TYPE Original Research PUBLISHED 20 October 2022 DOI 10.3389/fpsyt.2022.982583 Influence of clinical and OPEN ACCESS neurocognitive factors in EDITED BY Wing Chung Chang, The University of Hong Kong, psychosocial functioning after a Hong Kong SAR, China REVIEWED BY first episode non-affective Ellie Brown, The University of Melbourne, Australia Ernest Marek Tyburski, psychosis: Differences between Pomeranian Medical University in Szczecin, Poland males and females *CORRESPONDENCE Eduard Vieta evieta@clinic.cat Maria Serra-Navarro1,2† , Silvia Amoretti1,2,3,4† , Carla Torrent Norma Verdolini1,2,5 , María Florencia Forte1,3 , ctorrent@clinic.cat † These Ana M. Sánchez-Torres6,7 , Eduard Vieta1,2*, Derek Clougher1 , authors share first authorship Antonio Lobo2,8 , Ana González-Pinto2,9,10 , Rocío Panadero2,11 , SPECIALTY SECTION This article was submitted to Alexandra Roldán2,12 , André F. Carvalho13 , Schizophrenia, a section of the journal Elena de la Serna2,14 , Alba Toll2,15 , J. A. Ramos-Quiroga2,4,16,17 , Frontiers in Psychiatry Carla Torrent1,2*, Manuel J. Cuesta6,7 , Miguel Bernardo2,3 and RECEIVED 30 June 2022 ACCEPTED 28 September 2022 PEPs Group PUBLISHED 20 October 2022 1 Bipolar and Depressive Disorders Unit, Hospital Clinic of Barcelona, Institute of Neurosciences, CITATION IDIBAPS, University of Barcelona, Barcelona, Catalonia, Spain, 2 Biomedical Research Networking Serra-Navarro M, Amoretti S, Center for Mental Health Network (CIBERSAM), Barcelona, Spain, 3 Barcelona Clinic Schizophrenia Verdolini N, Forte MF, Unit, Hospital Clinic of Barcelona, Neuroscience Institute, August Pi I Sunyer Biomedical Research Sánchez-Torres AM, Vieta E, Institute (IDIBAPS), University of Barcelona, Barcelona, Spain, 4 Psychiatric Genetics Unit, Group of Clougher D, Lobo A, González-Pinto A, Psychiatry, Mental Health and Addictions, Vall d’Hebron Research Institute (VHIR), Barcelona, Panadero R, Roldán A, Carvalho AF, Catalonia, Spain, 5 Local Health Unit Umbria 1, Department of Mental Health, Mental Health Center de la Serna E, Toll A, of Perugia, Perugia, Italy, 6 Department of Psychiatry, Complejo Hospitalario de Navarra, Pamplona, Ramos-Quiroga JA, Torrent C, Spain, 7 IdiSNA, Navarra Institute for Health Research, Pamplona, Spain, 8 Department of Medicine Cuesta MJ, Bernardo M and PEPs and Psychiatry, Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza University, Group (2022) Influence of clinical Zaragoza, Spain, 9 Araba University Hospital, Bioaraba Research Institute, Vitoria-Gasteiz, Spain, 10 and neurocognitive factors Department of Psychiatry, University of the Basque Country (UPV-EHU), Vitoria-Gasteiz, Spain, 11 in psychosocial functioning after a first Department of Child and Adolescent Psychiatry, Hospital General Universitario Gregorio Marañón, episode non-affective psychosis: School of Medicine, Institute of Psychiatry and Mental Health, Universidad Complutense, IiSGM, Differences between males Madrid, Spain, 12 Department of Psychiatry, Hospital de la Santa Creu i Sant Pau, Institut and females. d’Investigació Biomèdica-Sant Pau (IIB-SANT PAU), Universitat Autònoma de Barcelona (UAB), Front. Psychiatry 13:982583. Barcelona, Spain, 13 Innovation in Mental and Physical Health and Clinical Treatment (IMPACT), doi: 10.3389/fpsyt.2022.982583 School of Medicine, Barwon Health, The Institute for Mental and Physical Health and Clinical Translation, Deakin University, Geelong, VIC, Australia, 14 Department of Child and Adolescent Psychiatry and Psychology, 2017SGR881, Institut Clínic de Neurociències, Hospital Clínic Universitari, CIBERSAM, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Department of Medicine, University of Barcelona, Barcelona, Spain, 15 Hospital del Mar Medical Research Institute (IMIM), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain, 16 Department of Psychiatry, Hospital Universitari Vall d’Hebron, Barcelona, Catalonia, Spain, 17 Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain Background: Deficits in psychosocial functioning are present in the early stages of psychosis. Several factors, such as premorbid adjustment, neurocognitive performance, and cognitive reserve (CR), potentially influence functionality. Sex differences are observed in individuals with psychosis in multiple domains. Nonetheless, few studies have explored the predictive Frontiers in Psychiatry 01 frontiersin.org Serra-Navarro et al. 10.3389/fpsyt.2022.982583 factors of poor functioning according to sex in first-episode psychosis (FEP). This study aimed to explore sex differences, examine changes, and identify predictors of functioning according to sex after onset. Materials and methods: The initial sample comprised 588 individuals. However, only adults with non-affective FEP (n = 247, 161 males and 86 females) and healthy controls (n = 224, 142 males and 82 females) were included. A comprehensive assessment including functional, neuropsychological, and clinical scales was performed at baseline and at 2-year follow-up. A linear regression model was used to determine the predictors of functioning at 2-year follow-up. Results: FEP improved their functionality at follow-up (67.4% of both males and females). In males, longer duration of untreated psychosis (β = 0.328, p = 0.003) and worse premorbid adjustment (β = 0.256, p = 0.023) were associated with impaired functioning at 2-year follow-up, while in females processing speed (β = 0.403, p = 0.003), executive function (β = 0.299, p = 0.020) and CR (β = −0.307, p = 0.012) were significantly associated with functioning. Conclusion: Our data indicate that predictors of functioning at 2-year follow- up in the FEP group differ according to sex. Therefore, treatment and preventative efforts may be adjusted taking sex into account. Males may benefit from functional remediation at early stages. Conversely, in females, early interventions centered on CR enhancement and cognitive rehabilitation may be recommended. KEYWORDS first episode non-affective psychosis, psychosocial functioning, sex differences, cognition, negative symptoms Introduction to enhance it given its potential protective properties (10– 12). However, younger age, poorer premorbid adjustment, and Psychosocial functioning deficits are present in the early male sex, are non-modifiable and represent a challenge to stages of psychosis (1, 2). Impairments are commonly observed treatment, given the non-modifiable and represent a challenge in daily life activities. Although symptomatic remission was to treatment, given their potential impact on psychosocial considered the critical treatment goal for a long time, and functioning (13–16). was the main focus in previous studies rather than functional Specific sex differences in neuroanatomy, recovery, there is increasing interest in addressing functional neurofunctionality, gender and hormonal steroids have impairment. In terms of functional and clinical improvement, been reported in schizophrenia (SZ) individuals (17–19). Men a recent meta-analysis found that long-term remission rate show more severe gross neuroanatomical abnormalities than after a first psychotic episode was 58% and the recovery females (20) and these differences have even been observed rate was 38% (3). According to the literature, several factors in individuals with high genetic risk for the development influence functionality. Certain factors are modifiable, including of SZ; males have more neuroanatomical alterations than duration of untreated psychosis (DUP), negative symptoms females when compared to same sex controls (18). In relation (4–6), family environment, neurocognitive performance and to hormonal steroids, Li et al. (21) found that estrogen cognitive reserve (CR) (1, 7, 8) and ergo are of potential deficiency is highly related to severity. Moreover, Mendrek et al. clinical importance for therapeutic interventions. CR is defined (20) identified an association between hormonal status and as the coping capacity of the adult brain for pathology that performance in neurocognitive domains. Regarding gender, a minimizes symptomatology (9). Recently, it has been studied in study from Lewine et al. (22) showed that female participants, severe mental disorders and interventions are being developed independent of sex and diagnosis, performed better than Frontiers in Psychiatry 02 frontiersin.org Serra-Navarro et al. 10.3389/fpsyt.2022.982583 males on neurocognition, with the exception of attention and psychosocial functioning. The present study addresses this executive function. gap in the literature by exploring these outcomes, while also To date, males with SZ present more cognitive impairments identifying predictors of functionality in males and females, than females and differences are less pronounced in the following a first episode non-affective psychosis. Specifically, early stages of illness (20). Although, sex differences have and based on the research to date, we propose the following been extensively described in first-episode psychosis (FEP), hypotheses: (1) differences will be found between males and mixed results have been found in neurocognitive performance. females in clinical and neurocognitive outcomes; (2) changes For example, research has found that females demonstrate from baseline to 2-year follow-up will be observed; and better premorbid adjustment (14, 23–25) and neurocognitive (3) we expect negative symptoms, neurocognition, CR and performance (14, 23) than their male counterparts. Conversely, DUP to be predictors of psychosocial functioning. Specific higher severity of negative symptoms and higher rates of sex differences are not hypothesized and will be explored substance use were more frequent in males (23). Moreover, accordingly. Similarly, the aims of the study were: (1) to lower educational level, earlier age at onset, more severe illness explore sex differences in clinical, psychosocial functioning course, poorer insight, more hospitalizations, and longer DUP and neurocognitive outcomes; (2) to examine changes in were more frequent in male subjects with psychosis (13, 15, neurocognition and functionality from baseline to 2-year 23, 25–27). Regarding cognitive factors, females demonstrated follow-up; and (3) to identify predictors of functionality in better social cognition and verbal memory than men (25, 27), males and females after a first episode non-affective psychosis. whilst males in the FEP group showed better performance on visuospatial (27) and working memory tasks (13). A limited number of studies have explored the predictive Materials and methods factors of poor psychosocial functioning according to sex in FEP. Mattsson et al. (24) examined sex differences in the prediction Study design and population of long-term outcomes in a group of 81 male and 72 females with FEP, and found that lower educational attainment level was The sample was obtained from the “Phenotype-genotype the primary predictor of unfavorable outcome in females and interaction. Application of a predictive model in first psychotic a low premorbid level of functioning in males. Nevertheless, episodes” (PEPs Project) study (32, 33). This is a multicenter, a notable limitation of this study was the lack of cognitive naturalistic, and longitudinal project under the umbrella of assessment despite cognitive performance being recognized as the Spanish Research Network on Mental Health (CIBERSAM) a reliable predictor of unfavorable outcomes in individuals (34).The background, rationale and study design have been with psychosis. Moreover, Willhite et al. (28) investigated sex previously presented (32, 33). All participants were evaluated differences in individuals at ultra-high-risk for developing a at two different time points. Individuals with FEP completed psychotic disorder and found that negative symptoms mediated the full test battery of sociodemographic, clinical, functional, differences in functioning between male and female subjects and neurocognitive assessments at both baseline and two-year with FEP. These findings suggest that sex-based symptom follow-up. The same evaluation was administered to HCs at both presentation and functional outcome may predate conversion stages, however, for the clinical assessment only the SCID-I- to psychosis (28). Therefore, identifying specific predictors II was assessed. according to sex may have important clinical implications for Initially, the sample was composed of 588 individuals: offering more personalized and targeted treatment in FEP. 335 participants with a FEP and 253 healthy controls (HC). There are two potential hypotheses that could explain these Inclusion criteria were: (1) aged between 7 and 35 years at the sex differences: hormone status and sex chromosomes. The time of first evaluation; (2) duration of psychotic symptoms first hypothesis is supported by the two peaks of incidence in ≤1 year; (3) signed informed consent and (4) ability to speak females and the finding that females with SZ have more severe Spanish. Exclusion criteria were as follows: (1) intellectual symptoms during the lower estrogen phase of their menstrual deficit according to DSM-IV criteria (including not only an cycle (21, 29). Moreover, a study by Kaneda and Ohmori (30) IQ below 70 but also impaired functioning); (2) history of showed that estradiol levels, a form of estrogen, are associated head injury with loss of consciousness and (3) organic disease with severity of negative symptoms in males and may be a with mental impact. biological marker. The second hypothesis is based on recent To ensure sample homogeneity, only adults with non- genetic studies, which show that x-chromosome instability is affective FEP and HCs were included. At two-year follow-up involved and may contribute to the development of psychosis and according to DSM-IV-TR, non-affective FEP diagnosis was (21, 31). considered as: schizophrenia, schizophreniform, schizoaffective Therefore, although research in the field is expanding, there disorders, and other psychoses not otherwise specified. remains a limited number of studies exploring sex differences Supplementary Figure 1 shows the flowchart for the selection in FEP, particularly in terms of clinical, neurocognitive, and of the 247 non-affective FEP at baseline. Frontiers in Psychiatry 03 frontiersin.org Serra-Navarro et al. 10.3389/fpsyt.2022.982583 The FEP group was matched by age (±10%), gender and Continuous Performance Test–II (CPT-II) (45), version 5; (2) parental socioeconomic status (±1 level). The exclusion criteria Verbal learning and memory, assessed with the Verbal Learning for HC were the same as the FEP group, but also included Test Spain Complutense for adults (TAVEC) (46); (3) Working the presence of a current or past psychotic disorder, major memory was assessed by the Digit Span Subtest and the Letter- depression or other psychiatric illness and having a first-degree Number Sequencing Subtest of the Wechsler Adult Intelligence relative with psychotic disorder history. In this study, 224 adult Scale (WAIS-III) (47); (4) Processing speed was assessed with HC were included. the Trail making test (Form A) (TMT-A) (48); (5) The executive Ethical approval was granted by the Hospital Clinic Ethics functions were evaluated using the Wisconsin Card Sorting and Research Board. The study followed the ethical principles Test (49), corrected by age and educational level; (6) Verbal of the Declaration of Helsinki and Good Clinical Practices. All fluency was evaluated using semantic fluency (animals) (50) participants provided written informed consent. and F-A-S tests (51); and (7) Managing Emotions was assessed with the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) (52). All neurocognitive measures were transformed Assessments into T-scores. Higher scores correspond to better performance in all neurocognitive domains except for attention. Clinical and sociodemographic assessment Sociodemographic and clinical data from all participants Cognitive reserve and premorbid adjustment were collected at baseline and at two years follow-up. assessment Hollingshead’s Two-Factor Index of Social Position (35) was Premorbid adjustment, namely levels of functioning before used to define parental socioeconomic status (SES); Duration the onset of psychosis, was assessed with The Premorbid of Untreated Psychosis (DUP) was estimated considering the Adjustment Scale (PAS) (53). Only childhood and early number of days between the presence of the first psychotic adolescence life periods have been taken into account since they symptoms and the beginning of adequate treatment, and are the two periods answered by all the participants. Higher antipsychotic mean doses were calculated by chlorpromazine scores indicate worse premorbid adjustment. equivalents (CPZ) based on international consensus (36). Drug Cognitive reserve (CR) was assessed using the three misuse habits were gathered using an adapted version of proposed proxy indicators of CR in FEP as described in previous the European Adaptation of a Multidimensional Assessment literature (10, 54–56). Proxy indicators include education, Instrument for Drug and Alcohol Dependence scale (37). The estimated premorbid IQ, leisure, social, and physical activities. Structured Clinical Interview for DSM (SCID-I-II) was used to Education was measured with: patient’s completed years of establish diagnoses according to DSM-IV criteria (38, 39) in the study, performance during school, and parents’ educational FEP group. Conversely, the SCID-I-II was administered to assess level. Estimated premorbid IQ and crystallized intelligence HC’s mental health to ensure that they met the inclusion criteria were evaluated with the vocabulary subtest of WAIS-III which and to rule out the exclusion criteria of the study. appears to remain stable during disease progression (57). In the FEP group, psychotic symptoms were assessed with A “cognitive reserve score” was created using a Principal the Positive and Negative Syndrome Scale (PANSS) (40), and Components Analysis (PCA) for each subject. Higher scores affective symptoms with the Montgomery-Asberg Depression correspond to better performance for each subject. Higher Rating Scale (MADRS) (41) and the Young Mania Rating Scale scores correspond to better performance. (YMRS) (42). A total score was obtained from each scale. Higher scores correspond to greater severity. Statistical analysis Functional assessment The Functioning Assessment Short Test (FAST) was used Neurocognitive variables were grouped using PCA. The to evaluate functional outcome (43, 44) from all participants. resulting cognitive domains were: sustained attention, verbal Higher scores represent higher disability. learning and memory, working memory, processing speed, executive functions, fluency, and emotion management (see Neurocognitive assessment Supplementary Table 1). Firstly, a multivariate analysis of A neurocognitive battery was used to evaluate different variance with two factors: (1) sex (female vs. male) and (2) group cognitive domains through standardized instruments. The (patients vs. HC) was conducted for demographic variables and neuropsychological assessment was made in the second month for cognitive functions. For cognitive functions, a multivariate of evaluation in order to ensure the psychopathologic stability of analysis of covariance with age and chlorpromazine equivalent individuals with FEP and was repeated in the two-year follow- as covariates was performed because FEP females and males up visit. The neurocognitive battery measured the following were statistically different in these variables. In a second step, cognitive domains: (1) Sustained attention was tested with the repeated measures multivariate analysis of covariance was used Frontiers in Psychiatry 04 frontiersin.org Serra-Navarro et al. 10.3389/fpsyt.2022.982583 to check the differences and changes in cognitive functions with p < 0.001), tobacco and cannabis use (χ2 = 35.732, p < 0.001 three factors: (1) sex (female vs. male), (2) group (patients vs. and χ2 = 39.332, p < 0.001, respectively), psychosocial HC), and (3) assessment (baseline and follow-up). In patients, functioning (t = 437.177, p < 0.001), cognitive reserve change scores were calculated using the reliable change index (F = 155.857, p < 0.001), premorbid adjustment (F = 252.087, (RCI). To check changes for psychosocial functioning, RCI was p < 0.001) and all cognitive measures. The male group was calculated following this formula: (T2 − T1)/SED, where T1 and younger (F = 6.572, p = 0.011), reported higher tobacco and T2 are the individual’s observed baseline and 2-years follow- cannabis use (χ2 = 9.832, p = 0.007 and χ2 = 31.307, p < 0.001, up scores, and SED is the standard error of the difference. respectively), higher CPZ (F = 5.720, p = 0.017), better attention For cognitive measures, corrections for measurement error and (F = 11.466, p = 0.001) and processing speed (F = 12.640, practice effects were then calculated for each participant using p < 0.001), higher CR (F = 6.160, p = 0.013), and worse the RCI, calculated as (T2 − T1) − (M2 − M1)/SED, where premorbid adjustment (F = 4.058, p = 0.045). No significant T1 and T2 are the individual’s observed baseline and 2-year effect for GroupXSex was observed. follow-up scores, M1 and M2 are the control group mean At two-year follow-up, there were main effects of group baseline and follow-up scores, and SED is the standard error of for tobacco use, psychosocial functioning and all cognitive difference. An RCI [alpha set to 0.10 (two-tailed)] greater than measures. The female group presented worse attention +1.645 is considered a significant change, while reliable decline (F = 24.176, p < 0.001) and processing speed (F = 8.402, occurs when values fall below −1.645 (58–60).In the third p = 0.004). Finally, there was a group x sex interaction step, in individuals with FEP, partial correlations controlling for for attention (F = 10.028, p = 0.002) (for more details see chlorpromazine equivalent at baseline were computed for the Supplementary Table 2). Supplementary Figure 2 shows continuous variables. The association between binary variables the mean psychosocial functioning and cognitive scores and the FAST score at 2-year follow-up was examined using with error bars in males and females with psychosis at a t-test, controlling again for the chlorpromazine equivalent baseline and follow-up. effects. Finally, variables that were significantly correlated with FAST (p < 0.05) were included in two linear regression models with backward elimination in both sexes. In this way, Changes in cognitive functions and we explored factors that predict psychosocial functioning at psychosocial functioning baseline and at 2-year follow-up, according to sex. Statistical Package for the Social Sciences (SPSS v26) was Results from the repeated measures ANOVA revealed a time used to analyze data. All statistical tests were carried out two- effect for psychosocial functioning (p < 0.001, ηp2 = 0.065) tailed, with an alpha level of significance set at p < 0.05. and all cognitive domains (values of partial eta squared range from 0.021 to 0.144) except attention (p = 0.097), indicating an improvement for both groups from baseline to the 2- Results year follow-up. An improvement in clinical status was also observed (values of partial eta squared range from 0.200 to Sociodemographic, clinical, functional 0.396). There was a significant time x group effect observed and cognitive characteristics of the only for psychosocial functioning (p < 0.001, ηp2 = 0.085), sample and sex differences indicating a significantly different effect in the FEP group over time compared with the HC group. No significant effect for A total of 247 FEP subjects (161 males and 86 females) TimeXGroupXSex was observed (see Table 2). and 224 HC (142 males and 82 females) were enrolled in this Supplementary Table 3 displays the percentage rates of study. At two-year follow-up 145 individuals with FEP and improvements, declines and stability on all cognitive domains 152 HC were re-evaluated as 102 subjects with FEP and 72 and psychosocial functioning as determined by the RCI. Most HC participants had withdrawn from the study due to a loss of the FEP improved their functionality on follow-up (67.4% of of follow-up or refusal of re-evaluation. The follow-up sample both males and females). Results herein indicate that although of the FEP group (n = 145) did not differ from the baseline working memory improved over time, females improved less sample in terms of sociodemographic, clinical, functional, and than males (p < 0.001, Cramer’s V = 0.403). No other significant neurocognitive performance. Similarly, HCs assessed at follow- group differences were observed. up (n = 152) showed no differences to the total sample of baseline HCs in terms of sociodemographic, functional, and the majority of cognitive domains. Predictors of psychosocial functioning A summary of the baseline sociodemographic and clinical characteristics of individuals with FEP and HC is shown in At baseline, in males with FEP, worse psychosocial Table 1. There were main effects of group for SES (χ2 = 23.165, functioning correlated with higher positive (r = 0.308, Frontiers in Psychiatry 05 frontiersin.org Frontiers in Psychiatry Serra-Navarro et al. TABLE 1 Sex differences in sociodemographic, clinical and functional characteristics at baseline for subjects with psychosis and healthy controls. Subjects with psychosis (n = 247) Healthy controls (n = 224) Effect Males (n = 161) Females (n = 86) Males (n = 142) Females (n = 82) Group Sex GroupXSex F or χ2 p ηp2 or F or χ2 p ηp2 or F or χ2 p ηp2 Cramér’s Cramér’s V V Sociodemographic variables Age (M ± SD) 24.96 ± 5.05 26.52 ± 5.31 25.58 ± 5.70 26.67 ± 5.50 0.542 0.462 0.001 6.572 0.011 0.014 0.204 0.652 0.000 SES, N (%) 23.165 <0.001 0.222 2.718 0.743 0.076 High 29 (18) 14 (16) 30 (21) 20 (24) Medium-High 13 (8) 12 (14) 28 (20) 15 (18) Medium 45 (28) 16 (19) 40 (28) 22 (27) Medium-Low 52 (32) 27 (31) 37 (26) 21 (26) Low 18 (11) 15 (17) 6 (4) 3 (4) Missing value 4 (3) 2 (2) 1 (1) 1 (1) Tobacco use: Yes N (%) 120 (75) 50 (58) 63 (44) 30 (37) 35.732 <0.001 0.275 9.832 0.007 0.144 Cannabis use: Yes N (%) 91 (57) 22 (26) 35 (25) 7 (9) 39.332 <0.001 0.289 31.307 <0.001 0.258 Clinical and functional variables (M ± SD) PANSS positive 18.48 ± 8.01 18.79 ± 7.66 – – – – – 0.082 0.774 0.000 – – – 06 PANSS negative 19.53 ± 7.16 18.35 ± 8.80 – – – – – 1.288 0.257 0.005 – – – PANSS general 38.06 ± 11.50 37.06 ± 12.34 – – – – – 0.402 0.527 0.002 – – – PANSS total 76.08 ± 21.71 74.20 ± 24.77 – – – – – 0.378 0.539 0.002 – – – MADRS score 12.01 ± 8.52 13.62 ± 9.72 – – – – – 1.802 0.181 0.007 – – – YMRS score 8.22 ± 9.67 9.28 ± 10.30 – – – – – 0.637 0.425 0.003 – – – DUP 104.85 ± 114.94 104.15 ± 136.91 – – – – – 0.002 0.968 0.000 – – – CPZ 666.26 ± 500.82 486.57 ± 354.59 – – – – – 5.720 0.017 0.012 – – – FAST 28.35 ± 15.64 30.71 ± 16.62 3.26 ± 8.92 3.10 ± 5.60 437.177 < 0.001 0.491 0.769 0.381 0.002 0.994 0.319 0.002 Cognitive measures (M ± SD) Attention 179.09 ± 42.58 191.47 ± 47.77 145.26 ± 22.36 158.53 ± 29.97 14.255 < 0.001 0.039 11.466 0.001 0.031 0.001 0.975 0.000 Verbal memory 198.97 ± 71.93 209.58 ± 72.73 285.41 ± 44.92 284.79 ± 50.17 48.118 < 0.001 0.108 0.006 0.937 0.000 0.097 0.756 0.000 Working memory 73.92 ± 14.51 69.26 ± 13.77 88.78 ± 12.99 88.82 ± 42.26 21.361 < 0.001 0.050 3.037 0.082 0.007 2.450 0.118 0.006 Processing speed 47.77 ± 11.43 42.78 ± 11.03 57.32 ± 8.85 55.41 ± 10.44 47.330 < 0.001 0.103 12.640 < 0.001 0.030 3.217 0.074 0.008 Executive function 200.81 ± 55.54 196.15 ± 68.07 231.80 ± 37.87 224.81 ± 47.01 6.766 0.010 0.018 0.617 0.433 0.002 0.082 0.774 0.000 10.3389/fpsyt.2022.982583 Fluency 60.30 ± 11.35 60.28 ± 12.78 77.97 ± 13.66 75.73 ± 13.49 66.683 < 0.001 0.145 1.686 0.195 0.004 0.243 0.622 0.001 Managing Emotions 259.83 ± 34.90 255.84 ± 28.04 283.87 ± 31.42 288.70 ± 35.21 33.350 < 0.001 0.078 0.070 0.792 0.000 2.101 0.148 0.005 Cognitive reserve and premorbid adjustment (M ± SD) < 0.001 frontiersin.org CR 75.12 ± 11.00 71.90 ± 12.28 88.85 ± 10.62 86.44 ± 10.85 155.857 0.270 6.160 0.013 0.014 0.128 0.721 0.000 PAS 48.96 ± 24.57 43.47 ± 23.41 17.20 ± 12.06 15.04 ± 9.18 252.087 < 0.001 0.362 4.058 0.045 0.009 0.769 0.381 0.002 M, Mean; SES, Socioeconomic status; PANSS, Positive and Negative Symptom Scale; MADRS, Montgomery-Asberg Depression Rating Scale; YMRS, Young Mania Rating Scale; DUP, Duration of Untreated Psychosis; CPZ, Chlorpromazine equivalents; FAST, Functioning Assessment Short Test; CR, Cognitive Reserve; PAS, Premorbid Adjustment Scale. Significant differences (p < 0.05) marked in bold. Serra-Navarro et al. 10.3389/fpsyt.2022.982583 TABLE 2 Changes in clinical, cognitive functions and psychosocial functioning. Time Time × Group Time × Sex Time × Group × Sex F p η p2 F p ηp2 F p ηp2 F p ηp2 Clinical and functional variables (M ± SD) PANSS positive 88.649 <0.001 0.384 – – – 0.289 0.592 0.002 – – – PANSS negative 35.570 <0.001 0.200 – – – 0.067 0.796 0.000 – – – PANSS general 84.817 <0.001 0.374 – – – 0.021 0.885 0.000 – – – PANSS total 93.167 <0.001 0.396 – – – 0.031 0.860 0.000 – – – MADRS score 42.766 <0.001 0.231 – – – 0.630 0.429 0.004 – – – YMRS score 36.806 <0.001 0.205 – – – 0.328 0.568 0.002 – – – FAST 19.709 <0.001 0.065 26.441 <0.001 0.085 0.024 0.876 0.000 0.773 0.380 0.003 Cognitive measures (M ± SD) Attention 2.775 0.097 0.013 0.444 0.506 0.002 1.044 0.308 0.005 3.131 0.078 0.014 Verbal memory 26.526 <0.001 0.096 0.975 0.324 0.004 0.350 0.555 0.001 0.001 0.980 0.000 Working memory 5.485 0.020 0.021 0.091 0.763 0.000 1.220 0.270 0.005 0.496 0.482 0.002 Processing speed 21.670 <0.001 0.077 3.172 0.076 0.012 0.031 0.860 0.000 1.810 0.180 0.007 Executive function 38.402 <0.001 0.144 0.416 0.520 0.002 1.120 0.291 0.005 0.779 0.379 0.003 Fluency 15.930 <0.001 0.062 0.529 0.468 0.002 0.031 0.861 0.000 0.130 0.718 0.001 Managing Emotions 8.817 0.003 0.037 0.156 0.694 0.001 0.013 0.908 0.000 0.728 0.394 0.003 PANSS, Positive and Negative Symptom Scale; MADRS, Montgomery-Asberg Depression Rating Scale; YMRS, Young Mania Rating Scale; FAST, Functioning Assessment Short Test. Significant differences (p < 0.05) marked in bold. p < 0.001), negative (r = 0.234, p = 0.004), depressive (r = 0.287, model and controlling for chlorpromazine equivalent, positive p < 0.001) and manic symptoms (r = 0.231, p = 0.005), poorer (β = 0.285, p < 0.001), depressive symptoms (β = 0.195, performance in processing speed (r = –0.183, p = 0.035) and p = 0.014) and adjustment (β = 0.213, p = 0.006) were social cognition (r = –0.213, p = 0.017), and worse premorbid significantly associated with worse FAST, with a higher effect adjustment (r = 0.228, p = 0.006). In females, FAST was exerted by positive symptoms. At follow-up, longer DUP also correlated with positive (r = 0.467, p < 0.001), negative (β = 0.328, p = 0.003) and worse premorbid adjustment (r = 0.613, p < 0.001), depressive (r = 0.358, p = 0.001), manic (β = 0.256, p = 0.023) were associated with impaired symptoms (r = 0.272, p = 0.017), and premorbid adjustment psychosocial functioning. (r = 0.433, p < 0.001). However, regarding neurocognitive In females, at baseline, negative (β = 0.655, p < 0.001), performance, a significant correlation was observed in sustained manic symptoms (β = 0.412, p < 0.001) and worse attention attention only (r = 0.299, p = 0.025). For HCs, FAST correlated performance (β = 0.248, p = 0.012) were significantly associated with premorbid adjustment (r = 0.324, p < 0.001) in males with worse functioning, while at follow-up processing speed and in verbal memory (r = –0.345, p = 0.003), verbal fluency (β = –0.403, p = 0.003), executive function (β = –0.299, p = 0.020) (r = –0.281, p = 0.018), and premorbid adjustment (r = 0.426, and CR (β = –0.307, p = 0.02) were significantly associated with p < 0.001) in females. No other variables correlated with FAST FAST, with a higher effect exerted by processing speed. at baseline (see Supplementary Table 4). At follow-up, worse psychosocial functioning in FEP males correlated with higher negative symptoms at baseline (r = 0.295, p = 0.003), longer DUP Discussion (r = 0.272, p = 0.010), higher CPZ (r = 0.295, p = 0.003), worse sustained attention (r = 0.346, p = 0.003), and worse premorbid Two main findings emerged from the present study. adjustment (r = 0.359, p < 0.001). In FEP females, FAST was Firstly, individuals with FEP had higher substance abuse, correlated with worse performance in processing speed (r = – lower SES, worse psychosocial functioning and neurocognitive 0.424, p = 0.005), executive function (r = –0.350, p = 0.029) performance in all cognitive domains in relation to the HC and lower cognitive reserve (r = –0.312, p = 0.032). In HCs group (27, 61). As expected, individuals with FEP present more none of the baseline variables were associated with psychosocial difficulties and impairments than the HC group. Secondly, functioning at follow-up (Table 3). different effects of sex were found regardless of the group. Results for linear regression are reported in Table 4. At The male group uses more tobacco and cannabis, are younger, baseline in FEP males, after including the variables that reached have higher CR and CPZ doses, worse premorbid adjustment statistical significance in bivariate analyses in the regression and perform better in attention and processing speed. These Frontiers in Psychiatry 07 frontiersin.org Frontiers in Psychiatry Serra-Navarro et al. TABLE 3 Correlations between psychosocial functioning (FAST) at follow-up and socio-demographic and clinical variables at baseline in subjects with psychosis and healthy controls. Subjects with psychosis (n = 145) Healthy controls (n = 152) Males (n = 97) Females (n = 48) Males (n = 101) Females (n = 51) Pearson p Pearson p Pearson p Pearson p Correlation, Correlation, Correlation, Correlation, Student t, X2 Student t, X2 Student t, X2 Student t, X2 Sociodemographic variables Age (M ± SD) –0.016 0.874 –0.200 0.188 –0.092 0.366 –0.064 0.660 SES (%) 1.635 0.159 0.435 0.782 0.562 0.691 0.671 0.616 Tobacco use: Yes N (%) 1.379 0.171 0.218 0.828 0.444 0.658 1.137 0.261 Cannabis use: Yes N (%) 1.739 0.085 0.228 0.821 –0.472 0.638 –0.054 0.957 Clinical and functional variables (M ± SD) PANSS positive 0.150 0.145 0.080 0.600 – – – – PANSS negative 0.295 0.003 –0.029 0.852 – – – – PANSS general 0.271 0.008 0.099 0.519 – – – – 08 PANSS total 0.289 0.004 0.067 0.662 – – – – MADRS score 0.166 0.107 0.226 0.135 – – – – YMRS score 0.023 0.822 0.085 0.579 DUP 0.272 0.010 0.063 0.690 – – – – Cognitive measures (M ± SD) Attention 0.346 0.003 0.261 0.129 0.009 0.932 0.088 0.549 Verbal memory –0.192 0.074 –0.181 0.264 0.035 0.739 0.180 0.220 Working memory –0.177 0.095 –0.031 0.844 –0.137 0.180 –0.062 0.674 Processing speed –0.101 0.342 –0.424 0.005 0.018 0.863 –0.068 0.644 Executive function –0.025 0.820 –0.350 0.029 0.110 0.298 –0.270 0.067 Fluency –0.064 0.559 –0.100 0.538 0.131 0.207 –0.181 0.223 Managing Emotions –0.118 0.281 –0.013 0.937 –0.074 0.477 0.056 0.706 10.3389/fpsyt.2022.982583 Cognitive reserve and premorbid adjustment (M ± SD) CR –0.135 0.206 –0.312 0.032 –0.046 0.654 0.039 0.795 PAS 0.359 < 0.001 0.268 0.090 0.103 0.314 0.039 0.795 frontiersin.org M, Mean; SES, Socioeconomic status; PANSS, Positive and Negative Symptom Scale; MADRS, Montgomery-Asberg Depression Rating Scale; YMRS, Young Mania Rating Scale; DUP, Duration of Untreated Psychosis; CPZ, Chlorpromazine equivalents; FAST, Functioning Assessment Short Test; CR, Cognitive Reserve; PAS, Premorbid Adjustment Scale. Significant differences (p < 0.05) marked in bold. Serra-Navarro et al. 10.3389/fpsyt.2022.982583 TABLE 4 Linear regression of the socio-demographic, clinical and neuropsychological variables associated with psychosocial functioning in males and females with psychosis. Model ßeta t p Males Baseline R = 0.452, R2 = 0.504, F = 12.045, df (3), p < 0.001 PANSS positive 0.285 3.684 <0.001 MADRS score 0.195 2.499 0.014 Premorbid adjustment 0.213 2.803 0.006 Constant 2.149 0.033 Follow-up R = 0.619, R2 = 0.383, F = 12.227, df (2), p <0.001 DUP 0.328 3.044 0.003 Premorbid adjustment 0.256 2.342 0.023 Constant 1.150 0.255 Females Baseline R = 0.770, R2 = 0.592, F = 17.063, df (4), p <0.001 PANSS negative 0.655 6.553 <0.001 YMRS score 0.412 4.387 <0.001 Sustained attention 0.248 2.599 0.012 Constant –1.054 0.297 Follow-up R = 0.692, R2 = 0.479, F = 8.030, df (3), p < 0.001 Processing speed –0.403 3.142 0.003 Executive function –0.299 2.434 0.020 Cognitive reserve –0.307 –2.153 0.038 Constant 0.655 0.516 Significant differences (p < 0.05) are bold. differences have been found in individuals with schizophrenia. in the present study no differences were found in regards to Males tend to show a higher incidence of the disorder, an clinical or functional aspects. This could be interpreted in light earlier age at onset, poorer premorbid adjustment, higher of the neurodegenerative hypothesis (64), suggesting that SZ is a rates of substance abuse, worse psychosocial functioning, and disorder that debuts at an early age, and from that moment on, a a more severe course of the disease, especially in negative neurodegenerative process begins and the subject progressively symptoms, while in the FEP group mixed results have been loses capacities. found (14, 62). In addition, males with psychosis require There are some possible explanations for the inconsistency higher doses of antipsychotic than females (21). In terms of in results. First, no specific scale was used to assess negative premorbid adjustment, no significant differences were found in symptoms as the PANSS was the chosen measurement in this our study, failing to replicate the results of Cotton et al. (63). study. Similar to our results, González-Rodríguez et al. (64) Previous literature suggests that males have greater negative found no significant gender differences in psychopathology symptoms than females with FEP, especially related to emotional assessed by the PANSS in FEP. Secondly, Willhite et al. withdrawal, blunted affects, and avolition-apathy (13, 25, 64, (28) found no differences at baseline in negative symptoms 65). However, in our study, no significant differences were found when they studied gender differences in a simple of high-risk in this regard. These results might be interpreted in the light individuals. Regarding processing speed, it has been shown that of different models that explain SZ spectrum disorders. The females with schizophrenia have poorer processing speed when neurodevelopmental model of SZ posits that the illness is the evaluated using the TMT-A (67). However, these findings were end stage of abnormal neurodevelopmental processes that began not replicated by Zanelli et al. (68) who found no sex differences years before the onset of the illness (63). Within this theoretical in neurocognition among FEP. The female group showed framework, an attempt to describe relationships between worse sustained attention performance than males. Research has sex/gender and indicators of neurodevelopment compromise in shown differences between sex, for example, females showed SZ has been made, but no associations regarding sex were found slower reaction times (69) and were less aroused than males (70). (62). In SZ, sex differences have been found, were men tend Similar results were described by Hsieh et al. (71) who evaluated to show a higher incidence of the disorder, an earlier age at sustained attention with the CPT in a sample of 900 adults and onset, poorer premorbid adjustment, higher rates of substance found that males outperformed females. Thus, sex differences in abuse, worse psychosocial functioning, and a more severe course neurocognitive performance are a controversial issue as results of the disease, especially in negative symptoms (14, 62, 66) remain inconclusive. The heterogeneity in the results may while in the FEP group mixed results have been found. In fact, be partly explained by differences in the studied populations, Frontiers in Psychiatry 09 frontiersin.org Serra-Navarro et al. 10.3389/fpsyt.2022.982583 FIGURE 1 Overview of the study population, the main results, and the recommended intervention. namely FEP or schizophrenia, as well as the subtest used to (77). In line with our results, a recent meta-analysis found that measure each domain. To compare the results and generalize there is a positive association between executive function and the findings, future research should endeavor to homogenize psychosocial function (78). evaluation tools to assess the neurocognitive domains and the Thus, it seems that the predictors of psychosocial stage of the illness. functioning at 2-year follow-up in the FEP group differ Regarding changes, both groups improved at follow-up according to sex (see Figure 1). These sex differences could and no differences were found between males and females. have important clinical implications, not only in terms of According to previous literature, FEP individuals improve diagnosis, but also in terms of therapeutic approach. In the in functional outcomes, achieved recovery and demonstrated case of the former, and in order to improve psychosocial symptom remission (54, 72). With reference to gender, we found functioning, the present study supports the need to perform a that men improved significantly more than women in working thorough assessment of CR, premorbid adjustment, DUP, and memory. To the best of our knowledge, this has not yet been neurocognitive status. In terms of therapeutic options, based documented in the current literature. on these results, we propose that males with FEP may benefit Although no clinical or psychosocial functioning differences from a functional remediation from early stages. Conversely, in have been found between sexes, it seems that the variables females, the implementation of early interventions centered on associated with poorer functioning differ according to sex. For CR enhancement and cognitive rehabilitation may be beneficial, the prediction of psychosocial functioning, worse premorbid as CR has been associated with better cognitive performance adjustment and higher were predictors of worse psychosocial and psychosocial functioning (1, 10, 54) and is a reliable functioning in males. The relationship between premorbid predictor of functionality in this group. adjustment and DUP with psychosocial functioning have been This study has certain limitations which must be taken into widely reported (73). Premorbid adjustment is also considered account. Firstly, when participants were evaluated, there was a predictor of clinical severity, especially for subjects with FEP no validated instrument to measure CR so criteria established presenting negative symptoms (5, 10). and replicated in previous studies were followed. Secondly, In females, worse processing speed, worse executive no specific scale was used to assess negative symptomatology. function and lower CR level predicted worse psychosocial Future studies making use of newer and improved negative functioning. In severe mental illness, CR has a significant symptom scales — such as the Brief Negative Symptom Scale influence on cognitive, clinical and functional outcomes (11, 74). (BNSS) (79) or the Clinical Assessment Interview for Negative In FEP, individuals with CR perform better in neurocognitive Symptoms (CAINS) (80) — may be more appropriate for scales and functioning (1, 10, 54). A lower educational level their evaluation. Thirdly, another limitation is the difference predicted worse results in females but not in males (24). between the group size of males and females. In the female Regarding processing speed, Lindgren et al. (75), reported that group, the small sample size may have interfered with it was associated with 1-year remission, occupational status, and the results (low statistical power). This is possibly due to maintaining of life goals and Milev et al. (76) found that in FEP, the naturalistic and multicentric nature of the study with verbal memory, processing speed, and attention were potential a representative sample of non-affective FEP in a stable targets for psychosocial interventions to improve outcome. In clinical phase recruited from the whole Spanish territory. fact, it has been shown that processing speed is related to Thus, further studies with larger sample sizes are required to functioning in individuals with ultra-high-risk for psychosis confirm these findings. Frontiers in Psychiatry 10 frontiersin.org Serra-Navarro et al. 10.3389/fpsyt.2022.982583 In conclusion, this study identified premorbid adjustment, Sant Pau, Institut d’Investigació Biomèdica-Sant Pau (IIB- and DUP as risk factors in males with FEP. Similarly, processing SANT PAU), Universitat Autònoma de Barcelona (UAB), speed, executive function and CR were recognized as modifiable Barcelona, Spain. Iñaki Zorrilla and Itxasco Gonzalez-Ortega: factors in females. These results suggest that the enhancement Biomedical Research Networking Center for Mental Health of modifiable factors may improve functional outcomes and Network (CIBERSAM), Barcelona, Spain; Araba University could be beneficial in the development of early intervention Hospital, Bioaraba Research Institute, Vitoria-Gasteiz, Spain; programs. Future studies, using larger sample sizes are needed University of the Basque Country (UPV-EHU), Vitoria- to determine which factors might influence the relationship Gasteiz, Spain. Concepción De-la-Cámara and Pedro Saz: between neurocognitive or clinical outcomes and functioning Biomedical Research Networking Center for Mental Health depending on sex. Finally, longitudinal studies would help to Network (CIBERSAM), Barcelona, Spain; Department of understand the long-term impact of these findings. Medicine and Psychiatry, Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza University, Zaragoza, Spain. Juan Nacher: Biomedical Research Networking Center for Mental Health Network (CIBERSAM), Barcelona, Data availability statement Spain; Neurobiology Unit, Program in Neurosciences and Interdisciplinary Research Structure for Biotechnology The raw data supporting the conclusions of this article will and Biomedicine (BIOTECMED), Universitat de València, be made available by the authors, without undue reservation. Biomedical Research Institute INCLIVA, Valencia, Spain. Esther Lorente: Neurobiology Unit, Program in Neurosciences and Interdisciplinary Research Structure for Biotechnology Ethics statement and Biomedicine (BIOTECMED), Universitat de València, Biomedical Research Institute INCLIVA, Valencia, Spain. The studies involving human participants were reviewed Teresa Legido: CIBERSAM, IDIBAPS, Department of Medicine, and approved by the Hospital Ethics Committee (2008/4232), University of Barcelona, Barcelona, Spain. Francesc Casanovas: according to the Declaration of Helsinki principles and CIBERSAM, IDIBAPS, Department of Medicine, University Good Clinical Practice guidelines, within the requirements of Barcelona, Barcelona, Spain. Nestor Arbelo: Barcelona of the Spanish Law and the State Regulatory Authority. The Clinic Schizophrenia Unit, Hospital Clinic of Barcelona, patients/participants provided their written informed consent to Neuroscience Institute, August Pi I Sunyer Biomedical Research participate in this study. Institute (IDIBAPS), University of Barcelona, Barcelona, Spain. Lidia Ilzarbe: Department of Psychiatry and Psychology, Institute of Neuroscience, Hospital Clinic de Barcelona, PEPs Group Barcelona, Spain. Josefina Castro-Fornieles: Biomedical Research Networking Center for Mental Health Network Jairo González-Díaz: Barcelona Clinic Schizophrenia (CIBERSAM), Barcelona, Spain; Department of Child and Unit, Hospital Clinic of Barcelona, Neuroscience Institute, Adolescent Psychiatry and Psychology, 2017SGR881, Hospital August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Clínic Universitari, Institut Clinic de Neurociències, Barcelona, University of Barcelona, Barcelona, Spain; UR Center for Spain. Immaculada Baeza: Biomedical Research Networking Mental Health - CERSAME, School of Medicine and Health Center for Mental Health Network (CIBERSAM), Barcelona, Sciences, Universidad del Rosario, Bogota DC, Colombia; Spain; Department of Child and Adolescent Psychiatry and Clínica Nuestra Señora de la Paz, Bogota DC, Colombia. Psychology, 2017SGR881, Hospital Clínic Universitari, Institut Lucila Barbosa: Barcelona Clinic Schizophrenia Unit, Hospital Clinic de Neurociències, Barcelona, Spain. Fernando Contreras: Clinic of Barcelona, Neuroscience Institute, August Pi I Biomedical Research Networking Center for Mental Health Sunyer Biomedical Research Institute (IDIBAPS), University of Network (CIBERSAM), Barcelona, Spain; Bellvitge University Barcelona, Barcelona, Spain. Covadonga M. Diaz-Caneja and Hospital, IDIBELL, Barcelona, Spain. Teresa Bobes Bascarán: Marta Rapado-Castro: Biomedical Research Networking Center Biomedical Research Networking Center for Mental Health for Mental Health Network (CIBERSAM), Barcelona, Spain; Network (CIBERSAM), Barcelona, Spain; Servicio de Salud Department of Child and Adolescent Psychiatry, Hospital del Principado de Asturias (SESPA) Oviedo, Instituto de General Universitario Gregorio Marañón, School of Medicine, Investigación Sanitaria del Principado de Asturias (ISPA), Institute of Psychiatry and Mental Health, Universidad Instituto Universitario de Neurociencias del Principado Complutense, IiSGM, Madrid, Spain. Carlo Alemany and de Asturias (INEUROPA), Oviedo, Spain; Department of Aina Avila-Parcet: Biomedical Research Networking Center Psychology, Universidad de Oviedo, Oviedo, Spain. Leticia for Mental Health Network (CIBERSAM), Barcelona, Spain; González-Blanco: Biomedical Research Networking Center Department of Psychiatry, Hospital de la Santa Creu i for Mental Health Network (CIBERSAM), Barcelona, Spain; Frontiers in Psychiatry 11 frontiersin.org Serra-Navarro et al. 10.3389/fpsyt.2022.982583 Servicio de Salud del Principado de Asturias (SESPA) Oviedo, Funding Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Instituto Universitario de Neurociencias del Principado This study was funded with the projects PI17/01066 de Asturias (INEUROPA), Oviedo, Spain; Department of and PI20/00344 by the Instituto de Salud Carlos III and Psychiatry, Universidad de Oviedo, Oviedo, Spain. Rafael co-funded by the Unión Europea (FEDER) “Una manera Segarra Echevarría and Arantzazu Zabala Rabadán: Biomedical de hacer Europa”. Research Networking Center for Mental Health Network (CIBERSAM), Barcelona, Spain; Cruces University Hospital, BioCruces Health Research Institute, University of the Basque Acknowledgments Country (UPV/EHU), Vizcaya, Spain. Roberto Rodriguez- Jimenez: Biomedical Research Networking Center for Mental We are extremely grateful to all participants. This study Health Network (CIBERSAM), Barcelona, Spain; Instituto is part of a coordinated-multicentre Project, funded by de Investigación Sanitaria Hospital 12 de Octubre (imas12), the Ministerio de Economía y Competitividad (PI08/0208; Madrid, Spain; CogPsy Group, Universidad Complutense de PI11/00325; PI17/01066; PI20/00344; and PI14/00612), Instituto Madrid (UCM), Madrid, Spain. Luis Sanchez-Pastor: Instituto de Salud Carlos III – Fondo Europeo de Desarrollo Regional, de Investigación Sanitaria Hospital 12 de Octubre (imas12), Unión Europea, Una manera de hacer Europa, Centro de Madrid, Spain. Judith Usall: Parc Sanitari Sant Joan de Déu, Investigación Biomédica en Red de salud Mental, CIBERSAM, Teaching, Research & Innovation Unit, Institut de Recerca Sant by the CERCA Programme/Generalitat de Catalunya and Joan de Déu, Sant Boi de Llobregat. Anna Butjosa: Biomedical Secretaria d’Universitats i Recerca del Departament d’Economia Research Networking Center for Mental Health Network I Coneixement (2017SGR1355). Departament de Salut de la (CIBERSAM), Barcelona, Spain; Hospital Infanto-juvenil Sant Generalitat de Catalunya, en la convocatoria corresponent a Joan de Déu, Institut de Recerca Sant Joan de Déu, Esplugues de l’any 2017 de Concessió de Subvencions del Pla Estratègic de Llobregat, Barcelona. Salvador Sarró and María Ángeles García Recerca i Innovació en Salut (PERIS) 2016–2020, Modalitat León: Biomedical Research Networking Center for Mental Projectes de Recerca Orientats A l’Atenció Primària, Amb Health Network (CIBERSAM), Barcelona, Spain; FIDMAG el Codi d’Expedient SLT006/17/00345. MB is also grateful Germanes Hospitalàries Research Foundation, Barcelona, Spain. for the support of the Institut de Neurociències, Universitat Ángela Ibáñez: Biomedical Research Networking Center for de Barcelona. SA has been supported by a Sara Borrell Mental Health Network (CIBERSAM), Barcelona, Spain; (CD20/00177), funded by Instituto de Salud Carlos III Department of Psychiatry, Hospital Universitario Ramón y (ISCIII), and co-funded by European Social Fund “Investing Cajal, IRYCIS, Universidad de Alcalá, Madrid, Spain. Lucía in your future”. NV thanks the BITRECS project, which Moreno-Izco: Department of Psychiatry, Complejo Hospitalario has received funding from the European Union’s Horizon de Navarra, Pamplona, Spain; IdiSNA, Navarra Institute for 2020 research and innovation programme under the Marie Health Research, Pamplona, Spain. Vicent Balanzá-Martinez: Skłodowska-Curie grant agreement No. 754550 and from Biomedical Research Networking Center for Mental Health “La Caixa” Foundation (ID 100010434), under the agreement Network (CIBERSAM), Barcelona, Spain; Department of LCF/PR/GN18/50310006. CT has been supported by a ‘Miguel Medicine, University of Valencia, Valencia, Spain. Servet’ postdoctoral contract (CPI14/00175), and Miguel Servet II contract (CPII19/00018). EV thanks the support of the Spanish Ministry of Science, Innovation and Universities Author contributions (PI15/00283; PI21/00787) integrated into the Plan Nacional de I + D + I y cofinanciado por el ISCIII-Subdirección General SA and MS-N designed the study, managed the literature de Evaluación y el Fondo Europeo de Desarrollo Regional searches and analyses, undertook the statistical analysis, and (FEDER); CIBERSAM; and the Comissionat per a Universitats i wrote the first draft of the manuscript. CT and EV revised the Recerca del DIUE de la Generalitat de Catalunya to the Bipolar first draft and added critical comments to guide the redaction Disorders Group (2017 SGR 1365) and the SLT006/17/00357 of the final manuscript. NV, MF, AS-T, DC, AL, AG-P, RP, AR, project, from PERIS 2016-2020 (Departament de Salut). CERCA AC, ES, AT, MC, and MB revised the second draft of the article Programme/Generalitat de Catalunya. A. Ibáñez thanks the and provided critical comments to guide the redaction of the support of the Madrid Regional Government and European final manuscript. All authors within the PEPs Group recruited Union Structural Funds (S2017/BMD3740; AGES-CM 2-CM), individuals with FEP and healthy controls at their centers, and the support of CIBERSAM. We also would like to thank the provided the anonymous data and revise the final manuscript authors of the PEPs group who participated in the development and approved the final manuscript. of this manuscript. Frontiers in Psychiatry 12 frontiersin.org Serra-Navarro et al. 10.3389/fpsyt.2022.982583 Conflict of interest de Salud Mental (CIBERSAM), Madrid Regional Government (S2010/BMD-2422 AGES; S2017/BMD-3740), JanssenCilag, EV has received grants and served as consultant, advisor Lundbeck, Otsuka, Pfizer, Ferrer, Juste, Takeda, Exeltis, Casen- or CME speaker for the following entities (unrelated to Recordati, Angelini. JG-D was partly funded by a grant from the present work): AB-Biotics, Abbott, Allergan, Angelini, Ministerio de Ciencia y Tecnologia – Republica de Colombia Dainippon Sumitomo Pharma, Ferrer, Gedeon Richter, Janssen, (Convocatoria 885/2020) and has been an advisor/speaker for, Lundbeck, Otsuka, Sage, Sanofi-Aventis, and Takeda. JR-Q was or received travel support from Janssen, Eurofarma, Servier, on the speakers’ bureau and/or acted as consultant for Eli- Sanofi, Lilly, and Pfizer. AI has received research support from Lilly, Janssen-Cilag, Novartis, Shire, Takeda, Bial, Shionogui, or served as speaker or advisor for Janssen-Cilag, Lundbeck Lundbeck, Almirall, Braingaze, Sincrolab, Medice and Rubió, and Otsuka. MR-C is a Ramon y Cajal Research Fellow (RYC- Raffo in the last 5 years. He also received travel awards (air 2017-23144), Spanish Ministry of Science, Innovation and tickets + hotel) for taking part in psychiatric meetings from Universities and was supported by a NARSAD independent Janssen-Cilag, Rubió, Shire, Takeda, Shionogui, Bial, Medice investigator grant (no. 24628) from the Brain and Behavior and Eli- Lilly. The Department of Psychiatry chaired by Research Foundation. MC has received grant support from him received unrestricted educational and research support Instituto de Salud Carlos III, Spanish Ministry of Science and from the following companies in the last 5 years: Eli-Lilly, Innovation (PI18/00753, PI21/00701) and the Alicia Koplowitz Lundbeck, Janssen-Cilag, Actelion, Shire, Ferrer, Oryzon, Roche, Foundation. CMD-C has received grant support from Instituto Psious, and Rubió. MB has been a consultant for, received de Salud Carlos III, Spanish Ministry of Science and Innovation grant/research support and honoraria from, and been on the (PI17/00481, PI20/00721, JR19/0024) and honoraria from speakers/advisory board of ABBiotics, Adamed, Angelini, Casen Exeltis and Angelini. Recordati, Janssen-Cilag, Menarini, Rovi and Takeda. NV has The remaining authors declare that the research was received financial support for CME activities and travel funds conducted in the absence of any commercial or financial from the following entities (unrelated to the present work): relationships that could be construed as a potential conflict of Angelini, Janssen-Cilag, Lundbeck, Otsuka. CDLC received interest. financial support to attend scientific meetings from Janssen, Almirall, Lilly, Lundbeck, Rovi, Esteve, Novartis, Astrazeneca, Pfizer and Casen Recordati. IB has received honoraria or Publisher’s note travel support to attend conferences from Angelini, Janssen and Otsuka-Lundbeck; and grants from Instituto de Salud Carlos All claims expressed in this article are solely those of the III, Spanish ministry of Health. LG-B has received honoraria authors and do not necessarily represent those of their affiliated for lecturing and/or travel grants for attending conferences organizations, or those of the publisher, the editors and the from the Spanish Foundation of Psychiatry and Mental Health, reviewers. Any product that may be evaluated in this article, or Otsuka, Lundbeck, Janssen-Cilag, Servier, Angelini and Pfizer. claim that may be made by its manufacturer, is not guaranteed NA has received CME-related financing from Janssen-Cilag, or endorsed by the publisher. Lundbeck, Adamed, Pfizer and Boston Scientific, outside the submitted work. 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