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Gene–environment (GxE) interactions have been related to psychosis spectrum disorders, involving multiple common genetic variants in multiple genes with very small effect sizes, and several environmental factors that constitute a dense network of exposures named the exposome. Here, we aimed to analyze GxE in a cohort of 310 first-episode psychotic (FEP) and 236 healthy controls, by using aggregate scores estimated in large populations such as the polygenic risk score for schizophrenia and (PRS-SCZ) and the Maudsley environmental risk score (ERS). In contrast to previous findings, in our study, the PRS-SCZ did not discriminate cases from controls, but the ERS score explained a similar percentage of the variance as in other studies using similar approaches. Our study supports a positive additive interaction, indicating synergy between genetic susceptibility to schizophrenia (PRS-SCZ dichotomized according to the highest quartile distribution of the control population) and the exposome (ERS > 75% of the controls). This additive interaction showed genetic and environmental dose dependence. Our study shows that the use of aggregate scores derived from large and powered studies instead of statistics derived from specific sample characteristics is a powerful tool for the study of the effects of GxE on the risk of psychotic spectrum disorders. In conclusion, by using a genetic risk score and an ERS we have provided further evidence for the role of GxE in psychosis.

Background Patients with schizophrenia display a wide and characteristic array of cognitive deficits. A range of factors has been shown to influence cognition, including cognitive reserve (CR). Amongst antipsychotics only clozapine has shown positive results on cognition to date. Although it is known that delayed initiation of clozapine may be related to poor clinical psychotic response, no previous results have been tested on relation to cognitive improvements. This study aimed to analyze the improvement in cognitive performance after starting clozapine treatment according to the early versus late treatment initiation after diagnosis. Methods 41 patients with schizophrenia were enrolled. All subjects were assessed clinically, neuropsychologically and functionally at baseline and at the 18th week of clozapine treatment. Premorbid IQ was calculated with the vocabulary subtest of the WAIS-III and it was considered a measure of CR. For study purposes, sample was divided into early or late treatment initiation of clozapine (± 3 years after diagnosis). Lineal mixed model analyses were used while confounding from different factors. Results There were no differences between groups in terms of gender, functional, clinical and neuropsychological outcomes at baseline and follow-up. Neither clozapine dose, nor plasma concentration of nor-clozapine, have been found to be different at 18 weeks. Significant difference in age was found (p Discussion There were no differences between groups at baseline, except for age. Patients who started an early treatment of clozapine improved more cognitive domains at 18-week that those who started it later. In both cases, CR is a key factor in predicting cognitive improvement. Reducing clozapine treatment delay might represent immediate prospective improvements on cognitive domains in comparison with delayed start. Time-wise cognitive monitoring and CR enhancement at early stages of the psychotic illness/treatment may be helpful in order to prevent cognitive impairment.

Background Neural correlates of psychotic disorders encompass multiple brain regions in multiple brain circuits, even at early stages. Previous research has characterized structural brain alterations in first-episode psychosis (FEP), but few studies have focused on the relationship between brain alterations and disease trajectories. First psychotic episodes typically evolve into a chronic course, affecting quality of life of patients and their families, with huge societal costs. Importantly, up to 80% of the patients relapse in the next five years after a first psychotic episode, with a significant risk of developing treatment resistance. Here, we investigated whether disease course may be predicted from brain structural assessments. Specifically, we measured structural covariance, a well-established approach to identify abnormal patterns of volumetric correlation across distant brain regions, which allows to incorporate network-level information to structural assessments. We performed a whole-brain structural covariance assessment of three bilateral regions form to three different cortical networks - dorsolateral prefrontal cortex (dlPFC) for the executive network, posterior cingulate cortex for the default mode network and insulae for the salience network - and subcortical structures (hippocampi, amygdalae and dorsomedial nucleus of the thalamus) that have shown to play a key role in schizophrenia. Methods We assessed a sample of 74 subjects from a multicenter, naturalistic, prospective and longitudinal study designed to evaluate clinical, neuropsychological, neuroimaging, biochemical, environmental and pharmacogenetic variables in first episode psychotic patients (PEPs project). Magnetic resonance imaging (MRI) scans were acquired at baseline and at 2-year follow-up, as well as clinical assessments. Psychotic symptoms were assessed using the Positive and Negative Symptom Scale (PANSS) due its widespread use in clinical studies and its reliability in assessing psychopathology across a range of patient populations. The sample was split in two groups as a function of the clinical improvement at 2-year follow-up: responders (i.e. 40% reduction in PANSS global score from baseline; n=29) and non-responders (n=45). Results Responder patients showed increase structural covariance between the left dlPFC and the left middle frontal gyrus, and between the right dlPFC and the right middle and superior gyrus, the left rectus and inferior frontal gyrus, the right hippocampus, and the vermis of the cerebellum. In addition, they showed increased structural covariance between the left anterior hippocampus and the ipsilateral middle occipital gyrus and the contralateral postcentral gyrus. Likewise, the structural covariance of right anterior hippocampus with right superior occipital gyrus and precentral gyrus was also increased in responder patients. Discussion This study shows, for the first time in the literature, that increased structural covariance at baseline within the executive network and between the hippocampi and posterior brain regions was associated with a superior treatment response at two-year follow-up. These results indicate that the integrity of structural networks should be taken into account to predict treatment outcome in FEP patients.

Background Cognitive impairment is considered a central feature of psychotic disorders, with an important impact on prognosis and functional outcome (Nuechterlein et al., 2011). Among the etiological explanations on psychosis, several hypotheses involving alterations in the immune / inflammatory system have been proposed and recent research links these inflammatory processes with cognitive function, suggesting that the presence of inflammation is associated with poorer cognitive performance (Ribeiro-Santos et al., 2014, Cabrera et al., 2016). The study of the influence of gender on the possible association between inflammatory biomarkers and cognitive performance may favor the implementation of personalized treatments. The aim of the study is to investigate the association between inflammatory biomarkers and gender-based cognition in a sample of first psychotic episode (FEP). A total of 92 patients with a FEP, 62 men and 30 women, recruited in five clinical centers were included. A neurocognitive assessment was performed and the expression of pro and anti-inflammatory mediators in peripheral blood mononuclear cells (PBMC) and plasma was measured. Methods In the neurocognitive evaluation the domains of attention, verbal and working memory and executive function were included. Other and clinical variables included the assessment of psychotic and affective symptoms, age, sex, educational level and socio-economic level. The expression of the proinflammatory mediators (NFκB, iNOS, COX-2, PGE2, NO-2 and TBARS) and anti-inflammatory (15d-PGJ2, PPARγ and IκBα) of the main intracellular inflammatory pathway was measured in PBMC and plasma. Results A correlation was made between inflammatory biomarkers and neurocognitive performance according to gender, and significant associations were selected to perform a subsequent hierarchical regression analysis. In the final model, only the expression of COX2 was associated with better performance in executive function in males (B = 0.504, p =

Background Cognitive dysfunction is as a hallmark feature of schizophrenia. Antipsychotic medication is effective for treating the positive symptoms of psychosis, but their potential for therapeutic effects on cognition continues to divide researchers. Improvements in clinical symptoms can occur independently of cognitive functioning, whereby typical antipsychotics improve different clinical domains, but have little or no efficacy for improving primary cognitive functions. However, it has been suggested that the second-generation antipsychotic clozapine can improve cognition in schizophrenia. Unusual cases, such as remitted patients who decide to stop taking clozapine, thus represent a unique opportunity to understand the effect of antipsychotic medication on cognition, as described in the case study below. Methods A 38-year old man suffered severe psychotic episodes at age 19, leading to a diagnosis of treatment-resistant schizophrenia. Clozapine was initiated at age 21, with excellent treatment response and complete remission of positive, negative and depressive symptoms. For the following 16 years, he had a full-time paid job, lived independently and had an ample social circle. For the last five years, he was stable and compliant taking 175 mg of clozapine, with clozapine levels in sub-therapeutic range (between 0.17 and 0.26 mg/L). He had no metabolic syndrome and no oversedation, but complained of hypersalivation and persistent memory problems. He decided, against advice, that medication was no longer needed and requested support for waning off clozapine. A five-month program was subsequently implemented, with 25 mg reductions of clozapine every six weeks. Four enhanced assessments were scheduled after two weeks on stable doses of 125, 75, 25 and 0 mg, respectively, which included the Brief Assessment of Cognition in Schizophrenia (BACS) and the Clinical Global Impression-Schizophrenia scale (CGI-SCH). Results At each level of clozapine dose, the patient continued to be stable. However, the patient showed impaired cognitive performance at the highest dose of clozapine titration (see T-scores from Table and figure), with improvements then shown at each level of dose reduction (75 and 25 mg). The final assessment was done after 6 weeks of not taking medication. At this time, he was admitted to hospital for psychotic relapse. Unfortunately, the patient refused to re-initiate clozapine and has remained floridly psychotic for 18 months. Our case suggests that cognitive impairment is dose-dependent with clozapine. As presented, the t-score of the patient at 125 mg was worse than normative data reported for healthy controls (z-score=0.50) and patients with schizophrenia treated with other first-or second generation antipsychotics (z-score=-1.42). However, cognitive performance of the patient was most notably impaired when medication-free. Discussion The longterm effects of high-dose antipsychotic medication on cognition in patients with schizophrenia are largely unknown. It is also possible that changes in cognitive states are either domain-specific with clozapine. Nonetheless, daily antipsychotic dose and polypharmacy have been shown to predict poor cognitive functioning. The present case is also a reminder that the appropriate long-term maintenance dose of clozapine is poorly understood. As this case suggests, the current recommended therapeutic levels of clozapine (0.35 to 0.50 mg/L) might be unnecessarily high for patients in full remission. Controlled studies are therefore needed to evaluate the potential for cognitive improvements in schizophrenia as a function of reduced clozapine dose, to ensure the optimal delivery needed not just for good clinical but also good cognitive outcome.