Schizophrenia Research 236 (2021) 19–28 Contents lists available at ScienceDirect Schizophrenia Research journal homepage: www.elsevier.com/locate/schres Impact of previous tobacco use with or without cannabis on first psychotic experiences in patients with first-episode psychosis Leticia González-Blanco a, María Paz García-Portilla a, *, Miguel Gutiérrez b, Gisela Mezquida c, Manuel J. Cuesta d, Elena Urbiola e, Silvia Amoretti c, Fe Barcones f, Ana González-Pinto b, Laura Pina-Camacho e, Iluminada Corripio g, Eduard Vieta h, Immaculada Baeza i, Alba Toll j, Pilar A. Sáiz a, Julio Bobes a, Miguel Bernardo c, PEPs Group a Department of Psychiatry, University of Oviedo, Biomedical Research Networking Center for Mental Health Network (CIBERSAM), Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Instituto de Neurociencias del Principado de Asturias (INEUROPA), Servicio de Salud del Principado de Asturias (SESPA), Oviedo, Spain b Department of Psychiatry, Araba University Hospital, Bioaraba Research Institute, Department of Neurosciences, University of the Basque Country, CIBERSAM, Alava, Spain c Barcelona Clinic Schizophrenia Unit, Hospital Clinic of Barcelona, Neuroscience Institute, CIBERSAM, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), University of Barcelona, Spain d Department of Psychiatry, Navarre Hospital Complex, IdiSNA, Navarre Institute for Health Research, Pamplona, Spain e Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, IiSGM, School of Medicine, Universidad Complutense, CIBERSAM, Madrid, Spain f Department of Family Medicine, Hospital Universitario Miguel Servet, Department of Medicine and Psychiatry, Universidad de Zaragoza, Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza, Spain g Psychiatry Department, Institut d’Investigació Biomèdica-Sant Pau (IIB-SANT PAU), Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona (UAB), CIBERSAM, Barcelona, Spain h Bipolar Disorders Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain i Child and Adolescent Psychiatry Service, Hospital Clinic of Barcelona, CIBERSAM, Barcelona, Spain j Hospital del Mar Medical Research Institute (IMIM), CIBERSAM, Barcelona, Spain A R T I C L E I N F O A B S T R A C T Keywords: Objective: There is high prevalence of cigarette smoking in individuals with first-episode psychosis (FEP) prior to Prodromal symptoms psychosis onset. The purpose of the study was to determine the impact of previous tobacco use with or without First psychotic symptoms cannabis on first psychotic experiences in FEP and the impact of this use on age of onset of symptoms, including Substance use prodromes. Methods: Retrospective analyses from the naturalistic, longitudinal, multicentre, “Phenotype-Genotype and Environmental Interaction. Application of a Predictive Model in First Psychotic Episodes (PEPs)” Study. The authors analysed sociodemographic/clinical data of 284 FEP patients and 231 matched healthy controls, and evaluated first psychotic experiences of patients using the Symptom Onset in Schizophrenia Inventory. Results: FEP patients had significantly higher prevalence of tobacco, cannabis, and cocaine use than controls. The FEP group with tobacco use only prior to onset (N = 56) had more sleep disturbances (42.9% vs 18.8%, P = 0.003) and lower prevalence of negative symptoms, specifically social withdrawal (33.9% vs 58%, P = 0.007) than FEP with no substance use (N = 70), as well as lower prevalence of ideas of reference (80.4% vs 92.4%, P = 0.015), perceptual abnormalities (46.4% vs 67.4%, P = 0.006), hallucinations (55.4% vs 71.5%, P = 0.029), and disorganised thinking (41.1% vs 61.1%, P = 0.010) than FEP group with previous tobacco and cannabis use (N = 144). FEP patients with cannabis and tobacco use had lower age at first prodromal or psychotic symptom (mean = 23.73 years [SD = 5.09]) versus those with tobacco use only (mean = 26.21 [SD = 4.80]) (P = 0.011). Conclusions: The use of tobacco alone was not related to earlier age of onset of a first psychotic experience, but the clinical profile of FEP patients is different depending on previous tobacco use with or without cannabis. * Corresponding author at: Área de Psiquiatría, Universidad de Oviedo, Julián Clavería 6, 33006 Oviedo, Spain. E-mail addresses: albert@uniovi.es (M.P. García-Portilla), MEZQUIDA@clinic.cat (G. Mezquida), elena.urbiola@iisgm.com (E. Urbiola), AMORETTI@clinic.cat (S. Amoretti), icorripio@santpau.cat (I. Corripio), vieta@clinic.cat (E. Vieta), frank@uniovi.es (P.A. Sáiz), bobes@uniovi.es (J. Bobes), BERNARDO@clinic.cat (M. Bernardo). https://doi.org/10.1016/j.schres.2021.07.017 Received 17 May 2020; Received in revised form 14 February 2021; Accepted 12 July 2021 Available online 5 August 2021 0920-9964/© 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). L. González-Blanco et al. Schizophrenia Research 236 (2021) 19–28 1. Introduction informed consent was obtained from all participants or their legal guardians. A higher prevalence of cigarette smoking has been reported in in­ dividuals with schizophrenia or first-episode psychosis (FEP) – at least 2.1. Participants twice that of the general population (Barnett et al., 2007; de Leon and Diaz, 2005; Kotov et al., 2010; Myles et al., 2012a). The association The sample consists of 335 individuals with FEP and 253 healthy between tobacco and psychosis has been widely studied, and a causal controls (HC) matched by age (±10%), sex and parental socio-economic relationship has been proposed between smoking and increased risk of status, enrolled in a naturalistic, longitudinal, multicentre study psychosis (Clark et al., 2018; Gurillo et al., 2015; Hunter et al., 2020; (Phenotype-Genotype and Environmental Interaction. Application of a Weiser et al., 2004), especially in individuals who start smoking at an Predictive Model in First Psychotic Episodes: PEPs study) (Bernardo earlier age (McGrath et al., 2016) and in individuals who are heavy et al., 2019; Salagre et al., 2019). Methodological aspects, including smokers (Kendler et al., 2015; Wium-Andersen et al., 2015). Most inclusion and exclusion criteria, have been described elsewhere (Ber­ studies agree that cigarette smoking generally begins before onset of nardo et al., 2013). psychosis (de Leon and Diaz, 2005; Smith et al., 2009); indeed, a meta- Individuals with missing data on age at first use of tobacco and analysis by Myles et al. (2012b) reported that tobacco use precedes the cannabis or onset of psychosis were excluded (N = 23), as well as in­ onset of psychosis by about five years. The relationship between dividuals who started using cannabis or tobacco after the earliest smoking and psychosis is not evidenced exclusively in the clinical pop­ symptom (N = 1). Also, individuals under 16 years of age and patients ulation. In the general population, tobacco use (van Gastel et al., 2013) who presented the earliest symptom before age 16 were excluded to and number of cigarettes per day (Bhavsar et al., 2018) has been asso­ minimize bias (mean age at onset of smoking in this sample was 15.45 ciated with an increase in psychotic experiences. However, a study years [SD = 2.85]) (N = 28). Thus, data from 283 FEP patients and 231 evaluating the role of tobacco use in the development of psychosis in HC were analysed (see Fig. 1). After removing individuals from the individuals at clinical high risk found that smoking status did not predict original sample, HC were no longer matched for socioeconomic status, conversion to psychosis (Ward et al., 2019). but no statistically significant differences in age and sex were detected More controversy exists regarding whether smoking is related to age [mean age: FEP 25.24 years (SD = 5.58), HC 25.22 years (SD = 5.83); of onset of psychosis. While some studies have reported an association sex: FEP 65.8% male, HC 63.2% male]. with an earlier onset of psychosis (Gurillo et al., 2015; McGrath et al., FEP patients were classified into 4 groups based on tobacco and/or 2016), others did not find a relationship when controlling for con­ cannabis use before onset of the earliest symptom, as follows: A. No founding factors such as the use of cannabis (Hickling et al., 2017; Myles cannabis or tobacco use (N = 70); B. Tobacco use only (N = 56); C. Both et al., 2012a). Furthermore, other studies have reported a later onset of tobacco and cannabis use (N = 144); D. Cannabis use only (N = 13). It is psychosis in smokers than non-smokers (Ma et al., 2010). worthy to highlight that 61 of these individuals had used cocaine at Inconsistent results have also been published regarding the symp­ some point in their life, and all had an age at first cocaine use less than or tomatology of smokers with psychosis. However, while there is a good equal (± 1 year) to the age when the earliest symptom emerged. Of deal of data on the effects of tobacco on symptom severity and functional those, 53 belonged to group C, 5 belonged to group B, 3 belonged to outcomes in patients with an established diagnosis of schizophrenia or group D, and none were in group A. the non-affective psychosis spectrum (Jiang et al., 2013; Krishnadas et al., 2012; Ma et al., 2010; Morisano et al., 2013; Vermeulen et al., 2.2. Assessment 2019, 2018), studies on individuals with FEP are much scarcer. Some suggest that smokers with FEP presented greater severity of both posi­ Baseline sociodemographic characteristics and clinical data were tive and negative symptoms and worse cognition and quality of life obtained from patients and controls: age, sex, marital status, living and (Grossman et al., 2017; Oluwoye et al., 2019), others did not find this work status, education level, and socioeconomic status based on relationship (Hickling et al., 2018, 2017; Sanchez-Gutierrez et al., 2018) parental sociodemographic status (Hollingshead and Redlich, 1958). or found the opposite results (Misiak et al., 2015). Substance use data were collected retrospectively using the semi- Bearing in mind the above, there are many questions related to the structured interview European Adaptation of Multidimensional Assess­ relationship between tobacco and psychosis still open to debate. Besides ment Instrument for Drug and Alcohol Dependence (EuropAsi) (Kokkevi the hypothesis of considering tobacco per se as a risk factor for psy­ and Stefanis, 1995). Lifetime and baseline use, age at first use of tobacco, chosis, its impact on the phenotypic expression of the disorder and, cannabis, and/or cocaine, and frequency or amount of tobacco and consequently, the possibility of inducing a differentiated entity in terms cannabis use were determined for the present study. Clinical psychosis of etiopathogeny, clinical features, prognosis, response to conventional spectrum diagnoses were established with semi-structured diagnostic treatments, and/or preventive interventions, remains unknown. interviews using the DSM-IV criteria (Bell, 1994). To our knowledge, there are very few studies about the effects of The first symptoms of the psychotic illness were systematic and tobacco on patients presenting with a first psychotic experience retrospectively evaluated using the Symptom Onset in Schizophrenia compared with those who did not use tobacco or used cannabis (SOS) inventory (Mezquida et al., 2018; Perkins et al., 2000) by expe­ concomitantly. Therefore, the main objective of the present study is to rienced psychiatrists or psychologists trained in the assessment tool. describe the clinical profile of the earliest symptom of psychotic illness Using a structured clinical interview, it assesses the frequency of in individuals with FEP based on previous tobacco use with or without occurrence of 16 symptoms that may appear at the onset of the cannabis use. Other secondary objectives of the study are to analyse if schizophrenia to dating the onset of the earliest symptom and the onset there is a differential effect of tobacco on the age of onset of psychosis, of psychosis, understood as the first psychotic experience (Perkins et al., understood as the first psychotic experience in FEP (Perkins et al., 2000), 2000). The SOS groups the symptoms in four categories: 1) General as well as to describe the pattern of tobacco and cannabis use in in­ prodromal symptoms (dysphoric mood, sleep disturbance, ideas of dividuals with FEP compared with healthy controls. reference, suspiciousness, thought disorder, perceptual abnormalities, deterioration in functioning, other - including for instance magical 2. Methods thinking, hoarding, …-); 2) Negative symptoms (social withdrawal, avolition, decreased expression and experience of emotion); 3) Positive The study was approved by the Clinical Research Ethics Committee symptoms (hallucinations and delusions); and 4) Disorganisation of each participating site and was conducted according to the ethical symptoms (disorganised thinking and behaviour). For each symptom, standards of the Declaration of Helsinki and current legislation. Written there are specific frequency criteria to determine its date of onset if the 20 L. González-Blanco et al. Schizophrenia Research 236 (2021) 19–28 2.3. Statistical analyses The software package IBM SPSS Statistics for Windows, Version 23.0, was used for statistical analyses. Data were expressed as percentages or mean and standard deviation (SD). First, we calculated the age of onset for each symptom by subtracting the patient's date of birth from the symptom's onset date to determine the age of onset of the earliest symptom. Regarding the onset of psy­ chosis, in this paper we only employed the estimation made by the interviewer. Comparisons between FEP patients and HC characteristics and sub­ stance use patterns were made using a Chi-squared test in the case of categorical variables and Student's t-test for independent samples for continuous variables. In FEP patients, differences among the four substance use groups with respect to continuous data were analysed using an analysis of variance (ANOVA) and a Bonferroni post hoc test, while differences in prevalence of each symptom among those four groups were compared using a Chi-squared test. Due to a potential confounding effect of the concomitant use of cocaine identified in some individuals (see Fig. 1), we repeated the same analyses excluding them. Finally, to minimize the effect of potential confounders (sex, age at the onset of the earliest symptom, socioeconomic status, and cocaine use), a multinomial logistic regression model (main effects model) was carried out using substance use groups as the dependent variable. All variables that were statistically significant in the bivariate analysis were included as independent vari­ ables, and “tobacco use only” was considered the category of reference. In all tests, differences were considered statistically significant when P < 0.05. Fig. 1. Flow chart of sample selection. 3. Results symptom occurs. For instance, in the case of delusions the date of onset 3.1. Characteristics and substance use patterns of FEP patients and corresponds with the first time the individual experienced the symptom healthy controls whereas, in the case of sleep disturbances or avolition, the date corre­ sponds when the individual started to suffer these symptoms daily or FEP patients and HC were comparable in age, sex, and marital status. almost daily. Concerning the date of onset of psychosis, the SOS provides However, differences were detected in education level (fewer than 50% three estimations made by the patient, the proxy, and the interviewer, of patients had high school or university studies versus nearly 75% of respectively. control subjects), in work status (16.8 vs 48.1% were employed, respectively), and socioeconomic status. Detailed data are presented in Table 1. Regarding substance use (Table 2), FEP patients had significantly Table 1 Sociodemographic characteristics of FEP patients and healthy controls. FEP group (N = 283) Control group (N = 231) Statistics P Mean SD Mean SD Age (years) 25.24 5.58 25.22 5.83 t = − 0.030 0.976 N % N % Sex (male) 187 65.8 146 63.2 X2 = 0.389 0.533 Married/Living as married 36 12.7 36 15.6 X2 = 0.896 0.344 Education level X2 = 65.386 <0.001 University studies 47 16.5 102 44.2 High school studies 66 23.2 66 28.6 Others 171 60.3 63 27.3 Work statusa X2 = 103.021 <0.001 Employed 47 16.8 108 48.1 Unemployed 98 35.1 18 7.8 Student 103 36.9 100 43.3 Others 31 11.1 2 0.9 Socioeconomic status*a X2 = 15.811 <0.001 High or medium-high 82 29.4 96 42.1 Medium 68 24.4 65 28.5 Low or medium-low 129 46.2 67 29.4 FEP, first-episode of psychosis; SD, standard deviation. * Parental sociodemographic status (Hollingshead and Redlich, 1958). a Missing data in FEP group (n = 279) and Control group (n = 228). 21 L. González-Blanco et al. Schizophrenia Research 236 (2021) 19–28 Table 2 Substance use data in FEP patients and healthy controls. FEP group (N = 283) Control group (N = 231) Statistics P Tobacco N % N % Lifetime users 201 70.8 106 45.9 X2 = 32.771 <0.001 Baseline users 191 67.3 97 42 X2 = 32.981 <0.001 Daily users 172 60.6 71 30.7 Sporadic users 19 6.7 26 11.3 Mean SD Mean SD Cigarettes/day 14.55 8.02 9.42 6.29 t = − 4.841 <0.001 Age at first use 15.44 2.85 15.47 2.87 t = 0.084 0.933 Years of regular use [at least 1 year] 7.98 [n = 187] 4.89 8.69 6.29 t = 1.002 0.317 [n = 83] Cannabis N % N % Lifetime users 157 55.3 68 29.4 X2 = 34.585 <0.001 Baseline users 133 46.8 48 20.8 X2 = 37.930 <0.001 Daily users 84 29.6 8 3.5 Weekly users 16 5.6 13 5.6 Monthly users 9 3.2 18 7.8 Sporadic users 24 8.5 9 3.9 Mean SD Mean SD Age at first use 16.19 3.00 16.51 1.86 t = 0.823 0.411 Years of regular use [at least 1 year] 5.68 [n = 132] 4.21 5.46 [n = 28] 4.21 t = − 0.248 0.804 Cocaine N % N % Lifetime users 61 21.5 17 7.4 X2 = 21.334 <0.001 Baseline users 39 13.7 11 4.8 X2 = 11.694 0.001 Mean SD Mean SD Age at first use 19.14 4.04 19.65 3.22 t = 0.474 0.637 FEP, first-episode of psychosis; SD, standard deviation. higher prevalence of tobacco, cannabis, and cocaine use than HC, both at the time of assessment and throughout their life (70.8%, 55.3%, 22.2% of FEP patients vs 44.9%, 29.4%, 7.4% of HC, respectively, all P ≤ 0.001). These differences were especially notable in the case of cannabis and cocaine (prevalence about two and three time higher, respectively). Among tobacco and cannabis smokers, there was also a greater intensity of use in the FEP group (both P < 0.001). However, there was no difference between the two groups in age at first use of the three substances, nor in years of regular use of cannabis and tobacco (detailed data in Table 2). 3.2. Age at psychosis onset based on substance use patterns FEP patients distributed into the four substance use groups were comparatively analysed. There were statistically significant differences among the four groups in age at the earliest symptom (F = 2.846, P = 0.038), as those with tobacco use only were older, but not in age at onset of psychosis (F = 2.637, P = 0.050). In post hoc analyses, these differ­ ences were detected solely between the group with tobacco use only (B) and the group with tobacco and cannabis use (C) (mean age at onset of Fig. 2. Age at psychosis onset based on substance use groups. psychosis: B = 26.31 [SD = 4.90] vs C = 23.90 [SD = 5.19], P = 0.033; mean age at the earliest symptom: B = 26.21 [SD = 4.80] vs C = 23.73 [SD = 5.09], P = 0.024) (Fig. 2). Table 3 shows the prevalence of each symptom based on substance use groups. There were no statistically significant differences between A 3.3. Profile of earliest symptom based on substance use patterns (no cannabis or tobacco use) and C (tobacco & cannabis use). Also, no statistically significant differences were detected between D (cannabis The prevalence of each SOS symptom in FEP patients is presented in only use) and any of the other three groups. However, differences were the Supplementary Material. At least one general prodromal symptom detected between group B (tobacco only user) vs group A on the one meeting the frequency threshold criteria was present in nearly 98% of hand and vs group C on the other. Thus, compared to individuals with no patients, being ideas of reference (88.7%), and suspiciousness (69.3%) substance use (group A), tobacco only users presented sleep distur­ the most common symptoms of this SOS group. While at least one bances much more frequently (more than 40% vs less than 20%) and negative symptom was present in half of the patients, at least one pos­ negative symptoms, specifically social withdrawal, less frequently. On itive symptom was present in more than 95% of the sample. Delusions the other hand, patients with use of both substances (group C), more were the most common symptom (95.1%). No difference was found in frequently presented ideas of reference, perceptual abnormalities, the initial clinical presentation based on sex (Supplementary Table S1). 22 L. González-Blanco et al. Schizophrenia Research 236 (2021) 19–28 Table 3 Differences in frequency of symptoms at onset in FEP patients by substance use group. A. Non tobacco or cannabis users (N = B. Tobacco only C. Tobacco & cannabis users (N = D. Cannabis only P* 70) users 144) users (N = 56) (N = 13) N % N % N % N % General prodromal symptoms 68 98.6 56 100.0 139 96.5 13 100 0.407 Dysphoric mood 17 24.6 17 30.4 33 22.9 5 38.5 0.498 Sleep disturbance 13 18.8 24 42.9 42 29.2 4 30.8 0.035a Ideas of reference 60 87.0 45 80.4 133 92.4 12 92.3 0.104b Suspiciousness 50 72.5 38 67.9 100 69.4 8 61.5 0.862 Thought disorder 43 62.3 27 48.2 87 60.4 8 61.5 0.373 Perceptual abnormalities 39 56.5 26 46.4 97 67.4 9 69.2 0.039c Deterioration in functioning 20 29.0 12 21.4 45 31.3 5 38.5 0.480 Others (obsessions, etc.) 9 13.6 12 21.4 30 20.8 4 33.3 0.368 Negative symptoms 42 60.9 21 37.5 71 51.4 6 46.2 0.075d Social withdrawal 40 58.0 19 33.9 69 47.9 5 38.5 0.055e Avolition 6 8.7 5 8.9 20 13.9 2 15.4 0.602 Decreased expression of emotions 9 13.0 4 7.1 14 9.7 3 23.1 0.336 Decreased experience of emotions 8 11.6 4 7.1 18 12.5 3 23.1 0.416 Positive symptoms 68 97.1 51 91.1 140 97.2 13 100 0.171 Hallucinations 41 58.6 31 55.4 103 71.5 9 69.2 0.099f Delusions 65 94.2 51 91.1 139 96.5 13 100 0.344 Disorganisation symptoms 40 58.0 29 51.8 92 63.9 9 69.2 0.283 Disorganised thinking 34 49.3 23 41.1 88 61.1 9 69.2 0.037g Disorganised behaviour 31 44.9 21 37.5 72 50.0 8 61.5 0.288 Post hoc analyses (chi-squared test): a Sleep disturbances: A vs B, P = 0.003; B vs C, P = 0.064. b Ideas of reference: B vs C, P = 0.015. c Perceptual abnormalities: B vs C, P = 0.006. d Negative symptoms: A vs B, P = 0.009. e Social withdrawal: A vs B, P = 0.007. f Hallucinations: B vs C, P = 0.029; A vs C, P = 0.058. g Disorganised thinking: B vs C, P = 0.010; B vs D, P = 0.067. * Differences between groups were tested for statistical significance using chi-squared test (degrees of freedom = 3). hallucinations, and disorganised thinking, compared with those who frequently. On the other hand, in comparison with both tobacco and used tobacco only. cannabis users, tobacco only users showed a lower prevalence of ideas of When the 61 subjects who had used cocaine at some point in their life reference, perceptual abnormalities, hallucinations, and disorganised (but started the use prior to the onset of the earliest symptom) were thinking. Furthermore, those patients who used tobacco only experi­ excluded from these analyses, identical results were obtained for dif­ enced the earliest symptom at an older age than those who used tobacco ferences in the prevalence of sleep disturbances (X2 = 7.344, P = 0.025), and cannabis concomitantly. This difference in age was not found be­ negative symptoms (X2 = 6.671, P = 0.036), social withdrawal (X2 = tween either of these two groups and the group of patients who did not 7.446, P = 0.024), disorganised thinking (X2 = 7.588, P = 0.023), and use tobacco or cannabis. Also, we did not find any difference between ideas of reference (X2 = 5.227, P = 0.073; B vs C: X2 = 5.213, P = 0.022). the group of cannabis only and the other three groups, although this can However, statistically significant differences disappeared for prevalence be explained by the small sample size of this group (n = 13). of hallucinations and perceptual abnormalities (data not shown). In this regard, tobacco alone does not seem to be related to an earlier Results from the multinomial regression analysis, using group B as age of onset of the first psychotic episode without concomitant use of category of reference, showed that differences previously detected be­ cannabis, as other studies have already reported (Hickling et al., 2017; tween the group B (“tobacco only”) and group A (“non cannabis or to­ Myles et al., 2012a). Furthermore, our study suggests that tobacco use bacco”), sleep disturbances (OR = 0.133–0.733) and social withdrawal also does not influence age of onset of the earliest symptom of psychosis (OR = 1.085–5.248), remained statistically significant in the model. On when compared with those who do not use. the other hand, the model exploring differences between the group B Our results confirm what has already been published, i.e. that FEP and group C (“tobacco & cannabis”) retained the variables disorganised patients use both tobacco and cannabis with greater frequency and in­ thinking (OR = 1.173–5.194) and ideas of reference (OR = tensity than the general population of the same age and sex (Grossman 1.206–12.262), along with cocaine use (OR = 3.355–33.483), male sex et al., 2017; Lally et al., 2019; Pauselli et al., 2018), with no difference in (OR = 0.132–0.608) and age at first symptom (OR = 0.830–0.956). relation to age of onset of this use. Our results for current smoking More statistical data (B, OR, and CI 95%) is presented on Table S2 of prevalence (67.3%) and lifetime use (70.8%) in our FEP sample do not Supplementary Material. reach the rates of 78% reported by Lally et al. (2019), but are higher than the rates of 58.9% and 57%, respectively, reported by two meta- 4. Discussion analyses (Gurillo et al., 2015; Myles et al., 2012b). Regarding the main objective of this study, we observed a differential 4.1. Symptom profiles in FEP patients clinical profile of the earliest symptom of psychosis in our FEP patients who used tobacco only before the development of symptoms, compared In the initial phase of the illness, almost all of our FEP patients have with the no substance use group and the cannabis and tobacco use had at least one general prodromal symptom of significant persistence, group. In comparison with patients with no tobacco or cannabis use, and more than 95% have experienced one positive symptom. Addi­ patients who used tobacco only presented sleep disturbances more tionally, about half have experienced at least some negative symptom­ frequently and negative symptoms, specifically social withdrawal, less atology from the early stages, which is striking considering that not all 23 L. González-Blanco et al. Schizophrenia Research 236 (2021) 19–28 FEP patients, including those with affective and non-affective psychosis, naturalistic and multicentre study, a large number of deeply phenotyped progress to a diagnosis of schizophrenia. sample of FEP patients from different regions in Spain were included in To our knowledge, this is the first study that explores differential this study; this sample may be considered representative of this popu­ clinical profiles of the earliest symptoms of psychosis in FEP patients lation and potentially generalisable. Furthermore, the group of healthy based on patterns of previous substance use. One of the most important controls has been matched to our study group, achieving a comparable findings of this study is that patients with FEP and a history of tobacco group in age and sex. To our knowledge, this is the first study analysing smoking had an increased prevalence of sleep disturbances as a general differences in prodromes of FEP patients based on previous substance prodromal symptom, reaching 43% in comparison with rates of less than use. In addition, although cannabis use has often been considered a 20% in non-smoking patients. Many studies have associated sleep confounding factor in previous research on tobacco and FEP, one problems with an increased risk of psychotic experience in clinical and strength of our study is the comparative analyses between a group of non-clinical populations (Davies et al., 2017; Lally et al., 2019; Pauselli patients with tobacco use only and patients with concomitant cannabis et al., 2018). These findings lead us to speculate whether sleep distur­ and tobacco use. Another strength is the use of a structured interview to bances may have played an important role in the previous findings assess first psychotic experience (first psychotic and general symptoms), relating tobacco to an increased risk of developing psychosis (Lunsford- that collects information from both patients and relatives or caregivers. Avery et al., 2017; Reeve et al., 2019). However, compared with patients who used cannabis concomitantly, 5. Conclusions FEP patients who used tobacco only showed less frequent positive symptoms, such as hallucinations, and disorganised thinking, and less In summary, in our study the use of tobacco alone was associated frequent general prodromes, such as perceptual abnormalities or ideas with a higher prevalence of specific general prodromal symptoms of of reference. Furthermore, some of the studies conducted to date have psychosis such as sleep disturbances, while tobacco plus cannabis use not found a significant relationship with clinical patterns of psychotic was associated with psychopathological thoughts as ideas of reference symptoms in tobacco smoking FEP patients (Hickling et al., 2018, 2017). and disorganised thinking. Thus, our results provide evidence against This data contrasts with the findings of other authors who have reported previous findings that relate tobacco alone to the onset of psychosis, as that the effect of tobacco on the onset of psychosis is causally related and this was only found for concomitant tobacco and cannabis users. How­ is independent of cannabis (Gurillo et al., 2015; Hunter et al., 2020; ever, despite this negative result, it is still important to monitor and McGrath et al., 2016). Nevertheless, it should be mentioned that when apply smoking prevention strategies in adolescents because cigarette use we repeated our analyses excluding patients who had used cocaine, is associated with greater subsequent initiation of other drugs such as differences in the prevalence of perceptual abnormalities and halluci­ cannabis (Tullis et al., 2003), indirectly advancing the age of onset of nations disappeared, but psychopathological thoughts (disorganised symptoms. Of note, there was a high concurrence of tobacco and thinking and ideas of reference) were maintained and were more prev­ cannabis use; in fact, nearly 75% of the cigarette smokers among our alent in patients using both substances. There were no changes when FEP patients had used cannabis. In this sense, and given the high prev­ comparing patients with and without tobacco use, as is logical for the alence of tobacco use in our FEP patients, we propose smoking cessation, few that were excluded from these groups. Identical results were ob­ not only in patients with established mental illness (Anthenelli et al., tained in the regression analysis that adjusted for cocaine use, sex, age at 2016; Garcia-Portilla et al., 2016; Sarramea et al., 2019), but from the first symptoms and socioeconomic status. early stages. Our findings also show lower prevalence of negative symptoms, such as social withdrawal, in FEP patients with tobacco use only comparing Funding with those with non-substance use, in keeping with prior research sug­ gesting that smoking is related to less severity of negative symptom­ This study received economic support from the Spanish Ministry of atology in patients with psychosis (Jiang et al., 2013; Misiak et al., Economic Affairs and Competitiveness, the Carlos III Health Care Insti­ 2015), but in contrast to other authors (Oluwoye et al., 2019; Vermeulen tute (Grant Number PI11/00325, PI14/00612), the European Regional et al., 2018). Although we cannot conclude that this is a causal effect, it Development Fund, the European Union, “Una manera de hacer Europa/ should be noted that every patient in our sample started smoking before A Way of Shaping Europe”, and CIBERSAM. onset of any general prodromal or negative symptom. Surprisingly, we found no difference in the prevalence of negative symptoms when CRediT authorship contribution statement comparing patients with no substance use with those who used tobacco plus cannabis, in contrast to Ferraro et al. (2020), who detected that Conceptualization, LGB, MPGP, and JB; methodology and formal lifetime cannabis use could be associated with less social withdrawal. analysis, LGB, MPGP; writing—original draft preparation, LGB and This study is part of a large multicentre study in patients with the MPGP; writing—review and editing, LGB, MPGP, MG, GM, MJC, EU, SA, first episode of psychosis; however, some limitations should be noted. FB, AGP, LPC, IC, EV, IB, AT, PAS, JB, MB and PEPs Group; project One of the main limitations is that the data related to the onset of sub­ coordinator: MB. All authors have read and agreed to the published stance use and the earliest symptom of psychosis were collected retro­ version of the manuscript. spectively in a structured interview with patient and family, with the possibility of potential memory bias. Instead, a prospective study would Declaration of competing interest allow us to draw conclusions about a causal relationship. Also, while the SOS inventory can identify a variety of early symptoms of psychosis, it LGB has received honoraria for lecturing and/or travel grants for does not include premorbid cognitive dysfunction that could have an attending conferences from the Spanish Foundation of Psychiatry and effect on the results obtained. On the other hand, current and prior Mental Health, European Psychiatric Association, Otsuka, Lundbeck, substance use were self-reported, and no laboratory test was used to Janssen-Cilag, Servier, Angelini and Pfizer. confirm this. Another limitation would be the lack of data on the use of MPGP has been a consultant to and/or has received honoraria/grants other drugs such as stimulants prior to the development of symptoms, from Angelini, Alianza Otsuka-Lundbeck, Instituto de Salud Carlos III, which could interfere, like cocaine use, in the results obtained in this Janssen-Cilag, Lundbeck, Otsuka, and Pfizer. study (Bramness and Rognli, 2016). Nevertheless, it should be noted that EV has received grants and served as consultant, advisor or CME we observed a low prevalence (less than 5%) in the use of stimulants at speaker for the following entities: AB-Biotics, Abbott, Allergan, Angelini, baseline assessment of patients with FEP. Dainippon Sumitomo Pharma, Galenica, Janssen, Lundbeck, Novartis, Moreover, the current study has important strengths. As a Otsuka, Sage, Sanofi-Aventis, and Takeda. 24 L. González-Blanco et al. Schizophrenia Research 236 (2021) 19–28 AGP has received grants and served as consultant, advisor or CME Alonso-Solís, Eva Grasa, Itxaso González-Ortega, Iñaki Zorrilla, Javier speaker for the following entities: Janssen-Cilag, Lundbeck, Otsuka, Santabárbara, Concepción De-la-Cámara, Eduardo Jesús Aguilar, Juan Pfizer, Sanofi-Aventis, Alter, Angelini, Exeltis, the Spanish Ministry of Nacher, Dani Bergé, Anna Mané, Laura Montejo, Gerard Anmella, Science and Innovation (CIBERSAM), the Ministry of Science (Carlos III Josefina Castro Fornieles, Elena de la Serna, Fernando Contreras, Cris­ Institute), the Basque Governement, the Stanley Medical Research tina Sáiz-Masvidal, Leticia García-Álvarez, Teresa Bobes-Bascarán, Institute. Arantzazu Zabala Rabadán, Rafael Segarra Echevarría, Luis Sanchez- PAS has been a consultant to and/or has received honoraria or grants Pastor, Roberto Rodriguez-Jimenez, Judith Usall, Anna Butjosa, Salva­ from Adamed, CIBERSAM, European Commission, GlaxoSmithKline, dor Sarró, Amalia Guerrero-Pedraza, Ángela Ibañez, María Ribeiro, Instituto de Salud Carlos III, Janssen-Cilag, Lundbeck, Otsuka, Pfizer, Vicent Balanzá-Martínez. Plan Nacional Sobre Drogas and Servier. JB has received research grants and served as consultant, advisor or Appendix A. Supplementary data speaker within de last 5 years for: AB-Biotics, Acadia Pharmaceuticals, Angelini, Casen Recordati, D&A Pharma, Exeltis, Gilead, GSK, Ferrer, Supplementary data to this article can be found online at https://doi. Indivior, Janssen-Cilag, Lundbeck, Mundipharma, Otsuka, Pfizer, org/10.1016/j.schres.2021.07.017. Reckitt-Benckiser, Roche, Sage Therapeutics, Servier, Shire, Schwabe Farma Ibérica, research funding from the Spanish Ministry of Economy References and Competiveness –Centro de Investigación Biomedica en Red area de Salud Mental (CIBERSAM) and Instituto de Salud Carlos III-, Spanish Anthenelli, R.M., Benowitz, N.L., West, R., St Aubin, L., McRae, T., Lawrence, D., Ascher, J., Russ, C., Krishen, A., Evins, A.E., 2016. Neuropsychiatric safety and Ministry of Health, Social Services and Equality - Plan Nacional sobre efficacy of varenicline, bupropion, and nicotine patch in smokers with and without Drogas- and the 7th Framework Program of the European Union. psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled MB has been a consultant for, received grant/research support and clinical trial. Lancet 387, 2507–2520. https://doi.org/10.1016/S0140-6736(16) 30272-0. honoraria from, and been on the speakers/advisory board of Adamed, Barnett, J.H., Werners, U., Secher, S.M., Hill, K.E., Brazil, R., Masson, K., Pernet, D.E., Angelini, Casen Recordati, Janssen-Cilag, Lundbeck, Otsuka, Menarini Kirkbride, J.B., Murray, G.K., Bullmore, E.T., Jones, P.B., 2007. Substance use in a and Takeda. population-based clinic sample of people with first-episode psychosis. Br. J. Psychiatry 190, 515–520. https://doi.org/10.1192/bjp.bp.106.024448. CDC received financial support to attend scientific meetings from Bell, C.C., 1994. DSM-IV: diagnostic and statistical manual of mental disorders. JAMA Janssen-Cilag, Almirall, Eli Lilly, Lundbeck, Rovi, Esteve, Novartis, and 272, 828–829. https://doi.org/10.1001/jama.1994.03520100096046. Astrazeneca. Bernardo, M., Bioque, M., Parellada, M., Saiz Ruiz, J., Cuesta, M.J., Llerena, A., Sanjuan, J., Castro-Fornieles, J., Arango, C., Cabrera, B., 2013. Assessing clinical and LGA has received honoraria from the 7th Framework Program Eu­ functional outcomes in a gene-environment interaction study in first episode of ropean Union. psychosis (PEPs). Rev. Psiquiatr. Salud Ment. 6, 4–16. https://doi.org/10.1016/j. RRJ has been a consultant for, spoken in activities of, or received rpsm.2012.11.001. grants from: Instituto de Salud Carlos III, Fondo de Investigación Sani­ Bernardo, M., Cabrera, B., Arango, C., Bioque, M., Castro-Fornieles, J., Cuesta, M.J., Lafuente, A., Parellada, M., Saiz-Ruiz, J., Vieta, E., 2019. One decade of the first taria (FIS), Centro de Investigación Biomédica en Red de Salud Mental episodes project (PEPs): advancing towards a precision psychiatry. Rev. Psiquiatr. (CIBERSAM), Madrid Regional Government (S2010/BMD-2422 AGES; Salud Ment. 12, 135–140. https://doi.org/10.1016/j.rpsm.2019.03.001. S2017/BMD-3740), JanssenCilag, Lundbeck, Otsuka, Pfizer, Ferrer, Bhavsar, V., Jauhar, S., Murray, R.M., Hotopf, M., Hatch, S.L., McNeill, A., Boydell, J., MacCabe, J.H., 2018. Tobacco smoking is associated with psychotic experiences in Juste, Takeda, Exeltis, Angelini. the general population of South London. Psychol. Med. 48, 123–131. https://doi. Other authors report no conflict of interest. org/10.1017/S0033291717001556. Bramness, J.G., Rognli, E.B., 2016. Psychosis induced by amphetamines. Curr. Opin. Psychiatry 29, 236–241. https://doi.org/10.1097/YCO.0000000000000254. Acknowledgements Clark, V., Conrad, A.M., Lewin, T.J., Baker, A.L., Halpin, S.A., Sly, K.A., Todd, J., 2018. Addiction vulnerability: exploring relationships among cigarette smoking, substance LGB, MPGP, PAS, JB thank the support of the Ministerio de Economía misuse, and early psychosis. J. Dual Diagn. 14, 78–88. https://doi.org/10.1080/ 15504263.2017.1416436. y Competitividad (PI11/00325; PI14/00612), Instituto de Salud Carlos Davies, G., Haddock, G., Yung, A.R., Mulligan, L.D., Kyle, S.D., 2017. A systematic III – Fondo Europeo de Desarrollo Regional. Unión Europea. Una manera review of the nature and correlates of sleep disturbance in early psychosis. Sleep de hacer Europa, Centro de Investigación Biomédica en Red de salud Med. Rev. 31, 25–38. https://doi.org/10.1016/j.smrv.2016.01.001. de Leon, J., Diaz, F.J., 2005. A meta-analysis of worldwide studies demonstrates an Mental (CIBERSAM), The Goverment of Principality of Asturias PCTI- association between schizophrenia and tobacco smoking behaviors. Schizophr. Res. 2018-2022 IDI/2018/235, Instituto de Investigación Biosanitaria del 76, 135–157. https://doi.org/10.1016/j.schres.2005.02.010. Principado de Asturias (ISPA) and INEUROPA. 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Assis­ tant Professor in Health Sciences (Psychiatry) at the University Myles, N., Newall, H., Compton, M.T., Curtis, J., Nielssen, O., Large, M., 2012a. The age at onset of psychosis and tobacco use: a systematic meta-analysis. Soc. Psychiatry of Oviedo and Psychiatrist at Mental Health Center of Corre­ Psychiatr. Epidemiol. 47, 1243–1250. https://doi.org/10.1007/s00127-011-0431-3. doria (Oviedo). Researcher of the Centro de Investigación Bio­ Myles, N., Newall, H.D., Curtis, J., Nielssen, O., Shiers, D., Large, M., 2012b. Tobacco use médica en Red de Salud Mental -CIBERSAM, supported by the before, at, and after first-episode psychosis: a systematic meta-analysis. J. Clin. Spanish Ministry of Economy and Competitiveness, and of the Psychiatric Research Group of the Instituto de Investigación Psychiatry 73, 468–475. https://doi.org/10.4088/JCP.11r07222. Oluwoye, O., Burduli, M.M.E., Chwastiak, L., Mcpherson, S., Mcclellan, J.M., Sanitaria del Principado de Asturias (ISPA). Collaboration in Mcdonell, M.G., 2019. In: Impact of Tobacco, Alcohol and Cannabis Use on National, European, WHO Research Projects, and linked as Co- Treatment Outcomes Among Patients Experiencing First Episode Psychosis : Investigator to 2 FIS Projects. Interested in clinical research, Data From the National RAISE-ETP Study, pp. 142–146. https://doi.org/10.1111/ focusing on schizophrenia and psychotic spectrum disorders. eip.12542. Pauselli, L., Birnbaum, M.L., Vazquez Jaime, B.P., Paolini, E., Kelley, M.E., Broussard, B., Compton, M.T., 2018. Demographic and socioenvironmental predictors of premorbid marijuana use among patients with first-episode psychosis. Schizophr. Res. 197, 544–549. https://doi.org/10.1016/j.schres.2018.01.020. María Paz García-Portilla. Dr. García-Portilla is currently Perkins, D.O., Leserman, J., Jarskog, L.F., Graham, K., Kazmer, J., Lieberman, A., 2000. Professor of Psychiatry at the University of Oviedo (Spain) and Characterizing and dating the onset of symptoms in psychotic illness: the symptom responsible for the Mental Health Center of La Eria (Oviedo) onset in schizophrenia (SOS) inventory. Schizophr. Res. 44, 1–10. with a catchment area of more than 80,000 people. I am co- Reeve, S., Sheaves, B., Freeman, D., 2019. Sleep disorders in early psychosis: incidence, principal investigator of the Group 05 (University of Oviedo) severity, and association with clinical symptoms. Schizophr. Bull. 45, 287–295. of the Centro de Investigación Biomédica en Red de Salud Mental https://doi.org/10.1093/schbul/sby129. -CIBERSAM, supported by the Spanish Ministry of Economy and Salagre, E., Arango, C., Artigas, F., Ayuso-Mateos, J.L., Bernardo, M., Castro-Fornieles, J., Competitiveness, and of the Psychiatric Research Group of the Bobes, J., Desco, M., Fananas, L., Gonzalez-Pinto, A., Haro, J.M., Leza, J.C., Instituto de Investigación Sanitaria del Principado de Asturias Mckenna, P.J., Meana, J.J., Menchon, J.M., Mico, J.A., Palomo, T., Pazos, A., (ISPA). My areas of interest are severe mental disorders, mainly Perez, V., Saiz-Ruiz, J., Sanjuan, J., Tabares-Seisdedos, R., Crespo-Facorro, B., schizophrenia and bipolar disorders, and I am co-author of Casas, M., Vilella, E., Palao, D., Olivares, J.M., Rodriguez-Jimenez, R., Vieta, E., more than 125 papers in peer-reviewed journals. 2019. CIBERSAM: ten years of collaborative translational research in mental disorders. Rev. Psiquiatr. Salud Ment. 12, 1–8. https://doi.org/10.1016/j. rpsm.2018.10.001. 26 L. González-Blanco et al. Schizophrenia Research 236 (2021) 19–28 Miguel Gutiérrez, MD, PhD is Doctor in Medicine. Professor of Laura Pina-Camacho, MD, PhD, is Consultant Psychiatrist and Psychiatry. Royal Academy of Medicine of the Basque Country. Postdoctoral Researcher at the Department of Child and Adolescent Psychiatry, Hospital General Universitario Gregorio Marañón, and Gregorio Marañon Health Research Insitute, in Madrid, Spain, and Visiting Lecturer of Child Psychiatry at Kings College London, in the UK. Over the past 15 years, she has moved from research with patients with neurodevelopmental disorders to subjects at high risk of developing these disorders (such as early preterm newborns). Her scientific activity has resulted in the publication of more than 20 scientific articles in journals of high impact factor and more than 10 book chapters. Iluminada Corripio. Dr. Corripio is a senior psychiatrist and head of the Psychotic Dis­ Gisela Mezquida, MSc, PhD. She is a research neuropsychol­ orders Research Group at Hospital de la Santa Creu i Sant Pau. Her line of research is ogist, graduated in Psychology (2007–11), Master in Neuro­ focused on new therapeutic strategies in treatment resistant schizophrenia, being coor­ science (2011− 12) and a Doctor in Medicine at the University dinator and principal investigator in the first and the second Deep Brain Stimulation of Barcelona (UB). She works at the schizophrenia group of the projects in schizophrenia respectively. She also has wide experience m-Health projects and Hospital Clínic de Barcelona (CIBERSAM/IDIBAPS/FCRB) and became part of the Innovation Committee of the Hospital de Sant Pau in 2018. Currently, is Associate professor at the medicine faculty, UB. She combines Dr. Corripio is also coordinating an integrated intervention program for patients with assistance, teaching and research focused on the study of the schizophrenia (AMA-DABLAM program) clinical, neurocognitive characteristics, biomarkers and gene- environment interactions of the first psychotic episodes and, especially, of the negative symptoms in schizophrenia. Mez­ Eduard Vieta is Professor of Psychiatry at the University of quida has a h-index of 8 and 33 publications, with more than Barcelona, head of the Department of Psychiatry and Psychol­ 200 citations. ogy at the Hospital Clinic, and Scientific Director of the Biomedical Network Research Center on Mental Health (CIBERSAM). He has been Neuroscience advisor for the Euro­ pean Union Presidency, Invited professor at Harvard Univer­ sity, and Honorary doctor by the University of Valencia. He is Elena Urbiola, MD, is Consultant Psychiatrist at Department of the most cited scientist worldwide in the field of bipolar dis­ Child and Adolescent Psychiatry, Hospital General Uni­ order and has been named one of the “world's most influential versitario Gregorio Marañón, and Gregorio Marañon Health minds”. Research Institute, in Madrid, Spain. She has produced posters and oral communications that have been exhibited at national and international conferences, in addition to book chapters and articles. Apart from her clinical experience with Autism, She is currently working in three Randomized Controlled Trials with different molecules for people with Autism Spectrum Disorders, she is part of AIMS2 Trials consortium. She is also developing a Alba Toll. Psychiatrist and Introduction on Mental Health new Randomized Controlled Trial for parenting groups for Research Master graduated from Universitat Autónoma de toddlers with autism (Incredible Years programme). Barcelona and Hospital del Mar (Barcelona, Spain). Member of executive board and investigation committee of Sociedad Española de Residentes de Psiquiatría from 2015 to 2016. Nowadays working as pre - doctoral researcher at Institut Hospital del Mar d'Investigacions Médiques (IMIM) and Silvia Amoretti. Dr. Amoretti is psychologist at the Hospital CIBERSAM. Sub - investigator and study coordinator in Clinic of Barcelona, researcher of the Barcelona Clinic Schizo­ research studies and clinical trials and skilled in first episode phrenia Unit at the IDIBAPS and at Institute of Neurosciences, psychosis, schizophrenia and neuroimaging. Author of articles and Investigator of the CIBERSAM (G04). She is teacher on the in national and international journals and symposiums in na­ Official Master Course on Initiation to Research in Mental tional and international congresses. Peer reviews in national Health and on Neuroscience of the Barcelona Univeristy. She and international journals as International Clinical has made outstanding contributions to the knowledge of Psychopharmacology. cognitive reserve with an H index of 8. Dr. Amoretti is also involved on several projects (FIS PI08/0208; PI11/00325; PI14/00612; SLT006/17/00345), all them focused on clinical and neurocognitive characterization of a sample of first epi­ Pilar A. Sáiz. Clinical Biochemistry and Psychiatrist, is Pro­ sodes of psychosis. fessor of Psychiatry at the University of Oviedo, Spain, and also member of the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), of the Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), and of the Instituto Universitario de Neurociencias del Principado de Asturias (INEUROPA). She has been involved in research of bio-psycho- social aspects of suicidal behaviour and major mental disorders for over 25 years and she is co-author of several publications ranging from biological aspects to psycho-social correlates of those disorders. 27 L. González-Blanco et al. Schizophrenia Research 236 (2021) 19–28 Julio Bobes. Professor of Psychiatry at the University of Miguel Bernardo is Professor of Psychiatry, University of Oviedo, currently heads the Psychiatry Area of the Department Barcelona. Founder and Director of the Clinic Schizophrenia of Medicine of the University and is Head of the Psychiatry Unit, (2000–2019). President of the Spanish Society of Bio­ Department of the Sanitary Area of Oviedo. He is the principal logical Psychiatry (2012–2016), and of the Spanish Foundation investigator of the Center for Biomedical Research in Mental of Psychiatry and Mental Health (2017–2018). Principal Health Network (CIBERSAM) of Oviedo. He has published more Investigator of CIBERSAM and Head of the Schizophrenia than 100 articles and is the author and coordinator of several Group of IDIBAPS. He has directed 25 doctoral theses. Author books, as well as a contributor to numerous chapters. His of more than 330 articles in scientific journals with an accu­ research interests include different aspects of the evaluation, mulated impact factor of 1090,172 (FI JCR 2018) and an H- management, treatment and impact of different psychiatric Index of 38 (WOS). He has been recognized International disorders. Distinguished Fellow by the American Psychiatric Association and Honorary Partner of several scientific societies. 28