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Early intervention in psychosis is crucial to improving patient response to treatment and the functional deficits that critically affect their long-term quality of life. Stratification tools are needed to personalize functional deficit prevention strategies at an early stage. In the present study, we applied topological tools to analyze symptoms of early psychosis patients, and detected a clear stratification of the cohort into three groups. One of the groups had a significantly better psychosocial outcome than the others after a 3-year clinical follow-up. This group was characterized by a metabolic profile indicative of an activated antioxidant response, while that of the groups with poorer outcome was indicative of oxidative stress. We replicated in a second cohort the finding that the three distinct clinical profiles at baseline were associated with distinct outcomes at follow-up, thus validating the predictive value of this new stratification. This approach could assist in personalizing treatment strategies.

Parkinson’s Disease is a neurodegenerative disorder characterized by the progressive loss of dopaminergic cells of thesubstantia nigra pars compacta. Even though successful transplantation of dopamine-producing cells into the striatum exhibits favourable effects in animal models and clinical trials; transplanted cell survival is low. Since every transplant elicits an inflammatory response which can affect cell survival and differentiation, we aimed to studyin vivoandin vitrothe impact of the pro-inflammatory environment on human dopaminergic precursors. We first observed that transplanted human dopaminergic precursors into the striatum of immunosuppressed rats elicited an early and sustained activation of astroglial and microglial cells after 15 days post-transplant. This long-lasting response was associated with Tumor necrosis factor alpha expression in microglial cells.In vitroconditioned media from activated BV2 microglial cells increased cell death, decreased Tyrosine hydroxylase -positive cells and induced morphological alterations on human neural stem cells-derived dopaminergic precursors at two differentiation stages: 19 days and 28 days. Those effects were ameliorated by inhibition of Tumor necrosis factor alpha, a cytokine which was previously detectedin vivoand in conditioned media from activated BV-2 cells. Our results suggest that a pro-inflammatory environment is sustained after transplantation under immunosuppression, providing a window of opportunity to modify this response to increase transplant survival and differentiation. In addition, our data show that the microglia-derived pro-inflammatory microenvironment has a negative impact on survival and differentiation of dopaminergic precursors. Finally, Tumor necrosis factor alpha plays a key role in these effects, suggesting that this cytokine could be an interesting target to increase the efficacy of human dopaminergic precursors transplantation in Parkinson’s Disease.

Background: Oxidative stress and glutathione (GSH) metabolism dysregulation has been implicated in the pathophysiology of schizophrenia. GAG-trinucleotide repeat (TNR) polymorphisms in the glutamate-cysteine ligase catalytic gene (GCLC), the rate-limiting enzyme for GSH synthesis, are associated with schizophrenia. In addition, GSH may serve as a reserve pool for neuronal glutamate (Glu) through the γ-glutamyl cycle. The aim of this study is to investigate brain [GSH] and its association with GCLC polymorphism, peripheral redox indices and brain Glu. Methods: Magnetic resonance spectroscopy was used to measure [GSH] and [Glu] in the medial prefrontal cortex (mPFC) of 25 early-psychosis patients and 33 controls. GCLC polymorphism was genotyped, glutathione peroxidases (GPx) and glutathione reductase (GR) activities were determined in blood cells. Results: Significantly lower [GSH mPFC ] in GCLC high-risk genotype subjects were revealed as compared to low-risk genotype subjects independent of disease status. In male subjects, [GSH mPFC ] and blood GPx activities correlate positively in controls ( P = .021), but negatively in patients ( P = .039). In GCLC low-risk genotypes, [Glu mPFC ] are lower in patients, while it is not the case for high-risk genotypes. Conclusions: GCLC high-risk genotypes are associated with low [GSH mPFC ], highlighting that GCLC polymorphisms should be considered in pathology studies of cerebral GSH. Low brain GSH levels are related to low peripheral oxidation status in controls but with high oxidation status in patients, pointing to a dysregulated GSH homeostasis in early psychosis patients. GCLC polymorphisms and disease associated correlations between brain GSH and Glu levels may allow patients stratification.

Sensory impairments constitute core dysfunctions in schizophrenia. In the auditory modality, impaired mismatch negativity (MMN) has been observed in chronic schizophrenia and may reflect N-methyl-d-aspartate (NMDA) hypo-function, consistent with models of schizophrenia based on oxidative stress. Moreover, a recent study demonstrated deficits in the N100 component of the auditory evoked potential (AEP) in early psychosis patients. Previous work has shown that add-on administration of the glutathione precursor N-acetyl-cysteine (NAC) improves the MMN and clinical symptoms in chronic schizophrenia. To date, it remains unknown whether NAC also improves general low-level auditory processing and if its efficacy would extend to early-phase psychosis. We addressed these issues with a randomized, double-blind study of a small sample (N=15) of early psychosis (EP) patients and 18 healthy controls from whom AEPs were recorded during an active, auditory oddball task. Patients were recorded twice: once prior to NAC/placebo administration and once after six months of treatment. The N100 component was significantly smaller in patients before NAC administration versus controls. Critically, NAC administration improved this AEP deficit. Source estimations revealed increased activity in the left temporo-parietal lobe in patients after NAC administration. Overall, the data from this pilot study, which call for replication in a larger sample, indicate that NAC improves low-level auditory processing in early psychosis.

Brazil is still very incipient in the use of Municipal Solid Waste (MSW) for the generation of fuels and electric energy. Law No. 12.305/10 establishes the National Solid Waste Policy (NSWP), considered efficient and adequate for solving the problems caused by MSW. However, NSWP is considered a process of high cost when compared to landfill. Due to the need to seek clean and renewable forms of energy, the pyrolysis process can be an alternative in the primary energy production. This is a thermochemical conversion process, which occurs at high temperatures and involves several chemical reactions, whose liquid organic aqueous fraction is called bio-oil. This work studied the physicochemical characteristics of some types of waste (food scraps, cardboard and paper) and their potential for power generation. The samples presented similar elemental composition and the moisture content for energy generation: 7 % for food scraps (FS), 6 % for cardboard and 4 % for paper. Thermogravimetric analysis were performed to establish that the optimum temperature pyrolysis, in addition to determining the ash content, values above 20 % may cause loss of energy in the process or soot in the liquid fraction. The lowest heating value (LHV) presented typical values of biomasses, between 13 MJ/kg and 20/MJ kg. Considering the obtained results, these samples presented energetic potential for use in the pyrolysis process.

Objective To examine the potential differential impact of childhood trauma, according to the age at the time of exposure, on the psychopathological profile of patients with early psychosis treated in a specialized 3-year program during the early phase of the disease. Methods 196 subjects with early psychosis aged 18-35 years were followed up prospectively over 36 months of treatment between 2004 and 2010. Patients who had faced at least 1 experience of abuse (physical, sexual, or emotional) or neglect (physical or emotional) were classified according to age at the time of the first exposure (early trauma: before 12 years of age; late trauma: from age 12 through 16 years) and then compared with unexposed patients (nontrauma). The level of symptoms was assessed using the Positive and Negative Syndrome Scale, the Young Mania Rating Scale, and the Montgomery-Asberg Depression Rating Scale. Results Exposure to 1 or more forms of trauma before 16 years of age was present in 31.63% of patients. Comparisons over the 3 years of treatment with the nontrauma patients revealed that (1) patients with early trauma showed consistently higher levels of positive (P = .006), depressive (P = .001), manic (P = .006), and negative (P = .029) symptoms and (2) patients with late trauma showed only more negative symptoms (P = .029). Conclusions These results suggest that the age at the time of exposure to trauma has a modulating effect on symptoms in patients with early psychosis. Various biological and psychological hypotheses can be proposed to explain this observation, and they need to be investigated in an experimental setting in order to develop therapeutic avenues.

Most specialized Early Psychosis (EP) programs include assertive outreach (AO) principles, either for all patients or as an intensive case management (ICM) subprogram in selected situations. The objective of this study is to examine prevalence, characteristics and outcomes of patients who needed additional ICM in a specialized EP program.In a 3-year prospective naturalistic study of 229 consecutive EP patients treated at TIPP-Lausanne we compared characteristics of those who needed ICM and those who did not.60 (26.2%) TIPP patients needed ICM. At baseline, ICM-patients showed a poorer academic premorbid functioning (p=0.019); lower level of insight (p0.001); had a previous history of alcohol (p=0.043) and cannabis (p=0.040) use. ICM-patients were less likely to be adherent to medication during the early phase of treatment but differences disappeared during follow-up. ICM-patients showed globally a poorer functional level and higher level of positive and negative symptoms during the follow-up.About one quarter of EP patients needed a combination of ICM and assertive outreach. Despite the high treatment adherence in both groups, psychotic symptoms remained higher in ICM-patients. In a real live setting with limited resources, combination of ICM and AO in selected situations seems a valid solution.

Biomarker-guided treatments are needed in psychiatry, and previous data suggest oxidative stress may be a target in schizophrenia. A previous add-on trial with the antioxidant N-acetylcysteine (NAC) led to negative symptom reductions in chronic patients. We aim to study NAC’s impact on symptoms and neurocognition in early psychosis (EP) and to explore whether glutathione (GSH)/redox markers could represent valid biomarkers to guide treatment. In a double-blind, randomized, placebo-controlled trial in 63 EP patients, we assessed the effect of NAC supplementation (2700 mg/day, 6 months) on PANSS, neurocognition, and redox markers (brain GSH [GSHmPFC], blood cells GSH levels [GSHBC], GSH peroxidase activity [GPxBC]). No changes in negative or positive symptoms or functional outcome were observed with NAC, but significant improvements were found in favor of NAC on neurocognition (processing speed). NAC also led to increases of GSHmPFC by 23% (P = .005) and GSHBC by 19% (P = .05). In patients with high-baseline GPxBC compared to low-baseline GPxBC, subgroup explorations revealed a link between changes of positive symptoms and changes of redox status with NAC. In conclusion, NAC supplementation in a limited sample of EP patients did not improve negative symptoms, which were at modest baseline levels. However, NAC led to some neurocognitive improvements and an increase in brain GSH levels, indicating good target engagement. Blood GPx activity, a redox peripheral index associated with brain GSH levels, could help identify a subgroup of patients who improve their positive symptoms with NAC. Thus, future trials with antioxidants in EP should consider biomarker-guided treatment.

Patients diagnosed with schizophrenia often present with low-level sensory deficits. It is an open question whether there is a functional link between these deficits and the pathophysiology of the disease, e.g. oxidative stress and glutathione (GSH) metabolism dysregulation. Auditory evoked potentials (AEPs) were recorded from 21 psychosis disorder patients and 30 healthy controls performing an active, auditory oddball task. AEPs to standard sounds were analyzed within an electrical neuroimaging framework. A peripheral measure of participants' redox balance, the ratio of glutathione peroxidase and glutathione reductase activities (GPx/GR), was correlated with the AEP data. Patients displayed significantly decreased AEPs over the time window of the P50/N100 complex resulting from significantly weaker responses in the left temporo-parietal lobe. The GPx/GR ratio significantly correlated with patients' brain activity during the time window of the P50/N100 in the medial frontal lobe. We show for the first time a direct coupling between electrophysiological indices of AEPs and peripheral redox dysregulation in psychosis patients. This coupling is limited to stages of auditory processing that are impaired relative to healthy controls and suggests a link between biochemical and sensory dysfunction. The data highlight the potential of low-level sensory processing as a trait-marker of psychosis.

xCT is the specific chain of the cystine/glutamate antiporter, which is widely reported to support anti-oxidant defenses in vivo. xCT is therefore at the crossroads between two processes that are involved in schizophrenia: oxidative stress and glutamatergic neurotransmission. But data from human studies implicating xCT in the illness and clarifying the upstream mechanisms of xCT imbalance are still scarce. Low glutathione (GSH) levels and genetic risk in GCLC (Glutamate–Cysteine Ligase Catalytic subunit), the gene of limiting synthesizing enzyme for GSH, are both associated with schizophrenia. In the present study, we aimed at determining if xCT regulation by the redox system is involved in schizophrenia pathophysiology. We assessed whether modulating GCLC expression impact on xCT expression and activity (i) in fibroblasts from patients and controls with different GCLC genotypes which are known to affect GCLC regulation and GSH levels; (ii) in rat brain glial cells, i.e., astrocytes and oligodendrocytes, with a knock-down of GCLC. Our results highlight that decreased GCLC expression leads to an upregulation of xCT levels in patients’ fibroblasts as well as in astrocytes. These results support the implication of xCT dysregulation in illness pathophysiology and further indicate that it can result from redox changes. Additionally, we showed that these anomalies may already take place at early stages of psychosis and be more prominent in a subgroup of patients with GCLC high-risk genotypes. These data add to the existing evidence identifying the inflammatory/redox systems as important targets to treat schizophrenia already at early stages., Schizophrenia: antioxidant deficit increases a key neurotransmitter transporter Deficit of antioxidant synthesis in schizophrenia leads to oxidative stress and changes in neurotransmitter transporter. Led by Kim Do, a team of researchers from Lausanne University in Switzerland investigated the role of the cell-surface transport protein xCT in schizophrenia. They found that an enzyme responsible for antioxidant production is disturbed in patients. This leads to decreased antioxidant levels and consequently to oxidative stress—i.e. the accumulation of reactive oxygen molecules, damaging the cells component and impairing cell functioning—which in turn affects the functioning of the antioxidant pathway, including xCT. xCT, which exports the neurotransmitter glutamate, is thus overproduced in schizophrenia. The resulting increase of neurotransmitter activity, alongside the increase in oxidative stress, is thought to play a major role in the pathophysiology of schizophrenia, including at early stages of the disease.

Background:While there is suggestion that early onset of psychosis is a determinant of outcome; knowledge regarding correlates of later onset age is more limited. This study explores the characteristics of patients developing psychosis after age 26, towards the end of the usual age range of early intervention programs, in order to identify potential specific needs of such patients.Methods:Two hundred and fifty-six early psychosis patients aged 18–35 were followed-up prospectively over 36 months. Patients with onset after 26 (“later onset”, LO) were compared to the rest of the sample.Results:LO patients (32% of the sample) had shorter DUP, were less likely to be male, had better premorbid functioning and were more likely to have been exposed to trauma. They had greater insight at presentation and less negative symptoms overall. The trajectories for positive and depressive symptoms were similar in both groups. Evolution of functional level was similar in both groups, but while LO patients recovered faster, they were significantly less likely to return to premorbid functional level.Conclusions:Later psychosis onset correlates with better premorbid functioning and higher rate of trauma exposure; the latter should therefore be a treatment focus in such patients. LO patients were less likely to return to premorbid functional level, which suggests that current treatment strategies may not be efficient to help patients maintain employment. The possibility of distinct illness mechanisms according to onset age and the more central role for trauma in patients with onset after age 26 needs to be further explored.

BackgroundEvidence suggests a relationship between exposure to trauma during childhood and functional impairments in psychotic patients. However, the impact of age at the time of exposure has been understudied in early psychosis (EP) patients.MethodTwo hundred and twenty-five patients aged 18–35 years were assessed at baseline and after 2, 6, 18, 24, 30 and 36 months of treatment. Patients exposed to sexual and/or physical abuse (SPA) were classified according to age at the time of first exposure (Early SPA: before age 11 years; Late SPA: between ages 12 and 15 years) and then compared to patients who were not exposed to such trauma (Non-SPA). The functional level in the premorbid phase was measured with the Premorbid Adjustment Scale (PAS) and with the Global Assessment of Functioning (GAF) scale and the Social and Occupational Functioning Assessment Scale (SOFAS) during follow-up.ResultsThere were 24.8% of patients with a documented history of SPA. Late SPA patients were more likely to be female (p= 0.010). Comparison with non-SPA patients revealed that: (1) both Early and Late SPA groups showed poorer premorbid social functioning during early adolescence, and (2) while patients with Early SPA had poorer functional level at follow-up with lower GAF (p= 0.025) and lower SOFAS (p= 0.048) scores, Late SPA patients did not.ConclusionOur results suggest a link between exposure to SPA and the later impairment of social functioning before the onset of the disease. EP patients exposed to SPA before age 12 may present long-lasting functional impairment, while patients exposed at a later age may improve in this regard and have a better functional outcome.

Schizophrenia is a complex psychiatric disorder characterized by disabling symptoms and cognitive deficit. Recent neuroimaging findings suggest that large parts of the brain are affected by the disease, and that the capacity of functional integration between brain areas is decreased. In this study we questioned (i) which brain areas underlie the loss of network integration properties observed in the pathology, (ii) what is the topological role of the affected regions within the overall brain network and how this topological status might be altered in patients, and (iii) how white matter properties of tracts connecting affected regions may be disrupted. We acquired diffusion spectrum imaging (a technique sensitive to fiber crossing and slow diffusion compartment) data from 16 schizophrenia patients and 15 healthy controls, and investigated their weighted brain networks. The global connectivity analysis confirmed that patients present disrupted integration and segregation properties. The nodal analysis allowed identifying a distributed set of brain nodes affected in the pathology, including hubs and peripheral areas. To characterize the topological role of this affected core, we investigated the brain network shortest paths layout, and quantified the network damage after targeted attack toward the affected core. The centrality of the affected core was compromised in patients. Moreover the connectivity strength within the affected core, quantified with generalized fractional anisotropy and apparent diffusion coefficient, was altered in patients. Taken together, these findings suggest that the structural alterations and topological decentralization of the affected core might be major mechanisms underlying the schizophrenia dysconnectivity disorder.

Schizophrenia pathophysiology implies both abnormal redox control and dysconnectivity of the prefrontal cortex, partly related to oligodendrocyte and myelin impairments. As oligodendrocytes are highly vulnerable to altered redox state, we investigated the interplay between glutathione and myelin. In control subjects, multimodal brain imaging revealed a positive association between medial prefrontal glutathione levels and both white matter integrity and resting-state functional connectivity along the cingulum bundle. In early psychosis patients, only white matter integrity was correlated with glutathione levels. On the other side, in the prefrontal cortex of peripubertal mice with genetically impaired glutathione synthesis, mature oligodendrocyte numbers, as well as myelin markers, were decreased. At the molecular levels, under glutathione-deficit conditions induced by short hairpin RNA targeting the key glutathione synthesis enzyme, oligodendrocyte progenitors showed a decreased proliferation mediated by an upregulation of Fyn kinase activity, reversed by either the antioxidant N-acetylcysteine or Fyn kinase inhibitors. In addition, oligodendrocyte maturation was impaired. Interestingly, the regulation of Fyn mRNA and protein expression was also impaired in fibroblasts of patients deficient in glutathione synthesis. Thus, glutathione and redox regulation have a critical role in myelination processes and white matter maturation in the prefrontal cortex of rodent and human, a mechanism potentially disrupted in schizophrenia.

In recent decades, several neurodegenerative diseases have been shown to be exacerbated by systemic inflammatory processes. There is a wide range of literature that demonstrates a clear but complex relationship between the central nervous system (CNS) and the immunological system, both under naïve or pathological conditions. In diseased brains, peripheral inflammation can transform "primed" microglia into an "active" state, which can trigger stronger pathological responses. Demyelinating diseases are a group of neurodegenerative diseases characterized by inflammatory lesions associated with demyelination, which in turn induces axonal damage, neurodegeneration, and progressive loss of function. Among them, the most important are multiple sclerosis (MS) and neuromyelitis optica (NMO). In this review, we will analyze the effect of specific peripheral inflammatory stimuli in the progression of demyelinating diseases and discuss their animal models. In most cases, peripheral immune stimuli are exacerbating.

Several lines of evidence implicate the fornix–hippocampus circuit in schizophrenia. In early-phase psychosis, this circuit has not been extensively investigated and the underlying mechanisms affecting the circuit are unknown. The hippocampus and fornix are vulnerable to oxidative stress at peripuberty in a glutathione (GSH)-deficient animal model. The purposes of the current study were to assess the integrity of the fornix–hippocampus circuit in early-psychosis patients (EP), and to study its relationship with peripheral redox markers. Diffusion spectrum imaging and T1-weighted magnetic resonance imaging (MRI) were used to assess the fornix and hippocampus in 42 EP patients compared with 42 gender- and age-matched healthy controls. Generalized fractional anisotropy (gFA) and volumetric properties were used to measure fornix and hippocampal integrity, respectively. Correlation analysis was used to quantify the relationship of gFA in the fornix and hippocampal volume, with blood GSH levels and glutathione peroxidase (GPx) activity. Patients compared with controls exhibited lower gFA in the fornix as well as smaller volume in the hippocampus. In EP, but not in controls, smaller hippocampal volume was associated with high GPx activity. Disruption of the fornix–hippocampus circuit is already present in the early stages of psychosis. Higher blood GPx activity is associated with smaller hippocampal volume, which may support a role of oxidative stress in disease mechanisms.

Background The recurrent ∼600 kb 16p11.2 BP4-BP5 deletion is among the most frequent known genetic aetiologies of autism spectrum disorder (ASD) and related neurodevelopmental disorders. Objective To define the medical, neuropsychological, and behavioural phenotypes in carriers of this deletion. Methods We collected clinical data on 285 deletion carriers and performed detailed evaluations on 72 carriers and 68 intrafamilial non-carrier controls. Results When compared to intrafamilial controls, full scale intelligence quotient (FSIQ) is two standard deviations lower in carriers, and there is no difference between carriers referred for neurodevelopmental disorders and carriers identified through cascade family testing. Verbal IQ (mean 74) is lower than non-verbal IQ (mean 83) and a majority of carriers require speech therapy. Over 80% of individuals exhibit psychiatric disorders including ASD, which is present in 15% of the paediatric carriers. Increase in head circumference (HC) during infancy is similar to the HC and brain growth patterns observed in idiopathic ASD. Obesity, a major comorbidity present in 50% of the carriers by the age of 7 years, does not correlate with FSIQ or any behavioural trait. Seizures are present in 24% of carriers and occur independently of other symptoms. Malformations are infrequently found, confirming only a few of the previously reported associations. Conclusions The 16p11.2 deletion impacts in a quantitative and independent manner FSIQ, behaviour and body mass index, possibly through direct influences on neural circuitry. Although non-specific, these features are clinically significant and reproducible. Lastly, this study demonstrates the necessity of studying large patient cohorts ascertained through multiple methods to characterise the clinical consequences of rare variants involved in common diseases.

Background: Schizophrenia is associated with neurocognitive dysfunction already in the early phase of the disease.1 However, cognitive impairments are actually poorly treated by pharmacological interventions, leaving severe problems in functioning.2 Increasing evidence suggest oxidative stress and redox dysregulation play a role in the emergence of psychosis.3 In particular, levels of glutathione (GSH) are lower in chronic schizophrenia.4 In addition, a previous trial with the antioxidant N-acetyl-cysteine (NAC) led to negative symptoms reduction in chronic patients.5 Therefore, we explored if NAC had also an impact on neurocognition in early psychosis (EP) patients. Methods: The study was a 6-month, double-blind, randomized, placebo-controlled trial of NAC supplementation (2700 mg/d) to standard medications. Neurocognition was assessed at baseline and at the end of treatment with the MATRICS Consensus Cognitive Battery (MCCB),6 excluding the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT). Sixty-one patients (31 NAC, 30 placebo) with a diagnostic of psychotic disorder and less than 12 months of antipsychotic treatment were enrolled. Results: We found significant interaction Time × Treatment in favor of NAC on the MCCB processing speed factor and for 2 of 3 processing speed’s tasks (Trail Making A and Verbal Fluency). The improvement in processing speed within the NAC group was correlated with a decrease in negative symptoms. In addition, it was possible to identify a subgroup of patients who responded to NAC treatment considering their biological variables. Indeed, patients having a low peroxidase (GPx) activity at baseline benefited more than others from NAC supplementation in terms of processing speed’s scores. Moreover, in those individuals only, the improvement in processing speed was related to a decrease of the GSH reductase (GR) activity and to a regulation of the balance GPx – GR. Conclusion: Addition of NAC improved processing speed in EP patients, in particular in those who displayed a low basal level of redox dysregulation. Further, larger studies on antioxidant interventions are needed to replicate these findings. This work was supported by the National Center of Competence in Research (NCCR) “SYNAPSY – The Synaptic Bases of Mental Diseases” financed by the Swiss National Science Foundation, Damm-Etienne Foundation, Alamaya Foundation, the Commonwealth of Massachusetts Center of Excellence in Clinical Neuroscience and Psychopharmacological Research (SCDMH82101008006, LJS), and the Weisman family (LJS). References 1.Mesholam-Gately et al. Neuropsychology. 2009;23(3). 2.Green et al. Schizophrenia Bulletin. 2000;26(1). 3.Do et al. Current Opinion in Neurobiology. 2009;19(2). 4.Do et al. European Journal of Neuroscience. 2000;12(10). 5.Berk et al. Journal of Biological Psychiatry. 2008;64. 6.Nuechterlein et al. American Journal of Psychiatry. 2008;165.

Background: Early interventions in psychosis are key to improving patients’ functional outcome, engagement, and quality of treatment. In this context, biomarkers that quantify disease state, course, or response to medication should be developed to aid in diagnostics and treatment decision at early stages of the disease. The present study aims at identifying metabolites and pathways that are early makers of psychosis and that distinguish biomarker-based categories (biotypes) of patients.

Background Various strategies have been proposed to improve recruitment of “at risk mental state” patients; they may have an impact on the type of patients who reach such programs. We describe the clinical program for “at-risk” patients implemented in 2014 in Lausanne and the characteristics of referrals over the years. Methods Help seeking patients aged 14 to 35 were initially referred by health care providers for a specialized evaluation in case of suspicion of a potential “prodromal psychotic state” and more recently selected by PQ-16 (Ising et al. 2012) (cut-off: 6/16). At-Risk Mental State (ARMS) was defined according to the Basic Symptoms criterion (COPER-COGDIS criteria) from the Schizophrenia Proneness Instrument – Adult version (SPI-A) and to the Clinical High Risk criteria of the Structured Interview for Prodromal Syndromes (SIPS). ARMS patients underwent an extensive clinical evaluation (including Mini-SCID, SOFAS, MARDS, Yung Mania Scale, etc.) and were followed-up every 6 months over 3 years. Results Within a catchment area of 260 000 inhabitants, 110 patients have been referred to our center since 2014 and 100 completed the investigation. 29 (29%) fulfilled ARMS criteria, 52 (52%) didn’t and 19 (19%) were already psychotic. The proportion of true ARMS patients decreased progressively over the years from 45% in 2014 and 2015, to only 22 and 13.9 % in 2016 and 2017. In our sample of help-seekers, the group of patients ARMS- negative received mostly a schizophrenia spectrum diagnosis (26/52 patients, 50%), associated with low psychosocial functioning, even when not in the precise range of at-risk criteria. Discussion The global prevalence (29%) of ARMS patients in our sample over the 4 years is marginally lower than previous reports on similar tertiary centers, which ranges from 33 to 51 % (Kline E., 2014). Our lower prevalence of ARMS patients within the sample may be linked to the limited resources we had to conduct an information strategy and our focus on psychologists and psychiatrists working at our department. The introduction in 2016 of more intense screening strategy based on the use of the PQ-16 lead to an increase in referral numbers but decreased the rate of ARMS among referred patients. Our results confirm the influence of the recruitment strategy and information campaigns on the prevalence of at-risk patients within a population of help-seekers. The prevalence of schizophrenia spectrum diagnosis in our group of patients ARMS-negative also suggests that a larger “vulnerability” model for psychosis, more sensitive to functioning and negative symptoms and not narrowed on the focus of the risk of imminent acute psychosis, may better fit patients’ needs.

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.

PurposeRecent evidence points to a critical role of redox dysregulation induced oxidative stress in the pathophysiology of early phases of schizophrenia. An add-on trial with n-acetyl-cysteine (NAC) led to a reduction in negative symptoms in chronic schizophrenia patients. Aim of this study was to explore impact of addition of NAC to standard treatment in early psychosis (EP) patients.MethodsDouble-blind, randomized, placebo-controlled trial of addition of NAC, 2700 mg daily, to antipsychotic treatment over 6 months. Monthly assessment of PANSS, GAF, SOFAS and antipsychotics treatment; quantification of brain glutathione levels (GSHmPFC) by 1H-magnetic-resonance-spectroscopy and of blood cells glutathione (GSHBC) and glutathione peroxidase activity (GPxBC) as marker of oxidation status at the beginning and end of treatment.ResultsOverall, 63 patients were included. Spectroscopy data showed that GSHmPFC increased by +23% in the NAC group, while it tended to decrease by −5% in the placebo group (P = 0.005). No significant difference between NAC and placebo was observed on global changes in negative symptoms, positive symptoms or functional outcome. However, in patients with high-baseline oxidation status (GPxBC>22.3U/gHb), subgroup explorations revealed an improvement of positive symptoms over time compared to patients with low-baseline GPx (P = 0.02).ConclusionsWhile addition of NAC induced an increase of brain GSH, it had no impact on symptomatic and functional outcome in EP patients. However, in patients with high oxidation status, addition of NAC leads to significantly greater improvement in positive symptoms. Future studies on antioxidant interventions in EP should consider biomarker-guided treatment.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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.

Schizophrenia is a complex psychiatric disorder characterized by disabling symptoms and cognitive deficit. Recent neuroimaging findings suggest that large parts of the brain are affected by the disease, and that the capacity of functional integration between brain areas is decreased. In this study we questioned (i) which brain areas underlie the loss of network integration properties observed in the pathology, (ii) what is the topological role of the affected regions within the overall brain network and how this topological status might be altered in patients, and (iii) how white matter properties of tracts connecting affected regions may be disrupted. We acquired diffusion spectrum imaging (a technique sensitive to fiber crossing and slow diffusion compartment) data from 16 schizophrenia patients and 15 healthy controls, and investigated their weighted brain networks. The global connectivity analysis confirmed that patients present disrupted integration and segregation properties. The nodal analysis allowed identifying a distributed set of brain nodes affected in the pathology, including hubs and peripheral areas. To characterize the topological role of this affected core, we investigated the brain network shortest paths layout, and quantified the network damage after targeted attack toward the affected core. The centrality of the affected core was compromised in patients. Moreover the connectivity strength within the affected core, quantified with generalized fractional anisotropy and apparent diffusion coefficient, was altered in patients. Taken together, these findings suggest that the structural alterations and topological decentralization of the affected core might be major mechanisms underlying the schizophrenia dysconnectivity disorder. Hum Brain Mapp, 36:354–366, 2015. © 2014 Wiley Periodicals, Inc.

The 2009 news in medicine regarding dependence confirm the bio-psycho-social field of addiction medicine and psychiatry. First a statement is made about the risk of cardiac arythmy in opioid substitution treatments. Then a review of the treatment of C hepatitis shows its importance in an addicted population. In the field of cognitive neuroscience, progress has been made in the knowledge of "craving" and of its endophenotypical components. Electronic medias related disorders are on the border of addiction: a case study is exploring this new domain. At last, recent datas are presented on the relationship between cannabis and psychosis.

Context Intervention in the prodromal phase of psychosis remains controversial due to poor specificity of current criterion and ethical issues arising when developing interventions. There is less controversy regarding the need for specialist first episode psychosis intervention programs. Aims In the context of the implementation of an early intervention strategy in Lausanne, we focused on a first episode psychosis program and checked if need for an early detection program for UHR subjects would emerge over time. We recently structured a specialist At Risk Mental State (ARMS) clinic. Methods Help seeking patients aged 14–35, referred for a 'prodromal psychotic state” are assessed with: Mini-SCID; SPI-A; SIPS-PANSS; MARDS; Yung Mania scale and classified as ARMS on the basis of SPI-Cy (COPER and COGDIS criteria) and SIPS criteria (APS; BLIPS or Genetic Criterion). Results Since January 2014, twenty-four patients were addressed to our clinic, and diagnoses were: ARMS (33%); first episode psychosis (8%); schizotypal disorder (25%); other axis I or II diagnosis (13%); drop out before diagnosis (5%); still in investigation (16%). Conclusions Our data shows that there is a need for specialist ARMS clinic when developing early intervention programs. The proximity with a well implanted first episode program offers the possibility to treat patients who have already developed full blown psychosis or for those who make the transition. Ethically, it is our impression that having both structures is necessary in order to have adequate treatment to offer is patients develop full blown psychosis.

BACKGROUND: Deletions and duplications of the 16p11.2 BP4-BP5 locus are prevalent copy number variations (CNVs), highly associated with autism spectrum disorder and schizophrenia. Beyond language and global cognition, neuropsychological assessments of these two CNVs have not yet been reported. METHODS: This study investigates the relationship between the number of genomic copies at the 16p11.2 locus and cognitive domains assessed in 62 deletion carriers, 44 duplication carriers, and 71 intrafamilial control subjects. RESULTS: IQ is decreased in deletion and duplication carriers, but we demonstrate contrasting cognitive profiles in these reciprocal CNVs. Deletion carriers present with severe impairments of phonology and of inhibition skills beyond what is expected for their IQ level. In contrast, for verbal memory and phonology, the data may suggest that duplication carriers outperform intrafamilial control subjects with the same IQ level. This finding is reminiscent of special isolated skills as well as contrasting language performance observed in autism spectrum disorder. Some domains, such as visuospatial and working memory, are unaffected by the 16p11.2 locus beyond the effect of decreased IQ. Neuroimaging analyses reveal that measures of inhibition covary with neuroanatomic structures previously identified as sensitive to 16p11.2 CNVs. CONCLUSIONS: The simultaneous study of reciprocal CNVs suggests that the 16p11.2 genomic locus modulates specific cognitive skills according to the number of genomic copies. Further research is warranted to replicate these findings and elucidate the molecular mechanisms modulating these cognitive performances.

Significance Early traumatic experiences interact with redox regulation and oxidative stress. Blood glutathione peroxidase (GPx) activity, involved in reducing peroxides, may reflect the oxidation status of the organism, thus allowing for the stratification of patients. Traumatized patients with psychosis who have a high blood oxidation status (high-GPx) have smaller hippocampal volumes (but not a smaller amygdala or intracranial volume), and this is associated with more severe clinical symptoms, while those with a lower oxidation status (low-GPx) showed better cognition and a correlated activation of the antioxidant thioredoxin/peroxiredoxin system. Thus, in patients with psychosis, traumatic experiences during childhood may interact with various redox systems, leading to long-term neuroanatomical and clinical defects. This redox profile may represent important biomarkers for patient stratification, defining treatment strategies at early stages of psychosis., Exposure to childhood trauma (CT) increases the risk for psychosis and affects the development of brain structures, possibly through oxidative stress. As oxidative stress is also linked to psychosis, it may interact with CT, leading to a more severe clinical phenotype. In 133 patients with early psychosis (EPP), we explored the relationships between CT and hippocampal, amygdala, and intracranial volume (ICV); blood antioxidant defenses [glutathione peroxidase (GPx) and thioredoxin/peroxiredoxin (Trx/Prx)]; psychopathological results; and neuropsychological results. Nonadjusted hippocampal volume correlated negatively with GPx activity in patients with CT, but not in patients without CT. In patients with CT with high GPx activity (high-GPx+CT), hippocampal volume was decreased compared with that in patients with low-GPx+CT and patients without CT, who had similar hippocampal volumes. Patients with high-GPx+CT had more severe positive and disorganized symptoms than other patients. Interestingly, Trx and oxidized Prx levels correlated negatively with GPx only in patients with low-GPx+CT. Moreover, patients with low-GPx+CT performed better than other patients on cognitive tasks. Discriminant analysis combining redox markers, hippocampal volume, clinical scores, and cognitive scores allowed for stratification of the patients into subgroups. In conclusion, traumatized EPP with high peripheral oxidation status (high-GPx activity) had smaller hippocampal volumes and more severe symptoms, while those with lower oxidation status (low-GPx activity) showed better cognition and regulation of GPx and Trx/Prx systems. These results suggest that maintained regulation of various antioxidant systems allowed for compensatory mechanisms preventing long-term neuroanatomical and clinical impacts. The redox marker profile may thus represent important biomarkers for defining treatment strategies in patients with psychosis.