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Review

Neuroinflammation and Oxidative Stress in Psychosis and Psychosis Risk

1
Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada
2
Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada
3
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada
4
Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada
*
Author to whom correspondence should be addressed.
Academic Editor: Yong-Ku Kim
Int. J. Mol. Sci. 2017, 18(3), 651; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18030651
Received: 20 December 2016 / Revised: 7 March 2017 / Accepted: 15 March 2017 / Published: 17 March 2017

Abstract

Although our understanding of psychotic disorders has advanced substantially in the past few decades, very little has changed in the standard of care for these illnesses since the development of atypical anti-psychotics in the 1990s. Here, we integrate new insights into the pathophysiology with the increasing interest in early detection and prevention. First, we explore the role of N-methyl-d-aspartate receptors in a subpopulation of cortical parvalbumin-containing interneurons (PVIs). Postmortem and preclinical data has implicated these neurons in the positive and negative symptoms, as well as the cognitive dysfunction present in schizophrenia. These neurons also appear to be sensitive to inflammation and oxidative stress during the perinatal and peripubertal periods, which may be mediated in large part by aberrant synaptic pruning. After exploring some of the molecular mechanisms through which neuroinflammation and oxidative stress are thought to exert their effects, we highlight the progress that has been made in identifying psychosis prior to onset through the identification of individuals at clinical high risk for psychosis (CHR). By combining our understanding of psychosis pathogenesis with the increasing characterization of endophenotypes that precede frank psychosis, it may be possible to identify patients before they present with psychosis and intervene to reduce the burden of the disease to both patients and families.
Keywords: schizophrenia; psychosis; neuroinflammation; oxidative stress schizophrenia; psychosis; neuroinflammation; oxidative stress

1. Introduction

Schizophrenia is a debilitating mental disorder that affects about one percent of the population. It is characterized by positive symptoms (e.g., abnormal perceptions and beliefs), negative symptoms (e.g., anhedonia and social withdrawal) and cognitive deficits. It is believed to be multifactorial and heterogeneous in its etiology, such that multiple pathological processes converge on a cluster of affiliated symptoms. Schizophrenia and other psychotic disorders are increasingly thought of as neurodevelopmental disorders, where multiple hits accumulate during critical periods of central nervous system (CNS) development to cause the disorders. The majority of patients with schizophrenia began with a prodromal phase characterized by subclinical symptoms of the disorder, which we will refer to hereafter as a state of clinical high risk for psychosis (CHR) [1,2,3,4]. In some studies, 22% of those meeting the criteria for CHR convert to a psychotic disorder at one year follow-up, as compared to 0.015% in the general population [5].
A growing body of literature supports a role for neuroinflammation and oxidative stress in the pathophysiology of psychosis. Although the underlying connection between these factors and development of psychosis is not yet clear, a promising target for these factors is a population of N-methyl-d-aspartate receptor (NMDAR)-containing parvalbumin interneurons (PVI) in the prefrontal cortex and hippocampus, which are likely disturbed during important developmental windows [6] (Figure 1).
In this review, we will propose a model suggesting how alterations in cellular homeostasis due to oxidative stress and immune dysfunction could lead to aberrant growth and/or pruning of these interneurons and lead to psychotic symptoms. We will then discuss efforts to characterize and intervene in the CHR population and discuss the implications of inflammation and oxidative stress to current and future therapies to try and prevent disease progression.

2. NMDAR Hypofunction and Psychosis

A major hypothesis about the origin of schizophrenia symptoms, is that they result from dysfunction in parvalbumin interneurons (PVIs), particularly through hypofunction of N-methyl-d-aspartate receptors (NMDARs) [7]. PVIs are fast-spiking GABAergic neurons that are crucial in synchronizing the firing of populations of pyramidal neurons in the cortex and generate the gamma oscillations associated with many of the higher-order cognitive processes that are interrupted in schizophrenia, such as working memory [7]. The first findings implicating NMDARs were studies of NMDAR antagonists, such as phencyclidine and ketamine, showing that subclinical doses of these drugs could mimic positive and negative symptoms, as well as cognitive deficits in healthy subjects [8]. These findings were further supported by other causes of NDMAR disruption, such as blockade by autoimmune antibodies in NMDAR encephalitis, which leads to severe psychosis and cognitive deficits [9,10]. In addition, NMDAR disruption may be upstream of the well-characterized hyperactivity of dopamine (D2) receptors in mesolimbic and mesocortical projections [11]. Whether cortical PVI disruptions are linked to mesolimbic dopaminergic dysfunction is not entirely clear, however, multiple studies have proposed that PVI disruption may cause dopamine dysfunction through loss of pyramidal cell inhibition in the hippocampal subiculum [11]. This disinhibition of pyramidal neurons leads to stimulation of the nucleus accumbens, followed by inhibition in ventral pallidum, effectively “taking the brake off”: the ventral tegmental area (VTA) dopamine release [12,13]. Thus, NMDAR hypofunction in PVIs may be a central feature of psychosis.
In addition, the healthy functioning of antioxidant and inflammatory/anti-inflammatory pathways may have important effects on the development and healthy functioning of PVIs. Decreased synapse density on the downstream pyramidal neuron, as measured by dendritic spine density, is a plausible mechanism by which disruptions in healthy development may occur [14]. This may occur in part through pathologically decreased perinatal growth or increased peripubertal pruning of these connections [7]. More precisely, since NMDARs play a key role in mediating long-term potentiation and other synaptic modifications that are dependent on the level of neuronal activity, low activity due to inflammation or oxidative stress could lead to long-term changes in PVIs, especially given that the relative number of NMDA receptors is highest perinatally, presumably because they play a critical role in deciding which neurons mature, and which are pruned [15]. In line with this, even mild antagonism of NMDARs in rodents postnatally can lead to lasting alterations in PVI number [16,17]. Moreover, PVIs are the last subset of interneurons to develop, which may explain how the effects of oxidative stress and inflammation (which are thought to be involved in the pathogenesis of many illnesses) may lead to the particular alterations seen in schizophrenia [7,18,19]. Thus, PVI NMDAR hypo-function seems to be an important factor in the development of psychosis.

3. Inflammation and Psychosis

Schizophrenia results from changes in the CNS that, at least for a significant subpopulation of patients, may result from neuroinflammation and abnormal immunological responses. Some of the first evidence for these effects came from epidemiological studies of the 1957 influenza pandemic showing a strong association between maternal infection in pregnancy and development of schizophrenia in offspring [20,21]. Subsequent studies demonstrated this effect to be dependent on immune activation and maternal cytokine release rather than the specific infectious agent [22,23]. Remarkably, it is suggested that as many as 14%–21% of schizophrenia cases could be prevented if maternal influenza infections were eliminated [24].
Another indicator of the importance of inflammation in schizophrenia comes from genetic studies. Multiple genome-wide association studies have implicated the major histocompatibility complex (MHC) island on chromosome 6, which is a cornerstone of the immune system, as having the strongest allelic association with schizophrenia [25,26]. In particular, the complement component 4 (C4 gene) within the human leukocyte antigen (HLA) island was found to have a strong association with schizophrenia [26]. C4 is involved in both opsonization of pathogens, and in synaptic pruning, which may provide one connection to the developmentally timed nature of schizophrenia risk [26]. There are many more examples of genetic predisposition resulting from variation in inflammatory gene complexes—for example polymorphisms in some pro-inflammatory cytokine gene complexes (e.g., interleukin-1β, IL1B) may be linked to increased likelihood of developing schizophrenia [27]. These large-scale genetic and epidemiological studies lend a great deal of credence to the idea that inflammation is important in the pathogenesis of schizophrenia, but the details of how come primarily from preclinical studies.

3.1. Evidence from Preclinical Models

Preclinical animal models have provided supporting evidence for the role of the immune system in the development of psychosis, including the disruption of PVI development [28]. Much of this evidence comes from maternal immune activation (MIA) models used to study this process, which attempt to study the predisposition to schizophrenia resulting from prenatal infection of the mother. MIA models use a variety of immunogenic agents such as the viral mimic poly I:C (polyriboinosinic–polyribocytidylic acid) or the bacterial mimic lipopolysaccharide (LPS). MIA models have reliably produced anatomical and behavioural alterations in the pups of exposed rodents that are thought to be analogous to human psychosis [29,30]. In addition, multiple changes in key neurotransmitter systems characteristic of schizophrenia have been noted in the MIA model, including hippocampal NMDAR hypofunction and enhanced sensitivity to acute dopaminergic stimulation [31]. Immunologic changes, such as “priming” of the CNS’s resident macrophages (microglia) may be one way in which MIA predisposes the offspring to psychosis. Rodent studies using the MIA model have also shown that maternal infection can increase the number and activation of microglia in the brain of pups even once they reach adolescence [32,33]. Given that microglia are the resident macrophages of the brain, and are instrumental in the process of synaptic pruning by actively engulfing synaptic material, they may be implicated in the structural aberrancies that are thought to result from abnormal pruning in schizophrenia [34]. This may be how activated microglia affect NMDAR-containing synapses, and microglia may be partly responsible for the hypofunction observed in PVIs in schizophrenia [35,36].

3.2. Clinical Studies

Studies of patients with schizophrenia typically examine inflammatory status after the illness is already established [37,38]. However, in CHR individuals, numerous inflammatory cytokines and markers appear to predict conversion to psychosis even before the onset of a diagnosable illness [39]. Furthermore, increases in peripheral inflammatory markers have been observed in first episode psychosis, and are linked to severity of psychopathology and cognitive impairment [40,41]. There is also some evidence of a chronic inflammatory state in patients with schizophrenia, including reductions in anti-inflammatory cytokines, and increases in inflammatory ones [42,43]. Finally, treatment with antipsychotic medication may act, at least in part, through an anti-inflammatory mechanism by modifying cytokine levels [43,44].
In addition to surrogate blood markers and post-mortem studies, a number of imaging studies have attempted to elucidate the role of inflammation in psychosis pathogenesis. However, given the complexity of immune responses in the brain, imaging neuroinflammation in vivo has posed a significant challenge [45,46,47]. Currently, positron emission tomography (PET) imaging of mitochondrial 18 kDa translocator protein (TSPO), which measures microglial activation, is the most valid approach for studying neuroinflammation in vivo [48]. Of nine studies that investigated in vivo brain neuroinflammation in schizophrenia to date [46,48,49,50,51,52,53,54,55], four studies reported higher neuroinflammation in medicated schizophrenia patients as compared to healthy volunteers [50,51,53,55]. However, three out of these four studies used a first-generation radioligand for TSPO, [11C]PK11195, which is known to have important methodological limitations. Furthermore, the only study showing positive results using a second-generation TSPO radioligand used an alternative methodology, which was not replicated when using the gold standard in the field [55,56]. Consistent with this, recent studies using second-generation TSPO radioligand and the gold standard methodology showed no significant differences in neuroinflammation between medicated [49] or drug-naïve [48] first-episode psychosis or schizophrenia patients [46] compared to healthy volunteers. Taken together, in vivo PET studies on neuroinflammation in schizophrenia do not support increased microglial activation, as most of the PET studies that reported increased neuroinflammation in patients with schizophrenia or in individuals with CHR had methodological limitations, while studies using validated methodologies with larger sample sizes did not observe a significant group effect [48]. Thus, it seems that neuroinflammation might only be present in a subgroup of patients, or only present at very early stages of the disease, or simply that we cannot observe it using our current in vivo probes.

4. Oxidative Stress and Psychosis

Reactive oxygen species (ROS) are by-products of aerobic metabolism, produced primarily in the mitochondria of cells throughout the human body. These chemical species are strongly implicated in aging and a plethora of disease processes due to their ability to chemically alter cellular components such as lipids and proteins [57]. Under normal circumstances, endogenous antioxidants such as glutathione (GSH), neutralize these factors and protect human tissues from excess damage [58]. Without sufficient antioxidant levels to keep ROS under control, neurotoxicity can occur through oxidation of macromolecules such as DNA, proteins, and fats, and though the activation of cell signalling pathways that alter cell behaviour [59]. Over time, these changes might lead to some of the structural and functional alterations that are seen in psychosis [60].

4.1. Preclinical Studies

Animal studies have been instrumental in understanding the developmental effects of oxidative imbalances on NMDAR function in the development of psychosis. For example, depletion of GSH postnatally leads to lasting psychosis-like symptomatology [61]. Furthermore, GSH deficits can reduce NMDAR function, which may in turn lead to decreases in cortical PVI number [16,62]. Moreover, studies preventing the formation of GSH through genetic modification of its biosynthetic enzyme, glutamate cysteine ligase (GCL) show oxidative stress that precedes PVI deficits, leading to long-term prefrontal and hippocampal PVI abnormalities with loss of synchronicity in high-frequency firing, and prolonged plasticity of hippocampal PVIs [63,64,65]. Conversely, pharmacological replenishment of GSH with its precursor, N-acetylcysteine (NAC) prevents PVI dysfunction in multiple rodent models of psychosis [66,67]. The severity of damage to PVIs may be due to the very high metabolic demands of these fast-spiking neurons, which requires a robust antioxidant system [6,68]. One mechanism by which the brain appears to protect PVIs is through a feedback loop between NMDAR activity and GSH synthesis. Increases in NMDAR activation lead to increases in GCL activity, while changes in oxidative stress regulate NMDAR activation at the GRIN2A subunit [69,70,71]. In line with this, repeated NMDAR antagonism with ketamine in rodents has been shown to cause elevations in brain superoxide radicals with dysfunction of PVIs that were preventable by inhibition of NADPH oxidase [72]. All of this points to a close relationship between GSH and NMDARs in mitigating oxidative damage in the brain, particularly in vulnerable fast-spiking PVIs. Thus, the disruption of this feedback loop by deficiencies in NMDAR could foreseeably lead to uncontrolled oxidation and neurotoxicity to PVIs.

4.2. Clinical Studies

As compared to animal studies, the picture of oxidative stress in humans with psychosis is much less clear. Most studies examine markers of oxidative status in blood, such as glutathione (GSH), superoxide dismutase (SOD) and markers of lipid oxidation, while others look at cerebrospinal fluid (CSF), post-mortem tissue, and in general, a number of these markers indicate oxidative imbalance [58,73,74,75,76]. Moreover, there may be a relationship between decreases in blood GSH and psychosis symptoms, as well as alterations of brain volume in schizophrenia [77,78]. The results of recent clinical trials suggest that administration of NAC in humans, when used with antipsychotic medications, may alleviate negative and cognitive symptoms in patients with schizophrenia [79,80]. Gene and protein alterations related to oxidative stress have also been noted. For instance, familial variations in a subunit of GCL, the enzyme responsible for GSH synthesis may increase the risk of schizophrenia up to four-fold [81]. On the other hand, levels of oxidative markers appear to vary significantly with clinical status in cross-sectional studies [58]. A recent extensive review on studies on the relationship between schizophrenia and oxidative stress found that peripheral markers of GSH were consistently decreased, but found equivocal results for other antioxidants such as superoxide dismutase and catalase [82]. One explanation for these inconsistencies may be the heterogeneous nature of schizophrenia in terms of etiology, medication adherence, or episodic variations in disease severity among patients [83]. For this reason, it may be more useful to characterize pro- and anti-oxidant factors according to their role as state markers (i.e., symptom-correlated) and trait markers (i.e., symptom independent). Using this methodology, a recent meta-analysis found that total antioxidant status, as well as red blood cell (RBC) catalase and plasma nitrite appeared to be state markers of schizophrenia, while RBC superoxide dismutase appeared to be a trait marker for schizophrenia [58].

4.3. Connections between Inflammation and Oxidative Stress

Oxidative stress and inflammation are intricately linked, and many of the deleterious effects of oxidative stress are likely mediated by inflammation, and vice versa. At a molecular level, oxidative stress induces inflammation via activation of nuclear factor κB (NF-κB), a rapid-acting transcriptional activator of inflammatory response that can also induce the production of more free radicals [84,85,86]. Conversely, the immune system is a major source of oxidative stress because activated microglia use NADPH oxidase to generate reactive superoxide to destroy pathogens, which can also damage the brain’s own neurons if not properly balanced with antioxidants [87]. Furthermore, some studies show that the development of psychosis in immune activation models may be mediated by an imbalance between pro-oxidants and anti-oxidants [88,89]. For example, one study using a maternal immune activation (MIA) model showed elevations in multiple markers of oxidative stress in the hippocampus of male offspring, including a decreased ratio of GSH to its reduced form, glutathione disulfide (GSSG) that was reversible by NAC administration [89]. Taken together, it appears that immune activation and oxidative stress may have a close reciprocal relationship in the development of psychosis, though the mechanisms are not fully understood.

5. Clinical Implications

The mainstay in schizophrenia management, treatment with antipsychotics, is associated with several side effects [90] and does not ameliorate cognitive or negative symptoms, which are closely linked to functional outcome [91]. Furthermore, only about 40% of patients have good adherence to their medications at any given time [92,93].
According to the current consensus on management of psychosis, early intervention in psychosis is associated with better outcome [94]. In order to do this effectively, it will be necessary to implement a clinical staging model that includes flagging of patients based on the progression of disease (e.g., high risk or first-episode psychosis) [94]. Given the current evidence on the implications of oxidative stress and neuroinflammation in the pathogenesis of schizophrenia, there is a great deal of interest in intervening in these processes as early as possible to prevent onset or slow progression of the disorder.
In terms of identifying individuals early, a recent multi-centre trial attempted to distinguish CHR individuals’ likelihood of conversion based on blood samples [95]. They were able to isolate 17 markers that were predictive of conversion, including multiple markers of inflammation and oxidative stress [39]. In this study, the use of multiple markers likely contributed to the success of the blood panel. The use of a panel of markers, such as the 10 proposed by Flatow et al., to measure total antioxidant status (TAS), may further increase the predictive value of such prognostic tests [58]. Further to the goal of early identification, there was a recent push for a new diagnostic label of ‘attenuated psychosis syndrome’ in the Diagnostic and Statistical Manual, Fifth Edition (DSM-V) [96]. Though the proposal was deemed premature due to problems with reliability in clinical assessment, the diagnostic construct remains a major subject of research into disease progression-modifying treatments [96]. There have been some clinical trials in CHR populations using prophylactic therapies in an attempt to prevent the conversion to schizophrenia [97,98,99,100,101,102,103,104,105]. These have included the use of omega-3 polyunsaturated fatty acids (PUFAs), anti-psychotic use, and numerous psychosocial and cognitive behavioural interventions. None of the studies using anti-psychotics found a significant difference in conversion rates, but treatment with PUFAs appeared to have a substantial effect on conversion despite lack of efficacy in full-blown psychosis, with a relative risk of 0.18 [106]. The success of PUFA treatment is very promising given its excellent tolerability, and led to reductions in conversion, better functioning and a general decrease in psychiatric morbidity at 6.7 years follow-up [107]. The mechanisms theorized to be at play in the use of PUFAs include anti-oxidant effect, enhanced mitochondrial performance, and protection of myelin sheath integrity [108,109,110], which have not been directly tested (i.e., no target engagement studies to date). Thus, the success of the trial with PUFAs provides a promising piece of evidence that intervening in inflammatory or oxidative processes early could reduce or prevent transition to psychosis and perhaps alter disease course.
However, these results must be interpreted with caution. The clinical trial on prophylactic PUFA administration [106,111] was not replicated in a very recent multicenter randomized clinical trial showing no significant effect of PUFA on conversion rate of individuals at ultra-high-risk for psychosis [105]. Thus, although inflammation and oxidative stress appear to be involved in developmental predisposition to schizophrenia, there are conflicting results on their involvement in the actual transition to psychosis. While some peripheral markers of inflammation appear to be elevated, recent brain imaging studies have shown no difference between CHR individuals and controls [46,48]. Furthermore, we were not able to find any published papers imaging in vivo glutathione levels in CHR individuals. One explanation for the lack of activated microglia in CHR may be that microglia do not require activation in order to undertake synaptic pruning [112]. In addition, contradictory or ambiguous results may result in part from heterogeneity in the pathogenesis and biochemical profile of different psychosis subgroups. For example, a recent landmark paper showed evidence of a correlation between inflammatory markers in schizophrenia and specific structural and functional alterations, likely reflecting an etiologic subgroup of patients [113]. This may point towards the need for a staging system based not only on clinical symptomatology, but also on underlying pathology and endophenotypes [114]. It is also worth noting that psychosocial interventions have shown neutral to positive results across multiple centres and trials, and as such are currently considered first-line treatment in CHR due to low side effects, although the underlying mechanism by which these interventions work is currently unknown [106].

6. Conclusions

Recent strides have been made in our understanding of schizophrenia as a disease, including the adoption of the NMDAR hypofunction hypothesis and a rapidly increasing interest in characterizing people in early stages of psychotic disorders. It is increasingly evident that oxidative balance and neuroinflammation interact with the developing brain during perinatal and peripubertal critical periods, especially relating to the formation and pruning of specific synapses formed by PVIs. How exactly this process works at a molecular level remains hazy at best, although it may involve dysfunctional microglia-mediated pruning, disruption of the feedback loop between oxidative stress and NMDAR, and loss of pyramidal dendritic spine density.
As preclinical trials continue to elucidate the complex inflammatory and oxidative processes that lead to the development of psychosis-like phenotypes, there must be a simultaneous push to understand the disease process in humans. Unfortunately, anti-psychotics are only effective for positive symptoms while negative and cognitive symptoms have the greatest contribution to functional outcome and quality of life of psychotic patients. More high-quality clinical trials that test for target engagement with large sample sizes on antioxidant and anti-inflammatory treatments are needed, along with research like the study by Perkins and colleagues [39], looking into prognostic and diagnostic indicators for psychosis. It is noteworthy that due to the complexity of oxidative stress and inflammatory pathways in the human body, as well as the off-target effects that medications could potentially have, future clinical trials ideally need to be more specific in terms of what they are targeting in the human body. This must be paired with more basic research using techniques such as PET and MRS that provide in vivo information about the inflammatory and oxidative processes that are occurring in high-risk individuals.

Acknowledgments

This study was funded by Meighen family directorate for high risk youth.

Author Contributions

Henry Barron, Sina Hafizi, Ana C. Andreazza, and Romina Mizrahi designed the study, and wrote the manuscript. All authors read and approved the final manuscript.

Conflicts of Interest

The authors declare no conflict of interest related to this work.

References

  1. Riecher, A.; Maurer, K.; Loffler, W.; Fatkenheuer, B.; der Heiden, W.; Hafner, H. Schizophrenia—A disease of young single males? Preliminary results from an investigation on a representative cohort admitted to hospital for the first time. Eur. Arch. Psychiatry Neurol. Sci. 1989, 239, 210–212. [Google Scholar] [CrossRef] [PubMed]
  2. Hafner, H.; Riecher-Rossler, A.; Hambrecht, M.; Maurer, K.; Meissner, S.; Schmidtke, A.; Fatkenheuer, B.; Loffler, W.; van der Heiden, W. Iraos: An instrument for the assessment of onset and early course of schizophrenia. Schizophr. Res. 1992, 6, 209–223. [Google Scholar] [CrossRef]
  3. Hafner, H.; Maurer, K.; Loffler, W.; an der Heiden, W.; Munk-Jorgensen, P.; Hambrecht, M.; Riecher-Rossler, A. The abc schizophrenia study: A preliminary overview of the results. Soc. Psychiatry Psychiatr. Epidemiol. 1998, 33, 380–386. [Google Scholar] [CrossRef] [PubMed]
  4. Hafner, H.; Maurer, K.; Loffler, W.; Riecherrossler, A. The influence of age and sex on the onset and early course of schizophrenia. Br. J. Psychiatry 1993, 162, 80–86. [Google Scholar] [CrossRef] [PubMed]
  5. Fusar-Poli, P.; Bonoldi, I.; Yung, A.R.; Borgwardt, S.; Kempton, M.J.; Valmaggia, L.; Barale, F.; Caverzasi, E.; McGuire, P. Predicting psychosis meta-analysis of transition outcomes in individuals at high clinical risk. Arch. Gen. Psychiatry 2012, 69, 220–229. [Google Scholar] [CrossRef] [PubMed]
  6. Hardingham, G.E.; Do, K.Q. Linking early-life nmdar hypofunction and oxidative stress in schizophrenia pathogenesis. Nat. Rev. Neurosci. 2016, 17, 125–134. [Google Scholar] [CrossRef] [PubMed]
  7. Hoftman, G.D.; Datta, D.; Lewis, D.A. Layer 3 excitatory and inhibitory circuitry in the prefrontal cortex: Developmental trajectories and alterations in schizophrenia. Biol. Psychiatry 2016. [Google Scholar] [CrossRef] [PubMed]
  8. Krystal, J.H.; Karper, L.P.; Seibyl, J.P.; Freeman, G.K.; Delaney, R.; Bremner, J.D.; Heninger, G.R.; Bowers, M.B., Jr.; Charney, D.S. Subanesthetic effects of the noncompetitive nmda antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch. Gen. Psychiatry 1994, 51, 199–214. [Google Scholar] [CrossRef] [PubMed]
  9. Schwarcz, R.; Bruno, J.P.; Muchowski, P.J.; Wu, H.Q. Kynurenines in the mammalian brain: When physiology meets pathology. Nat. Rev. Neurosci. 2012, 13, 465–477. [Google Scholar] [CrossRef] [PubMed]
  10. Dalmau, J.; Lancaster, E.; Martinez-Hernandez, E.; Rosenfeld, M.R.; Balice-Gordon, R. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol. 2011, 10, 63–74. [Google Scholar] [CrossRef]
  11. Howes, O.D.; Kapur, S. The dopamine hypothesis of schizophrenia: Version III—The final common pathway. Schizophr. Bull. 2009, 35, 549–562. [Google Scholar] [CrossRef] [PubMed]
  12. Grace, A.A. Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression. Nat. Rev. Neurosci. 2016, 17, 524–532. [Google Scholar] [CrossRef] [PubMed]
  13. Modinos, G.; Allen, P.; Grace, A.A.; McGuire, P. Translating the mam model of psychosis to humans. Trends Neurosci. 2015, 38, 129–138. [Google Scholar] [CrossRef] [PubMed]
  14. Lewis, D.A.; Hashimoto, T.; Volk, D.W. Cortical inhibitory neurons and schizophrenia. Nat. Rev. Neurosci. 2005, 6, 312–324. [Google Scholar] [CrossRef] [PubMed]
  15. Malenka, R.C.; Bear, M.F. LTP and LTD: An embarrassment of riches. Neuron 2004, 44, 5–21. [Google Scholar] [CrossRef] [PubMed]
  16. Wang, X.; Pinto-Duarte, A.; Sejnowski, T.J.; Behrens, M.M. How NOX2-containing NADPH oxidase affects cortical circuits in the NMDA receptor antagonist model of schizophrenia. Antioxid. Redox Signal. 2013, 18, 1444–1462. [Google Scholar] [CrossRef] [PubMed]
  17. Wang, C.Z.; Yang, S.F.; Xia, Y.; Johnson, K.M. Postnatal phencyclidine administration selectively reduces adult cortical parvalbumin-containing interneurons. Neuropsychopharmacology 2008, 33, 2442–2455. [Google Scholar] [CrossRef] [PubMed]
  18. Gulyas, A.I.; Megias, M.; Emri, Z.; Freund, T.F. Total number and ratio of excitatory and inhibitory synapses converging onto single interneurons of different types in the CA1 area of the rat hippocampus. J. Neurosci. 1999, 19, 10082–10097. [Google Scholar] [PubMed]
  19. Sullivan, E.M.; O’Donnell, P. Inhibitory interneurons, oxidative stress, and schizophrenia. Schizophr. Bull. 2012, 38, 373–376. [Google Scholar] [CrossRef] [PubMed]
  20. Barr, C.E.; Mednick, S.A.; Munk-Jorgensen, P. Exposure to influenza epidemics during gestation and adult schizophrenia: A 40-year study. Arch. Gen. Psychiatry 1990, 47, 869–874. [Google Scholar] [CrossRef] [PubMed]
  21. Mednick, S.A.; Machon, R.A.; Huttunen, M.O.; Bonett, D. Adult schizophrenia following prenatal exposure to an influenza epidemic. Arch. Gen. Psychiatry 1988, 45, 189–192. [Google Scholar] [CrossRef] [PubMed]
  22. Brown, A.S.; Patterson, P.H. Maternal infection and schizophrenia: Implications for prevention. Schizophr. Bull. 2011, 37, 284–290. [Google Scholar] [CrossRef] [PubMed]
  23. Feigenson, K.A.; Kusnecov, A.W.; Silverstein, S.M. Inflammation and the two-hit hypothesis of schizophrenia. Neurosci. Biobehav. Rev. 2014, 38, 72–93. [Google Scholar] [CrossRef] [PubMed]
  24. Brown, A.S. Prenatal infection as a risk factor for schizophrenia. Schizophr. Bull. 2006, 32, 200–202. [Google Scholar] [CrossRef] [PubMed]
  25. International Schizophrenia, C.; Purcell, S.M.; Wray, N.R.; Stone, J.L.; Visscher, P.M.; O'Donovan, M.C.; Sullivan, P.F.; Sklar, P. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 2009, 460, 748–752. [Google Scholar]
  26. Sekar, A.; Bialas, A.R.; de Rivera, H.; Davis, A.; Hammond, T.R.; Kamitaki, N.; Tooley, K.; Presumey, J.; Baum, M.; van Doren, V.; et al. Schizophrenia risk from complex variation of complement component 4. Nature 2016, 530, 177–183. [Google Scholar] [CrossRef] [PubMed]
  27. Ellman, L.M.; Deicken, R.F.; Vinogradov, S.; Kremen, W.S.; Poole, J.H.; Kern, D.M.; Tsai, W.Y.; Schaefer, C.A.; Brown, A.S. Structural brain alterations in schizophrenia following fetal exposure to the inflammatory cytokine interleukin-8. Schizophr. Res. 2010, 121, 46–54. [Google Scholar] [CrossRef] [PubMed]
  28. Steullet, P.; Cabungcal, J.; Monin, A.; Dwir, D.; O’Donnell, P.; Cuenod, M.; Do, K. Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: A “central hub” in schizophrenia pathophysiology? Schizophr. Res. 2016, 176, 41–51. [Google Scholar] [CrossRef] [PubMed]
  29. Piontkewitz, Y.; Arad, M.; Weiner, I. Abnormal trajectories of neurodevelopment and behavior following in utero insult in the rat. Biol. Psychiatry 2011, 70, 842–851. [Google Scholar] [CrossRef] [PubMed]
  30. Meyer, U.; Feldon, J. To poly(I:C) or not to poly(I:C): Advancing preclinical schizophrenia research through the use of prenatal immune activation models. Neuropharmacology 2012, 62, 1308–1321. [Google Scholar] [CrossRef] [PubMed]
  31. Meyer, U.; Feldon, J.; Schedlowski, M.; Yee, B.K. Towards an immuno-precipitated neurodevelopmental animal model of schizophrenia. Neurosci. Biobehav. Rev. 2005, 29, 913–947. [Google Scholar] [CrossRef] [PubMed]
  32. Bland, S.T.; Beckley, J.T.; Young, S.; Tsang, V.; Watkins, L.R.; Maier, S.F.; Bilbo, S.D. Enduring consequences of early-life infection on glial and neural cell genesis within cognitive regions of the brain. Brain Behav. Immun. 2010, 24, 329–338. [Google Scholar] [CrossRef] [PubMed]
  33. Juckel, G.; Manitz, M.P.; Brune, M.; Friebe, A.; Heneka, M.T.; Wolf, R.J. Microglial activation in a neuroinflammational animal model of schizophrenia—A pilot study. Schizophr. Res. 2011, 131, 96–100. [Google Scholar] [CrossRef] [PubMed]
  34. Paolicelli, R.C.; Bolasco, G.; Pagani, F.; Maggi, L.; Scianni, M.; Panzanelli, P.; Giustetto, M.; Ferreira, T.A.; Guiducci, E.; Dumas, L.; et al. Synaptic pruning by microglia is necessary for normal brain development. Science 2011, 333, 1456–1458. [Google Scholar] [CrossRef] [PubMed]
  35. Hayashi, Y.; Ishibashi, H.; Hashimoto, K.; Nakanishi, H. Potentiation of the NMDA receptor-mediated responses through the activation of the glycine site by microglia secreting soluble factors. Glia 2006, 53, 660–668. [Google Scholar] [CrossRef] [PubMed]
  36. Takaki, J.; Fujimori, K.; Miura, M.; Suzuki, T.; Sekino, Y.; Sato, K. l-glutamate released from activated microglia downregulates astrocytic l-glutamate transporter expression in neuroinflammation: The “collusion” hypothesis for increased extracellular l-glutamate concentration in neuroinflammation. J. Neuroin. 2012, 9, 275. [Google Scholar] [CrossRef] [PubMed]
  37. García-Bueno, B.; Bioque, M.; Mac-Dowell, K.S.; Barcones, M.F.; Martínez-Cengotitabengoa, M.; Pina-Camacho, L.; Rodríguez-Jiménez, R.; Sáiz, P.A.; Castro, C.; Lafuente, A. Pro-/anti-inflammatory dysregulation in patients with first episode of psychosis: Toward an integrative inflammatory hypothesis of schizophrenia. Schizophr. Bull. 2014, 40, 376–387. [Google Scholar] [CrossRef] [PubMed]
  38. Dickerson, F.; Stallings, C.; Origoni, A.; Schroeder, J.; Katsafanas, E.; Schweinfurth, L.; Savage, C.; Khushalani, S.; Yolken, R. Inflammatory markers in recent onset psychosis and chronic schizophrenia. Schizophr. Bull. 2016, 42, 134–141. [Google Scholar] [CrossRef] [PubMed]
  39. Perkins, D.O.; Jeffries, C.D.; Addington, J.; Bearden, C.E.; Cadenhead, K.S.; Cannon, T.D.; Cornblatt, B.A.; Mathalon, D.H.; McGlashan, T.H.; Seidman, L.J.; et al. Towards a psychosis risk blood diagnostic for persons experiencing high-risk symptoms: Preliminary results from the napls project. Schizophr. Bull. 2015, 41, 419–428. [Google Scholar] [CrossRef] [PubMed]
  40. Goldsmith, D.; Rapaport, M.; Miller, B. A meta-analysis of blood cytokine network alterations in psychiatric patients: Comparisons between schizophrenia, bipolar disorder and depression. Mol. Psychiatry 2016, 21, 1696–1709. [Google Scholar] [CrossRef] [PubMed]
  41. Martínez-Cengotitabengoa, M.; Micó, J.A.; Arango, C.; Castro-Fornieles, J.; Graell, M.; Payá, B.; Leza, J.C.; Zorrilla, I.; Parellada, M.; López, M.P. Basal low antioxidant capacity correlates with cognitive deficits in early onset psychosis: A 2-year follow-up study. Schizophr. Res. 2014, 156, 23–29. [Google Scholar] [CrossRef] [PubMed]
  42. Miller, B.J.; Buckley, P.; Seabolt, W.; Mellor, A.; Kirkpatrick, B. Meta-analysis of cytokine alterations in schizophrenia: Clinical status and antipsychotic effects. Biol. Psychiatry 2011, 70, 663–671. [Google Scholar] [CrossRef] [PubMed]
  43. Maes, M.; Bosmans, E.; Ranjan, R.; Vandoolaeghe, E.; Meltzer, H.Y.; de Ley, M.; Berghmans, R.; Stans, G.; Desnyder, R. Lower plasma CC16, a natural anti-inflammatory protein, and increased plasma interleukin-1 receptor antagonist in schizophrenia: Effects of antipsychotic drugs. Schizophr. Res. 1996, 21, 39–50. [Google Scholar] [CrossRef]
  44. Maes, M.; Bosmans, E.; Kenis, G.; de Jong, R.; Smith, R.S.; Meltzer, H.Y. In vivo immunomodulatory effects of clozapine in schizophrenia. Schizophr. Res. 1997, 26, 221–225. [Google Scholar] [CrossRef]
  45. Carter, C.S.; Bullmore, E.T.; Harrison, P. Is there a flame in the brain in psychosis? Biol. Psychiatry 2014, 75, 258–259. [Google Scholar] [CrossRef] [PubMed]
  46. Kenk, M.; Selvanathan, T.; Rao, N.; Suridjan, I.; Rusjan, P.; Remington, G.; Meyer, J.H.; Wilson, A.A.; Houle, S.; Mizrahi, R. Imaging neuroinflammation in gray and white matter in schizophrenia: An in vivo pet study with [18F]-FEPPA. Schizophr. Bull. 2015, 41, 85–93. [Google Scholar] [CrossRef] [PubMed]
  47. Pasternak, O.; Kubicki, M.; Shenton, M.E. In vivo imaging of neuroinflammation in schizophrenia. Schizophr. Res. 2016, 173, 200–212. [Google Scholar] [CrossRef] [PubMed]
  48. Hafizi, S.; Tseng, H.H.; Rao, N.; Selvanathan, T.; Kenk, M.; Bazinet, R.P.; Suridjan, I.; Wilson, A.A.; Meyer, J.H.; Remington, G.; et al. Imaging microglial activation in untreated first-episode psychosis: A pet study with [18F]FEPPA. Am. J. Psychiatry 2017, 174, 118–124. [Google Scholar] [CrossRef] [PubMed]
  49. Coughlin, J.; Wang, Y.; Ambinder, E.; Ward, R.; Minn, I.; Vranesic, M.; Kim, P.; Ford, C.; Higgs, C.; Hayes, L. In vivo markers of inflammatory response in recent-onset schizophrenia: A combined study using [11C]DPA-713 PET and analysis of CSF and plasma. Transl. Psychiatry 2016, 6, e777. [Google Scholar] [CrossRef] [PubMed]
  50. Doorduin, J.; de Vries, E.F.; Willemsen, A.T.; de Groot, J.C.; Dierckx, R.A.; Klein, H.C. Neuroinflammation in schizophrenia-related psychosis: A pet study. J. Nucl. Med. 2009, 50, 1801–1807. [Google Scholar] [CrossRef] [PubMed]
  51. Van Berckel, B.N.; Bossong, M.G.; Boellaard, R.; Kloet, R.; Schuitemaker, A.; Caspers, E.; Luurtsema, G.; Windhorst, A.D.; Cahn, W.; Lammertsma, A.A. Microglia activation in recent-onset schizophrenia: A quantitative (r)-[11C] PK11195 positron emission tomography study. Biol. Psychiatry 2008, 64, 820–822. [Google Scholar] [CrossRef] [PubMed]
  52. Takano, A.; Arakawa, R.; Ito, H.; Tateno, A.; Takahashi, H.; Matsumoto, R.; Okubo, Y.; Suhara, T. Peripheral benzodiazepine receptors in patients with chronic schizophrenia: A pet study with [11C]DAA1106. Int. J. Neuropsychopharmacol. 2010, 13, 943–950. [Google Scholar] [CrossRef] [PubMed]
  53. Holmes, S.E.; Hinz, R.; Drake, R.J.; Gregory, C.J.; Conen, S.; Matthews, J.C.; Anton-Rodriguez, J.M.; Gerhard, A.; Talbot, P.S. In vivo imaging of brain microglial activity in antipsychotic-free and medicated schizophrenia: A [11C](r)-PK11195 positron emission tomography study. Mol. Psychiatry 2016, 21, 1672–1679. [Google Scholar] [CrossRef] [PubMed]
  54. Van der Doef, T.F.; de Witte, L.D.; Sutterland, A.L.; Jobse, E.; Yaqub, M.; Boellaard, R.; de Haan, L.; Eriksson, J.; Lammertsma, A.A.; Kahn, R.S. In vivo (r)-[11C] PK11195 pet imaging of 18 kDa translocator protein in recent onset psychosis. NPJ Schizophr. 2016, 2, 16031. [Google Scholar] [CrossRef] [PubMed]
  55. Bloomfield, P.S.; Selvaraj, S.; Veronese, M.; Rizzo, G.; Bertoldo, A.; Owen, D.R.; Bloomfield, M.A.; Bonoldi, I.; Kalk, N.; Turkheimer, F. Microglial activity in people at ULTRA high risk of psychosis and in schizophrenia: An [11C] PBR28 pet brain imaging study. Am. J. Psychiatry 2015, 173, 44–52. [Google Scholar] [CrossRef] [PubMed]
  56. Narendran, R.; Frankle, W.G. Comment on analyses and conclusions of “microglial activity in people at ULTRA high risk of psychosis and in schizophrenia: An [11C] PBR28 pet brain imaging study”. Am. J. Psychiatry 2016, 173, 536–537. [Google Scholar] [CrossRef] [PubMed]
  57. Turrens, J.F. Mitochondrial formation of reactive oxygen species. J. Physiol. 2003, 552, 335–344. [Google Scholar] [CrossRef] [PubMed]
  58. Flatow, J.; Buckley, P.; Miller, B.J. Meta-analysis of oxidative stress in schizophrenia. Biol. Psychiatry 2013, 74, 400–409. [Google Scholar] [CrossRef] [PubMed]
  59. Machado, A.K.; Pan, A.Y.; da Silva, T.M.; Duong, A.; Andreazza, A.C. Upstream pathways controlling mitochondrial function in major psychosis a focus on bipolar disorder. Can. J. Psychiatry 2016, 61, 446–456. [Google Scholar] [CrossRef] [PubMed]
  60. Prabakaran, S.; Swatton, J.E.; Ryan, M.M.; Huffaker, S.J.; Huang, J.T.; Griffin, J.L.; Wayland, M.; Freeman, T.; Dudbridge, F.; Lilley, K.S.; et al. Mitochondrial dysfunction in schizophrenia: Evidence for compromised brain metabolism and oxidative stress. Mol. Psychiatry 2004, 9, 684–697. [Google Scholar] [CrossRef] [PubMed]
  61. Jacobsen, J.P.; Rodriguiz, R.M.; Mork, A.; Wetsel, W.C. Monoaminergic dysregulation in glutathione-deficient mice: Possible relevance to schizophrenia? Neuroscience 2005, 132, 1055–1072. [Google Scholar] [CrossRef] [PubMed]
  62. Steullet, P.; Neijt, H.C.; Cuenod, M.; Do, K.Q. Synaptic plasticity impairment and hypofunction of NMDA receptors induced by glutathione deficit: Relevance to schizophrenia. Neuroscience 2006, 137, 807–819. [Google Scholar] [CrossRef] [PubMed]
  63. Morishita, H.; Cabungcal, J.H.; Chen, Y.; Do, K.Q.; Hensch, T.K. Prolonged period of cortical plasticity upon redox dysregulation in fast-spiking interneurons. Biol. Psychiatry 2015, 78, 396–402. [Google Scholar] [CrossRef] [PubMed]
  64. Cabungcal, J.H.; Steullet, P.; Kraftsik, R.; Cuenod, M.; Do, K.Q. Early-life insults impair parvalbumin interneurons via oxidative stress: Reversal by N-acetylcysteine. Biol. Psychiatry 2013, 73, 574–582. [Google Scholar] [CrossRef] [PubMed]
  65. Steullet, P.; Cabungcal, J.H.; Kulak, A.; Kraftsik, R.; Chen, Y.; Dalton, T.P.; Cuenod, M.; Do, K.Q. Redox dysregulation affects the ventral but not dorsal hippocampus: Impairment of parvalbumin neurons, gamma oscillations, and related behaviors. J. Neurosci. 2010, 30, 2547–2558. [Google Scholar] [CrossRef] [PubMed]
  66. Cabungcal, J.H.; Counotte, D.S.; Lewis, E.M.; Tejeda, H.A.; Piantadosi, P.; Pollock, C.; Calhoon, G.G.; Sullivan, E.M.; Presgraves, E.; Kil, J.; et al. Juvenile antioxidant treatment prevents adult deficits in a developmental model of schizophrenia. Neuron 2014, 83, 1073–1084. [Google Scholar] [CrossRef] [PubMed]
  67. Otte, D.M.; Sommersberg, B.; Kudin, A.; Guerrero, C.; Albayram, O.; Filiou, M.D.; Frisch, P.; Yilmaz, O.; Drews, E.; Turck, C.W.; et al. N-acetyl cysteine treatment rescues cognitive deficits induced by mitochondrial dysfunction in g72/g30 transgenic mice. Neuropsychopharmacology 2011, 36, 2233–2243. [Google Scholar] [CrossRef] [PubMed]
  68. Cabungcal, J.H.; Steullet, P.; Morishita, H.; Kraftsik, R.; Cuenod, M.; Hensch, T.K.; Do, K.Q. Perineuronal nets protect fast-spiking interneurons against oxidative stress. Proc. Natl. Acad. Sci. USA 2013, 110, 9130–9135. [Google Scholar] [CrossRef] [PubMed]
  69. Papadia, S.; Soriano, F.X.; Leveille, F.; Martel, M.A.; Dakin, K.A.; Hansen, H.H.; Kaindl, A.; Sifringer, M.; Fowler, J.; Stefovska, V.; et al. Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses. Nat. Neurosci. 2008, 11, 476–487. [Google Scholar] [CrossRef] [PubMed]
  70. Baxter, P.S.; Bell, K.F.; Hasel, P.; Kaindl, A.M.; Fricker, M.; Thomson, D.; Cregan, S.P.; Gillingwater, T.H.; Hardingham, G.E. Synaptic NMDA receptor activity is coupled to the transcriptional control of the glutathione system. Nat. Commun. 2015, 6, 6761. [Google Scholar] [CrossRef] [PubMed]
  71. Lipton, S.A.; Choi, Y.B.; Takahashi, H.; Zhang, D.; Li, W.; Godzik, A.; Bankston, L.A. Cysteine regulation of protein function—as exemplified by NMDA-receptor modulation. Trends Neurosci. 2002, 25, 474–480. [Google Scholar] [CrossRef]
  72. Behrens, M.M.; Ali, S.S.; Dao, D.N.; Lucero, J.; Shekhtman, G.; Quick, K.L.; Dugan, L.L. Ketamine-induced loss of phenotype of fast-spiking interneurons is mediated by NADPH-oxidase. Science 2007, 318, 1645–1647. [Google Scholar] [CrossRef] [PubMed]
  73. Gawryluk, J.W.; Wang, J.F.; Andreazza, A.C.; Shao, L.; Young, L.T. Decreased levels of glutathione, the major brain antioxidant, in post-mortem prefrontal cortex from patients with psychiatric disorders. Int. J. Neuropsychopharmacol. 2011, 14, 123–130. [Google Scholar] [CrossRef] [PubMed]
  74. Do, K.Q.; Trabesinger, A.H.; Kirsten-Kruger, M.; Lauer, C.J.; Dydak, U.; Hell, D.; Holsboer, F.; Boesiger, P.; Cuenod, M. Schizophrenia: Glutathione deficit in cerebrospinal fluid and prefrontal cortex in vivo. Eur. J. Neurosci. 2000, 12, 3721–3728. [Google Scholar] [CrossRef] [PubMed]
  75. Wu, J.Q.; Kosten, T.R.; Zhang, X.Y. Free radicals, antioxidant defense systems, and schizophrenia. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2013, 46, 200–206. [Google Scholar] [CrossRef] [PubMed]
  76. Micó, J.A.; Rojas-Corrales, M.O.; Gibert-Rahola, J.; Parellada, M.; Moreno, D.; Fraguas, D.; Graell, M.; Gil, J.; Irazusta, J.; Castro-Fornieles, J. Reduced antioxidant defense in early onset first-episode psychosis: A case-control study. BMC Psychiatry 2011, 11, 26. [Google Scholar] [CrossRef] [PubMed][Green Version]
  77. Fraguas, D.; Gonzalez-Pinto, A.; Micó, J.A.; Reig, S.; Parellada, M.; Martínez-Cengotitabengoa, M.; Castro-Fornieles, J.; Rapado-Castro, M.; Baeza, I.; Janssen, J. Decreased glutathione levels predict loss of brain volume in children and adolescents with first-episode psychosis in a two-year longitudinal study. Schizophr. Res. 2012, 137, 58–65. [Google Scholar] [CrossRef] [PubMed]
  78. Yao, J.K.; Reddy, R.D.; van Kammen, D.P. Human plasma glutathione peroxidase and symptom severity in schizophrenia. Biol. Psychiatry 1999, 45, 1512–1515. [Google Scholar] [CrossRef]
  79. Lavoie, S.; Murray, M.M.; Deppen, P.; Knyazeva, M.G.; Berk, M.; Boulat, O.; Bovet, P.; Bush, A.I.; Conus, P.; Copolov, D.; et al. Glutathione precursor, N-acetyl-cysteine, improves mismatch negativity in schizophrenia patients. Neuropsychopharmacology 2008, 33, 2187–2199. [Google Scholar] [CrossRef] [PubMed]
  80. Matsuzawa, D.; Hashimoto, K. Magnetic resonance spectroscopy study of the antioxidant defense system in schizophrenia. Antioxid Redox Signal. 2011, 15, 2057–2065. [Google Scholar] [CrossRef] [PubMed]
  81. Tosic, M.; Ott, J.; Barral, S.; Bovet, P.; Deppen, P.; Gheorghita, F.; Matthey, M.L.; Parnas, J.; Preisig, M.; Saraga, M.; et al. Schizophrenia and oxidative stress: Glutamate cysteine ligase modifier as a susceptibility gene. Am. J. Hum. Genet. 2006, 79, 586–592. [Google Scholar] [CrossRef] [PubMed]
  82. Koga, M.; Serritella, A.V.; Sawa, A.; Sedlak, T.W. Implications for reactive oxygen species in schizophrenia pathogenesis. Schizophr. Res. 2016, 176, 52–71. [Google Scholar] [CrossRef] [PubMed]
  83. Lett, T.A.; Chakavarty, M.M.; Felsky, D.; Brandl, E.J.; Tiwari, A.K.; Gonçalves, V.F.; Rajji, T.K.; Daskalakis, Z.J.; Meltzer, H.Y.; Lieberman, J.A. The genome-wide supported microrna-137 variant predicts phenotypic heterogeneity within schizophrenia. Mol. Psychiatry 2013, 18, 443–450. [Google Scholar] [CrossRef] [PubMed]
  84. Hayden, M.S.; Ghosh, S. Signaling to NF-κB. G Dev. 2004, 18, 2195–2224. [Google Scholar] [CrossRef] [PubMed]
  85. Bitanihirwe, B.K.; Woo, T.U. Oxidative stress in schizophrenia: An integrated approach. Neurosci. Biobehav. Rev. 2011, 35, 878–893. [Google Scholar] [CrossRef] [PubMed]
  86. Liu, G.H.; Qu, J.; Shen, X. NF-κB/p65 antagonizes NRF2-are pathway by depriving CBP from NRF2 and facilitating recruitment of HDAC3 to MAFK. Biochim. Biophys. Acta 2008, 1783, 713–727. [Google Scholar] [CrossRef] [PubMed]
  87. Block, M.L.; Zecca, L.; Hong, J.S. Microglia-mediated neurotoxicity: Uncovering the molecular mechanisms. Nat. Rev. Neurosci. 2007, 8, 57–69. [Google Scholar] [CrossRef] [PubMed]
  88. Lante, F.; Meunier, J.; Guiramand, J.; de Jesus Ferreira, M.C.; Cambonie, G.; Aimar, R.; Cohen-Solal, C.; Maurice, T.; Vignes, M.; Barbanel, G. Late N-acetylcysteine treatment prevents the deficits induced in the offspring of dams exposed to an immune stress during gestation. Hippocampus 2008, 18, 602–609. [Google Scholar] [CrossRef] [PubMed]
  89. Lante, F.; Meunier, J.; Guiramand, J.; Maurice, T.; Cavalier, M.; de Jesus Ferreira, M.C.; Aimar, R.; Cohen-Solal, C.; Vignes, M.; Barbanel, G. Neurodevelopmental damage after prenatal infection: Role of oxidative stress in the fetal brain. Free Radic. Biol. Med. 2007, 42, 1231–1245. [Google Scholar] [CrossRef] [PubMed]
  90. Lambert, M.; Conus, P.; Eide, P.; Mass, R.; Karow, A.; Moritz, S.; Golks, D.; Naber, D. Impact of present and past antipsychotic side effects on attitude toward typical antipsychotic treatment and adherence. Eur. Psychiatry 2004, 19, 415–422. [Google Scholar] [CrossRef] [PubMed]
  91. Milev, P.; Ho, B.C.; Arndt, S.; Andreasen, N.C. Predictive values of neurocognition and negative symptoms on functional outcome in schizophrenia: A longitudinal first-episode study with 7-year follow-up. Am. J. Psychiatry 2005, 162, 495–506. [Google Scholar] [CrossRef] [PubMed]
  92. Valenstein, M.; Ganoczy, D.; McCarthy, J.F.; Kim, H.M.; Lee, T.A.; Blow, F.C. Antipsychotic adherence over time among patients receiving treatment for schizophrenia: A retrospective review. J. Clin. Psychiatry 2006, 67, 1542–1550. [Google Scholar] [CrossRef] [PubMed]
  93. García, S.; Martínez-Cengotitabengoa, M.; López-Zurbano, S.; Zorrilla, I.; López, P.; Vieta, E.; González-Pinto, A. Adherence to antipsychotic medication in bipolar disorder and schizophrenic patients: A systematic review. J. Clin. Psychopharmacol. 2016, 36, 355. [Google Scholar] [CrossRef] [PubMed]
  94. McGorry, P.D.; Killackey, E.; Yung, A. Early intervention in psychosis: Concepts, evidence and future directions. World Psychiatry 2008, 7, 148–156. [Google Scholar] [CrossRef] [PubMed]
  95. Addington, J.; Cadenhead, K.S.; Cornblatt, B.A.; Mathalon, D.H.; McGlashan, T.H.; Perkins, D.O.; Seidman, L.J.; Tsuang, M.T.; Walker, E.F.; Woods, S.W.; et al. North american prodrome longitudinal study (NAPLS 2): Overview and recruitment. Schizophr. Res. 2012, 142, 77–82. [Google Scholar] [CrossRef] [PubMed]
  96. Tsuang, M.T.; Van Os, J.; Tandon, R.; Barch, D.M.; Bustillo, J.; Gaebel, W.; Gur, R.E.; Heckers, S.; Malaspina, D.; Owen, M.J.; et al. Attenuated psychosis syndrome in DSM-5. Schizophr. Res. 2013, 150, 31–35. [Google Scholar] [CrossRef] [PubMed]
  97. McGlashan, T.H.; Zipursky, R.B.; Perkins, D.; Addington, J.; Miller, T.; Woods, S.W.; Hawkins, K.A.; Hoffman, R.E.; Preda, A.; Epstein, I.; et al. Randomized, double-blind trial of olanzapine versus placebo in patients prodromally symptomatic for psychosis. Am. J. Psychiatry 2006, 163, 790–799. [Google Scholar] [CrossRef] [PubMed]
  98. McGorry, P.D.; Nelson, B.; Phillips, L.J.; Yuen, H.P.; Francey, S.M.; Thampi, A.; Berger, G.E.; Amminger, G.P.; Simmons, M.B.; Kelly, D.; et al. Randomized controlled trial of interventions for young people at ULTRA-high risk of psychosis: Twelve-month outcome. J. Clin. Psychiatry 2013, 74, 349–356. [Google Scholar] [CrossRef] [PubMed]
  99. Phillips, L.J.; McGorry, P.D.; Yuen, H.P.; Ward, J.; Donovan, K.; Kelly, D.; Francey, S.M.; Yung, A.R. Medium term follow-up of a randomized controlled trial of interventions for young people at ULTRA high risk of psychosis. Schizophr. Res. 2007, 96, 25–33. [Google Scholar] [CrossRef] [PubMed]
  100. Addington, J.; Epstein, I.; Liu, L.; French, P.; Boydell, K.M.; Zipursky, R.B. A randomized controlled trial of cognitive behavioral therapy for individuals at clinical high risk of psychosis. Schizophr. Res. 2011, 125, 54–61. [Google Scholar] [CrossRef] [PubMed]
  101. Bechdolf, A.; Wagner, M.; Ruhrmann, S.; Harrigan, S.; Putzfeld, V.; Pukrop, R.; Brockhaus-Dumke, A.; Berning, J.; Janssen, B.; Decker, P.; et al. Preventing progression to first-episode psychosis in early initial prodromal states. Br. J. Psychiatry 2012, 200, 22–29. [Google Scholar] [CrossRef] [PubMed]
  102. Morrison, A.P.; French, P.; Parker, S.; Roberts, M.; Stevens, H.; Bentall, R.P.; Lewis, S.W. Three-year follow-up of a randomized controlled trial of cognitive therapy for the prevention of psychosis in people at ultrahigh risk. Schizophr. Bull. 2007, 33, 682–687. [Google Scholar] [CrossRef] [PubMed]
  103. Morrison, A.P.; French, P.; Stewart, S.L.; Birchwood, M.; Fowler, D.; Gumley, A.I.; Jones, P.B.; Bentall, R.P.; Lewis, S.W.; Murray, G.K. Early detection and intervention evaluation for people at risk of psychosis: Multisite randomised controlled trial. BMJ 2012, 344. [Google Scholar] [CrossRef] [PubMed]
  104. van der Gaag, M.; Nieman, D.H.; Rietdijk, J.; Dragt, S.; Ising, H.K.; Klaassen, R.M.; Koeter, M.; Cuijpers, P.; Wunderink, L.; Linszen, D.H. Cognitive behavioral therapy for subjects at ultrahigh risk for developing psychosis: A randomized controlled clinical trial. Schizophr. Bull. 2012, 38, 1180–1188. [Google Scholar] [CrossRef] [PubMed]
  105. McGorry, P.D.; Nelson, B.; Markulev, C.; Yuen, H.P.; Schäfer, M.R.; Mossaheb, N.; Schlögelhofer, M.; Smesny, S.; Hickie, I.B.; Berger, G.E. Effect of ω-3 polyunsaturated fatty acids in young people at ultrahigh risk for psychotic disorders: The neurapro randomized clinical trial. JAMA Psychiatry 2017, 74, 19–27. [Google Scholar] [CrossRef] [PubMed]
  106. Millan, M.J.; Andrieux, A.; Bartzokis, G.; Cadenhead, K.; Dazzan, P.; Fusar-Poli, P.; Gallinat, J.; Giedd, J.; Grayson, D.R.; Heinrichs, M.; et al. Altering the course of schizophrenia: Progress and perspectives. Nat. Rev. Drug Discov. 2016, 15, 485–515. [Google Scholar] [CrossRef] [PubMed]
  107. Amminger, G.P.; Schafer, M.R.; Schlogelhofer, M.; Klier, C.M.; McGorry, P.D. Longer-term outcome in the prevention of psychotic disorders by the vienna omega-3 study. Nat. Commun. 2015, 6, 7934. [Google Scholar] [CrossRef] [PubMed]
  108. Schlogelhofer, M.; Amminger, G.P.; Schaefer, M.R.; Fusar-Poli, P.; Smesny, S.; McGorry, P.; Berger, G.; Mossaheb, N. Polyunsaturated fatty acids in emerging psychosis: A safer alternative? Early Interv. Psychiatry 2014, 8, 199–208. [Google Scholar] [CrossRef] [PubMed]
  109. Bondi, C.O.; Taha, A.Y.; Tock, J.L.; Totah, N.K.; Cheon, Y.; Torres, G.E.; Rapoport, S.I.; Moghaddam, B. Adolescent behavior and dopamine availability are uniquely sensitive to dietary ω-3 fatty acid deficiency. Biol. Psychiatry 2014, 75, 38–46. [Google Scholar] [CrossRef] [PubMed]
  110. English, J.A.; Harauma, A.; Focking, M.; Wynne, K.; Scaife, C.; Cagney, G.; Moriguchi, T.; Cotter, D.R. Omega-3 fatty acid deficiency disrupts endocytosis, neuritogenesis, and mitochondrial protein pathways in the mouse hippocampus. Front. Genet. 2013, 4, 208. [Google Scholar] [CrossRef] [PubMed]
  111. Amminger, G.P.; Schafer, M.R.; Papageorgiou, K.; Klier, C.M.; Cotton, S.M.; Harrigan, S.M.; Mackinnon, A.; McGorry, P.D.; Berger, G.E. Long-chain ω-3 fatty acids for indicated prevention of psychotic disorders: A randomized, placebo-controlled trial. Arch. Gen. Psychiatry 2010, 67, 146–154. [Google Scholar] [CrossRef] [PubMed]
  112. Nayak, D.; Roth, T.L.; McGavern, D.B. Microglia development and function. Annu. Rev. Immunol. 2014, 32, 367–402. [Google Scholar] [CrossRef] [PubMed]
  113. Fillman, S.G.; Weickert, T.W.; Lenroot, R.K.; Catts, S.V.; Bruggemann, J.M.; Catts, V.S.; Weickert, C.S. Elevated peripheral cytokines characterize a subgroup of people with schizophrenia displaying poor verbal fluency and reduced broca’s area volume. Mol. Psychiatry 2016, 21, 1090–1098. [Google Scholar] [CrossRef] [PubMed]
  114. Klosterkötte, J. The clinical staging and the endophenotype approach as an integrative future perspective for psychiatry. World Psychiatry 2008, 7, 159–160. [Google Scholar] [CrossRef] [PubMed]
Figure 1. A simplified model of the link between neuroinflammation, oxidative stress and psychosis.
Figure 1. A simplified model of the link between neuroinflammation, oxidative stress and psychosis.
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