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Objective:Psychotic disorders exhibit a complex aetiology that combines genetic and environmental factors. Among the latter, obstetric complications (OCs) have been widely studied as risk factors, but it is not yet well understood how OCs relate to the heterogeneous presentations of psychotic disorders. We assessed the clinical phenotypes of individuals with a first episode of psychosis (FEP) in relation to the presence of OCs.Methods:Two-hundred seventy-seven patients with an FEP were assessed for OCs using the Lewis–Murray scale, with data stratified into three subscales depending on the timing and the characteristics of the obstetric event, namely: complications of pregnancy, abnormal foetal growth and development and difficulties in delivery. We also considered other two groups: any complications during the pregnancy period and all OCs taken altogether. Patients were clinically evaluated with the Positive and Negative Syndrome Scale for schizophrenia.Results:Total OCs and difficulties in delivery were related to more severe psychopathology, and this remained significant after co-varying for age, sex, traumatic experiences, antipsychotic dosage and cannabis use.Conclusions:Our results highlight the relevance of OCs for the clinical presentation of psychosis. Describing the timing of the OCs is essential in understanding the heterogeneity of the clinical presentation.

BackgroundSchizophrenia (SZ) is a complex brain disorder linked to cognitive and neurostructural abnormalities that involves genetic and environmental factors with obstetric complications (OCs) at birth conferring a high risk for the disease. Indeed, current research in the general population describes the deleterious effect of OCs on cognitive performance in adulthood. With this rationale, we aim to review the relationship between OCs and cognition in SZ and related psychotic disorders.MethodsA systematic review and meta-analysis describing cognitive function and OCs in patients with SZ and related disorders were conducted. PubMed, EmBase, SCOPUS, and the Cochrane Library were systematically searched to identify eligible studies up to January 2022. We calculated the effect sizes (Hedges' g) of cognitive domains within each study and quantified the proportion of between-study variability using the I2 statistic. Homogeneity was assessed using the Q-statistic (X2). The study was registered on PROSPERO (CRD42018094238).ResultsA total of 4124 studies were retrieved, with 10 studies meeting inclusion criteria for the systematic review and eight for meta-analysis. SZ subjects with OCs showed poor verbal memory [Hedges' g = −0.89 (95% CI −1.41 to −0.37), p < 0.001] and working memory performance [Hedges' g = −1.47 (95% CI −2.89 to −0.06), p = 0.01] in a random-effect model compared to those without OCs.ConclusionsOCs appear to have a moderate impact on specific cognitive such as working memory and verbal memory. Our findings suggest that OCs are associated with brain development and might underlie the cognitive abnormalities described at onset of psychosis.

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.

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.

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.

Schizophrenia is a complex disorder in which clinical symptomatology typically reflects underlying brain abnormalities that coalign with multiple physical health comorbidities. The pathogenesis of schizophrenia involves the interplay between genetic and environmental factors, with obstetric complications widely described as key players in elevating the risk of psychosis. In this regard, understanding the anatomical and functional alterations associated with obstetric complications may help to elucidate potential mechanisms through which birth complications could contribute to schizophrenia pathogenesis. We conducted a systematic review of the extant literature describing brain abnormalities and obstetric complications in patients with schizophrenia and related disorders in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines. A total of 471 studies were retrieved and screened, and 33 studies met inclusion criteria for our review. Studies varied considerably in their methods, with 11 studies employing computed tomography, 1 using magnetic resonance spectroscopy, and 21 using magnetic resonance imaging. The scientific quality of the included studies was assessed and documented. Obstetric complications increase the risk of provoking brain abnormalities. These abnormalities range from decreased gray matter volume and abnormal brain-ventricle ratios to a reduction of volume in limbic regions-which relate to what is commonly observed in schizophrenia. However, current evidence from neuroimaging studies remains scant in relation to establishing obstetric complications as an independent risk factor for schizophrenia.

Objective: This study was aimed at identifying differences in the prodromal symptoms and their duration, risk factors and markers of vulnerability in patients presenting a first episode mania (FEM) or psychosis (FEP) with onset in late adolescence or adulthood in order to guide tailored treatment strategies. Methods: Patients with a FEM or FEP underwent a clinical assessment. Prodromes were evaluated with the Bipolar Prodrome Symptom Scale-Retrospective (BPSS-R). Chi-squared tests were conducted to assess specific prodromal symptoms, risk factors or markers of vulnerability between groups. Significant prodromal symptoms were entered in a stepwise forward logistic regression model. The probabilities of a gradual versus rapid onset pattern of the prodromes were computed with logistic regression models. Results: The total sample included 108 patients (FEM = 72, FEP = 36). Social isolation was associated with the prodromal stage of a FEP whilst Increased energy or goal-directed activity with the prodrome to a FEM. Physically slowed down presented the most gradual onset whilst Increased energy presented the most rapid. The presence of obstetric complications and difficulties in writing and reading during childhood were risk factors for FEP. As for markers of vulnerability, impairment in premorbid adjustment was characteristic of FEP patients. No specific risk factor or marker of vulnerability was identified for FEM. Conclusion: Early characteristics differentiating FEP from FEM were identified. These findings might help shape early identification and preventive intervention programmes.

Cognitive impairment is an important feature of schizophrenia (SZ) and bipolar disorder (BP) with severity across the two disorders characterized by significant heterogeneity. Youth at family risk for SZ and BP were clustered based on cognitive function and examined in terms of the clinical, genetic, and brain imaging correlates of cluster membership.One hundred sixty participants, 32 offspring of patients with SZ, 59 offspring of patients with BP and 69 offspring of healthy control parents underwent clinical and cognitive assessments, genotyping and structural MRI. K-means clustering was used to group family risk participants based on cognitive measures. Clusters were compared in terms of cortical and subcortical brain measures as well as polygenic risk scores.Participants were grouped in 3 clusters with intact, intermediate, and impaired cognitive performance. The intermediate and impaired clusters had lower total brain surface area compared with the intact cluster, with prominent localization in frontal and temporal cortices. No between-cluster differences were identified in cortical thickness and subcortical brain volumes. The impaired cluster also had poorer psychosocial functioning and worse PRS-COG compared with the other 2 clusters and with offspring of healthy control parents, while there was no significant between-cluster difference in terms of PRS-SZ and PRS-BP. PRS-COG predicted psychosocial functioning, yet this effect did not appear to be mediated by an effect of PRS-COG on brain area.Stratification based on cognition may help to elucidate the biological underpinnings of cognitive heterogeneity across SZ and BP risk.

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.

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

El concepto de programación fetal metabólica, entendido como toda una serie de modificaciones epigenéticas que sufre el feto durante su periodo intrauterino en respuesta a los estímulos recibidos de la madre orientado a asegurar su supervivencia (1), tiene una importancia añadida en la salud mental infanto-juvenil. Actualmente se considera que los trastornos mentales severos (TMS), esquizofrenia, trastorno bipolar y trastorno depresivo mayor entre otros, tiene su origen en una combinación gen-ambiente, siendo las complicaciones obstétricas un factor ambiental bien replicado en diferentes estudios (2). La presencia de complicaciones obstétricas en estos pacientes se ha asociado a una edad de inicio más precoz del TMS (3), por ende, una mayor incidencia en la etapa infanto-juvenil.

Antipsychotic induced weight gain is a frequent reason for treatment discontinuation in psychosis, subsequently increasing the risk of relapse and negatively affecting patient well-being. The metabolic effect of weight gain and the subsequent risk of obesity constitute a major medical problem on the long term. Despite its consequences, to date few risk factors have been identified (age, gender, body mass index at baseline), with some authors suggesting the implication of early life stressful events, such as perinatal conditions. We aim to describe if a surrogate marker of intrauterine environment (birth weight) might predict weight gain in a cohort of 23 antipsychotic naïve patients at the onset of the psychotic disease evaluated during 16 weeks with olanzapine treatment and in another cohort of 24 psychosis-resistant patients initiating clozapine assessed for 18 weeks. Two independent linear mixed model analyses were performed in each cohort of patients, with prospective weight gain as the dependent variable, age, gender, body mass index, duration of treatment and time as independent variables. Only in naïve patients, weight gain due to antipsychotics was significantly associated with birth weight, while male gender and body mass index at baseline were associated in both cohorts of patients. Treatment-resistant psychotic patients under clozapine were older, had previous antipsychotic treatment and more years of disease, confounders that might have influence a non significant association. Our results suggest that early environmental events might be playing a role in weight evolution in naïve patients treated with antipsychotics.

Antipsychotic-induced weight gain has been especially related to clozapine and olanzapine. Underlying mechanisms in relation to food preferences with an increased food craving and consumption of specific nutrients have not been extensively studied in patients with serious mental illness (SMI). We aim to describe specific food preferences (craving) and subsequent food consumption in SMI patients starting clozapine, as well as their possible relation to weight and body mass index (BMI). An observational prospective follow-up study (18 weeks) was conducted in a cohort of 34 SMI patients who started clozapine due to resistant-psychotic symptoms. Anthropometric measures, Food Craving Inventory (FCI), and a food consumption frequency questionnaire were evaluated at baseline, weeks 8 and 18 of treatment. Statistical analysis included generalized estimating equations models with adjustment for potential confounding factors. No longitudinal changes over time were found across the different food craving scores after 18 weeks of treatment. However, adjusted models according to BMI status showed that the normal weight (NW) group presented an increased score for the “complex carbohydrates/proteins” food cravings (− 0.67; 95% CI [− 1.15, − 0.19]; P = 0.010), while baseline scores for “fast-food fats” cravings were significantly higher in the overweight/obese (OWO) group in comparison with NW patients (NW, 2.05; 95% CI [1.60, 2.49]; OWO, 2.81, 95% CI [2.37, 3.25]; P = 0.016). When considering if food craving could predict weight gain, only increments in “fast-food fats” cravings were associated (β = − 5.35 ± 1.67; 95% CI [− 8.64, − 2.06]; P = 0.001). No longitudinal differences were found for any of the food craving scores evaluated; however, in the NW group, food craving for “complex carbohydrates/proteins” changed. Thus, changes in “fast-food fats” cravings predicted weight increase in this sample. Interventions targeting food preferences may help to mitigate weight gain in patients starting treatment with clozapine.

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.

This independent research and manuscript writing and editing activities were funded by unconditional grant from Angelini Pharma Espan˜a SLU. Angelini Pharma Espan˜a SLU also funded the journal’s rapid service fee., The authors thank Isabel San Andre´s (Incimed, Madrid, Spain) for performing the literature search, This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors., Introduction To assess the risk of occurrence and potential determinants of metabolic disorders in adult patients treated with second-generation antipsychotics (SGAs) under real-world practice conditions. Methods MEDLINE, EMBASE, and PsycInfo were searched in July 2019 from database inception. We included population-based, longitudinal, comparative studies that report the results of the outcomes of interest for adult participants, including diabetes, ketoacidosis, hyperosmolar hyperglycemic state, weight gain/obesity, dyslipidemia, hypertension, and metabolic syndrome. Two reviewers independently extracted data on the study design, study quality, and study outcomes. Results We included 40 studies. Most studies showed that clozapine and olanzapine were associated with an increased likelihood of developing diabetes, while the results for risperidone and quetiapine were mixed. Although less well studied, ziprasidone and aripiprazole appeared to not be associated with the occurrence of diabetes. Information on antipsychotic-induced weight gain/obesity is extremely scarce. Regarding dyslipidemia, aripiprazole was not associated with an increased likelihood of developing dyslipidemia, clozapine was associated with an increased likelihood of developing dyslipidemia, and risperidone, olanzapine, quetiapine, and ziprasidone showed mixed results. Two studies suggested an association between ziprasidone and the occurrence of hypertension. Several studies found that the occurrence of a metabolic disorder acted as a risk factor for the development of other metabolic disorders. We did not find information on brexpiprazole, cariprazine, or lurasidone, and data on any long-acting SGA were lacking. Conclusion Although there are relevant differences among SGAs concerning the risk of metabolic disorders, it appears that none of the SGAs included in our review are fully devoid of these disturbances., Angelini Pharma Espana SLU

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.

Different therapeutic strategies are used for lowering prolactin concentrations in patients with psychotic disorders with antipsychotic-induced hyperprolactinaemia. We aimed to examine the evidence from open-label studies and randomized clinical trials (RCTs) that studied four prolactin-lowering therapeutic strategies in people with psychotic disorders and hyperprolactinaemia: 1) switching to prolactin-sparing antipsychotics; 2) adding aripiprazole; 3) adding dopamine agonists; and 4) adding metformin. RCTs were included in a meta-analysis. Effect sizes (Hedges' g) of prolactin reductions with each strategy were calculated. Withdrawal rates were also considered. We identified 26 studies. Nine studies explored switching antipsychotic treatment to aripiprazole (n = 4), olanzapine (n = 1), quetiapine (n = 2), paliperidone palmitate (n = 1) or blonanserin (n = 1). Twelve studies tested the addition of aripiprazole. Six studies explored the addition of cabergoline (n = 3), bromocriptine (n = 2) or terguride (n = 1). We also found one meta-analysis testing the addition of metformin to antipsychotic treatment but no other individual studies. A meta-analysis could only be performed for the addition of aripiprazole, the strategy with the best level of evidence. Five RCTs testing the addition of aripiprazole yielded a significant reduction in prolactin concentration compared to placebo (N = 3) or maintaining antipsychotic treatment (N = 2): Hedges' g was −1.35 (CI 95%: −1.93 to −0.76, p < 0.001). The three placebo-controlled RCTs for aripiprazole addition showed similar withdrawal rates for aripiprazole (10.1%) and placebo (11.5%), without significant differences in the meta-analysis. Our study suggests that, in terms of levels of evidence, adding aripiprazole is the first option to be considered for lowering prolactin concentrations in patients with schizophrenia and hyperprolactinaemia.

The role of genetics in cognitive remediation therapies in schizophrenia has not been completely understood yet. Different genes involved in neurotrophic, dopaminergic and serotonin systems have reported to influence cognitive functioning in schizophrenia. These genetic factors could also be contributing to the variability in responsiveness to cognitive treatments. No comprehensive synthesis of the literature of the role of genetics in the context of cognitive remediation has been conducted until now. We aimed to systematically review the published works through three electronic database searches: PubMed, Scopus, and the Cochrane Library. Eligible studies revealed a rising interest in the field although the number of published studies was rather small (n = 10). Eventually, promising results showing a relationship between some phenotypic variations based on different polymorphisms and different levels of responsivity to cognitive remediation therapies have been described although results are still inconclusive. In case those findings will be replicated, they could be guiding future research and informing clinical decision-making in the next future. Keywords: Cognitive remediation, Genetics, COMT, BDNF, EAAT2, 5-HT1A-R

© 2020 The Author(s)., The data presented in this paper describe supplementary material to the article entitled “Pharmacological treatment strategies for lowering prolactin in people with a psychotic disorder and hyperprolactinaemia: a systematic review and meta-analysis” [1]. Although raw data was published on the original article, additional raw data has been included in the current paper (new tables with socio-demographic and clinical characteristics of the samples of the studies included in the systematic review). Supplementary data also include the PICO scheme of the systematic review, PRISMA checklist, flow diagram, an explanation of the method for obtaining prolactin concentrations from published figures when data was only available in figures, list of the selected studies, risk of bias summary of all five randomized clinical trials evaluating the addition of aripiprazole for lowering prolactin (included in the meta-analysis in the original article). Extra analyses, figures and R code of the meta-analysis have been also included. Meta-analysis of randomized clinical trials (RCTs) considering aripiprazole addition for lowering prolactin in people with a psychotic disorder and hyperprolactinaemia were conducted with two softwares: 1) R and the metaphor package (for the meta-analysis of the primary outcome [prolactin reduction]); 2) MedCalc version 18.11 (for the meta-analysis of the secondary outcome [withdrawal rates]). Data from a sensitivity analysis (repeating the meta-analysis with only placebo-controlled RCTs) has been also included in the current article., Javier Labad and Itziar Montalvo have received an Intensification of the Research Activity Grant by the Health Department from the Generalitat de Catalunya (SLT006/17/00012 and SLT008/18/00074). Javier Labad has received an Intensification of the Research Activity Grant by the Instituto de Salud Carlos III (INT19/00071).

Background:Around 30% of patients with schizophrenia are considered treatment resistant (TRS). Only around 40% of TRS patients respond to clozapine. Long acting injectable antipsychotics could be a useful augmentation strategy for nonresponders.Methods:We conducted a multicenter, observational, naturalistic, retrospective, 6-month mirror-image study to evaluate the efficacy and tolerability of clozapine and paliperidone palmitate association in 50 patients with TRS and other psychotic disorders. Clinical outcomes and side effects were systematically assessed.Results:Six months after starting the combined treatment, participants showed a significant relief of symptoms, decreasing the Brief Psychiatric Rating Scale total score from 18.32 ± 7.71 to 7.84 ± 5.16 (p p p= 0.004).Conclusions:This study provides the first evidence that combining clozapine with paliperidone palmitate in patients with TRS and other psychotic disorders could be effective and safe, suggesting further research with randomized controlled trials of augmentation strategies for clozapine nonresponder patients.Policy Significance Statement:Patients with psychotic disorders such as schizophrenia show a variable response to antipsychotic treatments. Around 30% of patients are considered treatment resistant, indicated by insufficient symptom control to at least two different drugs. In these resistant cases, clozapine should be indicated, as it has shown to be superior to other options. However, only 40% of patients respond to clozapine, being necessary to establish which treatments could best potentiate clozapine action. Combining clozapine with long acting injectable antipsychotics, and particularly paliperidone palmitate, could be a useful strategy. We conducted a multicenter study of 50 patients with treatment-resistant schizophrenia and other psychotic disorders comparing the efficacy and tolerability in the 6 month-period prior and after starting the clozapine and paliperidone palmitate association. Our study suggests that this combination could be effective and safer, laying the groundwork for future clinical trials with this combination.

The fetal origin of adult disease hypothesis postulates that a stressful in utero environment can have deleterious consequences on fetal programming, potentially leading to chronic disease in later life. Factors known to impact fetal programming include the timing, intensity, duration and nature of the external stressor during pregnancy. As such, dynamic modulation of fetal programming is heavily involved in shaping health throughout the life course, possibly by influencing metabolic parameters including insulin action, hypothalamic-pituitary-adrenal activity and immune function. The ability of prenatal insults to program adult disease is likely to occur as a result of reduced functional capacity in key organs-a "thrifty" phenotype-where more resources are re-allocated to preserve critical organs such as the brain. Notably, it has been postulated that the manifestation of neuropsychiatric disorders in individuals priorly exposed to prenatal stress may arise from the interaction between hereditary factors and the intrauterine environment, which together precipitate disease onset by disrupting the trajectory of normal brain development. In this review we discuss the evidence linking prenatal programming to neuropsychiatric disorders, mainly schizophrenia, via a "Thrifty psychiatric phenotype" concept. We start by outlining the conception of the thrifty psychiatric phenotype. Next, we discuss the convergence of potential mechanistic pathways through which prenatal insults may trigger epigenetic changes that contribute to the increased morbidity and early mortality observed in neuropsychiatric disorders. Finally, we touch on the public health importance of fetal programming for these disorders. We conclude by providing a brief outlook on the future of this evolving field of research.

Cognitive deficits are a core feature of serious mental illnesses such as schizophrenia, major depressive disorder (MDD) and bipolar disorder (BD) and are a common cause of functional disability. There is limited efficacy of pharmacological interventions for improving the cognitive deficits in these disorders. As pro-cognitive pharmacological treatments are lacking, hormones or drugs that target the endocrine system may become potential candidates for 'repurposing' trials aiming to improve cognition. We aimed to study whether treatment with drugs targeting the hypothalamic-pituitary-adrenal (HPA) axis and sex steroids can improve cognition in patients with schizophrenia, MDD or BD. A systematic search was performed using PubMed (Medline), PsychInfo and clinicaltrials.gov, and a narrative synthesis was included. The systematic review identified 12 studies dealing with HPA-related drugs (mifepristone [n = 3], cortisol synthesis inhibitors [ketoconazole, n = 2], dehydroepiandrosterone [n = 5], fludrocortisone [n = 2]) and 14 studies dealing with sex steroids (oestradiol [n = 2], selective oestrogen receptor modulators [raloxifene, n = 7], pregnenolone [n = 5]). Positive trials were found for BD (mifepristone), MDD (dehydroepiandrosterone and fludrocortisone) and schizophrenia (dehydroepiandrosterone, raloxifene and pregnenolone). A replication of positive findings by at least two clinical trials was found for mifepristone in BD and raloxifene and pregnenolone in schizophrenia. The use of drugs targeting hormones related to the HPA axis and sex steroids is a promising field of research that might help to improve the cognitive outcome of patients with schizophrenia, bipolar disorder and major depressive disorder in the near future.

Lifetime prevalence of substance use disorders (SUD) in patients with schizophrenia is nearly 50%. Nicotine, alcohol, and cannabis are the substances most frequently used, with a high percentage of poly-substance users. There are few available data about pharmacological approaches in this population. Amongst antipsychotics, clozapine shows positive evidence in the literature. The aim of the present article is to provide systematic review on the efficacy of clozapine in SUD improvement in schizophrenic patients. PRISMA recommendations were followed (PROSPERO id: CRD42017059299). Five studies for nicotine use and nine studies for SUD (other than nicotine) were analyzed. Regarding nicotine use, results from randomized controlled trials (RCT) have found a decrease in nicotine use after 12 weeks of 200-600mg/day clozapine, as compared with lower doses. In SUD improvement (other than nicotine), RCT have shown superiority of clozapine when compared with risperidone, in short-term studies (from 4 to 12 weeks) performed in cannabis users. In long-term studies (1 year), clozapine was equal to ziprasidone in reducing cannabis use and equal to treatment as usual in reducing alcohol use. We conclude that positive results on nicotine use are scarce and derived from studies with a low degree of evidence. Evidence of clozapine on SUD (other than nicotine) is stronger, especially when clozapine is compared with first generation antipsychotics in poly-substance users. When compared with second generation antipsychotics, clozapine was superior to risperidone but equal to olanzapine or ziprasidone in poly-substance and cannabis users.

Negative symptoms are core symptoms of schizophrenia associated with poorer clinical outcome (Strauss et al., 2010). They can be clinically subdivided into primary and secondary features, representing different phenomenology and pathophysiological mechanisms (Miller et al., 1994). Secondary negative symptoms phenotypically present as primary symptoms, but are attributed to external causes. Positive symptom severity, depression and antipsychotic side-effects are known sources of secondary negative symptoms (Carpenter et al., 1985). Discriminating whether a negative symptom is primary or secondary is clinically relevant as it might require specific, and often opposite interventions (Miller et al., 1994). Despite the development of new symptom severity rating scales, none have considered this distinction.

[Background] Prolactin (Prl) is a pleiotropic hormone initially described for its regulation of lactation in mammals but later associated with metabolic and immune homeostasis, stress, inflammatory response and human behavior. Its regulation through dopamine receptors highlights its importance in psychiatry mostly because hyperprolactinemia is a common secondary side effect of dopamine antagonists. Despite its undeciphered patho-physiological mechanisms, hyperprolactinemia in naïve psychosis patients has been widely described. Its consequences might underlie the increased morbidity and early mortality found in naïve subjects as described in the general population where prolactin values have been correlated with inflammatory, immune and metabolic parameters., [Methods] We aimed to evaluate the correlation between prolactin values and other biochemical parameters (C-reactive Protein-CrP, blood cell count, lipid and hepatic profile, fasting glucose) in a cohort of first episode psychosis naïve subjects (N = 491) stratified by sex. Regression analyses with confounders were performed to evaluate the association., [Findings] Prl displayed significant correlations with C-Reactive Protein (CrP), Low-Density Lipoprotein (LDL), Aspartate Transaminase (AST) for females and High-Density Lipoprotein (HDL) and eosinophil count for males. However, and despite previous specific sex correlations, significant associations were described for CrP, HDL, LDL, AST and ALT without sex interaction and despite confounders such as age, Body Mass Index or smoking status., [Conclusions] Our results show a specific relation of Prl with immune and metabolic parameters describing a heterogeneous pattern. Our results suggest that prolactin might underlie the excess of morbidity and early mortality in naïve patients through a specific pathway., The present study was carried out at the Hospital Marqués de Valdecilla, University of Cantabria, Santander, Spain, under the following grant support: Instituto de investigación sanitaria Valdecilla, Spain INT/A20/04; Instituto de Salud Carlos III, Spain PI020499, PI050427, PI060507.

Background Schizophrenia is a complex medical entity with a reduced life expectancy, mostly due to an increased prevalence of cardiovascular diseases compared to the general population. An unbalanced immune response and a pro-inflammatory state might underlie this process. In treated patients, abnormal white blood cell (WBC), lymphocyte and neutrophil count suggests atypical immune response related to clinical variables. We aimed to test the hypothesis that newly diagnosed naive patients with non-affective psychosis would show abnormal blood cell count values after controlling for potential confounding factors compared to matched controls. Methods Seventy-five patients were compared with 80 controls matched for age, gender, body mass index and smoking. Analyses were conducted before and after controlling for smoking. Results Patients and controls displayed similar mean values (×103/μL [SD]) for WBC count 7.02 [2.2] vs 6.50 [1.7] (P = .159), neutrophil count 4.25 [1.8] vs 3.84 [1.3] (P = .110) and monocyte count 0.43 [0.2] vs 0.40 [0.1] (P = .326). After controlling for smoking, 38 non-smoking patients showed a higher WBC and neutrophil count compared with 49 matched controls. Respective means of 7.01 [2.2] vs 5.97 [1.4] (P = .011) for WBC and 4.24 [1.9] vs 3.51 [1.2] (P = .028) for neutrophil count. Monocyte count showed an increased mean value 0.43 [0.2] vs 0.36 [0.1] with a trend towards signification (P = .063). Conclusions These results suggest that abnormal immune response is present before the effects of medication and other confounders had taken place. Increased immune parameters might underlie the high ratio of medical co-morbidities described in schizophrenia.

Background Some studies have suggested that antipsychotic-naive patients with nonaffective psychosis (NAP) have glucose intolerance. Aims To conduct a systematic review and meta-analysis of fasting glucose (FG), two hour values in the oral glucose tolerance test (2HG), fasting insulin concentration (INS), and insulin resistance (IR). Method We identified possibly relevant studies, then selected studies, following usual guidelines, with two authors reviewing the manuscripts. We required studies to include subjects with nonaffective psychosis and control subjects. Results There were 911 patients and 870 control subjects in the analysis of FG; their average ages were respectively 28.7 and 29.5 years. Significant differences were found for all four variables, with effect size estimates ranging from 0.21 to 0.58. Conclusions As a group, at the time of first clinical contact for psychosis, people with NAP have a slight increase in FG, which most of them maintain in the normal range despite a small increase in IR by secreting additional INS. When faced with a physiological challenge such as a glucose tolerance test or antipsychotics, they are no longer able to maintain a normal glucose concentration.

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

Cognitive deficits are a core feature of serious mental illnesses such as major depression, bipolar disorder and schizophrenia and are a common cause of functional disability. However, the efficacy of pharmacological interventions for improving the cognitive deficits in these disorders is limited. As pro-cognitive pharmacological treatments are lacking, we aimed to review whether thyroid hormones or drugs that target prolactin may become potential candidates for 'repurposing' trials aiming to improve cognition. We conducted a narrative review focused on thyroid hormones and prolactin as potential targets for improving cognition in major mood disorders or schizophrenia. The role of thyroid hormones and prolactin on cognitive processes in non-psychiatric populations was also reviewed. Although clinical trials regarding these hormones are lacking, particularly in patients with schizophrenia, bipolar disorder or major depression, there is evidence from observational studies for the contribution of these hormones to cognitive processes. Patients with bipolar disorder and subclinical hypothyroidism show poorer cognitive function than euthyroid patients. In patients with early psychosis, lower free thyroxine concentrations have been associated with poorer attention whereas increased prolactin levels have been associated with poorer speed of processing. Only two small clinical trials tested the potential pro-cognitive effects of thyroid hormones, with positive findings for triiodothyronine (T3) treatment in patients receiving lithium or electroconvulsive therapy. In sum, thyroid hormones and prolactin might contribute to the cognitive performance of patients with major mood disorders and psychotic disorders. Thyroid hormones and prolactin-lowering drugs (e.g. cabergoline, aripiprazole) are candidate drugs to be tested in repurposing clinical trials aiming to improve the cognitive abilities of patients with major mood disorder and schizophrenia.

(1) Background: The cognitive reserve (CR) concept has not been precisely defined in severe mental disorders and has been estimated using heterogeneous methods. This study aims to investigate and develop the psychometric properties of the Cognitive Reserve Assessment Scale in Health (CRASH), an instrument designed to measure CR in people with severe mental illness; (2) Methods: 100 patients with severe mental illness (non-affective psychoses and affective disorders) and 66 healthy controls were included. The internal consistency and convergent validity of CRASH were assessed. Spearman’s correlations coefficients were also performed to examine the relationship between CRASH and neuropsychological tests, psychosocial functioning, and clinical course; (3) Results: The internal consistency was high (Cronbach’s alpha coefficient = 0.903). The CRASH global score had a large positive correlation with the Cognitive reserve questionnaire total score (r = 0.838, p < 0.001), demonstrating good convergent validity. The correlation coefficients between the CRASH total scores and clinical, functional, and neuropsychological performance were different between groups. In order to provide clinical interpretation, severity classification based on diagnosis (non-affective psychotic disorders, affective disorders, and healthy controls) have been created; (4) Conclusions: CRASH is the first CR measure developed specifically for patients with severe mental illness, facilitating reliable and valid measurement of this construct. The scale may aid in the stratification of patients and the implementation of personalized interventions.

During the last 10 years, early intervention in psychosis programs has been implemented by the Public Health System (PHS) in some of the 17 autonomous communities of Spain. Most of these programs have focused on assessment and intervention in patients with first episode psychosis (FEP), with only a minority including participants with an attenuated psychosis syndromes (APS). These are recruited both through self-referrals by help-seeking patients and through strategies actively seeking to recruit APS from within the community. In the existing programs so far, identification of APS is performed with the Structured Interview of Prodromal Symptoms (SIPS) and Scale of Prodromal Symptoms (SOPS), and Comprehensive Assessment of At-Risk Mental Status (CAARMS), translated into Spanish. Intervention approaches are documented in clinical practice guidelines sponsored by PHS authorities. Although there are some common features across the different programs such as first-line psychological treatments, there are other aspects, such as type of psychotherapy delivered or the indication or type of pharmacological treatments, which vary across programs. Thus, there is substantial variability in the assessment and intervention received by patients with APS throughout Spain. Research in patients with attenuated psychotic symptoms has grown exponentially in Spain in recent years, employing clinical, cognitive, hormonal, immunological, and neuroimaging measures, and has added to the collective body of research characterizing the APS and predictors of transition to psychosis. An illustration of a typical APS case with some characteristic features of current Spanish society is also presented.

Schizophrenia is a complex mental disorder with genetic and environmental components. Obstetric complications (OCs) are one of the most common environmental risk factors described. However, despite being different in timing and outcome, OCs are usually described as a homogeneous entity. In the present study, we evaluate the presence of different patterns of OCs evaluated with the Lewis-Murray Scale in chronic schizophrenia patients (n = 101) and their association with a crude marker of the intrauterine environment such as weight at birth.OCs related with abnormal fetal growth (p < 0.001) and OCs during gestation (p = 0.003) were associated with lower birth weight. However, difficulties in delivery, complications in pregnancy, and OCs all together (as a set) were not associated with weight at birth.Our results infer that OCs cannot be taken as a homogeneous group. Different patterns of OCs result in different birth weights, which is associated with specific metabolic, cognitive, and brain structure outcomes.

Cognitive impairment has been consistently found to be a core feature of serious mental illnesses such as schizophrenia and major mood disorders (major depression and bipolar disorder). In recent years, a great effort has been made in elucidating the biological causes of cognitive deficits and the search for new biomarkers of cognition. Microbiome and gut-brain axis (MGB) hormones have been postulated to be potential biomarkers of cognition in serious mental illnesses. The main aim of this review was to synthesize current evidence on the association of microbiome and gut-brain hormones on cognitive processes in schizophrenia and major mood disorders and the association of MGB hormones with stress and the immune system. Our review underscores the role of the MGB axis on cognitive aspects of serious mental illnesses with the potential use of agents targeting the gut microbiota as cognitive enhancers. However, the current evidence for clinical trials focused on the MGB axis as cognitive enhancers in these clinical populations is scarce. Future clinical trials using probiotics, prebiotics, antibiotics, or faecal microbiota transplantation need to consider potential mechanistic pathways such as the HPA axis, the immune system, or gut-brain axis hormones involved in appetite control and energy homeostasis.

Resumen Introduccion El trastorno limite de la personalidad (TLP) es un trastorno mental frecuente y grave. Su deteccion precoz es importante y para ello se requieren instrumentos fiables de cribado. Sin embargo, no existen hasta la fecha instrumentos de screening especificos para el TLP validados en poblacion castellanohablante. El McLean Screening Instrument for Borderline Personality Disorder (MSI-BPD) es un cuestionario autoinformado de 10 items que permite detectar la presencia de TLP de forma fiable y rapida. El objetivo de este estudio es la validacion del MSI-BPD para su uso en poblacion de habla espanola. Metodo Se examinaron las propiedades psicometricas de la version espanola del MSI-BPD en una muestra de 344 participantes (170 pacientes con orientacion diagnostica de TLP y 174 controles sanos). Resultados El analisis factorial exploratorio mostro la existencia de una estructura bifactorial. La escala presento una elevada consistencia interna (KR-20 = 0,873) y una optima fiabilidad test-retest (CCI = 0,87). Mediante un analisis de regresion logistica y con la DIB-R como referencia se establecio un punto de corte optimo de 7, obteniendo una adecuada sensibilidad (0,71) y especificidad (0,68). El area bajo la curva fue de 0,742 (IC 95% 0,660-0,824). El analisis discriminante permitio observar una capacidad clasificatoria de la escala del 72,8%. Conclusiones La version espanola del MSI-BPD presenta buenas propiedades psicometricas como instrumento de cribado del TLP. Su aplicacion en la practica clinica y en la investigacion puede ser de gran utilidad para la deteccion del TLP por su rapidez y facilidad de uso.

article i nfo Objective: The use of dopaminergic antagonist antipsychotics is associated with hyperprolactinemia, but some studieshavefoundincreasedprolactinconcentrationsinantipsychotic-naivepatientswithschizophreniaandre- lated disorders. We conducted a systematic review and meta-analysis of studies of prolactin in antipsychotic- naive patient with these disorders (PRISMA No. CRD42015016337). Data sources: PubMed (Medline), PsycInfo, and Web of Science were searched for articles from 1950 to the pres- ent in English. Study selection: Seven studies of males (N = 141 for patients, N = 191 for control subjects) and five studies of females (N = 67 and N = 116) met criteria for inclusion: data on blood prolactin concentrations for both control subjectsandantipsychotic-naivepatients with schizophreniaor a relateddisorder,with dataavailable separately for males and females. Data extraction: Data was extracted from the papers by one author and independently verified by a second. Results: The mean effect size for males was 1.02 (95% CI, 0.77, 1.26; p b 0.001) and 0.43 for females (95% CI 0.11, 0.76; p b 0.01). Meta-regression analyses for age, smoking, body mass index (BMI), year of publication, and cor- tisol were not significant. Funnel plots did not suggest the presence of a publication bias. Conclusions: Our meta-analyses found significantly increased prolactin levels in both male and female antipsychotic-naive patients with schizophrenia and related disorders. The small number of studies and limited matchingfor potentiallyconfounding variables insome of thestudies were limitationsof this analysis. Prolonged hyperprolactinemia may lead to sexual dysfunction and osteoporosis, and some antipsychotics cause additional elevation of prolactin concentrations. © 2016 Elsevier B.V. All rights reserved.

Though weight gain is a common side effect of antipsychotic treatment, there are no useful predictors of which patients are likely to be affected and to what degree. It has been shown that exposure to adverse conditions during intra-uterine life confers a vulnerability to the development of later life metabolic complications and low birth weight for gestational age has been shown to be a robust marker of such prenatal adversity. We hypothesised that patients with schizophrenia with a lower birth weight will have increased vulnerability to the weight inducing effects of antipsychotic treatment. The relationship between birth weight and total and central adiposity, measured as body mass index (BMI) and waist-to-hip ratio (WHR) respectively, was examined in three groups: drug naïve first episode of psychosis (FEP) patients (n=41), treatment resistant schizophrenia (TRS) patients (n=42) and matched healthy volunteers (n=72). All analyses were controlled for age, gender and duration of treatment exposure. We found that a lower birth weight was associated with higher BMI and WHR only in TRS patients but not in FEP or controls, suggesting that prenatal adversity, as indicated by the surrogate marker of a lower birth weight, confers an increased vulnerability to clozapine induced weight gain.