understand early schizophrenia-related psychosis neurochemistry: a review of human studies.

Schizophrenia is a chronic psychiatric disorder generally preceded by a so-called prodromal phase, which is characterized by attenuated psychotic symptoms. Advances in clinical research have enabled prospective identification of those individuals who are at clinical high risk (CHR) for psychosis, with the power to predict psychosis onset within the near future. Changes in several brain neurochemical systems and molecular mechanisms are implicated in the pathophysiology of schizophrenia and the psychosis spectrum, including the dopaminergic, γ-aminobutyric acid (GABA)-ergic, glutamatergic, endocannabinoid, and immunologic (i.e. glial activation) system and other promising future directions such as synaptic density, which are possible to quantify in vivo using positron emission tomography (PET). This paper aims to review in vivo PET studies in the mentioned systems in the early course of psychosis (i.e. CHR and first-episode psychosis (FEP)). The results of reviewed studies are promising; however, the current understanding of the underlying pathology of psychosis is still limited. Importantly, promising efforts involve the development of novel PET radiotracers targeting systems with growing interest in schizophrenia, like the nociceptive system and synaptic density.

Towards an Integrated View of Early Molecular Changes Underlying Vulnerability to Social Stress in Psychosis.

Psychotic disorders are heterogeneous and complex, involving many putative causal factors interacting along the course of disease development. Many of the factors implicated in the pathogenesis of psychosis also appear to be involved in disease onset and subsequent neuroprogression. Herein, we highlight the pertinent literature implicating inflammation and oxidative stress in the pathogenesis of psychosis, and the potential contribution of N-methyl-D-aspartate receptors (NMDARs). We also emphasize the role of peripubertal social stress in psychosis, and the ways in which hippocampal dysfunction can mediate dysregulation of the hypothalamic-pituitary-adrenal axis and cortisol release. Finally, we propose a model wherein inflammation and oxidative stress act as a first hit, producing altered parvalbumin interneuron development, NMDAR hypofunction, microglial priming, and sensitivity to a second hit of peripubertal social stress. With a greater understanding of how these factors interact, it may be possible to detect, prevent, and treat psychosis more effectively.