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Schizophrenia is frequently characterized by the presence of multiple relapses. Cognitive impairments are core features of schizophrenia. Cognitive reserve (CR) is the ability of the brain to compensate for damage caused by pathologies such as psychotic illness. As cognition is related to CR, the study of the relationship between relapse, cognition and CR may broaden our understanding of the course of the disease. We aimed to determine whether relapse was associated with cognitive impairment, controlling for the effects of CR. Ninety-nine patients with a remitted first episode of schizophrenia or schizophreniform disorder were administered a set of neuropsychological tests to assess premorbid IQ, attention, processing speed, working memory, verbal and visual memory, executive functions and social cognition. They were followed up for 3 years (n=53) or until they relapsed (n=46). Personal and familial CR was estimated from a principal component analysis of the premorbid information gathered. Linear mixed-effects models were applied to analyse the effect of time and relapse on cognitive function, with CR as covariate. Patients who relapsed and had higher personal CR showed less deterioration in attention, whereas those with higher CR (personal and familial CR) who did not relapse showed better performance in processing speed and visual memory. Taken together, CR seems to ameliorate the negative effects of relapse on attention performance and shows a positive effect on processing speed and visual memory in those patients who did not relapse. Our results add evidence for the protective effect of CR over the course of the illness. R. Rodriguez-Jimenez was supported by the Instituto de Salud Carlos III (PI19/00766; Fondo de Investigaciones Sanitarias/FEDER) and of Madrid Regional Government (S2017/BMD-3740)

Therapeutic Drug Monitoring (TDM) of antipsychotics in schizophrenia is a powerful tool that allows tailoring the treatment in an individualized approach. Our goals are to develop and validate a Dried Blood Spot (DBS) method for monitoring some commonly used antipsychotics (aripiprazole, clozapine, and paliperidone) and to evaluate its usefulness as a compliance biomarker, as well as in drug-dose adjustment to personalize the antipsychotic treatment to improve its efficacy and safety.31 first-psychotic episode (FEP) and schizophrenia patients were included; 5 refer to naïve FEP who started antipsychotic treatment; 26, to patients with more than one episode and under antipsychotic treatment: aripiprazole (7 cases), clozapine (17), paliperidone (11). For DBS sample collection, 25μl of capillary blood were placed in the spot of a FTA™DMPK-C-card. After completely dryness, antipsychotics were extracted and analyzed by a validated UHPLC-MS/MS-method. DBS antipsychotic results were compared with those obtained in venous blood/plasma.Aripiprazole, paliperidone and clozapine showed from good to excellent correlations between concentrations in venous blood and DBS capillary blood (rIn this study, for aripiprazole, dehydroaripiprazole, paliperidone, clozapine and desmethylclozapine, DBS has provided good analytical performance for TDM. Thus, DBS sampling can offer a great alternative over conventional sampling for plasma measurement. The assay provides good analytical performances for TDM and clinical research applicability, suggesting that DBS is a promising clinical application in TDM in psychiatry.

Background and Hypothesis A pro-inflammatory phenotype has been related to psychotic disorders. The neutrophil-lymphocyte ratio (NLR) is an accessible biomarker that could be helpful to characterize this systemic inflammation state. Study Design This study evaluated the NLR in a cohort of 310 subjects with a first episode of psychosis (FEP) and a matched group of 215 healthy controls, recruited in 16 Spanish centers participating in the PEPs Project. We investigated the NLR measures over 2 years in a prospective, naturalistic study. Study Results At baseline, the FEP group showed a significant higher mean NLR compared to the control group (1.96 ± 1.11 vs 1.72 ± 0.74, P = 0.03). These ratio differences between groups grew at the 24 months follow-up visit (2.04 ± 0.86 vs 1.65 ± 0.65, P < 0.001). Within the FEP group, there were no significant differences in NLR across the follow-up visits, between genders or diagnosis groups (affective vs nonaffective). NLR values did not correlate with the Positive and Negative Symptoms Scale scores. The group of patients who did not reach remission criteria at the end of the study showed a significant higher NLR than those who remitted (2.1896 ± 0.85 vs 1.95 ± 0.87, P = 0.042). A significant correlation between antipsychotic doses and NLR was found at the two-years follow-up visit (r=0.461, P < 0.001). Conclusions Our results highlight the existence of an underlying predisposition of FEP patients to present an increased mean NLR. The use of NLR in clinical practice could be helpful to identify this inflammatory imbalance.

BackgroundClinical intervention in early stages of psychotic disorders is crucial for the prevention of severe symptomatology trajectories and poor outcomes. Genetic variability is studied as a promising modulator of prognosis, thus novel approaches considering the polygenic nature of these complex phenotypes are required to unravel the mechanisms underlying the early progression of the disorder.MethodsThe sample comprised of 233 first-episode psychosis (FEP) subjects with clinical and cognitive data assessed periodically for a 2-year period and 150 matched controls. Polygenic risk scores (PRSs) for schizophrenia, bipolar disorder, depression, education attainment and cognitive performance were used to assess the genetic risk of FEP and to characterize their association with premorbid, baseline and progression of clinical and cognitive status.ResultsSchizophrenia, bipolar disorder and cognitive performance PRSs were associated with an increased risk of FEP [false discovery rate (FDR) ⩽ 0.027]. In FEP patients, increased cognitive PRSs were found for FEP patients with more cognitive reserve (FDR ⩽ 0.037). PRSs reflecting a genetic liability for improved cognition were associated with a better course of symptoms, functionality and working memory (FDR ⩽ 0.039). Moreover, the PRS of depression was associated with a worse trajectory of the executive function and the general cognitive status (FDR ⩽ 0.001).ConclusionsOur study provides novel evidence of the polygenic bases of psychosis and its clinical manifestation in its first stage. The consistent effect of cognitive PRSs on the early clinical progression suggests that the mechanisms underlying the psychotic episode and its severity could be partially independent.

Background: Cognitive reserve (CR) is a protective factor against cognitive and functional impairment in first-episode psychosis (FEP). The aim of this study was to evaluate the differences in clinical presentation accord-ing to the use of cannabis (cannabis users vs non-users) among patients presenting a FEP (non-affective vs af-fective psychosis), to investigate the impact of CR and cannabis use on several outcomes and to explore the potentially mediatory role played by CR in the relationship between cognitive domains or clinical status and functionality, depending on the use of cannabis. Methods: Linear regression analysis models were carried out to assess the predictive value of CR on clinical, functional and cognitive variables at baseline and at two-year follow-up. The mediation analyzes were performed according to the principles of Baron and Kenny. Results: CR was associated with better cognitive performance, regardless of cannabis consumption or diagnosis. In both diagnoses, CR was associated with better clinical and functional outcomes in those patients who did not use cannabis. In terms of mediation procedure, CR mediates the relationship between some cognitive domains and functioning at follow-up only in patients without cannabis use. Limitations: The small sample size of the affective group. Conclusions: CR plays a differential role in the outcome of psychoses according to whether patients are cannabis users or not. Both in affective and non-affective groups CR exerted a greater effect in patients without cannabis use. Our results suggest that the deleterious effect of cannabis use on functioning in FEP surpasses the protective effect of CR.

Background: Suicide is probably one of the worst potential complications for people with schizophrenia. Even though the use of antipsychotic medication is essential in reducing suicidal behaviour, the use of psychological treatments seems to be in the same way necessary. Cognitive Behavioural Therapy (CBT) is an evidence-based form of psychotherapy that is constantly trying to synchronise with the latest recommendations from the research. The goal of the present work is to systematically review the scientific evidence from published studies testing the effectiveness of CBT designed to deal with suicide in patients with schizophrenia. Methods: We searched using multiple terms related to suicide prevention based on CBT in schizophrenia. Two databases (Medline and SCOPUS) were scrutinised for the electronic search, and different reference lists from previous reviews were also hand-checked. Results: We identified 5 randomised and controlled trials of CBT that included suicide-related cognitions or behaviours as a primary outcome measure. CBT focusing on suicidal cognitions and behaviours was found to be effective in reducing suicidal ideation. As the number of studies fulfilling the inclusion criteria is small, and the assessment of outcomes is heterogeneous, we did not perform a meta-analysis and present results in a narrative way. Conclusion: Research on CBT focused on suicide prevention in patients with schizophrenia is promising, but current evidence is notoriously insufficient. Although those therapies seemed to be efficacious in the prevention of suicide, scarcity of randomised clinical trials specifically focusing on suicide is probably the most important issue to be faced. Given the current evidence, clinicians should be familiar with CBT techniques focusing on suicidal cognitions. However, suicide prevention and treatment in those with schizophrenia is complex, and many other factors such as possible earlier use of clozapine, optimizing adherence to medication, and other psychosocial aspects should be addressed. A combination of different strategies appears to be mandatory.

Psychotic disorders typically manifest from late adolescence to early adulthood, and an earlier onset might be associated with greater symptom severity and a worse long-term prognosis. This study aimed to compare the cognitive characteristics of patients with first-episode psychosis (FEP) by their age at onset. We included 298 patients diagnosed with FEP and classified them as having an early onset (EOS), youth onset (YOS), or adult onset (AOS) based on age limits of ≤ 18 years (N = 61), 19-24 years (N = 121), and ≥ 25 years (N = 116), respectively. Socio-demographic and clinical variables included age at baseline, gender, socio-economic status, antipsychotic medication, DSM-IV diagnoses assessed by clinical semi-structured interview, psychotic symptom severity, and age at onset. Neuropsychological assessment included six cognitive domains: premorbid intelligence, working memory, processing speed, verbal memory, sustained attention, and executive functioning. The EOS group had lower scores than the YOS or AOS groups in global cognition, executive functioning, and sustained attention. Although the scores in the YOS group were intermediate to those in the EOS and AOS groups for most cognitive factors, no statistically significant differences were detected between the YOS and AOS groups. Age at onset results in specific patterns of cognitive interference. Of note, impairment appears to be greater with EOS samples than with either YOS or AOS samples. A longitudinal study with a larger sample size is needed to confirm our findings.

European Community, FP7 [HEALTH-F2-2009-241909]; Spanish Ministry of Science and Innovation; Instituto de Salud Carlos III [SAM16PE07CP1, PI16/02012, PI19/024]; CIBERSAM; Madrid Regional Government [B2017/BMD-3740 AGES-CM-2]; Fundación Familia Alonso and Fundación Alicia Koplowitz, Fusar-Poli, L., Pries, L.-K., van Os, J., Radhakrishnan, R., Pençe, A.Y., Erzin, G., Delespaul, P., Kenis, G., Luykx, J.J., Lin, B.D., Akdede, B., Binbay, T., Altınyazar, V., Yalınçetin, B., Gümüş-Akay, G., Cihan, B., Soygür, H., Ulaş, H., Cankurtaran, E.Ş., Kaymak, S.U., Mihaljevic, M.M., Andric-Petrovic, S., Mirjanic, T., Bernardo, M., Mezquida, G., Amoretti, S., Bobes, J., Saiz, P.A., García-Portilla, M.P., Sanjuan, J., Aguilar, E.J., Santos, J.L., Jiménez-López, E., Arrojo, M., Carracedo, A., López, G., González-Peñas, J., Parellada, M., Maric, N.P., Atbaşoğlu, C., Üçok, A., Alptekin, K., Saka, M.C., Aguglia, E., Arango, C., Rutten, B.P., Guloksuz, S., Genetic Risk and Outcome of Psychosis (GROUP) investigators

Lockdown caused by COVID-19 pandemic has a negative impact on mental health. The aim was to assess self-reported neurocognitive symptoms during the lockdown and identify associated vulnerable and protective factors in a sample of psychiatric patients in a Spanish population. These results are part of the Barcelona ResIlience Survey for Mental Health COVID-19 (BRIS-MHC) project. Neurocognitive symptoms were assessed through an online survey considering the five items that represented self-reported neurocognitive complaints. We split the sample into two groups based on the severity of the self-reported neurocognitive complaints: intact cognitive function/mild cognitive impairment (CI-) and moderate/severe cognitive impairment (CI+). Univariate analyses were used to compare both groups in terms of sociodemographic and clinical variables. Multiple logistic regression models were carried out to identify clinical variables and coping strategies associated with neurocognitive symptoms. 198 patients with different psychiatric diagnoses were included in this study. One hundred seventeen patients were classified in the CI- group and 81 in the CI+ group. Depressive symptoms and negative psychotic-like symptoms were vulnerable factors for neurocognitive impairment. Coping strategies of performing physical activity, carrying out relaxing activities and maintaining a routine were protective factors against cognitive impairment. Lockdown situation negatively impact on neurocognitive function. Psychopathological symptoms and coping strategies were associated with neurocognitive symptoms during lockdown in subjects with psychiatric illness. The early treatment of psychopathological symptoms in psychiatric patients and promoting coping strategies during lockdown should be considered an intervention strategy against cognitive impairment.

The EUGEI project was supported by the European Community's Seventh Framework Program under grant agreement No. HEALTH-F2-2009-241909 (Project EU-GEI). Dr O'Donovan is supported by MRC programme grant (G08005009) and an MRC Centre grant (MR/L010305/1), Henquet, C., Van Os, J., Pries, L.K., Rauschenberg, C., Delespaul, P., Kenis, G., Luykx, J.J., Lin, B.D., Richards, A.L., Akdede, B., Binbay, T., Altlnyazar, V., Yallnçetin, B., Gümüş-Akay, G., Cihan, B., Soygür, H., Ulaş, H., Cankurtaran, E.S., Kaymak, S.U., Mihaljevic, M.M., Petrovic, S.S., Mirjanic, T., Bernardo, M., Mezquida, G., Amoretti, S., Bobes, J., Saiz, P.A., Garciá-Portilla, M.P., Sanjuan, J., Aguilar, E.J., Santos, J.L., Jiménez-López, E., Arrojo, M., Carracedo, A., López, G., González-Penãs, J., Parellada, M., Maric, N.P., Atbaşoelu, C., Ucok, A., Alptekin, K., Saka, M.C., Arango, C., O'Donovan, M., Rutten, B.P.F., Gülöksüz, S.

Functional impairment is a defining feature of psychotic disorders. The Functional Assessment Short Test (FAST) is one of the most widely used instruments to measure psychosocial functioning. However, cut-offs of impairment have been well-established for bipolar disorders, but not for other clinical populations. This study aims to analyse psychometric properties of the FAST and establish their corresponding cut-off values for the different severity gradations in a first-episode of non-affective psychosis (FEP) patients. Global Assessment Functioning (GAF) and FAST ratings from 212 non-affective FEP and 204 healthy controls were analyzed. The psychometric properties of FAST (internal consistency, concurrent validity, discriminant validity, factorial analyses and sensitivity to change) were analyzed. The severity gradations of the FAST were defined by the congruence between two grading methods: linear regression analysis (LRA) and percentiles. The FAST showed strong psychometric properties. LRA with the GAF scores yielded the following equation: GAFscore= 80.83 – 0.639*FASTscore. The FAST ranges in non-affective FEP patients derived from LRA and percentiles, were as follows: 0-9 (No impairment); 10-19 (Minimal impairment); 20-34 (Mild impairment); 35-45 (Moderate impairment); 46-72 (Severe impairment). Patients with no functional impairment had a higher socioeconomic status, fewer depressive and negative symptoms, lower severity of illness and higher cognitive reserve level than the others groups. In conclusion, the FAST shows optimal psychometric properties which corroborate its applicability in FEP populations. It is a well-demonstrated valid instrument and the present cut-off scores could be implemented in clinical and research practice to assess properly the psychosocial functional outcome of non-affective FEP populations.

espanolIntroduccion Los pacientes que logran remision clinica tras un primer episodio psicotico (PEP) presentan menor recidiva, menor consumo de recursos sanitarios y mejor calidad de vida, incluso 20 anos despues. El objetivo de este estudio fue determinar las variables relacionadas con la remision en una cohorte multicentrica de pacientes espanoles, asi como sus repercusiones en los resultados funcionales. Metodos En este estudio longitudinal de seguimiento prospectivo, se incluyo a 244 pacientes de PEP con edades comprendidas entre los siete y los 35 anos. Se definio la remision, de acuerdo con los criterios del Grupo de Trabajo para la Remision en Esquizofrenia. Los datos demograficos, premorbidos, clinicos y de funcionalidad fueron evaluados basalmente, y durante las cuatro visitas a lo largo de dos anos. Resultados Ciento sesenta y dos sujetos (66,4%) cumplieron los criterios de remision. Dichos sujetos se caracterizaron por ser respondedores mayores y tempranos, tener mejor ajuste premorbido, mayor percepcion, mejor resultado funcional y menor sintomatologia negativa, en comparacion con los sujetos sin remision. Discusion Aunque las tasas de remision y los factores predictivos descritos en la literatura son muy heterogeneos, la tasa de remision en nuestra muestra fue similar a la tasa previamente reportada. La respuesta temprana al tratamiento, el nivel de percepcion y la gravedad de los sintomas negativos fueron factores predictivos significativos de la remision. De igual modo, la funcionalidad basal y a los dos anos de seguimiento fueron significativamente mejores en los sujetos con remision. Los criterios de remision propuestos tienen una capacidad discriminatoria adecuada para los resultados funcionales y sintomaticos en esta muestra de PEP, enmarcada dentro del proyecto PEPs. EnglishIntroduction Patients that achieve clinical remission after a first episode of psychosis (FEP) present fewer relapses, lower consumption of health care resources and a better quality of life even twenty years later. This study aimed to determine the variables related to remission on a multicenter cohort of Spanish patients and its repercussions in functional outcomes. Methods 244 FEP patients aged 7–35 years were included in this longitudinal prospective follow-up study. Remission was defined according to the Remission in Schizophrenia Working Group criteria. Demographic, premorbid, clinic, and functionality data were assessed at baseline and in four visits throughout two-years. Results 162 subjects (66.4%) met remission criteria. These subjects were characterized by being older and earlier responders, they presented better premorbid adjustment, more insight, better functional outcome, and lower negative symptomatology in comparison to non-remitted. Discussion Although remission rates and predictors described in the literature are very heterogeneous, the remission rate in our sample was similar to those previously reported. Early response to the treatment, level of insight, and negative symptoms severity were significant predictors of remission. Baseline and two-years follow-up functionality were significantly better in subjects in remission as well. Proposed remission criteria have an adequate discriminatory capacity for functional and symptomatic outcomes in this FEP sample framed in the PEPs Project.

The relationship between structural brain alterations and prediction of clinical improvement in first-episode psychosis (FEP) has been scarcely studied. We investigated whether structural covariance, a well-established approach to identify abnormal patterns of volumetric correlation across distant brain regions, which allows incorporating network-level information to structural assessments, is associated with longitudinal clinical course. We assessed a sample of 74 individuals from a multicenter study. Magnetic resonance imaging scans were acquired at baseline, and clinical assessments at baseline and at a 2-year follow-up. Participants were split in two groups as a function of their clinical improvement after 2 years (i.e., ≥ 40% reduction in psychotic symptom severity, (n = 29, n = 45)). We performed a seed-based approach and focused our analyses on 3 cortical and 4 subcortical regions of interest to identify alterations in cortical and cortico-subcortical networks. Improvers presented an increased correlation between the volumes of the right posterior cingulate cortex (PCC) and the left precentral gyrus, and between the left PCC and the left middle occipital gyrus. They also showed an increased correlation between right posterior hippocampus and left angular gyrus volumes. Our study provides a novel mean to identify structural correlates of clinical improvement in FEP, describing clinically-relevant anatomical differences in terms of large-scale brain networks, which is better aligned with prevailing neurobiological models of psychosis. The results involve brain regions considered to participate in the multisensory processing of bodily signals and the construction of bodily self-consciousness, which resonates with recent theoretical accounts in psychosis research.

The prevention of relapse may be a key factor to diminish the cognitive impairment of first-episode schizophrenia (FES) patients. We aimed to ascertain the effects of relapse, and dopaminergic and anticholinergic treatment burdens on cognitive functioning in the follow-up.Ninety-nine FES patients participated in this study. Cognitive assessments were performed at baseline and after 3 years of follow-up or, in those patients who relapsed, aftergt;2 months of stabilization of the new acute psychotic episode. The primary outcomes were final cognitive dimensions.Repeated measures MANOVA analyses showed improvements in the whole sample on the end-point assessments in processing speed and social cognition. However, only impairment in social cognition showed a significant interaction with relapse by time in this sample. Relapse in FES patients was significantly associated with poor performance on end-point assessments of working memory, social cognition and global cognitive score. Anticholinergic burden, but not dopaminergic burden, was associated with verbal memory impairment. These significant associations resulted after controlling for baseline cognitive functioning, relapse and dopaminergic burden.The relationship between relapse and cognitive impairment in recovered FES patients seems to be particularly complex at the short-term follow-up of these patients. While relapse was associated with working memory, social cognition impairments and global cognitive score, anticholinergic burden might play an additional worsening effect on verbal memory. Thus, tailoring or changing antipsychotics and other drugs to reduce their anticholinergic burden may be a potential modifiable factor to diminish cognitive impairment at this stage of the illness.

BackgroundThere is evidence that environmental and genetic risk factors for schizophrenia spectrum disorders are transdiagnostic and mediated in part through a generic pathway of affective dysregulation.MethodsWe analysed to what degree the impact of schizophrenia polygenic risk (PRS-SZ) and childhood adversity (CA) on psychosis outcomes was contingent on co-presence of affective dysregulation, defined as significant depressive symptoms, in (i) NEMESIS-2 (n = 6646), a representative general population sample, interviewed four times over nine years and (ii) EUGEI (n = 4068) a sample of patients with schizophrenia spectrum disorder, the siblings of these patients and controls.ResultsThe impact of PRS-SZ on psychosis showed significant dependence on co-presence of affective dysregulation in NEMESIS-2 [relative excess risk due to interaction (RERI): 1.01, p = 0.037] and in EUGEI (RERI = 3.39, p = 0.048). This was particularly evident for delusional ideation (NEMESIS-2: RERI = 1.74, p = 0.003; EUGEI: RERI = 4.16, p = 0.019) and not for hallucinatory experiences (NEMESIS-2: RERI = 0.65, p = 0.284; EUGEI: −0.37, p = 0.547). A similar and stronger pattern of results was evident for CA (RERI delusions and hallucinations: NEMESIS-2: 3.02, p < 0.001; EUGEI: 6.44, p < 0.001; RERI delusional ideation: NEMESIS-2: 3.79, p < 0.001; EUGEI: 5.43, p = 0.001; RERI hallucinatory experiences: NEMESIS-2: 2.46, p < 0.001; EUGEI: 0.54, p = 0.465).ConclusionsThe results, and internal replication, suggest that the effects of known genetic and non-genetic risk factors for psychosis are mediated in part through an affective pathway, from which early states of delusional meaning may arise.

BackgroundFunctional impairment is a defining feature of psychotic disorders. A range of factors has been shown to influence functioning, including negative symptoms, cognitive performance and cognitive reserve (CR). However, it is not clear how these variables may affect functioning in first-episode psychosis (FEP) patients. This 2-year follow-up study aimed to explore the possible mediating effects of CR on the relationship between cognitive performance or specific clinical symptoms and functional outcome.MethodsA prospective study of non-affective FEP patients was performed (211 at baseline and 139 at follow-up). CR was entered in a path analysis model as potential mediators between cognitive domains or clinical symptoms and functioning.ResultsAt baseline, the relationship between clinical variables or cognitive performance and functioning was not mediated by CR. At follow-up, the effect of attention (p = 0.003) and negative symptoms (p = 0.012) assessed at baseline on functioning was partially mediated by CR (p = 0.032 and 0.016), whereas the relationship between verbal memory (p = 0.057) and functioning was mediated by CR (p = 0.014). Verbal memory and positive and total subscales of PANSS assessed at follow-up were partially mediated by CR and the effect of working memory on functioning was totally mediated by CR.ConclusionsOur results showed the influence of CR in mediating the relationship between cognitive domains or clinical symptoms and functioning in FEP. In particular, CR partially mediated the relationship between some cognitive domains or clinical symptoms and functioning at follow-up. Therefore, CR could improve our understanding of the long-term functioning of patients with a non-affective FEP.

The BDNF and MTHFR genes are independently linked to the pathogenesis of schizophrenia and its neuroimaging correlates. The aim of this study was to explore, for the first time, the individual and interactional effects of the Val66Met and C677T polymorphisms on hippocampal atrophy in first-episode psychosis (FEP).Multi-site case-control study based on clinical, genetic (rs 6265, rs 1801133) and structural magnetic resonance imaging data from 98 non-affective FEP patients and 117 matched healthy controls (HC). Hippocampal volume was estimated using FreeSurfer software and this volume was compared between diagnostic (FEP vs HC) and genotype (Val66Met, C677T) groups. The BDNF Val66Met x MTHFR C677T effect on hippocampal volume was further evaluated through stratified analyses.After applying Bonferroni correction, diagnosis showed a significant effect for adjusted left and right hippocampal volume (FEP HC). Stratified analyses showed that the interactive effect contributed to adjusted hippocampal size in both the HC (left and right hippocampus) and FEP groups (right hippocampus); among BDNF Met carriers, those with the CT-TT genotype exhibited decreased hippocampal volume compared to individuals with the homozygous normal CC genotype.Our results provide preliminary evidence indicating that the Val66Met x C677T interaction may be a potential genetic risk factor for reduced hippocampal size in both healthy controls and in patients with FEP. Further research in independent samples including different ethnic groups is warranted to confirm this new finding.

To explore the influence of cardiovascular risk factors (CVRFs) on cognitive symptoms, functional impairment, and systemic inflammatory markers in first-episode psychosis (FEP) patients at baseline and 2-year follow-up. Method: In a sample of 70 FEP patients and 85 age- and sex-matched healthy controls, we assessed nine modifiable CVRFs. All participants were classified into two subgroups according to their CVRF profile: lower (0-1 CVRFs) or higher (≥2 CVRFs). The following outcomes were measured at baseline and 2-year follow-up: cognition; functional outcomes; and white blood cell (WBC) subtype. Adjusted general linear models were conducted to study the effect of diagnosis and CVRF profile on cognition, functioning, WBC, and longitudinal changes in these variables. At baseline, FEP patients with a higher CVRF profile showed a significantly slower performance on the TMT-A test for psychomotor speed and higher lymphocyte levels than patients with a lower CVRF profile. No longitudinal changes were observed in primary outcomes at 2-year follow-up. Among FEP patients with a higher CVRF profile, slower psychomotor speed performance did not correlate with increased lymphocyte levels. Our findings suggest that the cognitive effects of CVRFs manifest early in the course of psychosis, thus highlighting the importance of targeting both CVRFs and cognitive deficits in FEP.

Background: Traumatic life events (TLEs) are one of the most robust environmental risk factors for the onset of first-episode psychosis (FEP). Aims: To explore TLEs in FEP patients and healthy controls (HC), to analyze gender differences and to examine whether TLEs were associated with sociodemographic, clinical and psychofunctional variables in all FEP sample and split by age. Methods: Descriptive and cross-sectional study. Three hundred and thirty-five FEP and 253 HC were recruited at 16 Spanish mental health research centers. The Traumatic Experiences in Psychiatric Outpatients Questionnaire was administered. Results: We found a higher number of TLEs in FEP than in HC, and the proportion of individuals with three or more TLEs was significantly higher in the FEP group. No differences were found in terms of gender and age. There was no relationship between total number of TLEs and psychotic symptomatology and functional outcomes. Conclusions: The number and cumulative TLEs should be taken into account in the detection, epidemiology and process of recovery in FEP.

Obstetric complications (OCs) may contribute to the heterogeneity that characterizes psychiatric illness, particularly the phenotypic presentation of first episode psychoses (FEP). Our aim was to examine the relationship between OCs and socio-demographic, clinical, functioning and neuropsychological characteristics in affective and non-affective FEP. We performed a cross-sectional,study where we recruited participants with FEP between 2011 and 2021, and retrospectively assessed OCs using the Lewis-Murray scale. OCs were used as a dichotomous variable and further stratified into three subtypes: complications of pregnancy, abnormal fetal growth and development, and difficulties in delivery. We performed a logistic stepwise forward regression analysis to examine variables associated with the presence of OCs. Of the 104 participants (67 affective FEP and 37 non-affective FEP), 31.7% (n = 33) had experienced OCs. Subjects with OCs showed a more gradual emergence of prodromal symptoms as well as higher negative and total Positive and Negative Syndrome Scale (PANSS) scores. In the multivariate analysis, the presence of OCs was independently associated with a younger age at first episode of any type (OR = 0.904, p = 0.003) and slower emergence of prodromal symptoms (OR = 0.274, p = 0.011). When considering specific types of OCs, those related with fetal growth were associated with worse neuropsychological performance, while OCs at delivery were related to earlier onset of illness and more severe symptoms. In conclusion, OCs signaled a specific FEP phenotype characterized by earlier and more protracted onset of illness as well as more burdensome symptoms, independently of FEP type (i.e., affective vs non-affective). These results indicate a potential target of early intervention in FEP.

Neurotrophins have been proposed to be involved in biological mechanisms which might underlie different clinical outcomes in schizophrenia. The aims of the present study were to examine the BDNF/NGF plasma levels in a cohort of first-episode schizophrenia (FES) patients in remission as potential biological predictors of relapse; to study the associations between these neurotrophins and the symptomatology severity through different stages after a FES in two independent cohorts. 2EPs-Cohort: 69 first-episode in clinical remission were included. BDNF/NGF plasma levelsand symptom severity were measured at enrollment and at 3-year or at the time of the second episode/relapse. FLAMM-PEPs-Cohort: 65 first-episodes were also included. BDNF/NGF and symptom severity were obtained at enrollment and 2-year follow-up. Symptomatology was assessed with the Marder-PANSS-Factor scores. Plasma neurotrophins did not differ significantly over time and neither BDNF/NGF were predictors of relapse. Besides, in remission stages, baseline BDNF levels showed significant correlations with both positive and negative symptoms (p

Network analysis is an important conceptual and analytical approach in mental health research. However, few studies have used network analysis to examine the structure of cognitive performance in psychotic disorders. We examined the network structure of the cognitive scores of a sample of 207 first-episode psychosis (FEP) patients and 188 healthy controls. Participants were assessed using a battery of 10 neuropsychological tests. Fourteen cognitive scores encompassing six cognitive domains and premorbid IQ were selected to perform the network analysis. Many similarities were found in the network structure of FEP patients and healthy controls. Verbal memory, attention, working memory and executive function nodes were the most central nodes in the network. Nodes in both groups corresponding to the same tests tended to be strongly connected. Verbal memory, attention, working memory and executive function were central dimensions in the cognitive network of FEP patients and controls. These results suggest that the interplay between these core dimensions is essential for demands to solve complex tasks, and these interactions may guide the aims of cognitive rehabilitation. Network analysis of cognitive dimensions might have therapeutic implications that deserve further research. © 2022

Antipsychotic-associated weight gain is a common adverse effect with several negative outcomes in the clinical evolution of patients, which might also affect patients' self-identity from physical appearance and imply treatment discontinuation. However, recent research has drawn attention to an unexpected clinical improvement associated with weight gain, mostly in patients under treatment with clozapine or olanzapine.Twenty-three treatment-resistant psychosis patients initiating clozapine were evaluated. Longitudinal psychopathological assessment through the Positive and Negative Syndrome Scale (PANSS) and anthropometric evaluation were performed at baseline, week 8, and 18.Body mass index (BMI) change during clozapine treatment was associated with clinical improvement measured with PANSS total score at week 8 (P = 0.021) while showed a trend at week 18 (P = 0.058). The PANSS general score was also associated with weight gain at week 8 (P = 0.022), whereas negative subscale score showed a trend at week 8 (P = 0.088) and was associated between week 8 and 18 (P = 0.018). Sex differences applied at week 8 for PANSS total score, where clinical improvement was significantly associated with BMI in male subjects (P = 0.024). We also stratified for time to initiate clozapine, finding significant associations in negative symptom at week 8 (P = 0.023) and week 18 (P = 0.003) for subjects, which started clozapine after 3 years of illness.Our results suggest that in subjects initiating clozapine, clinical improvement is associated with BMI increase, mostly in negative symptom and in patients after 3 years of antipsychotic use. Our findings were already described in the preantipsychotic era, suggesting some pathophysiological mechanism underlying both conditions.

Objective: To study the differences in early-life characteristics between patients with an early onset of psychotic disorders (EOP, aged < 18 years) versus adult onset of psychotic disorders (AOP, aged >= 18 years) and to identify predictors of earlier onset. Methods: 278 patients with a first episode of psychosis between the ages of 7 and 35 years were recruited as part of a multicenter prospective longitudinal study conducted in Spain between January 1, 2009, and December 31, 2011, with diagnoses made for AOP using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) and for EOP using the Schedule for Affective Disorders and Schizophrenia for School-Aged Children (K-SADS). Early-stage factors such as prenatal, perinatal, and other premorbid factors were registered and compared between EOP and AOP patients. To analyze the association between baseline variables and outcome, univariate and multivariate logistic regression models were used, and the association or odds ratios (ORs) for significant risk factors were calculated. Results: 224 patients with AOP (mean +/- SD age = 25.6 +/- 5.0 years; 65.6% male) and 54 patients with EOP (16.1 +/- 1.7 years; 68.5% male) were included. Univariate analysis revealed significant differences between the groups. Specifically, compared to AOP subjects, EOP patients had more frequent obstetric complications (OCs) (P

This study is part of a coordinated-multicentre Project, funded by the Ministerio deEconomia y Competitividad (PI08/0208; PI11/00325; PI14/00612), Instituto de Salud Car-los III–Fondo Europeo de Desarrollo Regional, Union Europea, Una manera de hacer Eu-ropa, Centro de Investigacion Biomedica en Red de salud Mental, CIBERSAM, by theCERCA Programme/Generalitat de Catalunya and Secretaria d’Universitats i Recerca delDepartament d’Economia I Coneixement (2017SGR1355), Departament de Salut de laGeneralitat de Catalunya, en la convocatoria corresponent a l’any 2017 de concessio desubvencions del Pla Estrategic de Recerca i Innovacio en Salut (PERIS) 2016-2020,modalitat Projectes de recerca orientats a l’atencio primaria, amb el codi d’expedientSLT006/17/00345

Aims Here, we present a clustering strategy to identify phenotypes of antipsychotic (AP) response by using longitudinal data from patients presenting first-episode psychosis (FEP). Method One hundred and ninety FEP with complete data were selected from the PEPs project. The efficacy was assessed using total PANSS, and adverse effects using total UKU, during one-year follow-up. We used the Klm3D method to cluster longitudinal data. Results We identified four clusters: cluster A, drug not toxic and beneficial; cluster B, drug beneficial but toxic; cluster C, drug neither toxic nor beneficial; and cluster D, drug toxic and not beneficial. These groups significantly differ in baseline demographics, clinical, and neuropsychological characteristics (PAS, total PANSS, DUP, insight, pIQ, age of onset, cocaine use and family history of mental illness). Conclusions The results presented here allow the identification of phenotypes of AP response that differ in well-known simple and classic clinical variables opening the door to clinical prediction and application of personalized medicine.

Alterations of the endocannabinoid system (ECS) may play an important role in the development of schizophrenia and other psychotic disorders. Cannabis use is one of the environmental factors more repeatedly related to an increase the risk of developing a psychotic episode, while its use modifies the ECS normal function. In the present study we purposed to examine the gene by environment (GxE) interaction between 15 selected single nucleotide polymorphisms (SNPs) related to the ECS and cannabis use in a cohort of 321 patients with a first episode of psychosis (FEP) and 241 matched healthy controls. We found the fatty-acid amide hydrolase (FAAH) rs2295633 SNP genetic polymorphism was associated with a greater risk of presenting a FEP in subjects with relevant cannabis use, but not in subjects without a history of cannabis use. The probability of presenting a FEP was tenfold higher (OR: 10.69) in cannabis users who were homozygote carriers of the T allele of the FAAH rs2295633 SNP, compared to users of cannabis without this genotype. We also found that a higher a proportion of TT carriers of the FAAH rs2295633 SNP with a positive history of cannabis use was treated with high potency antipsychotic. This study has identified a GxE-environment interaction between a genetic polymorphism from the ECS and cannabis use involved in the risk of presenting a FEP. Although this preliminary data should be replicated with independent samples, our results highlight the importance of the pro-psychotic effects of exogenous cannabis use over the ECS in certain subjects.

Core dysfunctions proposed for psychotic disorders include prefrontal cortex (PFC) dopaminergic hypoactivity, executive function (EF) deficits and reduced gray matter in the PFC. The Val variant of COMT ValThe effect of COMT on both EF performance and prefrontal volume (PFC-VOL) was tested in 158 first episode psychosis (FEP) patients and 141 healthy controls (HC) matched for age (range 9-35 years), sex, ethnicity, handedness and COMT ValCOMT influenced the diagnostic differences mainly in PFC-VOL, but also in EF performance. FEP-Val carriers showed lower EF scores and reduced PFC-VOL compared to the HC group but also poorer EF performance than FEP Met/Met. Poorer EF performance was associated with smaller PFC-VOL, and both were related to increased severity of negative symptoms, poorer premorbid adjustment, and lower estimated premorbid IQ in FEP patients.Our findings suggest that COMT Val

Background: Resilience is a process that allows recovery from or adaptation to adversities. The aim of this study was to evaluate state resilience during the COVID-19 pandemic in psychiatric patients (PP), unaffected relatives (UR) and community controls (CC). Methods: This study is part of the Barcelona ResIlience Survey for Mental Health COVID-19 (BRIS-MHC) project. Logistic regression models were performed to identify mental health outcomes associated with bad state resilience and predictors of good state resilience. The association between state resilience and specific affective temperaments as well as their influence on the association between depressive symptoms and state resilience were verified. Results: The study recruited 898 participants that took part in the survey. The presence of depressive symptoms was a predictor of bad state resilience in PP (β=0.110, OR=1.117, p=0.028). No specific mental health outcome was associated with bad state resilience in UR and CC. Predictors of good state resilience in PP were having pursued hobbies/conducted home tasks (β=1.261, OR=3.528, p=0.044) and level of organization in the family (β=0.986, OR=2.682, p=0.008). Having a controlling family was inversely associated with good state resilience in CC (β=-1.004, OR=0.367, p=0.012). The association between bad state resilience and depressive symptoms was partially mediated by affective temperaments. Limitations: Participants self-reported their psychiatric diagnoses, their relatives’ diagnoses or the absence of a psychiatric disorder, as well as their psychiatric symptoms. Conclusions: Enhancing resilience and coping strategies in the face of the COVID-19 pandemic might have important implications in terms of mental health outcomes.

Objective The period immediately after the onset of first-episode psychosis (FEP) may present with high risk for suicidal ideation (SI) and attempts, although this risk may differ among patients. Thus, we aimed to identify trajectories of SI in a 2-years follow-up FEP cohort and to assess baseline predictors and clinical/functional evolution for each trajectory of SI. Methods We included 334 FEP participants with data on SI. Growth mixture modeling was used to identify trajectories of SI. Putative sociodemographic, clinical, and cognitive predictors of the distinct trajectories were examined using multinomial logistic regression. Results We identified three distinct trajectories: Non-SI trajectory (85.53% sample), Improving SI trajectory (9.58%), and Worsening SI trajectory (6.89%). Multinomial logistic regression model revealed that greater baseline pessimistic thoughts, anhedonia, and worse perceived family environment were associated with higher baseline SI followed by an Improving trajectory. Older age, longer duration of untreated psychosis, and reduced sleep predicted Worsening SI trajectory. Regarding clinical/functional evolution, individuals within the Improving SI trajectory displayed moderate depression at baseline which ameliorated during the study period, while the Worsening SI subgroup exhibited persistent mild depressive symptoms and greater functional impairment at follow-up assessments. Conclusion Our findings delineated three distinct trajectories of SI among participants with FEP, one experiencing no SI, another in which SI might depend on acute depressive symptomatology, and a last subset where SI might be associated with mild but persistent clinical and functional impairments. These data provide insights for the early identification and tailored treatment of suicide in this at-risk population.

European Community's Seventh Framework Program, European Commission [HEALTH-F2-2009-241909]; Scientific and Technological Research Council of Turkey, 2219 International Postdoctoral Research Fellowship Program; Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (SAM16PE07CP1, PI16/02012, and PI19/024)..., Erzin, G., Pries, L.-K., van Os, J., Fusar-Poli, L., Delespaul, P., Kenis, G., Luykx, J.J., Lin, B.D., Richards, A.L., Akdede, B., Binbay, T., Altınyazar, V., Yalınçetin, B., Gümüş-Akay, G., Cihan, B., Soygür, H., Ulaş, H., Cankurtaran, E.Ş., Kaymak, S.U., Mihaljevic, M.M., Andric-Petrovic, S., Mirjanic, T., Bernardo, M., Mezquida, G., Amoretti, S., Bobes, J., Saiz, P.A., García-Portilla, M.P., Sanjuan, J., Aguilar, E.J., Santos, J.L., Jiménez-López, E., Arrojo, M., Carracedo, A., López, G., González-Peñas, J., Parellada, M., Maric, N.P., Atbaşoğlu, C., Ucok, A., Alptekin, K., Saka, M.C., Arango, C., O'Donovan, M.C., Rutten, B.P.F., Guloksuz, S., Genetic Risk and Outcome of Psychosis (GROUP) investigators

Background: premorbid IQ (pIQ) and age of onset are predictors of clinical severity and long-term functioning after a first episode of psychosis. However, the additive influence of these variables on clinical, functional, and recovery rates outcomes is largely unknown. Methods: we characterized 255 individuals who have experienced a first episode of psychosis in four a priori defined subgroups based on pIQ (low pIQ < 85; average pIQ ≥ 85) and age of onset (early onset < 18 years; adult onset ≥ 18 years). We conducted clinical and functional assessments at baseline and at two-year follow-up. We calculated symptom remission and recovery rates using the Positive and Negative Symptoms of Schizophrenia Schedule (PANSS) and the Global Assessment Functioning (GAF or Children-GAF). We examined clinical and functional changes with pair-wise comparisons and two-way mixed ANOVA. We built hierarchical lineal and logistic regression models to estimate the predictive value of the independent variables over functioning or recovery rates. Results: early-onset patients had more severe positive symptoms and poorer functioning than adult-onset patients. At two-year follow-up, only early-onset with low pIQ and adult-onset with average pIQ subgroups differed consistently, with the former having more negative symptoms (d = 0.59), poorer functioning (d = 0.82), lower remission (61% vs. 81.1%), and clinical recovery (34.1% vs. 62.2%). Conclusions: early-onset individuals with low pIQ may present persistent negative symptoms, lower functioning, and less recovery likelihood at two-year follow-up. Intensive cognitive and functional programs for these individuals merit testing to improve long-term recovery rates in this subgroup. This work was supported by the Spanish Ministry of Science and Innovation. Instituto de Salud Carlos III, PI02/1248, PI03032, PI05/0678, PI08/0208 PI09/01442, PI11/00325, PI12/1303, PI14/00612, PI15/00723, PI17/009977, PI18/00753 cofinanced by ERDF Funds from the European Commission, “A way of making Europe”, CIBERSAM. Madrid Regional Government (B2017/BMD-3740 AGES-CM-2). The CERCA Program/Generalitat de Catalunya And Secretaria d’Universitats i Recerca del Departament d’Economia I Coneixement (2017SGR1355). Departament de Salut de la Generalitat de Catalunya, en la convocatoria corresponent a l’any 2017 de concessió de subvencions del Pla Estratègic de Recerca i Innovació en Salut (PERIS) 2016-2020, modalitat Projectes de recerca orientats a l’atenció primària, amb el codi d’expedient SLT006/17/00345. European Union Structural Funds. European Union Seventh Framework Program under grant agreements FP7-HEALTH-2009-2.2.1-2-241909 (Project EU-GEI), FP7-HEALTH-2009-2.2.1-3-242114 (Project OPTiMISE), FP7-HEALTH-2013-2.2.1-2-603196 (Project PSYSCAN) and FP7-HEALTH-2013-2.2.1-2-602478 (Project METSY); and European Union H2020 Program under the Innovative Medicines Initiative 2 Joint Undertaking (grant agreement No 115916, Project PRISM, and grant agreement No 777394, Project AIMS-2-TRIALS), Fundación Familia Alonso, Fundación Alicia Koplowitz and Fundación Mutua Madrileña.

BackgroundPrevious literature supports antipsychotics’ (AP) efficacy in acute first-episode psychosis (FEP) in terms of symptomatology and functioning but also a cognitive detrimental effect. However, regarding functional recovery in stabilised patients, these effects are not clear. Therefore, the main aim of this study is to investigate dopaminergic/anticholinergic burden of (AP) on psychosocial functioning in FEP. We also examined whether cognitive impairment may mediate these effects on functioning.MethodsA total of 157 FEP participants were assessed at study entry, and at 2 months and 2 years after remission of the acute episode. The primary outcomes were social functioning as measured by the functioning assessment short test (FAST). Cognitive domains were assessed as potential mediators. Dopaminergic and anticholinergic AP burden on 2-year psychosocial functioning [measured with chlorpromazine (CPZ) and drug burden index] were independent variables. Secondary outcomes were clinical and socio-demographic variables.ResultsMediation analysis found a statistical but not meaningful contribution of dopaminergic receptor blockade burden to worse functioning mediated by cognition (for every 600 CPZ equivalent points, 2-year FAST score increased 1.38 points). Regarding verbal memory and attention, there was an indirect effect of CPZ burden on FAST (b = 0.0045, 95% CI 0.0011–0.0091) and (b = 0.0026, 95% CI 0.0001–0.0006) respectively. However, only verbal memory post hoc analyses showed a significant indirect effect (b = 0.009, 95% CI 0.033–0.0151) adding premorbid IQ as covariate. We did not find significant results for anticholinergic burden.ConclusionCPZ dose effect over functioning is mediated by verbal memory but this association appears barely relevant.

Altres ajuts: Ministerio de Ciencia, Innovación y Universidades; Fondo Europeo de Desarrollo Regional (FEDER); CIBER of Mental Health (CIBERSAM); CERCA Programme (Generalitat de Catalunya); Ministerio de Economía y Competitividad; Fundació La Caixa (ID 100010434, under the agreement LCF/PR/GN18/50310006). The extreme variability in symptom presentation reveals that individuals diagnosed with a first-episode psychosis (FEP) may encompass different sub-populations with potentially different illness courses and, hence, different treatment needs. Previous studies have shown that sociodemographic and family environment factors are associated with more unfavorable symptom trajectories. The aim of this study was to examine the dimensional structure of symptoms and to identify individuals' trajectories at early stage of illness and potential risk factors associated with poor outcomes at follow-up in non-affective FEP. One hundred and forty-four non-affective FEP patients were assessed at baseline and at 2-year follow-up. A Principal component analysis has been conducted to identify dimensions, then an unsupervised machine learning technique (fuzzy clustering) was performed to identify clinical subgroups of patients. Six symptom factors were extracted (positive, negative, depressive, anxiety, disorganization and somatic/cognitive). Three distinct clinical clusters were determined at baseline: mild; negative and moderate; and positive and severe symptoms, and five at follow-up: minimal; mild; moderate; negative and depressive; and severe symptoms. Receiving a low-dose antipsychotic, having a more severe depressive symptomatology and a positive family history for psychiatric disorders were risk factors for poor recovery, whilst having a high cognitive reserve and better premorbid adjustment may confer a better prognosis. The current study provided a better understanding of the heterogeneous profile of FEP. Early identification of patients who could likely present poor outcomes may be an initial step for the development of targeted interventions to improve illness trajectories and preserve psychosocial functioning.

The EUGEI project was supported by the European Community’s Seventh Framework Program under grant agreement no. HEALTH-F2-2009-241909 (Project EU-GEI). Dr O’Donovan is supported by MRC programme grant (G08005009) and an MRC Centre grant (MR/ L010305/1). Dr Rutten was funded by a VIDI award number 91718336 from the Netherlands Scientific Organisation. Drs Guloksuz and van Os are supported by the Ophelia research project, ZonMw grant number: 636340001. Dr Arango was supported by the Spanish Ministry of Science and Innovation; Instituto de Salud Carlos III (SAM16PE07CP1, PI16/02012, PI19/024); CIBERSAM; Madrid Regional Government (B2017/BMD-3740, AGES-CM-2); Fundación Familia Alonso and Fundación Alicia Koplowitz., Pries, L.-K., Dal Ferro, G.A., Van Os, J., Delespaul, P., Kenis, G., Lin, B.D., Luykx, J.J., Richards, A.L., Akdede, B., Binbay, T., Altlnyazar, V., Yallnçetin, B., Gümüş-Akay, G., Cihan, B., Soygür, H., Ulaş, H., Åžahin Cankurtaran, E., Ulusoy Kaymak, S., Mihaljevic, M.M., Andric Petrovic, S., Mirjanic, T., Bernardo, M., Mezquida, G., Amoretti, S., Bobes, J., Saiz, P.A., Garciá-Portilla, M.P., Sanjuan, J., Aguilar, E.J., Santos, J.L., Jiménez-López, E., Arrojo, M., Carracedo, A., López, G., González-Penãs, J., Parellada, M., Maric, N.P., AtbaşoÄalu, C., Ucok, A., Alptekin, K., Can Saka, M., Arango, C., O'Donovan, M., Tosato, S., Rutten, B.P.F., Guloksuz, S., and Genetic Risk and Outcome of Psychosis (GROUP) investigators

Highlights • Survey comparing data from community controls and psychiatric illnesses. • Lockdown had a higher psychological impact in psychiatric patients. • Patients with depression or anxiety symptoms reported more psychological distress. • Psychiatric patients used less adaptive copings strategies to face the lockdown., Background : The aim of this study was to evaluate potential differences about the effects of the COVID-19 pandemic and lockdown between community controls (CC) and patients with a mental illness (MI) in a Spanish population during the state of emergency. Methods : Individuals with a psychiatric condition and the general population were invited to complete an anonymous online survey. Bivariate analyses were used to compare them in a broad range of measures: sociodemographic, clinical variables, behavioral changes related to the lockdown and coping strategies to face it. Two groups of different psychiatric disorders were compared: depression or anxiety disorders (D+A) versus bipolar disorder and schizophrenia related disorders (BD+SCZ). Results : 413 CC and 206 MI were included in the study. CC reported to use more adaptive coping strategies as following a routine, talking to friends/relatives, practicing physical exercise and maintaining a balanced diet. MI reported significantly more anxiety and depression symptoms during the lockdown when compared to CC. Gaining weight, sleep changes, and tobacco consumption were more prevalent in the MI group. The D+A group showed significantly more psychological distress and negative expectations about the future, suffered more sleep disturbances when compared to BD+SCZ, whilst reported to practice more exercise. Limitations : psychiatric disorders were self-reported. Conclusions : Imposed restrictions and uncertainty during confinement had a higher psychological impact in individuals with a psychiatric illness, with less healthy behavior strategies to face the situation. Developing interventions to mitigate negative mental health outcomes among this vulnerable population will be essential in the coming months.

Up to 80% of first-episode psychosis patients suffer a relapse within five years of the remission. Relapse should be an important focus of prevention given the potential harm to the patient and family. It threatens to disrupt their psychosocial recovery, increases the risk of resistance to treatment and has been associated with greater direct and indirect costs for society. Based on a previous project entitled "Genotype-phenotype and environment. Application to a predictive model in first psychotic episodes" (PEPs Project), the project "Clinical and neurobiological determinants of second episodes of schizophrenia. Longitudinal study of first episode of psychosis" was designed, also known as the 2EPs Project. It aimed to identify and characterize those factors that predict a relapse within the years immediately following a first episode. This project has focused on following the clinical course, with neuropsychological assessments, biological and neuroanatomical measures, genetic adherence and physical health monitoring in order to compare a subgroup of patients with a second episode to another group of patients which remains in remission. The main objective of the present article is to describe the rationale of the 2EPs Project, explaining the measurement approach adopted and providing an overview of the selected clinical and functional measures. 2EPs Project is a multicenter, coordinated, naturalistic, longitudinal follow-up study over three years in a Spanish sample of patients in remission after a first-psychotic episode of schizophrenia. It is closely monitoring the clinical course of the cases recruited to compare the subgroup of patients with a second episode to that which remains in remission. The sample is composed of 223 subjects recruited from 15 clinical centres in Spain with experience of the preceding PEPs Study project, albeit 2EPs being an expanded version with new basic groups in biological research. From the total sample recruited, 63 patients presented a relapse (44%). 2EPs arose to characterize first episodes in an exhaustive, novel and multimodal way, thus contributing towards the development of a predictive model of relapse. Identifying the characteristics of patients who relapse could improve early detection and intervention.

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.

The EUGEI project was supported by the European Community’s Seventh Framework Program under grant agreement No. HEALTH-F2- 2009-241909 (Project EU-GEI). Dr. Arango was supported by the Spanish Ministry of Science and Innovation; Instituto de Salud Carlos III (SAM16-PE07CP1, PI16/02012, PI19/024); CIBERSAM (...), Fusar-Poli, L; Pries, LK; van Os, J; Erzin, G; Delespaul, P; Kenis, G; Luykx, JJ; Lin, BCD; Richards, AL; Akdede, B; Binbay, T; Altinyazar, V; Yalincetin, B; Gumus-Akay, G; Cihan, B; Soygur, H; Ulas, H; Cankurtaran, ES; Kaymak, SU; Mihaljevic, MM; Andric-Petrovic, S; Mirjanic, T; Bernardo, M; Mezquida, G; Amoretti, S; Bobes, J; Saiz, PA; Garcia-Portilla, MP; Sanjuan, J; Aguilar, EJ; Santos, JL; Jimenez-Lopez, E; Arrojo, M; Carracedo, A; Lopez, G; Gonzalez-Penas, J; Parellada, M; Maric, NP; Atbasoglu, C; Ucok, A; Alptekin, K; Saka, MC; Aguglia, E; Arango, C; O'Donovan, M; Rutten, BPF; Guloksuz, S