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Research in schizophrenia (SZ) emphasizes the need for new therapeutic approaches based on antioxidant/anti-inflammatory compounds and psycho-social therapy. A hallmark of SZ is a dysfunction of parvalbumin-expressing fast-spiking interneurons (PVI), which are essential for neuronal synchrony during sensory/cognitive processing. Oxidative stress and inflammation during early brain development, as observed in SZ, affect PVI maturation. We compared the efficacy of N-acetyl-cysteine (NAC) and/or environmental enrichment (EE) provided during juvenile and/or adolescent periods in rescuing PVI impairments induced by an additional oxidative insult during childhood in a transgenic mouse model with gluthation deficit (Gclm KO), relevant for SZ. We tested whether this rescue was promoted by the inhibition of MMP9/RAGE mechanism, both in the mouse model and in early psychosis (EP) patients, enrolled in a double-blind, randomized, placebo-controlled clinical trial of NAC supplementation for 6 months. We show that a sequential combination of NAC+EE applied after an early-life oxidative insult recovers integrity and function of PVI network in adult Gclm KO, via the inhibition of MMP9/RAGE. Six-month NAC treatment in EP patients reduces plasma sRAGE in association with increased prefrontal GABA, improvement of cognition and clinical symptoms, suggesting similar neuroprotective mechanisms. The sequential combination of NAC+EE reverses long-lasting effects of an early oxidative insult on PVI/perineuronal net (PNN) through the inhibition of MMP9/RAGE mechanism. In analogy, patients vulnerable to early-life insults could benefit from a combined pharmacological and psycho-social therapy.

Background The ability to recognize whether sensory consequences have been self-generated or externally produced is an important element of motor control and self-monitoring. Deficits in self-monitoring have been proposed to cause abnormal bodily experiences and psychotic symptoms such as hallucinations. A recent study designed a robotic system that applies sensorimotor stimulation in healthy subjects and safely induces mild presence hallucinations (PH) and passivity experiences (Blanke et al., 2014). PH are defined as the sensation that someone is close by when actually no one is present and passivity experiences are characterized by perceptions or beliefs that an external agent is controlling one’s actions, perceptions, and/or thoughts. Although, both symptoms occur in schizophrenia and Parkinson’s disease, their neural mechanisms are unknown. Methods Here, we first investigated the neural mechanisms of PH and passivity experiences in 25 healthy subjects. We developed a new MR-compatible robotic system able to generate the aforementioned sensorimotor conflicts, while recording subjects’ brain activity using fMRI. In addition, we applied lesion network mapping to 11 neurological patients with symptomatic PH and compared both populations to find a common PH network. In a final step, we investigated the relevance of the PH network by analyzing the connectivity of the PH network in resting state fMRI data from 58 psychotic patients. Results We first evaluated the regions associated with the general sensorimotor conflict, which revealed the left sensorimotor area, the left putamen, the right inferior parietal lobule and the right cerebellum. Then, we analyzed the regions that were more activated during the condition eliciting PH and passivity experiences and found the inferior frontal gyrus (IFG), the insula, the superior medial gyrus and the middle temporal gyrus (MTG). Comparison of these two networks with the symptomatic PH network in neurological patients highlighted the IFG, the MTG and the vPMc. The resting state analysis within those regions in psychotic patients revealed no global differences between the groups but a functional connectivity decrease between MTG and IFG (bilaterally) specific for psychotic patients experiencing passivity experiences. Discussion Collectively, we showed that through the use of a robotic system generating sensorimotor conflicts, the neural correlates of induced-PH and passivity experiences can be studied in healthy subjects in a controlled manner. In addition, we found two networks associated with induced-PH and passivity experience. Of these regions, three were also recruited in patients with PH of neurological origin, forming the PH network. MTG-IFG connectivity in the PH network was altered selectively in psychotic patients with passivity experiences, revealing the relevance of the neural mechanisms of PH and passivity experiences in psychosis.

Background Psychosis is often depicted as a disruption of the self-model. Patients suffering from psychosis report many symptoms relating to deficiencies in the minimal self, including loss of the sense of control over their actions (Sense of Agency) as well as numerous disturbances of body representation (e.g. Body Ownership). Positive symptoms of psychosis such as passivity symptoms and auditory hallucinations (termed first-rank symptoms) are characterized by a diminished demarcation of self-other boundaries, causing misattribution of self-generated actions to external sources. It has been suggested that this deficiency in self-monitoring in schizophrenia is due to abnormal sensorimotor prediction mechanisms, causing a loss of agency for actions and thoughts. While the neurobiological underpinnings of schizophrenia are yet unclear, many studies have reported aberrant neural connectivity in schizophrenia patients which may impact sensorimotor prediction and integration. Methods Recently, we have shown that introducing sensorimotor conflict (SMC) can induce psychosis like symptoms in healthy patients. Employing a master-slave robotic system we induced a conflict by introducing a delay between the participants’ movements and the haptic feedback. The SMC caused a feeling of a Presence (FoP) which is a first rank symptom of psychosis. The FoP is also found in neurological patients with lesions in cortical regions of the temporoparietal cortex, insular cortex and fronto-parietal cortex related to abnormal bodily self-representation. Here, we tested if SMC may cause misattribution of auditory stimuli and if this is related to neural connectivity. We tested first episode psychosis patients (N=31) with and without first rank symptoms (related to the sense of control over actions and thoughts) as well as healthy participants (N=20) on an auditory attribution task while inducing conflict with the master-slave robot. Results We found that when a SMC was introduced patients with first rank symptoms showed a decrease in their ability to judge if the auditory stimuli were in their own voice or the voice of another person. Resting state functional connectivity analysis indicated that the first rank patients had reduced connectivity in the network related to the SMC, but not in other control regions. Furthermore, the reduced functional connectivity correlated with the rates of auditory misattribution. Conclusions Our results show that induction of SMC can cause auditory misattributions, and that this is related to reduced cortical communication in regions related to sensorimotor body representation. These findings connect two influential theories of psychosis linking cognitive theories of sensorimotor prediction error in schizophrenia with systems level theories of neural disconnectivity. Understanding these neurocognitive mechanisms underlying the disruption of the self-model in psychosis may allow novel approaches in early diagnosis and treatment of these conditions.

Background Specialist early intervention (SEI) service models are designed to treat symptoms, promote social and vocational recovery, prevent relapse, and resource and up skill patients and their families. While the immediate benefits of SEI are clear, and have been demonstrated, the long-term impact of SEI on illness course is less clear. The First Episode Outcome Study involves the long-term follow-up of a representative sample of first episode psychosis patients who were first treated at the Early Psychosis Prevention and Intervention Centre (EPPIC) between 1998 and 2000. In this presentation the preliminary data on physical health outcomes are reported. Methods Between January 1998 and December 2000, 661 patients between the ages of 15–29 years were treated at the Early Psychosis Prevention and Intervention Centre, Melbourne Australia. The 18-month treatment characteristics of this cohort have been extensively examined in the First Episode Psychosis Outcome Study (FEPOS). The long-term outcomes of this cohort are now being examined in a new study (known as FEPOS15). Results The rates of self-report physical health problems in 100 participants 15 years after being treated for a first episode psychosis were significant for high cholesterol (41%), asthma (33.7%), chronic pain (25.3%), allergies (19.3%), respiratory problems (16.9%) anemia (12.2%), arthritis (12.0%), hepatitis C (10.8%) and diabetes (6.3%). Cardiovascular problems were also noted including heart attack (2.4%), other heart problems (8.4%), and stroke (3.6%). Sexual health problems are explored. Physical health findings pertaining to Coroners’ findings on those who had died will be also used to describe the long-term impacts of psychotic disorder. Discussion This follow-up study is one of the longest, largest and most comprehensive studies of the multidimensional outcomes of a SEI service for psychosis. The physical health outcomes of individuals 15-years after the first episode psychosis are poor. The importance of monitoring and managing physical health problems in those with psychotic disorder is highlighted.

Background Pharmacological, neurochemical and electrophysiological studies provide compelling evidence that N-methyl-D-aspartate-receptor (NMDAR) hypofunction is a pathologic feature of schizophrenia (SZ). GWAS studies highlighted risk genes such as Serine Racemase (SRR), which synthesizes D-Serine (D-Ser), the co-agonist of glycine site at NMDARs, and Serine Hydroxymethyltransferase (SHMT1) which synthesizes L-Serine (L-Ser), the substrate of SRR. Around 30% of patients do not respond to dopamine modulation and are considered to suffer from treatment resistant SZ (TRS). While the exact cause of TRS remains unclear, multiple lines of evidence suggest the involvement of a dysregulation of the Glutamate (Glu) neurotransmission. To test the hypothesis whether Glu system dysregulation mediated by NMDAR hypofunction is an underlying mechanism of TRS, we investigate the Glu and D-Ser pathways in TRS and treatment responder (RESP) early psychosis patients (EPP). Methods From a total of 621 EPP aged 18 to 35, included in the TIPP (early Intervention Program in Lausanne, Baumann & al., 2013), 225 EPP were classified as TRS (n=33) or RESP (n=192) according to the strict Treatment Response and Resistance in Psychosis (TRRIP) criteria (Howes & al., 2017), with compliance ascertained by antipsychotic plasma levels. A matched healthy control (HC) group (N=114) was also recruited (DIGS criteria). No patient was taking clozapine at baseline. Clinical data was collected over a 3-year period. At baseline, following systems were assessed: 1) D-Ser pathway: plasmatic D-Ser, L-Ser and Glycine by HPLC (Hashimoto & al., 2016), protein levels of SRR and SHMT1 by ELISA; 2) Glu pathway: Glu and glutamine in plasma (HPLC) and prefrontal cortex (magnetic resonance spectroscopy, Xin & al., 2016). Results D-Ser pathway: in TRS, SRR levels were decreased by 56% as compared to RESP. Interestingly, we observed a positive correlation between plasma levels of D-Ser (SRR metabolite) and L-Ser (SRR substrate) in the TRS (r= 0.58; p =0.0015) but not in the RESP group, suggesting that SRR dysregulation might be a limiting factor in TRS patients. Moreover, in TRS patients, SHMT1 levels were decreased by 15% as compared to RESP, with a positive correlation between the substrate and metabolite of SHMT1, glycine and L-Ser (r =0.48; p =0.011). Dysregulation of SHMT1 might thus be a limiting factor in the TRS group. As compared to HC, L-Ser and D-Ser were significantly increased in patients (p Glu pathway: comparing TRS with RESP patients, plasma Glu levels were increased in the TRS group (p Global Assessment of Functioning (GAF): at baseline, TRS and RESP displayed the same range of GAF. After a 3-year follow-up, TRS patients had poorer functioning as compared to RESP group (p Discussion Taken together, our results suggest that the TRS group, in which the levels of SRR and SHMT1 were lower and Glu plasma levels were higher, display a different regulation of the synthesis, degradation and/or accumulation of D-Ser and Glu as compared to the RESP group. However, replication in larger groups is needed. Moreover, our findings highlighted a dysregulation of D-Ser and Glu pathways in TRS patients in their early phase of psychosis. On the clinical side, our results confirm the significantly poorer functioning outcome in TRS patients.

Background The Clinical High Risk state (CHR) concept was implemented to promote the early detection of young help-seeking patients with higher risk of psychotic transition. This category is based on specific clinical criteria (EPA, 2015) and require narrow frequency/duration ratings of subclinical positive psychotic symptoms to allow its definition. Prevalence of CHR “category” appears nevertheless rare in help-seeking young people and the rate of psychotic transition of CHR state is lower than predicted by early studies. Therefore, the binary outcome of transition to psychosis proposed by the “CHR model” actually fails to be an efficient marker to stratify, in neurobiological studies, people with different psychopathological trajectories, notably those who develop psychosis from those who do not. In order to rely on a vulnerability model for schizophrenic psychosis more sensitive to psychosocial functioning and negative dimension, we study prospectively with three years of follow-up a population of help-seekers addressed for clinical suspicion of prodromal state of psychosis. We aimed here to identify subgroups of patients in a sample of subclinical psychotic states using psychological and cognitive outcomes as profiling criteria, focusing not only on transition but also on psychosocial functioning as main outcome. Methods A total of 32 help-seeking adolescents and young adults aged 14 to 35 were referred by health care providers for a specialized evaluation in case of suspicion of a prodromal psychotic state and/or detected by the French version of the Prodromal Questionnaire (PQ-16; cut-off 6/16). Their CHR status was assessed by the Structured Interview for Psychosis-Risk Syndromes (SIPS) and the Schizophrenia Proneness Instrument, Adult (SPI-A). Individuals included in the study presented either a CHR status, a subclinical CHR status or negative symptomatology. All subjects performed an additional neuropsychological battery and blood test for redox markers (Glutathione Peroxidase (GPx) and Glutathione Reductase (GR) activities) (Xin et al, 2016). Based on their clinical profile, we made a stratification of the patients using a Principal Component Analysis. Results Cognitive and psychological outcome stratification of all help-seekers revealed two subgroups (called group1 and group2) of patients with distinct profiles. Individuals in group1 (n=18) had greater levels of basic symptoms and general symptomatology. On the other hand, in group2 (n=14), individuals showed a weaker self-esteem and a lower rate of “living independently”. Cognitive scores for speed processing, attention, verbal learning and social cognition were significantly lower in group2 compared to group1. In addition, these cognitive outcomes were negatively correlated with negative symptoms only in group2. Analysis of redox markers revealed a positive correlation between GPx and GR activities in group1, a correlation disrupted in group2. Discussion Stratification of a cohort of young help-seekers with suspicion of prodromal psychosis, regardless of their CHR status, allowed us to distinguish two subgroups with different clinical profiles: group1 with higher levels of basic symptoms and general symptomatology, and group2 with weaker self-esteem, less autonomy and poorer neurocognition. In addition, analysis of redox markers revealed a redox dysregulation in patients with poorer cognitive profile. Considering the impact of neurocognitive impairment on functioning, special focus to patients of group2 is needed, mostly in clinical practice. Moreover, they might benefit of supplementation with antioxidant compounds such as NAC, which may improve cognitive deficits (Conus et al, 2018).

Background: Specialist early intervention (SEI) service models are designed to treat symptoms, promote social and vocational recovery, prevent relapse, and resource and up skill patients and their families. While the immediate benefits of SEI are clear, and have been demonstrated, the long-term impact of SEI on illness course is less clear. The First Episode Outcome Study involves the long-term follow-up of a representative sample of first-episode psychosis patients who were treated at the Early Psychosis Prevention and Intervention Centre (EPPIC) between 1998 and 2000. The aim of this presentation is 3-fold: (1) to describe the methodology of FEPOS long-term follow-up; (2) to present preliminary mortality data; and (3) examine the preliminary characteristics of those who have been contacted and interviewed. Methods: Between January 1998 and December 2000, 661 patients between the ages of 15 and 29 years were treated at the Early Psychosis Prevention and Intervention Centre, Melbourne, Australia. The 18-month treatment characteristics of this cohort have been extensively examined in the FEPOS. The long-term outcomes of this cohort are now being examined in a new study (known as FEPOS15). Results: Characteristics of 46 individuals who are deceased will be described. The clinical, functional, physical health, and quality-of-life characteristics of the first 100 individuals who have been contacted will also be discussed. Conclusion: This follow-up study is one of the longest, largest, and most comprehensive studies of the multidimensional outcomes of an SEI service for psychosis.

Background Beneficial effects of N-acetyl-cysteine (NAC) on negative symptoms in chronic schizophrenia have been reported in two studies. A recent study in early psychosis from our group, did not report significant improvement in negative symptoms (potentially linked to the modest baseline levels) but showed improvement in cognition (i.e. processing speed) and an increase in the brain antioxidant glutathione (GSH) levels, indicating good target engagement.1 Indeed, research in animal models highlights the critical role of redox regulation by brain GSH for white matter maturation and maintenance. Given the strong evidence of white matter (WM) alterations in schizophrenia as well as the current lack of etiological treatments, redox dysregulation is an interesting target. The current study aims at investigating the impact of NAC, a precursor of GSH, the main antioxidant in the brain, on WM integrity in patients in the early psychosis phase. We focused on the fornix bundle that has been shown to be impaired in an animal model of oxidative stress2 (i.e. impaired GSH synthesis) as well as in early psychosis patients.3 Methods WM diffusion properties were estimated using generalized fractional anisotropy (gFA) computed from diffusion spectrum imaging (DSI) brain scans acquired in patients who received either NAC (n=10; mean age=25.3 ± 5.7; males/females 9/1) or placebo (n=10; mean age=24.8 ± 7.9; males/females 5/5) as add-on treatment over 6-months. GSH levels were measured in the medial prefrontal cortex using Magnetic Resonance Spectroscopy (MRS). Results A non-parametric longitudinal voxel-based analysis limited to the fornix revealed a time x treatment interaction which reached significance in the body of the fornix (corrected p

Background Schizophrenia is a neurodevelopmental disease arising from complex interactions between genetic and environmental factors that cause disconnectivity within core brain networks including the thalamus. The thalamus has a central role in the pathophysiology of schizophrenia, however to what extent and how it is affected at the microstructural level is still a matter of debate. In the current study, we apply the Neurite Orientation Dispersion and Density Imaging (NODDI) [1], a recently developed MRI technique, which allows the estimation of the microstructural complexity of dendrites and axons in vivo. Methods Twenty-three patients with schizophrenia (SCHZ) were recruited from the Service of General Psychiatry (Lausanne University Hospital, Switzerland) (40.18 ± 9.2yo; 18/5 males/females) and 27 healthy controls (HC) (37.7 ± 7.95yo; 18/9 males/females). Magnetization-Prepared Rapid Acquisition Gradient Echo (MPRAGE) and a diffusion spectrum imaging (DSI) was performed on a 3-Tesla scanner (MAGNETOM Trio a Tim system, Siemens, Germany). Thalamus segmentation was performed on the MPRAGE sequence with an in house-pipeline using Freesurfer v5.0.0 for segmentation which was then refined to remove voxels within the ventricles and/or overlapping the internal capsule [2]. Orientation Dispersion Index (ODI), Intracellular Volume Fraction (ICVF) and, Isotropic Volume Fraction (ISOVF) were estimated based on the DSI sequence with NODDI [1]. General Linear Models (GLM) were estimated with outcome measures (ICVF, ISOVF, ODI) as dependent variables, group membership as a fixed factor (HC vs. SCHZ) and age and gender as potential covariates. References 1Battistella G, Najdenovska E, Maeder P, et al. Robust thalamic nuclei segmentation method based on local diffusion magnetic resonance properties. Brain Struct Funct 2016. DOI:10.1007/s00429-016-1336-4. 2Zhang H, Schneider T, Wheeler-kingshott CA, Alexander DC. NeuroImage NODDI : Practical in vivo neurite orientation dispersion and density imaging of the human brain. Neuroimage 2012; 61: 1000–16. Results Mean ODI was significantly increased in schizophrenia patients compared to controls in the right thalamus (F(1,48)=5.032, p= .030, np2 = .095) and in the left thalamus (F(1,48)=4.500, p= .039, np2 = .086). When controlled for age and gender, the difference remained significant for the right thalamus (F(1, 46) = 4.197, p = .046, np2 = .084) but reduced to trend level for the left thalamus (F(1, 46) = 4.029, p = .051, np2 = .081). There were no significant differences on the other measures (ICVF, ISOVF). Discussion Our results show that the thalamus is affected in patients with SCHZ at the microstructural level. The observed increase in ODI, which estimates the dispersion of neurite orientations, suggests disrupted neurite organization in patients as compared to HC.

Background The high prevalence of obesity in patients suffering from psychosis is a major concern as it dramatically increases the mortality rates of such patients in the long term. The mechanisms by which these patients develop overweight are poorly understood. It has been suggested that exposure to Childhood Trauma (CT) may play a role in the risk for obesity; however, whether this is the case for Early Psychosis (EP) patients and independently of the impact of medication has yet to be investigated. In addition, it is unknown whether the age at the time of exposure to CT can modulate the link between CT and obesity in EP patients. Methods 136 EP patients aged 18–35 were recruited from the Treatment and Early Intervention in Psychosis Program (TIPP-Lausanne). Body Mass Index (BMI), Weight Gain (WG) and Waist Circumference (WC) were measured and monitored prospectively after psychotropic prescription during a follow-up period of 1 year (patients were assessed at baseline, after 1, 2, 3, 6 months and 1 year of antipsychotic treatment). Patients were classified into Early-Trauma if they had faced at least one experience of abuse (physical, sexual, or emotional) or neglect (physical or emotional) before age 12, and Late-Trauma if the exposure had occurred between ages 12 and 16. Linear Mixed effect models with a random intercept were used to investigate the impact of Trauma (early or late) on the metabolic parameters longitudinally, Marko Chain Monte Carlo (MCMC) method was used to adjust these models with sufficiently large number of MCMC iterations. Models were adjusted for age, socioeconomic status, baseline BMI, medication intake prior to the first assessment and during the treatment phase, and by the diagnosis of depression. Results Patients were more likely to have a diagnosis of Schizophrenia (61%; N=83), they had a mean age of 26 at the time of first assessment, and exposure to 1 or more forms of traumatic experiences before 16 years of age was present in 32% of the sample. No differences between groups were found at baseline in terms of BMI or WC. Late-Trauma patients, when compared to Non-Trauma patients showed greater WCs during the follow-up (p=0.012). No differences between Early or Late-Trauma patients and Non-Trauma patients were found in any of the other outcome measures during the follow up. Baseline BMI and treatment duration were significantly associated with the level of BMI and WC during the follow up. None of the other potential confounding factors were significantly associated with the outcome measures during the follow up. Discussion Exposition to trauma during adolescence in EP patients is associated with a higher risk of greater WC during the early phase of the disease, independently of the medication intake, depression and other confounding factors. Specific preventive measures should be addressed in these patients in order to reduce the risk of obesity. Depending on the timing of traumatic exposure, different developmental mechanisms may underlie this differential possible impact on WC. Further studies on interactions between central consequences of traumatism and metabolic syndrome are warranted.

Background Oxidative stress, coupled with dysregulation of inflammation, NMDAR and dopamine, is involved in schizophrenia (SZ) pathophysiology. Earlier add-on clinical trials showed in chronic SZ patients that NAC, a precursor of glutathione (GSH), an important cerebral antioxidant, improved negative symptoms, mismatch negativity and local synchronization. We hypothesized that NAC at an earlier stage of illness would have a greater impact. Methods Early psychosis patients (EP, less than 5 years of illness, N=63; NAC=32, placebo=31) were supplemented with NAC (2.7g/day, 6 months) in a double-blind randomized placebo-controlled trial. Outcome measures: PANSS and neurocognition (MATRICS Consensus Cognitive Battery; n=36); quantification of medial prefronfal cortex glutathione (GSHmPFC) by 1H-magnetic-resonance-spectroscopy, of white matter diffusion properties estimated by generalized fractional anisotropy (gFA) computed from diffusion spectrum imaging (DSI), of blood cells GSH (GSHBC) and GSH peroxidase activity (GPxBC) at start and end of trial Results While PANSS negative and positive were not affected by NAC, NAC improved Processing Speed (NAC > Placebo; F(1, 30)=5.849, p=.022), favoring 2 of 3 processing speed tasks (Trail Making A, F(1, 30)=4.279, p=.048 & Verbal Fluency, F(1, 30)=5.749, p=.023). GSHmPFC (+23%, p=0.005) and GSHBC (+19%, p=0.05) were increased following NAC treatment. In patients with high-baseline GPxBC (>22.3U/gHb), subgroup explorations revealed an improvement of PANSS positive compared to placebo (p=0.02). The change of PANSS positive correlated negatively with that of GPxBC activity, showing that the improvement paralleled the restoration of redox status. NAC group showed 11% increase in fornix white matter integrity as measured by gFA, correlating with an increase in GSHmPFC over the 6-months period. Discussion This is the first clinical trial assessing the impact of NAC treatment in a sample of EP and the potential predictive role of peripheral biomarkers of redox dysregulation. The hypothesis that NAC would be beneficial to negative symptoms in EP was not confirmed in this small sample, most likely in reason of their very low level at baseline. The NAC induced GSHmPFC increase demonstrates its target engagement. NAC improved Processing Speed showing a therapeutic enhancement of cognitive functions. Most importantly, NAC improved fornix integrity, in association with brain GSH elevation, demonstrating for the first time that a redox regulator can enhance structural connectivity. Peripheral redox status allows identifying a subgroup of patients with improved positive symptoms. Future biomarker guided antioxidant interventions in larger EP samples should replicate these findings.

Background In schizophrenic patients, increasing evidence suggests that oxidative stress is involved on the disease pathophysiology. Estimation of the level of glutathione (GSH), main actor of the brain redox dysregulation, has revealed a decreased GSH levels in early psychosis patients (EPP). N-Acetyl-Cysteine (NAC) is an antioxidant and precursor of GSH, almost devoid of side effects. In chronic patients, add-on of NAC improved negative symptoms and reduced side effects of antipsychotics. In a recent double-blind randomized placebo-controlled trial, early psychosis patients received NAC supplementation. Whether NAC treatment leads to improvement in FC in EPP is unknown. Given the known connectivity disruptions in schizophrenia and given that GSH levels correlated with FC within the cingulate cortex, we investigate the effect of NAC supplementation during 6 months in EPP on cingulum cortex FC. Methods 20 EPP which constitutes a subgroup of the double-blind randomized placebo-controlled trial by [7] were scanned. T1-weighted volumes (1 mm in-plane, 1.2 mm slice thickness, TR/TE/TI 2300/2.98/900ms) and resting-state fMRI (gradient-echo-EPI sequence, 3.3x3.3x3.3 mm3, TR/TE 1920/30ms) recording were acquired on a Siemens-3T scanner in EPP who received either NAC (n=9) or placebo (n=11) as add-on treatment at baseline (T1) and follow-up (T2) after 6 months. A control group (n=93) was scanned in the same conditions. Data were processed with CMTK using a 68 regions parcellation according to a state-of-the-art pipeline. Time series were averaged over the Freesurfer regions and Pearson’s correlation was used as FC measure. We investigated FC changes occurring in the cingular cortices between T1 and T2 for NAC and placebo EPP and between EPP and CTRL by looking at the FC strength of these regions. Moreover, we assessed global efficiency and edge betweenness centrality (BC) for the whole brain network. Results FC between caudal and isthmus cingulate cortices increases significantly after 6 months for patients who received NAC supplementation (p=0.01) but not for patients who received the placebo. FC of these regions was also higher in patients after 6 months of NAC supplementation (but not in placebo or baseline patients). Regarding the local network measures, BC differences are observed for the same regions. Indeed, edge BC increases between caudal and isthmus cingulate regions after NAC supplementation compared to placebo (p=0.015). At the nodal level, the increase of BC can be mainly ascribed to the isthmus cingulate cortex (p=0.01). Discussion NAC supplementation has an impact on FC between caudal and isthmus cingulate regions in our dataset. NAC increases FC strength between these two regions. This strength is significantly higher than for matched control subjects. NAC has a stimulating effect on FC in regions along the cingulum bundle. This FC change could be partially explained by the changes in BC. The edge BC of the caudal and isthmus cingulate connection is increased for NAC subjects: a highest number of shortest paths go through this connection. It shows a growing importance of this edge in connecting the frontal and posterior regions of the brain network. A higher number of subjects would allow to confirming the robustness of these findings. This is a first study assessing the impact of NAC treatment on FC in a sample of EPP. After 6 months, NAC improves FC in caudal anterior and isthmus cingulate cortices. This FC increase is characterized by a higher BC in these brain areas, improving the connection between the frontal and posterior regions along the cingulum bundle. These results suggest that FC along the cingulum may be a biomarker for NAC treatment response.

Because increasing evidence point to the convergence of environmental and genetic risk factors to drive redox dysregulation in schizophrenia, we aim to clarify whether the metabolic anomalies associated with early psychosis reflect an adaptation to oxidative stress. Metabolomic profiling was performed to characterize the response to oxidative stress in fibroblasts from control individuals (n = 20) and early psychosis patients (n = 30), and in all, 282 metabolites were identified. In addition to the expected redox/antioxidant response, oxidative stress induced a decrease of lysolipid levels in fibroblasts from healthy controls that were largely muted in fibroblasts from patients. Most notably, fibroblasts from patients showed disrupted extracellular matrix- and arginine-related metabolism after oxidative stress, indicating impairments beyond the redox system. Plasma membrane and extracellular matrix, 2 regulators of neuronal activity and plasticity, appeared as particularly susceptible to oxidative stress and thus provide novel mechanistic insights for pathophysiological understanding of early stages of psychosis. Statistically, antipsychotic medication at the time of biopsy was not accounting for these anomalies in the metabolism of patients' fibroblasts, indicating that they might be intrinsic to the disease. Although these results are preliminary and should be confirmed in a larger group of patients, they nevertheless indicate that the metabolic signature of reactivity to oxidative stress may provide reliable early markers of psychosis. Developing protective measures aimed at normalizing the disrupted pathways should prevent the pathological consequences of environmental stressors.