European Neuropsychopharmacology 49 (2021) 54–68 www.elsevier.com/locate/euroneuro The effect of family environment and psychiatric family history on psychosocial functioning in first-episode psychosis at baseline and after 2 years Norma Verdolini a,1, Silvia Amoretti b,c,d,e,1, Gisela Mezquida b,c,d,e, Manuel J. Cuesta f,g, Laura Pina-Camacho d,h, Clemente García-Rizo b,c,d,e, Antonio Lobo i,j, Ana González-Pinto k, Jessica Merchán-Naranjo d,h, Iluminada Corripio d,l, Estela Salagre a, Immaculada Baeza m, Daniel Bergé d,n,o, Marina Garriga a, Miquel Bioque b,c,d,e, Catalina Vallespir a, Maria Serra a, Eduard Vieta a,∗, Miguel Bernardo b,c,d,e,2 a Bipolar and Depressive Disorders Unit, Hospital Clinic, University of Barcelona, Institute of Neuroscience, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain b Barcelona Clinic Schizophrenia Unit, Hospital Clinic of Barcelona, Neuroscience Institute, Barcelona, Spain c Department of Medicine, Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain d Biomedical Research Networking Center for Mental Health Network (CIBERSAM), Barcelona, Spain e August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain f Department of Psychiatry, Complejo Hospitalario de Navarra, Pamplona, Spain g Navarra Institute for Health Research (IdiSNA), Pamplona, Spain h Department of Child and Adolescent Psychiatry, Institute of Psychatry and Mental Health, Hospital General Universitario Gregorio Marañon, IiSGM, School of Medicine, Universidad Complutense, Madrid, Spain i Department of Medicine and Psychiatry. Universidad de Zaragoza, Spain j Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza, Spain k Hospital Universitario de Alava, UPV/EHU, BIOARABA, CIBERSAM, Vitoria, Spain Location of work and address for reprints: Bipolar and Depressive Disorders Unit, Hospital Clinic, University of Barcelona, Institute of Neuroscience, IDIBAPS, CIBERSAM, 170 Villarroel st, 12-0 08036, Barcelona, Catalonia, Spain ∗ Corresponding author. E-mail address: EVIETA@clinic.cat (E. Vieta). 1The first two authors contributed equally to this work 2PEPs Group. https://doi.org/10.1016/j.euroneuro.2021.03.015 0924-977X/© 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) European Neuropsychopharmacology 49 (2021) 54–68 l Psychiatry Department, Institut d’Investigació Biomèdica-Sant Pau (IIB-SANT PAU), Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain m Department of Child and Adolescent Psychiatry and Psychology, Clínic Institute of Neurosciences, Hospital Clínic de Barcelona, 2017SGR881, University of Barcelona, CIBERSAM, IDIBAPS, Barcelona, Spain n Hospital del Mar Medical Research Institute (IMIM), Spain o Autonomous University of Barcelona (UAB), Spain Received 5 June 2020; received in revised form 1 March 2021; accepted 15 March 2021 KEYWORDS Abstract First-episode The aim of the present study was to evaluate the contribution of family environment styles and psychosis; psychiatric family history on functioning of patients presenting first-episode psychosis (FEP). Family environment; Patients with FEP and healthy controls (HC) were assessed at baseline and after 2 years. The Psychiatric family Functional Assessment Short Test (FAST) was used to assess functional outcome and the Family history; Environment Scale (FES) to evaluate family environment. Linear regressions evaluated the ef- Psychosocial fect that family environment exerts on functioning at baseline and at 2-year follow-up, when functioning; FEP patients were diagnosed according to non-affective (NA-PSYCH) or affective psychoses (A- Non-affective PSYCH). The influence of a positive parents’ psychiatric history on functioning was evaluated psychoses; through one-way between-groups analysis of covariance (ANCOVA) models, after controlling Affective psychoses for family environmental styles. At baseline, FEP patients presented moderate functioning im- pairment, significantly worse than HC (28.65±16.17 versus 3.25±7.92; p<0.001, g = 1.91). At 2-year follow-up, the functioning of NA-PSYCH patients was significantly worse than in A-PSYCH (19.92±14.83 versus 12.46±14.86; p = 0.020, g = 0.50). No specific family environment style was associated with functioning in FEP patients and HC. On the contrary, a positive psychi- atric father’s history influenced functioning of FEP patients. After 2 years, worse functioning in NA-PSYCH patients was associated with lower rates of active-recreational and achievement orientated family environment and with higher rates of moral-religious emphasis and control. In A-PSYCH, worse functioning was associated with higher rates of conflict in the family. Both family environment and psychiatric history influence psychosocial functioning, with important implications for early interventions, that should involve both patients and caregivers. © 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) (NA-PSYCH) and affective psychoses (A-PSYCH). The ma- 1. Introduction jority of affective patients show better functioning and lower negative symptoms than NA-PSYCH (Amoretti et al., Patients suffering from a first-episode psychosis (FEP) 2018; Torrent et al., 2018). In addition, they differ in pre- present functional impairment, involving social and occu- morbid functioning, which was associated with clinical and pational activities (Parellada et al., 2015; Raghavan et al., psychosocial functioning in FEP patients, both in adults 2017; Rosa et al., 2012; Stouten et al., 2017). Disability gen- (White et al., 2009) and children and adolescents (Payá erally persists despite clinical symptom remission. Around et al., 2013). 75% of FEP patients achieve symptomatic remission with Family environment plays a major role in individual func- antipsychotic treatment (Santesteban-Echarri et al., 2017). tioning. Among university students, higher rates of con- Nonetheless, social and vocational recovery was observed flict and control were positively associated with depressive only in the 31% of the Early Psychosis Prevention and Inter- symptoms, while cohesion in the family was a protective vention centre (EPPIC) cohort (Henry et al., 2010). More- factor (Yu et al., 2015). An increasingly large number of over, in a three-year Chinese longitudinal study, six out of studies have found an association between negative fam- ten FEP patients still exhibited functional disability after ily environment and poor prognosis in patients at high risk symptomatic remission (Chang et al., 2012). of suffering psychosis (O’Brien et al., 2006), in FEP patients Long-term functioning in FEPs was influenced by the (Lee et al., 2014; Norman et al., 2005) but also in bipolar duration of untreated psychosis (DUP), positive and neg- disorder (BD) (Kim, 2004) and schizophrenia (Cañivé et al., ative symptoms and premorbid adjustment (Santesteban- 1995; Pitschel-Walz et al., 2001). Family exerts its effect Echarri et al., 2017). Furthermore, cognitive reserve (CR) as an environmental factor that is capable to act as a pro- (Amoretti et al., 2019, 2018, 2016), social cognition tective or a risk factor on long-term outcomes in FEP pa- (González-Ortega et al., 2019) and coming from disadvan- tients (Norman et al., 2005). Initial treatment seeking, ad- taged socioeconomic strata have been related to poor psy- herence, and social support also depended on family envi- chosocial functioning (Hall et al., 2019). ronment (Quach et al., 2009). Moreover, the long-term functioning of FEP patients de- In addition, the genetic load conferred by a positive psy- pends on the differentiation at follow-up in non-affective chiatric family history should be taken into account. A psy- 55 N. Verdolini, S. Amoretti, G. Mezquida et al. chiatric family history is considered to be a proxy mea- DSM (SCID-I-II) (First et al., 1997, 1996) and diagnoses were sure of genetic risk (Lu et al., 2018). Moreover, it relies on determined according to DSM-IV criteria. The diagnoses of familial-environmental factors (Kendler and Neale, 2009). A the patients who completed the study were based on infor- positive family history of psychosis was found to be associ- mation gathered up to the 2-year follow-up visit, taking into ated with an higher risk of psychosis in siblings (Otero et al., consideration potential changes across time and in order 2011) who presented earlier age of onset (AAO), more se- to ensure diagnostic stability. Diagnoses of schizophrenia, vere negative symptoms and longer DUP (Esterberg and schizophreniform, schizoaffective disorders and psychoses Compton, 2012). that are not otherwise specified were categorized into NA- The interaction of family environment and a positive fam- PSYCH, whereas BD or first manic episodes with psychotic ily history of psychosis was evaluated. González-Pinto and symptoms were grouped as A-PSYCH. colleagues (González-Pinto et al., 2011) identified that in- dependently of the family history of psychosis, a negative family environment increased the risk of psychosis. More- 3. Assessments over, at baseline, the influence of a positive family environ- ment exerted a protective effect on the presence of psy- The complete assessment planning of the original co- chosis, particularly in those patients with a positive family hort study is reported by Bernardo and colleagues history of psychosis, but not in those without. (Bernardo et al., 2013). Nonetheless, little is known about the implication of fam- ily environment and a psychiatric family history on function- ing at follow-up of FEP patients, particularly depending on their final diagnosis (NA-PSYCH versus A-PSYCH). However, a 3.1. Functional assessment better understanding of this interrelationship is essential for the development of future interventions focused on func- The overall functional outcome was assessed, both at base- tional recovery and addressing not only FEP patients but also line and at 2-year follow-up, by means of the Function- their families. ing Assessment Short Test (FAST) (Rosa et al., 2007). The The aim of this study was to evaluate the contribution of FAST assessment refers to the last 15 days and comprises the perceived family environment styles on functioning in a 24 items, which are divided in 6 specific areas of function- cohort of FEP patients compared to healthy controls (HC) at ing: autonomy, occupational functioning, cognitive func- baseline, and of NA-PSYCH and A-PSYCH patients at 2 years. tioning, financial issues, interpersonal relationships and Furthermore, the possible influence on functioning exerted leisure time. It has shown high internal consistency, high by a positive psychiatric family history has been assessed. validity and strong test-retest reliability (Rosa et al., 2007), also in FEP patients (González-Ortega et al., 2010). The FAST total score (range 0–72) is calculated as the sum of 2. Experimental procedures each of the 24 item scores, with higher scores indicating worse functioning. Thresholds of severity are: no impair- This study is part of the “Phenotype-genotype inter- ment in functioning (scores between 0 and 11), mild im- action. Application of a predictive model in first psy- pairment (scores between 12 and 20), moderate impairment chotic episodes” - PEPs Project, a multicentre, naturalis- (scores between 21 and 40), and severe impairment (scores tic and longitudinal study on FEP patients (Bernardo et al., > 40) (Bonnín et al., 2018). 2013), under the umbrella of the Spanish Research Net- work on Mental Health (CIBERSAM) (Bernardo et al., 2019; Salagre et al., 2019). The PEPs Project was approved by 3.2. Family environmental styles the Clinical Research Ethics Committee of all participat- ing centres. The procedures followed were in accordance The Family Environment was assessed, both at baseline and with those of the World Medical Association and the Dec- at the 2-year follow-up, by the Family Environment Scale laration of Helsinki. Informed consent was obtained from (FES) (Moos and Moos, 1976). FES is a self-reporting instru- all participants. A total of 335 patients with a FEP and 253 ment focused on the measurement and description of the healthy controls (HC) were recruited from 16 centres lo- interpersonal relationships among family members. Three cated throughout the Spanish territory from April 2009 to separate forms of the FES are available: the Real Form April 2011. (Form R), which measures people’s perceptions of their ac- For the purpose of the present study only FEP patients tual family environments; the Ideal Form (Form I), which as- 1. aged between 18 and 35 years, 2. With a functional as- sesses individuals’ perceptions of their ideal family environ- sessment at baseline, 3. With a final diagnosis of A-PSYCH ment; the Expectations Form (Form E) in which participants or NA-PSYCH after 2 years of follow-up, were included. The indicate what they expect a family environment will be like. patients were matched with HC by age (± 10%), gender and In the present study, the Real Form (Form R) was used. FES parental socioeconomic status (± 1 level). The exclusion cri- evaluates family emotional climate in different categories: teria for HC were the same as for patients and also included COHESION (C) for mutual reliance; EXPRESSIVITY (EX), the 1. The presence of a current or past psychotic disorder or extent to which family members express their feelings di- major depression and 2. Having one or both the parents suf- rectly; CONFLICTS (CON) for open expression of anger, ag- fering from a psychotic disorder. gressiveness and conflict; INDEPENDENCE (IND), the extent Patients with a FEP and HC were evaluated at baseline to which family members are independent in their deci- and at follow-up with the Structured Clinical Interview for sions; ACHIEVEMENT ORIENTATION (AO) for an achievement 56 European Neuropsychopharmacology 49 (2021) 54–68 orientated environment; INTELLECTUAL–CULTURAL ORIEN- Step 2. Evaluation of family environmental styles: Family TATION (ICO) for political, intellectual, cultural interests; environmental styles scores were defined for FEP patients ACTIVE–RECREATIONAL ORIENTATION (ARO) for participation and HC, at baseline, and for A-PSYCH and NA-PSYCH pa- in social activities; MORAL–RELIGIOUS EMPHASIS (MRE) for tients, at the 2-year follow-up. Differences between the the importance given to ethical and religious practices and groups were examined using unpaired t-tests. Differences values; ORGANIZATION (ORG) for the organization in activ- in clinical variables depending on the family environmental ities and responsibilities; and CONTROL (CTL), the extent styles were assessed for the different subgroups and at dif- to which the family considers rules and established proce- ferent time points. Significant clinical variables at bivariate dures. analyses were entered in multiple regressions for the differ- The first four subscales refer to personal growth; AO, ICO, ent family styles. Bonferroni correction was applied. ARO and MRE reflect the directions of personal growth em- Step 3. Association of family environmental styles and phasized in the family and the implication of the family in functioning: Hierarchical multiple regressions were used different activities whilst the last two subscales, ORG and to assess the ability of the different family environmental CTL, are for system maintenance. styles to predict functioning (FAST total score), at baseline, The 10 subscales show inter-correlations averaging in FEP patients and HC, and at the 2-year follow-up, in A- around 0.20 and adequate internal consistency (Cronbach’s PSYCH and NA-PSYCH patients, after controlling for the in- alphas range from 0.64 to 0.79). Eight-week test–retest re- fluence of SES and cohabitation condition, due to their influ- liabilities ranged from 0.68 to 0.86 (Moos, 1990). The test– ence on both individual functioning and family environment retest reliability of the Spanish version ranged from 0.68 to (Conger et al., 2010). 0.86 for the 10 subscales (Moos, R.H., Moss, B.S., Trickett, Step 4. Effect of positive parents’ psychiatric history on E., 1995). functioning: Differences between the groups for positive parents’ psychiatric history were examined using the Chi- square test. Clinical differences and environmental styles between those with or without a positive parents’ psychi- 3.3. Parents’ history of psychiatric disorders atric history were assessed. One-way between-groups anal- ysis of covariance (ANCOVA) models were conducted to eval- The participants at baseline were asked to report family his- uate the effect exerted by a positive parent’s psychiatric tory of psychiatric disorders, namely affective and psychotic history on functioning. The independent variable was the disorders. A positive family history for psychotic disorders presence or absence of a positive parents’ psychiatric his- was not present in HC since it represented an exclusion cri- tory and the dependent variable was the FAST total score terion of the study. Patients and HC were classified into two (baseline or at 2-year follow-up). Scores on the different categories: (1) those with one or both parents suffering from family environmental styles were used as covariates. The a psychiatric disorder, and (2) those without parents’ his- models were run only if at least one subject presented a tory of psychiatric disorders. A sub-classification of positive positive parent’s (or father’s or mother’s) psychiatric his- or negative psychiatric history in the mother or in the father tory. was made. Normality of distribution was assessed and held, other- wise non-parametrical alternatives were used. Preliminary checks were conducted to ensure that there was no viola- 4. Statistical analysis tion of the assumptions of normality, linearity, homogene- ity of variances, homogeneity of regression slopes, and reli- The statistical analysis proceeded in different steps: able measurement of the covariates. All p-values were two- Step 1. Evaluation of functioning: FAST total score and tailed and statistical significance was set at p<0.05. Statis- subdomains scores were defined and compared for FEP tical analyses were performed using the Statistical Package patients and HC at baseline and for A-PSYCH and NA- for Social Sciences (SPSS, 23.0 version for Windows). PSYCH patients at 2-year follow-up. Functional differ- ences among the groups were examined using unpaired t-tests and effect sizes were calculated (Hedges, 1981; 5. Results Hedges and Olkin, 1985). Differences in functioning depend- ing on socioeconomic status (SES) and cohabitation condi- 5.1. Characteristics of the sample tion were assessed using the Kruskal-Wallis H test. The cor- relation between functioning at different time points and According to the inclusion criteria of the present study, 283 clinical variables (Positive and Negative Syndrome Scale- FEP patients (mean age=25.40±5.30, 66.1% males) and 211 PANSS, Montgomery-Asberg Depression Rating Scale-MADRS HC (mean age=25.83±5.68, 64% males) were considered. and the Young Mania Rating Scale-YMRS and Clinical Global FEP patients reported a mean DUP of 98.30±118.94 days, Impression-CGI scores) was assessed through Pearson corre- the mean AAO was 25.01±5.35 years, the mean chlorpro- lation. An evaluation of the percentage of A-PSYCH or NA- mazine equivalents (CPZ) were 591.90±470.33 doses and PSYCH patients presenting at follow-up with a moderate or the mean CGI was 4.04±1.55. severe impairment in functioning (FAST total score ≥ 21) At the 2-year follow-up, the patient group divided in despite clinical remission (YMRS total score ≤ 12 + MADRS the NA-PSYCH (n = 244, 86.2%; mean age=25.42±5.21, total score ≤ 6 + a score of ≤ 3 on the PANSS items P1, 65.6% males) and the A-PSYCH (n = 39, 13.8%; mean P2, P3, N1, N4, N6, G5, and G9) (Herrmann et al., 1998; age=25.28±5.88, 69.2% males) groups. NA-PSYCH patients Mohammadi et al., 2018; Os et al., 2006) was conducted. and A-PSYCH patients did not differ in terms of AAO (NA- 57 N. Verdolini, S. Amoretti, G. Mezquida et al. PSYCH=25.10±5.21 versus A-PSYCH=24.91±6.17 years, The results of the bivariate analyses and of the multiple t=−0.193, p = 0.847), CPZ (NA-PSYCH=118.74±237.07 ver- regression models assessing the association of specific clini- sus A-PSYCH=76.54±173.45 doses, t=−1.066, p = 0.287) cal variables with the different family environmental styles or CGI (NA-PSYCH=1.62±1.73 versus A-PSYCH=1.54±1.31, are reported in the Supplementary Table (ST) 1 and 2, re- t=−0.338, 0.737). The mean DUP of NA-PSYCH pa- spectively. tients was significantly longer than for A-PSYCH pa- tients (104.87±122.92 versus 58.51±81.78 days, t=−2.862, p = 0.006, g = 0.39). 5.4. Association of family environmental styles Subjects that did not undergo a functional assessment and functioning (Step 3) at follow-up were considered as drop-outs from the study and represented a percentage as high as 40.6% for FEP At baseline, the linear models were not significant neither patients (n = 115, of which at follow-up NA-PSYCH=102, for HC (F(12,188)=0.701, p = 0.749) nor for FEP patients 88.7% and A-PSYCH=13, 11.3%) and 31.8% (n = 67) for HC. (F(12,232)=1.282, p = 0.230) and no family environment The difference in drop-out rates between FEP patients and style was associated with functioning. HC only reached a trend towards significance (X2 =3.726, At the 2 years, in the NA-PSYCH group (F(12,86)=3.638, p = 0.054). In the comparison between NA-PSYCH versus A- p<0.001), worse functioning was negatively associated with PSYCH, the difference was not significant (NA-PSYCH: com- ARO (β=- 0.304, p = 0.012) and AO (β=- 0.303, p = 0.004) pleters n = 142, 58.2% versus non-completers n = 102, and positively associated with MRE (β=0.200, p = 0.045) 41.8%; A-PSYCH: completers n = 26, 66.7% versus non- and CTL (β=0.268, p = 0.015). SES and cohabitation condi- completers n = 13, 33.3%; X2 =0.680, p = 0.410). In all the tion were entered at Step 1, explaining 6.8% of the variance groups, completers did not differ from those who did not in functioning. After entry of the different family environ- complete the study in terms of FAST global scores. Among mental styles, the total variance explained by the model HC, non-completers had lower SES (X2 =11.706, p = 0.020), was 24.4%. education (X2 =10.913, p = 0.028) and CR (t = 4.350, In the A-PSYCH group (F(12,5)=5.249, p = 0.04) worse p<0.001, g = 0.66) than those who completed the follow- functioning was associated with CON (β=0.718, p = 0.015). up. Among FEP patients, lower CR (t = 2.186, p = 0.030, SES and cohabitation condition were entered at Step 1, ex- g = 0.28) was reported for those who did not complete plaining 11% of the variance in functioning. After entry of the follow-up. The same happened in the NA-PSYCH group the different family environmental styles, the total variance (t = 2.013, p = 0.045, g = 0.28) but no differences were explained by the model was 75%. identified in the A-PSYCH group. 5.5. Effect of positive parents’ psychiatric 5.2. Evaluation of functioning (Step 1) history on functioning (Step 4) Table 1 summarizes the functional characteristics and dif- Table 2 reports data on parents’ history of psychiatric dis- ferences among groups. orders with a comparison between diagnostic groups at dif- In HC, FAST scores did not vary significantly between ferent time points. baseline and the 2-year follow-up (p = 0.593). At the 2- Differences in environmental styles among those with or year follow-up, both A-PSYCH and NA-PSYCH patients pre- without a family history of psychiatric disorders are re- sented average mild impairment but the functioning in NA- ported in the ST3. PSYCH patients was significantly worse than in A-PSYCH pa- As for HC, after adjusting for environmental family styles tients (mean (M)=19.92±14.83 versus M = 12.46±14.86; scores, there was no significant difference on functioning at t=−2.355, p = 0.020, g = 0.5), with significant dif- baseline between those with or without a parents’ psychi- ferences particularly in the interpersonal relationships atric history (p = 0.496). No relationship was found between (M = 4.78±4.07 versus M = 2.42±3.93; t=−2.729, any environmental family styles and FAST at baseline (see p = 0.007, g = 0.58) and autonomy (M = 2.91±2.86 ver- Fig. 2). sus M = 1.27±2.22; t=−3.394, p = 0.002, g = 0.59) subdo- As for FEP, there was no significant difference on func- mains. tioning at baseline between those with or without a parents’ Seventy (49.3%) out of 142 NA-PSYCH patients presented (p = 0.550) or a mother’s (p = 0.561) psychiatric history af- moderate or severe impairment. Among these, the 28.6% ter adjusting for environmental family styles scores. On the (n = 20) presented at the 2-year follow-up a moderate or se- contrary, when father’s psychiatric history was used as the vere impairment in functioning, despite clinical remission. independent variable, a significant difference was found be- 4 out of 26 (15.4%) A-PSYCH patients presented moderate or tween those with or without a father’s psychiatric history on severe impairment, all despite clinical remission. functioning at baseline (yes: adjusted mean (adjM)=39.93 versus no: adjM=27.42; F(1, 247)=6.601, p = 0.011, par- tial eta squared=0.027). No relationship was found between 5.3. Evaluation of family environmental styles any environmental family styles and FAST at baseline. As (Step 2) for the association with clinical variables, FEP patients with a father’s positive history presented higher PANSS negative Fig. 1 refers to family environmental styles across diagnostic symptoms (yes: M = 23.4 ± 6.74 versus no: M = 18.31±7.73, groups and time periods. t=−2.494, p = 0.013, g = 0.66) and higher CPZ doses 58 European Neuropsychopharmacology 49 (2021) 54–68 Table 1 Functioning across diagnostic groups. FEP (n = 283) HC (n = 211) Baseline Mean (SD) Mean (SD) t Pg Overall functioning (FAST total score) 28.65 (16.17) 3.25 (7.92) 22.98 < 0.001 1.91 Autonomy 4.23 (3.33) 0.32 (1.12) 18.41 < 0.001 1.48 Occupational functioning 7.9 (5.3) 0.79 (2.34) 20.10 < 0.001 1.65 Cognitive functioning 5.96 (3.8) 0.9 (2.18) 18.64 < 0.001 1.57 Financial issues 1.63 (1.8) 0.25 (0.93) 11.03 < 0.001 0.92 Interpersonal relationships 6.73 (4.86) 0.69 (2.29) 18.32 < 0.001 1.52 Leisure time 2.20 (1.83) 0.3 (0.97) 15.27 < 0.001 1.24 NA-PSYCH (n = 142) HC (n = 144) 2-year follow-up Mean (SD) Mean (SD) t pg Overall functioning (FAST total score) 19.92 (14.83) 2.97 (8.52) −11.825 < 0.001 1.40 Autonomy 2.91 (2.88) 0.33 (1.43) −9.597 < 0.001 1.14 Occupational functioning 5.61 (5.13) 0.53 (1.74) −11.199 < 0.001 1.33 Cognitive functioning 3.78 (3.58) 0.97 (2.17) −8.037 < 0.001 0.95 Financial issues 0.99 (1.54) 0.15 (0.81) - 5.711 < 0.001 0.68 Interpersonal relationships 4.78 (4.07) 0.62 (2.29) −10.637 < 0.001 1.26 Leisure time 1.85 (1.69) 0.38 (1.02) −8–872 < 0.001 1.05 A-PSYCH (n = 26) HC (n = 144) 2-year follow-up Mean (SD) Mean (SD) t pg Overall functioning (FAST total score) 12.46 (14.86) 2.97 (8.52) −3.163 0.004 0.97 Autonomy 1.27 (2.22) 0.33 (1.43) −2.090 0.046 0.60 Occupational functioning 3.92 (4.79) 0.53 (1.74) −3.571 0.001 1.38 Cognitive functioning 3 (3.75) 0.97 (2.17) −2.685 0.012 0.82 Financial issues 0.69 (1.54) 0.15 (0.81) − 1.740 0.093 0.57 Interpersonal relationships 2.42 (3.93) 0.62 (2.29) − 2.273 0.031 0.69 Leisure time 1.15 (1.15) 0.38 (1.02) −2.498 0.018 0.74 NA-PSYCH (n = 142) A-PSYCH (n = 26) 2-year follow-up Mean (SD) Mean (SD) t pg Overall functioning (FAST total score) 19.92 (14.83) 12.46 (14.86) − 2.35 0.020 0.50 Autonomy 2.91 (2.86) 1.27 (2.22) −3.39 0.002 0.59 Occupational functioning 5.61 (5.13) 3.92 (4.79) −1.56 0.121 0.33 Cognitive functioning 3.78 (3.58) 3 (3.75) −1.01 0.311 0.21 Financial issues 0.99 (1.54) 0.69 (1.54) −0.89 0.374 0.19 Interpersonal relationships 4.78 (4.07) 2.42 (3.93) −2.72 0.007 0.58 Leisure time 1.85 (1.69) 1.15 (1.51) −1.95 0.053 0.42 A-PSYCH=affective psychoses; FAST=Functioning Assessment Short Test; FEP=first episode psychosis; HC=healthy control; n=number; NA-PSYCH=non-affective psychoses; SD=standard deviation; g=Hedges’ g effect size. (yes: M = 868.23±532.21 versus no: M = 575.51±462.42, 97)=7.291, p = 0.008, partial eta squared=0.077), MRE t=−2.362, p = 0.019, g = 0.63). (F(1, 97)=6.208, p = 0.015, partial eta squared=0.066) and In the NA-PSYCH subgroup, there was no significant CTL (F(1, 97)=4.959, p = 0.029, partial eta squared=0.053) difference between those with or without a parents’ and mother’s (F(1, 97)=0.355, p = 0.553, AO (F(1, psychiatric history on functioning at the 2-year follow- 97)=6.763, p = 0.011, partial eta squared=0.071), ARO up (p = 0.522), after adjusting for environmental fam- (F(1, 97)=7.574, p = 0.007, partial eta squared=0.079), ily styles scores. On the contrary, significant relation- MRE (F(1, 97)=5.310, p = 0.024, partial eta squared=0.057) ship were found between FAST at baseline and AO (F(1, and CTL (F(1, 97)=5.504, p = 0.021, partial eta 97)=6.828, p = 0.011, partial eta squared=0.072), ARO squared=0.059) psychiatric history were used as the in- (F(1, 97)=7.421, p = 0.008, partial eta squared=0.078), dependent variables. As for the association with clinical MRE (F(1, 97)=5.369, p = 0.023, partial eta squared=0.057) variables, higher levels of CGI indicating higher sever- and CTL (F(1, 97)=4.982, p = 0.028, partial eta ity of the disease were reported for those with a pos- squared=0.054). The same results were obtained when fa- itive parents’ psychiatric history (yes: M = 2.11±1.77 ther’s (F(1, 97)=0.013, p = 0.910, AO (F(1, 97)=6.781, versus no: M = 1.50±1.70, t=−2.166, p = 0.031, p = 0.011, partial eta squared=0.072), ARO (F(1, g = 0.36). 59 N. Verdolini, S. Amoretti, G. Mezquida et al. BASELINE 2-YEAR FOLLOW-UP p<0.001 p<0.017 p=0.018 p<0.001p=0.916 p<0.001 p<0.001p=0.392 p=0.001 p=0.023 p=0.303 p=0.574 p=0.231 p=0.042 p=0.641 p=0.188 p=0.208 p=0.110 p=0.0902 p=0.913 g=0.36 g=0.23 g=0.21 g=0.33 g=0.00 g=0.62 g=0.87 g=0.08 g=0.29 g=0.21 g=0.21 g=0.13 g=0.28 g=0.50 g=0.08 g=0.31 g=0.30 g=0.38 g=0.02 g=0.02 70 51.89 51.99 52.71 53.92 56.38 50.76 48.4 49.76 50.91 49.75 46.61 47.2 46.08 47.8 47.8 50.61 51.06 52.74 52.86 54.52 51 49.17 49.29 45.89 70 49.18 51.69 50.69 48.1 60 46.52 45.38 52.67 52.33 48.29 48.86 45.87 46.67 48.34 60 46.9 46.62 43.52 50 50 40 40 30 30 20 20 10 10 0 0 C EX CON IND AO ICO ARO MRE ORG CTL C EX CON IND AO ICO ARO MRE ORG CTL FEP HC NA-PSYCH A-PSYCH 2-YEAR FOLLOW-UP 2-YEAR FOLLOW-UP p<0.118 p=0.003 p=0.182 p=0.353 p=0.388p<0.001 p<0.001p=0.078 p=0.700 p<0.001 p=0.965 p=0.271 p=0.602 p=0.036p=0.893 p=0.416 p=0.023p=0.514 p=0.941 p=0.047 g=0.21 g=0.33 g=0.18 g=0.12 g=0.11 g=0.52 g=0.82 g=0.23 g=0.05 g=0.48 g=0.01 g=0.26 g=0.12 g=0.70 g=0.03 g=0.19 g=0.54 g=0.15 g=0.02 g=0.47 70 50.61 51.06 54.76 58.36 70 52.67 52.33 54.76 58.36 51.16 53.71 51.16 53.71 52.57 54.62 52.74 49.18 51.69 44.24 52.57 54.62 52.86 54.52 51 44.24 48.86 45.87 46.67 50.69 46.9 48.29 46.62 60 48.34 60 43.52 48.1 47.68 46.88 44.75 47.68 46.88 44.75 50 50 40 40 30 30 20 20 10 10 0 0 C EX CON IND AO ICO ARO MRE ORG CTL C EX CON IND AO ICO ARO MRE ORG CTL NA-PSYCH HC A-PSYCH HC Fig. 1 Mean scores with error bars of family enviroment styles across diagnostic groups and time points. Among A-PSYCH patients, there was no significant differ- PSYCH patients presented moderate or severe functioning ence between those with or without a parents’ psychiatric impairment at 2 years. In addition, a proportion of pa- history on functioning at the 2-year follow-up (p = 0.537), tients, both in the NA-PSYCH and in the A-PSYCH group, after adjusting for environmental family styles scores. presented moderate or severe impairment in functioning at 2 years despite clinical remission (one out of three pa- tients in the NA-PSYCH group, less than a quarter of the patients in the A-PSYCH group). Similar rates were reported 6. Discussion in previous studies (Chang et al., 2012; Henry et al., 2010). As a consequence, the changes in functioning across time In the present study, at baseline no specific family environ- points can be partly explained by the clinical severity of mental style was associated with functioning in both FEP pa- the patients at baseline and their improvement at 2 years tients and HC, but in the FEP group worse functioning was but the impairment in functioning at follow-up might not related with positive father’s history of psychiatric disor- only be explained by their clinical condition. These find- ders. On the contrary, at the 2-year follow-up, worse func- ings indicate that functional recovery at follow-up in FEP tioning in NA-PSYCH patients was associated with the per- patients does not only depend on clinical remission and it ception of higher rates of moral-religious emphasis and con- should be considered as important as symptomatic recovery trol in their family and lower rates of active-recreational (Santesteban-Echarri et al., 2017). and achievement orientation. Worse functioning was associ- Previous literature identified that family environment ated with higher conflicts in the family of A-PSYCH patients. plays a major role in longitudinal functioning in individu- At the beginning of the study FEP patients presented als at-risk of psychosis and FEP patients (O’Brien et al., moderate impairment that improved in 2 years, with mild 2006; Schlosser et al., 2010). Interestingly, in the present impairment in both NA-PSYCH and A-PSYCH patients. More- study environmental family styles perceived by the patients over, the global functioning of NA-PSYCH patients was sig- were significantly associated with functioning at-follow-up nificantly worse than in A-PSYCH, in line with previous lit- in both NA-PSYCH and A-PSYCH patients. Particularly, higher erature (Thonse et al., 2018). Notably, half of the NA- 60 European Neuropsychopharmacology 49 (2021) 54–68 Table 2 Parents’ history of psychiatric disorders across diagnostic groups ∗ . FEP(n = 283) HC (n = 211) Baseline (yes reported) n (%) n (%) X2 /FE p Parents’ history of psychiatric disorders 51 (18) 26 (12.3) 2.566 0.109 - Psychotic disorders† 15 (-) – - Bipolar disorders 2 (5.6) 4 (15.4) - Depressive disorders 34 (94.4) 22 (84.6) 1.669 0.196 Father’s history of psychiatric disorders 15 (5.3) 15 (7.1) 0.412 0.521 - Psychotic disorders† 9 (-) – - Bipolar disorders 1 (16.7) 2 (13.3) - Depressive disorders 5 (83.3) 13 (86.7) 0.039 1.000 Mother’s history of psychiatric disorders 42 (14.8) 14 (6.6) 7.302 0.007 - Psychotic disorders† 9 (-) – - Bipolar disorders 2 (6.1) 2 (14.3) - Depressive disorders 31 (93.9) 12 (85.7) 0.854 0.572 NA-PSYCH (n = 244) A-PSYCH (n = 39) 2-year follow-up (yes reported) n (%) n (%) FE p Parents’ history of psychiatric disorders 47 (19.3) 4 (10.3) 1.846 0.260 - Psychotic disorders 13 (27.7) 2 (50) - Bipolar disorders 2 (5.9) 0 0.125 1.000 - Depressive disorders 32 (94.1) 2 (100) Father’s history of psychiatric disorders 13 (5.3) 2 (5.1) 0.003 1.000 - Psychotic disorders 7 (53.8) 2 (100) - Bipolar disorders 1 (7.7) 0 - Depressive disorders 5 (38.5) 0 1.538 0.463 Mother’s history of psychiatric disorders 40 (16.4) 2 (5.1) 3.376 0.087 - Psychotic disorders 9 (22.5) 0 - Bipolar disorders 2 (5) 0 - Depressive disorders 29 (72.5) 2 (100) 0.745 0.540 A-PSYCH=affective psychoses; FE=Fisher’s exact test; FEP=first episode psychosis; HC=healthy control; n=number; NA-PSYCH=non- affective psychoses; SD=standard deviation. ∗ individuals can present more than one different psychiatric disorders in their parents’ history. †not included in the model because HC with a positive parents’ history for psychotic disorders were excluded from the study. rates of moral-religious emphasis and control in NA-PSYCH ception of family independence. This finding might seem patients and the perception of conflicts in the family in A- at odds with the fact that higher rates of family con- PSYCH patients represented risk factors for worse individual trol were associated with worse functioning. Nonetheless, functioning. These results met previous literature findings. Spiegel and Wissler (Spiegel and Wissler, 1986), assessing In particular, families perceived as conflict-ridden or con- a mixed cohort of patients during one year after an in- trolling were related to negative functioning in adolescents ward hospitalization, reported that patients whose fami- (Burt et al., 1988). Similarly, in the present study families lies encouraged independence rated themselves as doing of FEP patients in comparison with HC were characterized more poorly at follow-up and being less adapted. They con- by higher rates of conflicts and control. clude that this might reflect the poor self-perception of pa- In previous studies assessing family environmental styles tients in family settings and might more acutely sense the with the FES, the impact of family environment was also fo- limitations associated with their illness. In addition, psy- cused on evaluating longitudinal outcomes in terms of clin- chotic relapses were predicted by the fathers’ scores on ical features, such as relapses or re-hospitalizations. Inter- moral-religious emphasis perceived in the family (Cañivé estingly, their findings on clinical outcomes resemble our et al., 1995). Hafner and Miller (1991) identified that the findings on psychosocial functioning at follow-up. In a Span- fathers’ scores on moral-religious emphasis were associated ish study assessing patients with schizophrenia outcomes af- with higher number of days of hospitalization of siblings ter a nine-month follow-up, patients’ perception of family with schizophrenia. In terms of protective factors, in the control predicted psychotic relapses and re-hospitalization same study higher fathers’ scores on achievement orien- (Cañivé et al., 1995). Surprisingly, not only family con- tation were associated with a better outcome (Hafner and trol but also family independence predicted psychotic re- Miller, 1991). In the present study, higher rates of achieve- lapses (Cañivé et al., 1995). In the present study, inde- ment and active-recreational orientation within the fam- pendence was not significantly associated with function- ily were protective factors from worse individual function- ing in NA-PSYCH patients, but NA-PSYCH patients scored ing in NA-PSYCH patients. In the subsample of patients significantly higher than A-PSYCH patients for their per- suffering from schizophrenia of the study by Spiegel and 61 N. Verdolini, S. Amoretti, G. Mezquida et al. Fig. 2 The effect of family environmental styles or parents’ history of psychiatric disorders on functioning. Wissler (1986), a strong correlation was found between symptoms in comparison with those without psychosis active-recreational orientation in the family at baseline and (Hua et al., 2011). a better self-rated patient adjustment at short and long- High rates of psychiatric disorders are commonly present term follow-up. In a research done in patients with history in families of FEP patients, underlining the high vulnerabil- of psychosis (González-Pinto et al., 2011), it was found that ity to psychiatric disorders in these families (Faridi et al., families with affected relatives protect themselves from 2009). In the present study, at baseline FEP patients’ func- psychosis with positive environmental factors such as co- tioning was not associated with any specific family envi- hesion and intellectual-cultural activities. Consistently, in ronment style. Contrarily, worse baseline functioning was previous studies positive remarks, family warmth and an found for those FEP patients with a father’s history of psy- optimal level of family involvement predicted improved so- chiatric disorder, even after controlling for the different cial functioning at follow-up in patients at risk of psychoses family styles. A positive family history of psychosis was (O’Brien et al., 2006; Schlosser et al., 2010). already seen to have a significant association with long- As for A-PSYCH patients, a more conflictive family envi- term occupational and global outcome in patients with ronment represented a risk factor for worse individual func- schizophrenia (Käkelä et al., 2014). In a study assessing tioning. High levels of conflicts were reported in the envi- the possible effect exerted by positive or negative family ronment of BD families in previous studies (Barron et al., styles against the development of psychosis,González-Pinto 2014; Reinares et al., 2016). Reinares et al. (2016) identi- et al. (2011) found that the FES subscales with a signif- fied that individual psychosocial functioning positively cor- icant effect on the presence of psychosis were CON and related with cohesion and active-recreational orientation MRE, with a tendency to significance for CTL, whilst the within the family and negatively correlated with control. protective factors on the presence of psychosis were ICO Even though conflict was not directly associated with psy- and ARO. These family styles were associated with func- chosocial functioning, it was related with substance use. tioning in NA-PSYCH and A-PSYCH patients in the present As a consequence, the authors concluded that family con- study. It seems that the genetic load conferred by a psy- flict should be an important target for family intervention chiatric family history has a higher influence on functioning in BD (Reinares et al., 2016). In addition, in a cohort of at baseline, when the patient develops psychotic symptoms patients with different psychiatric diagnoses, family con- for the first time. Then, the family environment exerts its flict was seen to predict re-hospitalization at 3 months influence on functioning only when the illness was already (Spiegel and Wissler, 1986). In a follow-up study assessing established according to specific diagnoses, with manifested children and adolescents presenting a FEP (Otero et al., worse functioning in the presence of a disturbed family 2011), more problems in communication in families at environment. baseline correlated with higher rates of psychopathology The reason why different family styles can confer a risk at one year. Moreover, less cohesion and poorer over- towards the development of an affective versus a non- all functioning was found in BD children with psychotic affective psychosis is still not clear. In general, emotion- 62 European Neuropsychopharmacology 49 (2021) 54–68 ally neglectful and controlling parents’ attitude were asso- though it might have been interesting and informative if ciated with an increased overall risk of psychiatric symp- parents had completed the same scale as well. Nonethe- toms in children (Young et al., 2011). Adolescents suffer- less, in previous research significant levels of consistency ing from BD acknowledged significantly more conflicts with in reports of family environment across family members their parents in comparison to either controls or adolescents were reported (De Ross et al., 1999; Kaur, 2013). The is- suffering from unipolar depression. As for psychoses, care- sue whether FEP patients experience a “bias” in the per- givers who considered their relatives as chronic and who re- ception of the family environment in comparison to HC ported weaker beliefs in treatment generally use less cop- is unexplored in the current literature that actually de- ing strategies such as seeking social support and education serve attention in future research. Similarly, the differ- and problem-solving with higher denial and disengagement ences in the perception of the family environment in NA- (Gerson et al., 2011). Moreover, a positive family history PSYCH than in A-PSYCH should be further evaluated. The does not only confer a genetic liability but might shape FAST severity thresholds were derived from the article by family relationship and interactions (Stapp et al., 2020). Bonnín et al. (2018), which stated severity groups consider- Patients with parent’s history of psychiatric disorders tend ing a population of euthymic A-PSYCH patients. Anyway, no to perceive more negative family environment styles in the study was published so far establishing FAST severity thresh- present study. In previous literature, parents with psychosis olds for FEP patients. The final limitation would be the di- reported that all domains of parenting appear to be affected agnostic instability of FEP. However, in this study the diag- by psychosis, i.e. the difficulty in concentration because noses were established in evaluations after 2 years of mon- of hallucinations had negative impact on their abilities to itoring. Despite the limitations, this is the first study, to the provide protection, expressivity and control (Strand et al., best of our knowledge, to consider the effect exerted on 2017). Furthermore verbal aggression was high in couples functioning in FEP patients by family aspects, both envi- with an adult having BD (Serravalle et al., 2020) and this ronmental and derived from the genetic load to psychiatric might have consequences on the relationship and develop- disorders. Moreover, the study relies on a 2-year prospec- ment of siblings. Finally, a positive family history correlated tive follow-up period, allowing for causal interpretation of with worse clinical indicators such as higher severity of neg- the results. Family environment has been poorly evaluated ative symptoms and higher doses of treatment in FEP pa- in previous studies. A recent study pairing polygenic risk tients and higher severity of the disease in the group of NA- score for schizophrenia with an aggregate environmental PSYCH patients at follow-up, in line with previous literature score provided evidence for gene-environment interaction (Käkelä et al., 2018, 2017). in a FEP sample (Bernardo et al., 2017; Mas et al., 2020). The present study has limitations. Data on trauma, abuse Consequently, the exposome score for schizophrenia may be of drugs and early adjustment were retrospectively assessed further enriched by inclusion of other exposures that have at baseline, with the possibility of a recall bias. Recall bias been associated with psychosis phenotype, such as family could apply to the determination of the parents’ history of environment. psychiatric disorders. To reduce this risk, we considered a The present article underlined the importance of both positive parents’ history of psychiatric disorders only when perceived family environment and the genetic load on the a psychiatric disorder was formally diagnosed and required functioning of patients presenting first-episode psychosis, treatment. The small sample size of the A-PSYCH group can with differences on the effect exerted at baseline or after 2 limit generalizability of the results and the possibility to years, when specific diagnoses are established. Considering compare A-PSYCH and NA-PSYCH. Only patients experienc- the worldwide initiatives to establishing preventive strate- ing for the first time psychotic symptoms during an affec- gies, such as the European College of Neuropsychopharma- tive episode were included in the study, representing a se- cology Network on the Prevention of Mental Disorders and lected group of A-PSYCH patients, with difficulty of recruit- Mental Health Promotion (ECNP PMD-MHP) (Fusar-Poli et al., ment. The family history of psychiatric disorders was not 2019), these findings shed light on the importance of iden- assessed through a semi-structured interview administered tifying not only individuals at risk for developing a psy- to the parents of the participants. Moreover, low rates of chiatric disorder but also families with a higher dysfunc- psychiatric family history were identified in the A-PSYCH tional load. Interventions apply both at the individual level, group. Recruiting bias could be a risk. Indeed, drop-outs with a particular focus on functioning (Fowler et al., 2018), are a threat for any longitudinal study. The different po- and to families (Dillinger and Kersun, 2019). Early inter- tential sources of drop-outs, such as failure to contact re- ventions (Carvalho et al., 2020), and particularly family in- search participants and to achieve cooperation, were partly terventions aimed at improving the family environment by reduced because patients were not only evaluated for re- minimizing conflict and enhancing cohesion, organization, search purposes but also for clinical reasons. Nonetheless, intellectual and recreational orientation might be useful rates of drop-outs in the present study were moderately in reducing the family burden and the patient’s individual high but in line with the rates reported in previous longitu- functioning. dinal studies including FEP patients (Menezes et al., 2006). Furthermore, HC drop-outs and patients did not differ from completers in terms of functioning, which represented the main objective of the present study. Unfortunately, rates Role of the funding source of re-hospitalization and relapses were not collected and future studies on the family environment of FEP patients The funding sources were not involved in the study design, should focus on these aspects. As for the family environ- conduct, monitoring and preparation of the final database mental styles, only patients were tested with the FES even and had no influence on the final data analysis of this report. 63 N. Verdolini, S. Amoretti, G. Mezquida et al. Contributors Biomédica en Red de Salud Mental (CIBERSAM), Madrid Re- gional Government (S2010/ BMD-2422 AGES), JanssenCilag, NV and SA designed the study, managed the literature Lundbeck, Otsuka, Pfizer, Ferrer, Juste, Takeda, Exeltis, An- searches and analyses, undertook the statistical analysis, gelini, Casen-Recordati. and wrote the first draft of the manuscript. MG-R reports grants from INSTITUTO CARLOS III, grants EV and MG revised the first draft and added critical com- from ADAMED, non-financial support from JANSSEN–CILAG, ments to guide the redaction of the final manuscript. non-financial support from LUNDBECK-OTSUKA, non- GM, MJC, LP-C, CG-R, AL, AG-P, JM-N, IC, ES, IB, DB, MG, financial support from PFIZER, non-financial support from MBi, MS and CV revise the second draft of the article and ANGELINI, outside the submitted work. provided critical comments to guide the redaction of the VB-M has received grants and served as consultant, ad- final manuscript. visor, or continu-ing medical education speaker during the All the authors within the PEPs Group recluted patients last 5 years for thefollowing entities: Angelini Spain, An- and healthy controls at their centers, provided the anoni- gelini Portugal, AstraZeneca, Bristol-Myers-Squibb, Ferrer, mous data and revise the final manuscript. Janssen, Juste, Lundbeck, NutriciónMédica, and Otsuka. All authors approved the final manuscript. AI has served as speaker or advisor for the following companies: Adamed, Bristol-Myers Squibb, Ferrer, Janssen- Cilag, Lundbeck, Pfizer, Servier and Otsuka. Declaration of Competing Interest IP has received CME-related honoraria, or consulting fees from ADAMED, Janssen-Cilag and Lundbeck. EV has received research support from or served as The rest of authors report no biomedical financial inter- consultant, adviser or speaker for AB-Biotics, Actavis, ests or potential conflicts of interest related to the present Allergan, Angelini, AstraZeneca, Bristol-Myers Squibb, article. Dainippon Sumitomo Pharma, Ferrer, Forest Research In- stitute, Gedeon Richter, Glaxo-Smith-Kline, Janssen, Lund- beck, Otsuka, Pfizer, Roche, Sanofi-Aventis, Servier, Shire, Sunovion, Takeda, Telefónica, the Brain and Behaviour Acknowledgment Foundation, the Spanish Ministry of Science and Innovation (CIBERSAM), the Seventh European Framework Programme We are extremely grateful to all participants. (ENBREC), and the Stanley Medical Research Institute, unre- This study is part of a coordinated-multicentre Project, lated to the present work. funded by the Ministerio de Economía y Competitividad MB has been a consultant for, received grant/research (PI08/0208; PI11/00325; PI14/00612), Instituto de Salud support and honoraria from, and been on the speak- Carlos III – Fondo Europeo de Desarrollo Regional. Unión ers/advisory board of ABBiotics, Adamed, AMGEN, Eli Lilly, Europea. Una manera de hacer Europa, Centro de Investi- Ferrer, Forum Pharmaceuticals, Gedeon, Janssen-Cilag, gación Biomédica en Red de salud Mental, CIBERSAM, by the Lundbeck, Otsuka, Pfizer and Roche. CERCA Programme / Generalitat de Catalunya AND Secre- MBi has been a consultant for, received grant/research taria d’Universitats i Recerca del Departament d’Economia support and honoraria from, and been on the speak- I Coneixement (2017SGR1355). Departament de Salut de la ers/advisory board of, has received honoraria from talks Generalitat de Catalunya, en la convocatoria corresponent and/or consultancy of Adamed, Angelini, Ferrer, Janssen- a l’any 2017 de concessió de subvencions del Pla Estratègic Cilag, Lundbeck, Otsuka, Pfizer and Sanofi. de Recerca i Innovació en Salut (PERIS) 2016–2020, modali- AG-P has received grants and served as consultant, ad- tat Projectes de recerca orientats a l’atenció primària, amb visor or CME speaker for the following entities: Janssen- el codi d’expedient SLT006/17/00345. Cilag, Lundbeck, Otsuka, Pfizer, Sanofi-Aventis, Alter, An- NV thanks the support of the BITRECS project, which gelini, Exeltis, the Spanish Ministry of Science and Innova- has received funding from the European Union’s Horizon tion (CIBERSAM), the Ministry of Science (Carlos III Insti- 2020 research and innovation program under the Marie tute), the Basque Government, and the European Frame- Skłodowska-Curie grant agreement No 754550 and from “La work Program of Research. Caixa” Foundation (ID 100010434), under the agreement IB has received honoraria or travel support from Otsuka- LCF/PR/GN18/50310006. She also would like to thank Miss Lundbeck, Angelini and Janssen, research support from Fun- Evelyn Williams for the English correction and Mr Gabriele dación Alicia Koplowitz and grants from Spanish Ministry of Mollica for technical support. Health, Instituto de Salud Carlos III. SA has been supported by a Sara Borrell (CD20/00177), CG-R has received grants from/or served as consultant, funded by Instituto de Salud Carlos III (ISCIII) and co-funded advisor or speaker for the following entities Adamed, An- by European Social Fund "Investing in your future”. gelini, Janssen-Cilag and Lunbeck. EV thanks the support of the Spanish Ministry of Science, MG served as consultant or advisor for Ferrer, Lundbeck Innovation and Universities (PI15/00283, PI18/00805) inte- and Janssen. grated into the Plan Nacional de I + D + I y cofinanciado por CDe-la-C. received financial support to attend scientific el ISCIII-Subdirección General de Evaluación y el Fondo Eu- meetings from Janssen-Cilag, Almirall, Eli Lilly, Lundbeck, ropeo de Desarrollo Regional (FEDER); the Instituto de Salud Rovi, Esteve, Novartis, and Astrazeneca. Carlos III; the CIBER of Mental Health (CIBERSAM); the Secre- RR-J has been a consultant for, spoken in activities of, or taria d’Universitats i Recerca del Departament d’Economia received grants from: Instituto de Salud Carlos III, Fondo i Coneixement (2017 SGR 1365) and the CERCA Programme de Investigación Sanitaria (FIS), Centro de Investigación / Generalitat de Catalunya. He would like to thank the De- 64 European Neuropsychopharmacology 49 (2021) 54–68 partament de Salut de la Generalitat de Catalunya for the 26 Department of Psychiatry, Universidad de Oviedo, PERIS grant SLT006/17/00357. Oviedo, Spain ES is supported by the Instituto de Salud Carlos III through 27 Department of Psycology, Universidad de Oviedo, a ‘Rıo Hortega’ contract (CM19/00123), co-financed by the Oviedo, Spain European Social Fund. 28 University of the Basque Country (UPV/EHU), Depart- MG has received grants from the Spanish Ministry of ment of Neurosciences Economy and Competitiveness, Instituto de Salud Carlos 29 BioCruces Health Research Institute. Vizcaya, Spain III through a ‘Rıo Hortega’ contract (CM17/00102), FEDER, 30 Instituto de Investigación Sanitaria Hospital 12 de Oc- Centro de Investigación Biomédica en Red de Salud Mental tubre (imas12), Madrid, Spain (CIBERSAM), Secretaria d’Universitats i Recerca del Depar- 31 CogPsy Group, Universidad Complutense de Madrid tament d’Economia i Coneixement (2017SGR1365), and the (UCM), Madrid, Spain CERCA Programme/Generalitat de Catalunya, all of them 32 Research and Development Unit, Parc Sanitari San Joan unrelated to the current work. de Dèu - Sant Boi de Llobregat, Barcelona, Catalonia IP thanks the support of the Spanish Ministry of Science 33 Parc Sanitari Sant Joan de Déu, Institut de Recerca Sant and Innovation (PI18/01001). Joan de Déu, Sant Boi de Llobregat, Barcelona, Catalonia AI thanks the support of the Spanish Ministry of Science, 34 FIDMAG Germanes Hospitalàries Research Foundation, Innovation and Universities (PI16/00834) integrated into the Barcelona, Spain Plan Nacional de I + D + I y cofinanciado por el ISCIII- 35 Department of Psychiatry, Hospital Universitario Ramón Subdirección General de Evaluación y el Fondo Europeo y Cajal, IRYCIS, Biomedical Research Networking Center for de Desarrollo Regional (FEDER); CIBERSAM; and the Project Mental Health (CIBERSAM) Universidad de Alcalá, Madrid, B2017/BMD-3740 Ayudas I + D en Biomedicina de la Comu- Spain nidad de Madrid, cofinanciada por Fondo Social Europeo y 36 Departament de Medicina, Universitat de València, Fondo Europeo de Desarrollo Regional, 2014–2020, de la Co- València, Spain munidad de Madrid. We also would like to thank the authors of the PEPs group who participated in the development of this manuscript, Supplementary materials namely, Gómez M2 , Sagué M16 , Molina M4,8 , Abregú-Crespo R4,8 , Supplementary material associated with this article can be Alonso-Solís A4,12 , Grasa E4,12 , Gonzalez-Ortega I17 , García found, in the online version, at doi:10.1016/j.euroneuro. S17 , De-la-Cámara C9,18 , Saz P9,10 , Gonzalez JC19 , Gadea 2021.03.015. M20 , Martínez L21 , Monserrat C21 , Pacchiarotti I1 , Giménez A1 , Castro-Fornieles J13 , de la Serna E4,13 , Contreras F4,22 , Saiz-Masvidal C4,22 , González-Blanco L4,23,24,25,26,27 , References Bobes-Bascarán T4,23,24,25,26,27 , Gutiérrez Fraile M4,11 , Za- Amoretti, S., Bernardo, M., Bonnin, C.M., Bioque, M., Cabrera, B., bala Rabadán A4,28,29 , Fares-Otero NE30 , Rodriguez-Jimenez Mezquida, G., Solé, B., Vieta, E., Torrent, C., 2016. 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