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Background: Consistent evidence supports the involvement of genetic and environmental factors, and their interactions, in the etiology of psychosis. First-episode psychosis (FEP) comprises a group of disorders that show great clinical and long-term outcome heterogeneity, and the extent to which genetic, familial and environmental factors account for predicting the long-term outcome in FEP patients remains scarcely known. Methods: The SEGPEPs is an inception cohort study of 243 first-admission patients with FEP who were followed-up for a mean of 20.9 years. FEP patients were thoroughly evaluated by standardized instruments, with 164 patients providing DNA. Aggregate scores estimated in large populations for polygenic risk score (PRS-Sz), exposome risk score (ERS-Sz) and familial load score for schizophrenia (FLS-Sz) were ascertained. Long-term functioning was assessed by means of the Social and Occupational Functioning Assessment Scale (SOFAS). The relative excess risk due to interaction (RERI) was used as a standard method to estimate the effect of interaction of risk factors. Results: Our results showed that a high FLS-Sz gave greater explanatory capacity for long-term outcome, followed by the ERS-Sz and then the PRS-Sz. The PRS-Sz did not discriminate significantly between recovered and non-recovered FEP patients in the long term. No significant interaction between the PRS-Sz, ERS-Sz or FLS-Sz regarding the long-term functioning of FEP patients was found. Conclusions: Our results support an additive model of familial antecedents of schizophrenia, environmental risk factors and polygenic risk factors as contributors to a poor long-term functional outcome for FEP patients. [ABSTRACT FROM AUTHOR]

The validation of nosological diagnoses in psychiatry remains a conundrum. Leonhard's (1979) nosology seems to be one of the few acceptable alternative categorical models to current DSM/ICD systems. We aimed to empirically validate Leonhard's four classes of psychoses: systematic schizophrenia (SSch), unsystematic (USch), cycloid psychosis (Cyclo), and manic-depressive illness (MDI) using a comprehensive set of explanatory validators. 243 patients with first-episode psychosis were followed between 10 and 31 years. A wide-ranging assessment was carried out by collecting data on antecedent, illness-related, concurrent, response to treatment, neuromotor abnormalities, and cognitive impairment variables. Compared with USch, Cyclo, and MDI, SSch displayed a pattern of impairments significantly larger across the seven blocks of explanatory variables. There were no significant differences between Cyclo and MDI in explanatory variables. Except for the majority of illness-onset features, USch displayed more substantial abnormalities in the explanatory variables than Cyclo and MDI. SSch and MDI showed higher percentages of correctly classified patients than USch and Cyclo in linear discriminant analyses. Partial validation of Leonhard's classification was found. SSch showed differences in explanatory variables with respect to Cyclo and MDI. USch showed also significant differences in explanatory variables regarding Cyclo and MDI, although with a lower strength than SSch. There was strong empirical evidence of the separation between both Leonhard's schizophrenia subtypes; however, the distinction between the Cyclo and MDI groups was not empirically supported. A mild to moderate discriminative ability between Leonhard's subtypes on the basis of explanatory blocks of variables was observed. [ABSTRACT FROM AUTHOR]

Introduction: Psychopathological symptoms and cognitive impairment are core features of patients with psychotic disorders. Executive dysfunctions are within the most commonly observed deficits and the Wisconsin Card Sorting Test (WCST) is the test most extensively used for their assessment. Yet, the structure of executive deficits remains unclear, as there may be different underlying processes. Objectives: The study's aims were to explore and compare the network structure of the WCST measures in psychosis and their unaffected siblings. Methods: Subjects were 298 patients with a DSM 5 diagnosis of psychotic disorder and 89 of their healthy siblings. The dimensionality and network structure of the 13 WCST measures were examined by means of the Exploratory Graph Analysis (EGA) and centrality parameters. Results: The WCST network structure comprised 4 dimensions: Perseveration (PER), Inefficient sorting (IS), Failure to maintain set (FMS) and Learning (LNG). Patient and sibling groups showed a similar network structure and in both cases the network structure was reliably estimated. Conclusions: Perseveration measures reflect the inability to switch sorting rules when necessary. Scores for the IS dimension can occur when the subject ineffectively tries to test different sorting hypotheses, changing at random the response. FMS reflects the subject's strategy when he/she is able to find out the sorting rule, but is unable to keep applying that rule long enough. LNG comprised conceptual ability and learning items. The lack of significant difference between network structures is in keeping with results from exploratory and confirmatory studies demonstrating an invariant cognitive factor structure between schizophrenia patients and their unaffected siblings. [ABSTRACT FROM AUTHOR]

Introduction: Cognitive deficits are common, clinically relevant and closely linked to poor functional outcomes in everyday functioning in patients with schizophrenia and other psychoses. Objectives: To ascertain to which extent a polydiagnostic assessment of schizophrenia is associated with clinically-derived criteria of cognitive impairment and gold-standard neuropsychological assessment. Methods: We assessed 98 patients with a psychotic disorder. We tested if patients met criteria for schizophrenia according to five diagnostic classifications: Krapelin, Bleuler, Schneider, ICD-10 and DSM-IV. Also, we applied a set of clinically-derived criteria to assess cognitive impairment associated with psychosis (CIAPs). Goldstandard neuropsychological assessment was administered, covering the cognitive domains included in the MATRICS Cognitive Battery: attention, processing speed, verbal memory, visual memory, working memory, executive function and social cognition. MANOVAs were performed to test the association between polydiagnostic and clinically-derived criteria and neuropsychological assessment. Results: MANOVA profile analyses revealed that patients who met CIAPs criteria showed cognitive impairment in all the cognitive domains except for social cognition. Patients diagnosed with Kraepelin's criteria showed significant differences in processing speed, visual memory, working memory and GCI. Patients fulfilling Bleuler and DSM-IV criteria showed significant deficits in processing speed and verbal memory, respectively. Schneider and ICD-10 diagnostic criteria did not reveal differences in cognition between patients who fulfilled these criteria. Conclusions: CIAPs criteria were the most accurate classifying patients with cognitive impairment, followed by Kraepelin's criteria, which were the ones among diagnostic criteria which better differentiated patients regarding cognitive impairment. These criteria take into consideration the outcome in addition to symptoms. [ABSTRACT FROM AUTHOR]

Introduction: Cognitive impairments in psychotic disorders have been reported as a continuum in severity, from schizophrenia spectrum disorders (more severe) to affective disorders (less severe) (Hill et al 2013). However, findings to date have been inconsistent (Reichenberg et al 2019). Objectives: To establish the cognitive profiles in the MATRICS Consensus Cognitive Battery (MCCB) of a sample of patients with psychotic disorders, according to their diagnosis. Methods: 172 outpatients with psychosis were assessed with the MCCB. Patients were grouped considering their diagnosis: Schizophrenia spectrum disorders (SSD, n=69); Affective disorders (AD, n=46), Schizoaffective disorders (SAD, n=39), Other psychoses(OP, n=18), including patients with one or more psychotic episodes in the past which remitted and do notmeet diagnostic criteria for a current psychotic disorder. Results: Patients with SSD showed worse performance on attention, verbal and visual learning, and combined score of the MCCB, with respect to the OP group. They also underperformed AD group in verbal learning and social cognition. AD patients showed worse performance than OP patients in processing speed and visual learning tasks. SAD patient only showed significant differences in attention scores, with respect to OP patients (Table 1, Fig. 1). [ABSTRACT FROM AUTHOR]

Introduction: Early Intervention Services for Early-Phase Psychosis have shown efficacy and effectiveness (Correl C, JAMA). In Pamplona, Spain, there is an Early Intervention Program that has been providing multiprofesional assistance for First Psychotic Patients for the last two years. Objectives: The aim of this study is to analize the longitudinal effects of the different interventions in several clinical variables applied to 240 patients during two years of follow-up: CASH dimensions, substance abuse, antipsychotic type and dosage, remission rates, re-hospitalization rates and DSM 5 diagnoses. Methods: We apply an standard evaluation protocol to every patient at different times: premorbid, initial time and at months 6, 12, 18 and 24. We analyse the data with the SPSS statistical program to see the results in these variables. Results: The positive and disorganized dimensions show an evident decline during the treatment. The doses of antipsychotic drugs are low and tend to decline. 87% of patients are in monotherapy. The most frequent DSM5 basal diagnosis is Brief Psychotic Episode, but during de follow-up the Diagnosis of Schizophrenia increase from 14,6% at baseline up to 46,2% at month 24. The remission rates are about 65% after 24 months. Conclusions: Early Intervention Services improve psychopathological dimensions, prevents from re-hospitalization, allows the use of lower doses of Antipsychotic Drugs and improve the rates of remission. However, the diagnosis of Schizophrenia is high, so there is no evidence that these programs prevents from chronicity, but provide a better quality of life. [ABSTRACT FROM AUTHOR]

Introduction: Early Intervention Services for Early-Phase Psychosis have shown efficacy and effectiveness (Correl C, JAMA). In Pamplona, Spain, there is an Early Intervention Program that has been providing multiprofesional assistance for First Psychotic Patients for the last two years. Objectives: The aim of this study is to analize the longitudinal effects of the different interventions in several functional variables: GAF, Occupational State, CGI-CogS, QLS, Sofas and WHODAS II applied to 240 patients during two years of follow-up. Methods: We apply an standard evaluation protocol to every patient at different times: premorbid, initial time and at months 6, 12, 18 and 24. We analyse the data with the SPSS statistical program to see the results in these variables. Results: The GAF scale shows a decline during the first 6 months, but tends to reach and maintain the premorbid levels after a year of treatment. Regarding baseline, patients with normalized jobs or studies are 60.7%. This percentage persists during the next months of follow-up but decline at the 24th month Both the Whodas and Sofas scale show improvement tends. The QLS results show a progresional improvement in every subcale during the whole time of follow-up. Conclusions: The Early Intervention Services in Psychosis improve, not only psychopatological dimension but also functional areas, what is important for the whole recovery of First Psychotic Patients. [ABSTRACT FROM AUTHOR]

Introduction: Psychiatric diagnoses are derived from expert opinion (1). Since no objective tests or markers are on the horizon, clinical psychiatry is anchored to "the patient's altered experience, expression and existence, associated with suffering in self and/or others"(2). Many studies have examined diagnostic stability over time. In the last years investigators have been reporting prospective and retrospective consistencies of diagnoses between two time points, specially in first episodes of psychosis (3). Objectives: To examine the prospective and retrospective stability of diagnostic categories 2 years after the first episode of psychosis Methods: Data were examined from the First Episode Psychosis Program of Navarra (PEPsNA), a prospective observational study of a cohort of patients with first-episode psychosis in Navarra (Spain). Diagnosis was assigned using DSM-IV-TR at baseline and 24 months later. Diagnoses were divided into 5 categories: Affective psychosis, Schizophrenia spectrum psychosis, Schizoaffective disorder, acute psychosis and other diagnoses. Diagnostic change was examined using prospective and retrospective consistency Results:Atotal of 78 first-episode psychosis cases with baseline and 24 months follow-up were identified. Table 1 shows the diagnosis movement matrix, and Figure 1 its graphical representation. Of cases, 71.8% (56/78) had the same baseline and 24 months followup diagnosis. Prospective and retrospective consistencies are shown in Table 2 Conclusions: The prospective and retrospective consistencies of Schizophrenia spectrum psychosis and acute psychosis were higher than others. Affective psychosis and Schizoaffective disorder show very variable consistencies. [ABSTRACT FROM AUTHOR]

Introduction: In Pamplona, Spain, there is an Early Intervention Program that has been providing assistance for First Psychotic Patients for the last two years. Objectives: To analyze the longitudinal effects of the different interventions in clinical variables applied to 211 patients during two years of follow-up: CASH dimensions, substance abuse, antipsychotic type and dosage, remission rates, re-hospitalization rates and all-cause-of-treatment-dropout and DSM 5 diagnoses Methods: We apply a standarized evaluation protocol to every patient at different times: premorbid, initial time, and every three months during follow up. Results: The CASH positive dimension (delusions and hallucinations) had a mean score at baseline of 3.77, showing an evident decline during the follow-up. The same happened with the disorganized dimension. We found no significant differences in the negative, motor and affective dimensions. Regarding remission rates from the 6 to the 24 months we found a decline in the rates, accordingly to the increase in re-hospitalization rates. Some of these cases were due to treatment dropout. The doses of antipsychotic treatment are lower at the end of follow-up Substance abuse rates are lower within the first six months, but after this time the percentage of non-consumers declines. The most frequent DSM 5 basal diagnosis is Brief Psychotic Episode, but during follow-up the diagnosis of Schizophrenia increase from 14.6% at baseline up to 46.2% at month 24. Conclusions: The Early Intervention Services improve, psychopathological dimensions and decrease re-hospitalization rates. [ABSTRACT FROM AUTHOR]

Introduction: Early Intervention Services for Early-Phase Psychosis have shown efficay and effectiveness (Correl C, JAMA). In Pamplona, Spain, there is an Early Intervention Program that has been providing assistance for First Psychotic Patients for the last two years. Objectives: The aim of this study is to analyze the longitudinal effects of the different interventions in several functional variables: GAF, occupational state, CGI-CogS, QLS, SOFAS andWHODASII scales applied to 204 patients during two years of follow-up. Methods: We apply a standardized evaluation protocol to every patient at different times: premorbid, initial time, and every three months during follow up. The QLS, SOFAS andWHODASII scales are applied at 6, 12, 18 and 24 months of follow-up. We analyze the data with the SPSS statistical program to see the results in these variables. Results: Occupational state: regarding baseline, patients with normalized jobs/studies are 60.7%. This percentage persist during months 6, 12 and 18, but decline at month 24 (lower sample size) The GAF scale shows a decline during the first six months, but tends to reach the premorbid levels after a year of treatment. The WHODAS II results don't show any improvement until month 24 We haven't found any improvent in the SOFAS scale. The QLS results shows a progresional improvent in every subscale during the time of follow-up Conclusions: The Early Intervention Services improve, not only psichopatological dimensions but also functional factors, what is important for the hole recovery of First Psychotic Patients. [ABSTRACT FROM AUTHOR]

Introduction: A program of First Episodes Psychosis has been implemented in Navarra Objectives: To describe the baseline sociodemographic and clinical characteristics of patients attending the PEPsNa. Methods: We present the baseline results of the sample Results: To date, 211 patients have been treated. Mean age: 29.9 years (SD: 10.5). Gender: 67.8% male. Ethnicity: 73% Caucasian, 15.2% Latin American, 5.7% African and 3.8% Arab. Marital status: 70% were single. Housing: 49.5% live with their parents or family. Employment and occupation: 42.7% of patients have a job or carry out standardised studies. 33.5% are long-term unemployed. DUP: The duration of untreated psychosis is 19.5 months (SD 46.9). The premorbid GAF score is 71.5 and the GAF score of the episode is 30.35. Referrals: 56.7% of patients are referred from the acute psychiatric hospitalization unit and a 30% from Mental Health Centres. Substance abuse: only 20% of patients do not consume any substance. The most consumed drugs are alcohol (75%), cannabis (57.8%) and stimulants (37%). Baseline diagnosis: brief psychotic disorder (42.9%), unspecified psychotic disorder (20%), schizophrenia (14.6%) and substance-induced psychotic disorder (11.7%). Psychopathology: CASH (global rating) for psychotic syndrome: 3.7 (SD 1.1); disorganised syndrome: 2.2 (SD 1.5); negative syndrome: 1.2 (SD 1.3). Treatment: 15.5% of patients received no antipsychotic treatment. The most frequent antipsychotic is risperidone (40.8%). Basal metabolic syndrome: 4% of patients meet criteria. Conclusions: We highlight data such as a short dup that may be related early intervention, substance use is very frequent and Metabolic Syndrome is present from the beginning of the disease. [ABSTRACT FROM AUTHOR]

Introduction: Cognitive impairment is a key feature in patients with psychotic disorders. The Montreal Cognitive Assessment (MoCA) is a brief tool that has been shown to be effective in identifying mild cognitive impairment and early dementia. Objectives: This study explores the usefulness of this instrument to detect cognitive impairment in long-term psychotic disorders. Methods: One hundred-forty stabilized patients were re-evaluated more than 15 years after a First Episode of Psychosis (FEP). Patients were psychopathologically assessed, and the MoCA test and Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) battery were administered. Two cut-off scores for cognitive impairment using the MATRICS battery were applied (T score <40 and <30). Results: Concurrent validation was found between the total scores of the MoCA and MATRICS. We also found significant associations between 5 out of 7 MoCA subtests (visuospatial-executive, attention, language, abstraction and delayed recall) and MATRICS subtests but not for the naming and orientation MoCA subtests. Receiver operating characteristic (ROC) analysis suggested a <25 cut-off for cognitive impairment instead of the original <26. Conclusions: Our results suggest that the MoCA test is a useful screening instrument for assessing cognitive impairment in psychotic patients and has some advantages over other available instruments, such as its ease-of-use and short administration time. [ABSTRACT FROM AUTHOR]

Background: First-episode psychotic disorders comprise a heterogeneous phenotype with a complex etiology involving numerous common small-effect genetic variations and a wide range of environmental exposures. We examined whether a family of schizophrenia spectrum disorder (FH-Sz) interacts with an environmental risk score (ERS-Sz) regarding the outcome of patients with non-affective first episode psychosis (NAFEP)., Methods: We included 288 patients with NAFEP who were evaluated after discharge from an intensive 2-year program. We evaluated three outcome measures: symptomatic remission, psychosocial functioning, and personal recovery. We analyzed the main and joint associations of a FH-Sz and the ERS-Sz on the outcomes by using the relative excess risk due to interaction (RERI) approach., Results: A FH-Sz showed a significant association with poor symptomatic remission and psychosocial functioning outcomes, although there was no significant interaction between a FH-Sz and the ERS-Sz on these outcomes. The ERS-Sz did not show a significant association with poor symptomatic remission and psychosocial functioning outcomes, even though the magnitude of the interaction between ERS-Sz and FH-Sz with the later outcome was moderate (RERI = 6.89, 95% confidence interval -16.03 to 29.81). There was no association between a FH-Sz and the ERS-Sz and personal recovery., Conclusions: Our results provide further empirical support regarding the contribution of FH-Sz to poor symptomatic remission and poor psychosocial functioning outcomes in patients with NAFEP.

Background: Evidence suggests a possible relationship between exposure to childhood adversity (CA) and functional impairment in psychosis. However, the impact of CA on long-term outcomes of psychotic disorders remains poorly understood., Methods: Two hundred and forty-three patients were assessed at their first episode of psychosis for CA and re-assessed after a mean of 21 years of follow-up for several outcome domains, including symptoms, functioning, quality of life, cognitive performance, neurological dysfunction, and comorbidity. The unique predictive ability of CA exposure for outcomes was examined using linear regression analysis controlling for relevant confounders, including socioeconomic status, family risk of schizophrenia, and obstetric complications., Results: There were 54% of the patients with a documented history of CA at mild or higher levels. CA experiences were more prevalent and severe in schizophrenia than in other psychotic disorders ( p < 0.001). Large to very large effect sizes were observed for CA predicting most role functioning variables and negative symptoms (Δ R 2 between 0.105 and 0.181). Moderate effect sizes were observed for positive symptoms, personal functioning, impaired social cognition, impaired immediate verbal learning, poor global cognition, internalized stigma, poor personal recovery, and drug abuse severity (Δ R 2 between 0.040 and 0.066). A dose-response relationship was observed between levels of CA and severity of outcome domains., Conclusion: Our results suggest a strong and widespread link between early adversity exposure and outcomes of psychotic disorders. Awareness of the serious long-term consequences of CA should encourage better identification of those at risk and the development of effective interventions.

Background: Although diagnostic instability in first-episode psychosis (FEP) is of major concern, little is known about its determinants. This very long-term follow-up study aimed to examine the diagnostic stability of FEP diagnoses, the baseline predictors of diagnostic change and the timing of diagnostic change., Methods: This was a longitudinal and naturalistic study of 243 subjects with FEP who were assessed at baseline and reassessed after a mean follow-up of 21 years. The diagnostic stability of DSM-5 psychotic disorders was examined using prospective and retrospective consistencies, logistic regression was used to establish the predictors of diagnostic change, and survival analysis was used to compare time to diagnostic change across diagnostic categories., Results: The overall diagnostic stability was 47.7%. Schizophrenia and bipolar disorder were the most stable diagnoses, with other categories having low stability. Predictors of diagnostic change to schizophrenia included a family history of schizophrenia, obstetric complications, developmental delay, poor premorbid functioning in several domains, long duration of untreated continuous psychosis, spontaneous dyskinesia, lack of psychosocial stressors, longer duration of index admission, and poor early treatment response. Most of these variables also predicted diagnostic change to bipolar disorder but in the opposite direction and with lesser effect sizes. There were no significant differences between specific diagnoses regarding time to diagnostic change. At 10-year follow-up, around 80% of the diagnoses had changed., Conclusions: FEP diagnoses other than schizophrenia or bipolar disorder should be considered as provisional. Considering baseline predictors of diagnostic change may help to enhance diagnostic accuracy and guide therapeutic interventions.

Background: Ovarian cancer (OC) is the leading cause of death from gynecologic malignancies in the Western world. Contributing factors include a high frequency of late-stage diagnosis, the development of chemoresistance, and the evasion of host immune responses. Currently, debulking surgery and platinum-based chemotherapy are the treatment cornerstones, although recurrence is common. As the clinical efficacy of immune checkpoint blockade is low, new immunotherapeutic strategies are needed. Chimeric antigen receptor (CAR) T cell therapy empowers patients' own T cells to fight and eradicate cancer, and has been tested against various targets in OC. A promising candidate is the MUC16 ectodomain. This ectodomain remains on the cell surface after cleavage of cancer antigen 125 (CA125), the domain distal from the membrane, which is currently used as a serum biomarker for OC. CA125 itself has not been tested as a possible CAR target. In this study, we examined the suitability of the CA125 as a target for CAR T cell therapy., Methods: We tested a series of antibodies raised against the CA125 extracellular repeat domain of MUC16 and adapted them to the CAR format. Comparisons between these candidates, and against an existing CAR targeting the MUC16 ectodomain, identified K101 as having high potency and specificity. The K101CAR was subjected to further biochemical and functional tests, including examination of the effect of soluble CA125 on its activity. Finally, we used cell lines and advanced orthotopic patient-derived xenograft (PDX) models to validate, in vivo, the efficiency of our K101CAR construct., Results: We observed a high efficacy of K101CAR T cells against cell lines and patient-derived tumors, in vitro and in vivo. We also demonstrated that K101CAR functionality was not impaired by the soluble antigen. Finally, in direct comparisons, K101CAR, which targets the CA125 extracellular repeat domains, was shown to have similar efficacy to the previously validated 4H11CAR, which targets the MUC16 ectodomain., Conclusions: Our in vitro and in vivo results, including PDX studies, demonstrate that the CA125 domain of MUC16 represents an excellent target for treating MUC16-positive malignancies., Competing Interests: Competing interests: SW, EMI, DJW, NPC and EB have filled a patent application on chimeric antigen receptor for ovarian cancer. The other authors declare no conflict of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Cognitive deficits are already present before psychosis onset but are a key feature of first-episode psychosis (FEP). The objective of this study was to investigate the cognitive outcomes of a cohort of FEP patients who were diagnosed using the clinical staging approach and were followed for up to 21 years. We analyzed data from 173 participants with first-admission psychosis who were followed-up for a mean of 20.9 years. The clinical staging assessment was adapted from the clinical staging framework developed by McGorry et al. 1 Cognitive assessment was performed using the MATRICS Consensus Cognitive Battery (MMCB) at the end of follow-up. FEP patients who were longitudinally diagnosed in the lowest clinical stages (stages 2A and 2B) showed better performance in attention, processing speed, and MCCB overall composite score than those in the highest clinical stages (stages 4A and 4B). There was a significant linear trend association between worsening of all MCCB cognitive functions and MCCB overall composite score and progression in clinical staging. Furthermore, the interval between two and five years of follow-up appears to be associated with deficits in processing speed as a cognitive marker. Our results support the validation of the clinical staging model over a long-term course of FEP based on neuropsychological performance. A decline in some cognitive functions, such as processing speed, may facilitate the transition of patients to an advanced stage during the critical period of first-episode psychosis., (Copyright © 2024 Sociedad Española de Psiquiatría y Salud Mental (SEPSM). Published by Elsevier España S.L.U. All rights reserved.)

Patients with first-episode psychoses (FEP) exhibit heterogeneity in clinical manifestations and outcomes. This study investigated the long-term trajectories of six key psychopathological dimensions (reality-distortion, negative, disorganization, catatonia, mania and depression) in patients diagnosed with FEP. A total of 243 patients were followed up for 20 years and the trajectories of the dimensions were analysed using growth mixture modelling. These dimensions showed varied course patterns, ranging from two to five trajectories. Additionally, the study examined the predictive value of different factors in differentiating between the long-term trajectories. The exposome risk score showed that familial load, distal and intermediate risk factors, acute psychosocial stressors and acute onset were significant predictors for differentiating between long-term psychopathological trajectories. In contrast, polygenic risk score, duration of untreated psychosis and duration of untreated illness demonstrated little or no predictive value. The findings highlight the importance of conducting a multidimensional assessment not only at FEP but also during follow-up to customize the effectiveness of interventions. Furthermore, the results emphasize the relevance of assessing premorbid predictors from the onset of illness. This may enable the identification of FEP patients at high-risk of poor long-term outcomes who would benefit from targeted prevention programs on specific psychopathological dimensions., Competing Interests: Declaration of Competing Interest The authors reported no conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

Background: This study compares the effectiveness of a new early intervention service for firstepisode psychosis (FEP) in patients under conventional treatment. Six primary and 10 secondary outcome measures are used to better characterize the comparative effectiveness between two FEP groups., Methods: This study plans to enroll 250 patients aged 15-55 years with FEP from all inpatient and outpatient mental health services and primary health care from January 2020 until December 2022. The control group will be composed of 130 FEP patients treated in mental health centers in the 2 years prior to the start of PEPsNa (Programa de Primeros Episodios de Psicosis de Navarra). The primary outcome measures are symptomatic remission, functional recovery, personal recovery, cognitive performance, functional capacity in real-world settings, and costs. The secondary outcome measures are duration of untreated psychosis, substance abuse rate, antipsychotic monotherapy, minimal effective dose of antipsychotic drugs, therapeutic alliance, drop-out rate, number of relapses, global mortality and suicidality, resource use, and general satisfaction in the program., Discussion: This study arises from the growing need to broaden the scope of outcome measures in FEP patients and to account for unmet needs of recovery for FEPs. It aims to contribute in the dissemination of the NAVIGATE model in Europe and to provide new evidence of the effectiveness of early intervention services for stakeholders of the National Health Service., (Copyright © 2022 Sociedad Española de Psiquiatría y Salud Mental (SEPSM). Published by Elsevier España S.L.U. All rights reserved.)

Background: First-episode psychosis is a critical period for early interventions to reduce the risk of poor outcomes and relapse as much as possible. However, uncertainties about the long-term outcomes of symptomatology remain to be ascertained., Methods: The aim of the present study was to use network analysis to investigate first-episode and long-term stages of psychosis at three levels of analysis: micro, meso and macro. The sample was a cohort of 510 patients with first-episode psychoses from the SEGPEP study, who were reassessed at the long-term follow-up (n = 243). We used the Comprehensive Assessment of Symptoms and History for their assessments and lifetime outcome variables of clinical relevance., Results: Our results showed a similar pattern of clustering between first episodes and long-term follow-up in seven psychopathological dimensions at the micro level, 3 and 4 dimensions at the meso level, and one at the macro level. They also revealed significant differences between first-episode and long-term network structure and centrality measures at the three levels, showing that disorganization symptoms have more influence in long-term stabilized patients., Conclusions: Our findings suggest a relative clustering invariance at all levels, with the presence of two domains of disorganization as the most notorious difference over time at micro level. The severity of disorganization at the follow-up was associated with a more severe course of the psychosis. Moreover, a relative stability in global strength of the interconnections was found, even though the network structure varied significantly in the long-term follow-up. The macro level was helpful in the integration of all dimensions into a common psychopathology factor, and in unveiling the strong relationships of psychopathological dimensions with lifetime outcomes, such as negative with poor functioning, disorganization with high antipsychotic dose-years, and delusions with poor adherence to treatment. These results add evidence to the hierarchical, dimensional and longitudinal structure of psychopathological symptoms and their clinical relevance in first-episode psychoses., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose: Fluorescence imaging (FLI) using targeted near-infrared (NIR) conjugates aids the detection of tumour lesions pre- and intraoperatively. The optimisation of tumour visualisation and contrast is essential and can be achieved through high tumour-specificity and low background signal. However, the choice of fluorophore is recognised to alter biodistribution and clearance of conjugates and is therefore a determining factor in the specificity of target binding. Although ZW800-1, IRDye® 800CW and ICG are the most commonly employed NIR fluorophores in clinical settings, the fluorophore with optimal in vivo characteristics has yet to be determined. Therefore, we aimed to characterise the impact the choice of fluorophore has on the biodistribution, specificity and contrast, by comparing five different NIR fluorophores conjugated to folate, in an ovarian cancer model., Procedures: ZW800-1, ZW800-1 Forte, IRDye® 800CW, ICG-OSu and an in-house synthesised Cy7 derivative were conjugated to folate through an ethylenediamine linker resulting in conjugates 1-5, respectively. The optical properties of all conjugates were determined by spectroscopy, the specificity was assessed in vitro by flow cytometry and FLI, and the biodistribution was studied in vivo and ex vivo in a subcutaneous Skov-3 ovarian cancer model., Results: We demonstrated time- and receptor-dependent binding of folate conjugates in vitro and in vivo. Healthy tissue clearance characteristics and tumour-specific signal varied between conjugates 1-5. ZW800-1 Forte (2) revealed the highest contrast in folate receptor alpha (FRα)-positive xenografts and showed statistically significant target specificity. While conjugates 1, 2 and 3 are renally cleared, hepatobiliary excretion and no or very low accumulation in tumours was observed for 4 and 5., Conclusions: The choice of fluorophore has a significant impact on the biodistribution and tumour contrast. ZW800-1 Forte (2) exhibited the best properties of those tested, with significant specific fluorescence signal., (© 2021. The Author(s).)

This study was aimed at characterizing long-term outcomes of first-admission psychosis and examining their baseline predictors. Participants were assessed at baseline for 38 candidate predictors and re-assessed after a median follow-up of 21 years for symptomatic, functional, and personal recovery. Associations between the predictors and the outcomes were examined using univariate and multivariate Cox regression models. At baseline, 623 subjects were assessed for eligibility, 510 met the inclusion/exclusion criteria and 243 were successfully followed-up (57.3% of the survivors). At follow-up, the percentages of subjects achieving symptomatic, functional, and personal recovery were 51.9%, 52.7%, and 51.9%, respectively; 74.2% met at least one recovery criterion and 32.5% met all three recovery criteria. Univariate analysis showed that outcomes were predicted by a broad range of variables, including sociodemographics, familial risk, early risk factors, premorbid functioning, triggering factors, illness-onset features, neurological abnormalities, deficit symptoms and early response to treatment. Many of the univariate predictors became nonsignificant when entered into a hierarchical multivariate model, indicating a substantial degree of interdependence. Each single outcome component was independently predicted by parental socioeconomic status, family history of schizophrenia spectrum disorders, early developmental delay, childhood adversity, and mild drug use. Spontaneous dyskinesia/parkinsonism, neurological soft signs and completion of high school remained specific predictors of symptomatic, functional, and personal outcomes, respectively. Predictors explained between 27.5% and 34.3% of the variance in the outcomes. In conclusion, our results indicate a strong potential for background and first-episode characteristics in predicting long-term outcomes of psychotic disorders, which may inform future intervention research., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Nitroreductases (NTR) are a family of bacterial enzymes used in gene directed enzyme prodrug therapy (GDEPT) that selectively activate prodrugs containing aromatic nitro groups to exert cytotoxic effects following gene transduction in tumours. The clinical development of NTR-based GDEPT has, in part, been hampered by the lack of translational imaging modalities to assess gene transduction and drug cytotoxicity, non-invasively. This study presents translational preclinical PET imaging to validate and report NTR activity using the clinically approved radiotracer, 18 F-FMISO, as substrate for the NTR enzyme. Methods: The efficacy with which 18 F-FMISO could be used to report NfsB NTR activity in vivo was investigated using the MDA-MB-231 mammary carcinoma xenograft model. For validation, subcutaneous xenografts of cells constitutively expressing NTR were imaged using 18 F-FMISO PET/CT and fluorescence imaging with CytoCy5S, a validated fluorescent NTR substrate. Further, examination of the non-invasive functionality of 18 F-FMISO PET/CT in reporting NfsB NTR activity in vivo was assessed in metastatic orthotopic NfsB NTR expressing xenografts and metastasis confirmed by bioluminescence imaging. 18 F-FMISO biodistribution was acquired ex vivo by an automatic gamma counter measuring radiotracer retention to confirm in vivo results. To assess the functional imaging of NTR-based GDEPT with 18 F-FMISO, PET/CT was performed to assess both gene transduction and cytotoxicity effects of prodrug therapy (CB1954) in subcutaneous models. Results: 18 F-FMISO retention was detected in NTR + subcutaneous xenografts, displaying significantly higher PET contrast than NTR - xenografts ( p < 0.0001). Substantial 18 F-FMISO retention was evident in metastases of orthotopic xenografts ( p < 0.05). Accordingly, higher 18 F-FMISO biodistribution was prevalent ex vivo in NTR + xenografts. 18 F-FMISO NfsB NTR PET/CT imaging proved useful for monitoring in vivo NTR transduction and the cytotoxic effect of prodrug therapy. Conclusions: 18 F-FMISO NfsB NTR PET/CT imaging offered significant contrast between NTR + and NTR - tumours and effective resolution of metastatic progression. Furthermore, 18 F-FMISO NfsB NTR PET/CT imaging proved efficient in monitoring the two steps of GDEPT, in vivo NfsB NTR transduction and response to CB1954 prodrug therapy. These results support the repurposing of 18 F-FMISO as a readily implementable PET imaging probe to be employed as companion diagnostic test for NTR-based GDEPT systems., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Our current ability to predict the long-term course and outcome of subjects with a first-episode of psychosis (FEP) is limited. To improve our understanding of the long-term outcomes of psychotic disorders and their determinants, we designed a follow-up study using a well-characterized sample of FEP and a multidimensional approach to the outcomes. The main goals were to characterize the long-term outcomes of psychotic disorders from a multidimensional perspective, to address the commonalities and differential characteristics of the outcomes, and to examine the common and specific predictors of each outcome domain. This article describes the rationale, methods, and design of a longitudinal and naturalistic study of subjects with epidemiologically defined first-admission psychosis. Methods: Eligible subjects were recruited from consecutive admissions between January 1990 and December 2009. Between January 2018 and June 2021, we sought to trace, re-contact, and re-interview the subjects to assess the clinical course, trajectories of symptoms and functioning, and the different outcomes of psychotic disorders. Since this is a naturalistic study, the research team will not interfere with the subjects' care and treatment. Predictors include antecedent variables, first-episode characteristics, and illness-related variables over the illness course. We assess eight outcome domains at follow-up: psychopathology, psychosocial functioning, self-rated personal recovery, self-rated quality of life, cognitive performance, neuromotor dysfunction, medical and psychiatric comorbidities, and mortality rate. The range of the follow-up period will be 10-31 years with an estimated mean of 20 years. We estimate that more than 50% of the baseline sample will be assessed at follow-up. Discussion: The study design was driven by the increasing need to refine the ability to predict the different clinical outcomes in FEP, and it aims to close current gaps in knowledge, with a broad approach to both the definition of outcomes and their determinants. To the best of our knowledge, this study is one of the few attempting to characterize the very long-term outcome of FEP and the only study addressing eight major outcome domains. We hope that this study helps to better characterize the long-term outcomes and their determinants, enabling better risk stratification and individually tailored, person-based interventions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Peralta, Moreno-Izco, García de Jalón, Sánchez-Torres, Janda, Peralta, Fañanás, Cuesta and SEGPEPs Group.)

Cognitive impairment is a key feature in patients with psychotic disorders. The Montreal Cognitive Assessment (MoCA) is a brief tool that has been shown to be effective in identifying mild cognitive impairment and early dementia. This study explores the usefulness of this instrument to detect cognitive impairment in long-term psychotic disorders. One hundred-forty stabilized patients were re-evaluated more than 15 years after a First Episode of Psychosis (FEP). Patients were psychopathologically assessed, and the MoCA test and MATRICS Consensus Cognitive Battery (MCCB) were administered. Two cut-off scores for cognitive impairment using the MCCB were applied (T score <40 and < 30). Concurrent validation was found between the total scores of the MoCA and MCCB. We also found significant associations between 5 out of 7 MoCA subtests (visuospatial-executive, attention, language, abstraction and delayed recall) and MCCB subtests but not for the naming and orientation MoCA subtests. Receiver operating characteristic (ROC) analysis suggested a <25 cut-off for cognitive impairment instead of the original <26. Our results suggest that the MoCA test is a useful screening instrument for assessing cognitive impairment in psychotic patients and has some advantages over other available instruments, such as its ease-of-use and short administration time., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Motor abnormalities (MAs) are highly prevalent in patients with first-episode psychosis both before any exposure and after treatment with antipsychotic drugs. However, the extent to which these abnormalities have predictive value for long-term psychosocial functioning is unknown. One hundred antipsychotic-naive first-episode psychosis (FEP) patients underwent extensive motor evaluation including catatonic, parkinsonism, dyskinesia, akathisia and neurological soft signs. Patients were assessed at naïve state and 6months later. Patients were followed-up in their naturalistic treatment and settings and their psychosocial functioning was assessed at 6-month, 1year, 5year and 10years from the FEP by collecting all available information. A set of linear mixed models were built to account for the repeated longitudinal assessment of psychosocial functioning during the follow-up regarding to the five domains of MAs (catatonic, parkinsonism, akathisia, dyskinesia and neurologic soft-signs) at index episode at antipsychotic naïve state and after 6months of FEP. Basic epidemiological variables, schizophrenia diagnosis and average of chlorpromazine equivalent doses of antipsychotic drugs were included as covariates. Catatonic signs and dyskinesia at drug-naïve state were significantly associated with poor long-term psychosocial functioning. Moreover, higher scores on parkinsonism, akathisia, neurological soft signs and catatonic signs at 6-month of FEP but not dyskinesia showed significant associations with poor long-term psychosocial functioning. Our results added empirical evidence to motor abnormalities as core manifestations of psychotic illness before and after antipsychotic treatment with high predictive value for poor long-term psychosocial functioning in FEP patients., (Copyright © 2018 Elsevier B.V. All rights reserved.)

This study aimed to characterize the deficit syndrome in drug-naive schizophrenia patients and to examine the relationship between deficit features and primary neurological abnormalities. Drug-naive schizophrenia patients (n = 102) were examined at baseline for demographics, premorbid functioning, duration of untreated illness (DUI), psychopathology, neurological signs, and deficit symptoms, and reassessed at 1-year follow-up. Neurological abnormalities were examined before inception of antipsychotic medication and included four domains of spontaneous movement disorders (SMD) and four domains of neurological soft signs (NSS). Patients fulfilling the deficit syndrome criteria at the two assessments (n = 20) were compared with nondeficit patients (n = 82) across demographic, clinical, and neurological variables. Deficit and nondeficit groups showed similar demographic characteristics and levels of psychotic, disorganization, and depressive symptoms. Compared with nondeficit patients, deficit patients showed poorer premorbid adjustment, higher premorbid deterioration, a lengthier DUI, and much poorer functional outcome. Relative to the nondeficit patients, those with the deficit syndrome showed higher levels of SMD--excepting akathisia--and NSS. This association pattern was also evident for deficit and neurological ratings in the whole sample of schizophrenia patients. Parkinsonism, motor sequencing, and release signs were all independently related to the deficit syndrome. These findings confirm that the deficit/nondeficit categorization is replicable and reliable in first-admission patients and raise the possibility that premorbid deterioration, deficit symptoms, and neurological abnormalities represent a triad of manifestations that share common underlying neurobiological mechanisms. More specifically, the data are consistent with a neurodevelopmental model of deficit symptoms involving basal ganglia dysfunction.

Background: Duration of untreated psychosis (DUP) has been significantly associated with poor clinical and social outcomes in First Episode Psychosis (FEP) patients, but an association with cognitive outcomes has not been clearly established., Method: Seventy-seven consecutively admitted, drug-naïve patients with FEP were assessed at baseline and at 1month and 6months. Underlying dimensions of DUP (general prodrome and positive, negative and disorganisation symptoms) were assessed using the Symptom Onset in Schizophrenia (SOS) inventory (Perkins et al., 2000). To assess the effect of DUP on the neuropsychological status of the patients, a linear mixed-effect model was fitted to each neuropsychological dimension. These models included a dichotomised version of DUP (short versus long duration) as a fixed effect, several adjusting variables to account for patient differences, and a random effect to incorporate the longitudinal structure of the data., Results: Patients with a short duration of untreated negative symptoms (DUNS) or a short duration of untreated positive symptoms (DUPS) outperformed patients with a long duration of untreated symptoms on memory tasks and a pre-attentional visual task but not on measures of verbal fluency, attention, reaction time, visual processing and executive functions., Conclusions: This study provides additional support for an early intervention to shorten DUP to facilitate a better outcome in memory and attentional domains of FEP patients., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: To analyse the diagnostic concordance between the paediatric and mental health (MH) services., Materials and Methods: Two hundred and seven patients from 0 to 16 years referred from paediatrics to the Estella Mental Health Centre during 2006 and 2007. Concordance between global Kappa Index and specific diagnosis was calculated with Epidat 3.1. An analysis was made for each diagnostic category of the percentage of cases where the diagnosis made in paediatrics was confirmed in Mental Health., Results: The global diagnostic concordance between both medical care levels has a Kappa Index of 0.58. There is a wide variability in the concordance between the different diagnoses. The concordance is weak (0.2-0.4) for specific developmental disorder, affective disorders and adaptative disorders. A moderate concordance (0.41-0.6) is obtained for mental retardation, pervasive developmental disorder, z diagnostics, and sibling rivalry disorder. Concordance is good for attention deficit disorder with hyperactivity, anxiety disorder and conduct disorder. Finally, the diagnostic concordance is very good for enuresis and encopresis and for eating disorders., Conclusions: The diagnostic concordance obtained between paediatric services and the mental health centre is moderate. A wide variability is obtained in the concordance between different diagnoses.

Aim: To determine the influence of the cognitive state on the presence of different frailty factors in the elderly., Methods: Study of an outpatient elderly population with chronic diseases (resident at home or institutionalised), the presence of different frailty risk factors and their relation to cognitive state (measured using the mini-mental state examination-MEC)., Results: Study of 147 elderly people with an average age of 71.4 years and a similar proportion of men (74; 50.3%) and women (73; 49.7%). Thirty-four subjects (23.1%) institutionalised in residences. The percentage of patients showing cognitive impairment (MEC<24 points) is 12.9% (19 cases). Presence of frailty risk factors: low social support: 7.5% (11); falls: 17% (25); urinary incontinence: 18.4% (27); depression: 13.6% (20); anxiety-insomnia: 29.9% (44); hospitalisation-readmissions: 21.8% (32); multiple medications (>3 medicines): 53.7% (79); pluripathology (> or =3 diseases): 36.1% (53). The frailty factors that have a significant relation in patients with cognitive impairment (MEC<24) are falls [OR=59.5 (CI 95%=14.7-240.6)] (p<0.0001), urinary incontinence [OR=31.2 (8.9-109.1)] (p<0.0001), hospitalisation-readmissions [OR=32.9 (8.6-125.8)] (p<0.0001) and depression [OR=7.8 (2.5-23.5)] (p<0.0001). With respect to scoring on the MEC by percentiles, the risk factors that showed a tendency of lineal appearance are falls (p<0.0001), urinary incontinence (p<0.0001), hospitalisation-readmissions (p<0.0001) and pluripathology (p=0.002)., Conclusions: Cognitive impairment marks the appearance in a significant form of frailty factors in the elderly, such as falls, urinary incontinence, hospitalisation-readmissions and depression. This relation is not only appreciable in patients with an established cognitive impairment (MEC<24 points), but there is also a trend to appear as this impairment progresses, with a statistical relation for falls, urinary incontinence, hospitalisation-readmissions and pluripathology.

Background: To determine the influence of age, education, admission in nursing homes and chronic diseases (arterial hypertension, diabetes, hyperlipidaemia, anxiety and depression) on the cognitive state of the population over 65 years of age., Material and Methods: A study was made of a geriatric outpatient population (patients living at home or institutionalised) with chronic diseases, who showed cognitive deterioration and depressive symptoms. The cognitive mini-exam (CME) and the geriatric depression scale (Yesavage) were administered., Results: One hundred and forty-seven patients participated, with an average age of 71.4 years and a similar proportion of men (74; 50.3%) and women (73; 49.7%). Thirty-four subjects (23.1%) were living in nursing homes. The most prevalent diseases were hypertension (50%), anxiety-insomnia (30%), diabetes (22%), arthrosis (22%), depression (13%) and hypercholesterolaemia (12%). Half of the patients (79; 53.7%) were following treatment with more than three medicines; 60 (40.6%) with between two and three medicines, and only 8 (5.5%) were taking no medication. The percentage of subjects living in an institution increased with age. The consumption of medicines was also higher amongst the more elderly. The scores on the cognitive scale (CME) decrease with age and were also lower amongst subjects who live in institutions (above all if they suffer from depression). The patients who took psychotropics had lower scores on the CME. Although performances on the CME are lower amongst subjects with a low level of education, the differences do not reach statistical significance. The presence of hyperlipidaemia also decreased the results of the CME., Conclusions: The socio-health factors that altered performance negatively in the cognitive mini-exam are advanced age and institutionalisation. These results are also significantly influenced by depressive disease, hyperlipidaemia and the consumption of medicines that affect the cognitive state.

Both suicidal behaviour and consumated suicide are an important problem for public health throughout the world, which is why it is important to understand its determinant factors. Autolytic conduct is a complex and non-aleatory act in which socio-demographic, psychological and biological factors intervene. This study analyses the most important risk factors in autolytic behaviour. It is important to have a good understanding of these factors to be able to adequately evaluate autolytic risk and, as far as possible, to prevent autolytic behaviour.