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Impact of cognitive reserve in clinical, neurocognitive and lifestyle factors in chronic schizophrenia and early stages of schizophrenia
Silvia Amorettia,b,c,d,e,1, Gerard Anmellad,e,1, Miquel Bernardoc,
Corresponding author
bernardo@clinic.cat

Corresponding author.
, Miqueu Alfonsof, Carla Hernandezf, María Paz García-Portillag,h,i,j,k, Leticia González-Blancog,h,i,j,k, Gemma Safontl, Ignasi Garridol, Monica Sanchez-Autetf, Belén Arranzf
a Group of Psychiatry, Mental Health and Addictions, Vall d’Hebron Research Institute (VHIR), Barcelona, Catalonia, Spain
b Psychiatric Genetics Unit, Vall d’Hebron Research Institute (VHIR), Biomedical Research Networking Center for Mental Health Network (CIBERSAM), ISCIII, Barcelona, Catalonia, Spain
c Departament de Medicina, Institut de Neurociències (UBNeuro), Barcelona Clinic Schizophrenia Unit, Hospital Clínic de Barcelona, Institut de Neurociències (UBNeuro), Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Universitat de Barcelona (UB), Barcelona, Spain
d Departament de Medicina, Facultat de Medicina i Ciències de la Salut, Institute of Neurosciences (UBNeuro), Bipolar and Depressive Disorders Unit, Hospital Clinic de Barcelona, Universitat de Barcelona (UB), Barcelona, Spain
e Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
f Parc Sanitari Sant Joan de Deu, CIBERSAM, Barcelona, Spain
g Department of Psychiatry, Universidad de Oviedo, Spain
h CIBERSAM, Oviedo, Spain
i Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
j Instituto Universitario de Neurociencias del Principado de Asturias (INEUROPA), Oviedo, Spain
k Servicio de Salud del Principado de Asturias (SESPA), Oviedo, Spain
l Hospital Universitari Mútua Terrassa, CIBERSAM, Spain
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Path analyses&#58; effect of subject on cognitive domains or clinical symptoms mediated by cognitive reserve&#46; <span class="elsevierStyleItalic">B</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>unstandardized values&#59; <span class="elsevierStyleItalic">&#946;</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>standardized values&#46; &#42;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#46; Mediation was identified if the following criteria were met&#58; &#40;1&#41; the independent variable was significantly related to the dependent variable &#40;path c&#41;&#59; &#40;2&#41; the independent variable was significantly related to the proposed mediator &#40;path a&#41;&#59; &#40;3&#41; the proposed mediator was significantly related to the dependent variable when controlling for the effects of the independent variable &#40;path b&#41;&#59; &#40;4&#41; the independent variable was not significantly related to the dependent variable when controlling for the effects of the proposed mediator &#40;path c&#8217;&#41;&#46;</p>"
        ]
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">In recent years&#44; there has been a great deal of interest in the study of cognitive reserve &#40;CR&#41; in mental disorders&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">1</span></a> A higher CR level has been associated with later age of onset&#44; lower negative symptoms&#8217; severity&#44; better neurocognitive performance and better psychosocial functioning in people with a first-episode of psychosis &#40;FEP&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">2&#8211;6</span></a> schizophrenia &#40;SCZ&#41;<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">7&#44;8</span></a> and bipolar disorder&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">9&#8211;11</span></a> Thus&#44; it has been suggested that CR may be a relevant factor in improving our understanding of the heterogeneity found in persons with severe mental illness&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">CR is determined by genetic and environmental factors&#46; Some environmental factors include potentially modifiable factors such as education&#44; lifestyle and mental and physical activity&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">12</span></a> However&#44; CR differs depending on pathology<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">7</span></a> and it has been shown that in SCZ and related disorders the quantity of accumulated CR can be interfered by the disorder itself&#46; In fact&#44; a lower intelligence quotient &#40;IQ&#41;&#44; a component of CR&#44; has been associated in children with increased vulnerability to develop a psychiatric disorder&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">13</span></a> When comparing CR level&#44; it is higher in healthy controls than patients&#44; and it has been shown that CR correctly classified the samples into patient or controls in ranges between 71&#46;4 and 79&#46;8&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">2&#44;14&#44;15</span></a> Amongst patients&#44; CR is higher in affective patients compared to non-affective&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">3</span></a> This fact may be due to cognitive deficits&#44; lower premorbid IQ&#44; education-occupation level and leisure activities that have been linked to SCZ&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">15</span></a> It has been shown that unhealthy behaviours&#44; such as poor nutrition&#44; and physical inactivity&#44; could be related with lower CR<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">16</span></a> and associated with worse cognitive performance&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">17</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Although there is evidence that higher CR is a protective factor and it has been related to better prognosis&#44; to date no studies have explored the CR level and its impact according to the stage of the disease&#58; ESP or chronic SCZ&#46; There is controversy in the literature about the stability of intelligence in SCZ&#46; While in a study that compared current and premorbid IQ showed that approximately 70&#37; of schizophrenia patients showed deterioration of IQ&#44;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">18</span></a> another study did not find significant changes in IQ&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">19</span></a> With the chronicity of the disease&#44; other aspects that are part of the CR concept&#44; such as social&#44; intellectual and leisure activities may also be affected&#46; Identifying clinical&#44; functional and neurocognitive phenotypes according to the estimated level of CR might provide relevant information that may allow us to define early personalized intervention and person-focused therapy&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">This study aims at identifying potential unfolding differences of the psychotic illness by comparing the impact of CR on neurocognitive performance&#44; psychosocial functioning and clinical outcomes in patients in the ESP and SCZ patients&#46; We also analyzed whether a healthy lifestyle &#40;diet factors and lifestyle habits&#41;&#44; intestinal permeability and anthropometric measurements were associated with CR and whether CR moderates the effects of unhealthy lifestyle on clinical&#44; functional and cognitive outcomes&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Material and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Sample</span><p id="par0025" class="elsevierStylePara elsevierViewall">The sample of this study came from an observational&#44; cross-sectional and multisite study including four centres in Spain &#40;PI17&#47;00246&#41;&#46; Rationale&#44; objective and protocol have been previously described&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">20</span></a> A total of 553 adult patients with DSM-5 schizophrenia spectrum disorder at any stage of the disease were included&#46; For the current study we only included patients who had a score of Cognitive Reserve Assessment Scale in Health &#40;CRASH&#41; scale&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">14</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The inclusion criteria were&#58; &#40;1&#41; adults over 18 years of age&#59; &#40;2&#41; ability to speak Spanish correctly and &#40;3&#41; signed informed consent&#46; Exclusion criteria were&#58; &#40;1&#41; history of head trauma with loss of consciousness and &#40;2&#41; organic disease with mental repercussions&#59; &#40;3&#41; presence of an acute inflammatory process&#58; &#40;3&#46;1&#41; fever &#40;&#62;38<span class="elsevierStyleHsp" style=""></span>&#176;C&#41; or infection in the two weeks prior to the baseline interview&#44; or &#40;3&#46;2&#41; have received vaccinations in the past 4 weeks&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Patients were divided into&#58; &#40;1&#41; ESP group&#58; those patients who had experienced their FEP over the previous 5 years&#59; &#40;2&#41; patients with SCZ&#58; those who had experienced their FEP more than 5 years ago and had a diagnosis of schizophrenia&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">This study was conducted in accordance with the ethical principles of the Declaration of Helsinki and Good Clinical Practice and the Hospital Clinic Ethics and Research Board&#46; All participants provided written informed consent prior to their inclusion in the study&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Assessment</span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Sociodemographic assessment</span><p id="par0045" class="elsevierStylePara elsevierViewall">Including age&#44; gender&#44; drug misuse habits&#44; years of illness duration&#44; first-degree relative with schizophrenia and diagnoses&#46; Diagnostic was determined according to the diagnostic criteria of DSM-5 &#40;Diagnostic and Statistical Manual of Mental Disorders&#41; &#40;American Psychiatric Association&#44; 2013&#41;&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Anthropometric assessment</span><p id="par0050" class="elsevierStylePara elsevierViewall">Anthropometric measurements included weight&#44; height&#44; body mass index &#40;BMI&#41;&#44; body circumference and blood pressure&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Intestinal permeability&#44; diet&#44; and physical exercise assessment</span><p id="par0055" class="elsevierStylePara elsevierViewall">Lifestyle habits were assessed with the Mediterranean Diet Adherence Screener &#40;MEDAS&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">21&#44;22</span></a> and the Short Scale of Physical Activity &#40;IPAQ&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">23</span></a> MEDAS is a validated questionnaire of Mediterranean diet adherence consisting of 14-items&#44; used in the Prevenci&#243;n con Dieta Mediterr&#225;nea &#40;PREDIMED&#41; study&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">24</span></a> MEDAS score was calculated by assigning a score of 1 and 0 for each item&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">IPAQ &#8220;activity&#8221; assesses specific types of activity such as walking&#44; moderate-intensity activities and vigorous intensity activities&#46; Frequency &#40;measured in days per week&#41; and duration &#40;time per day&#41; are collected separately for each specific type of activity&#46; IPAQ &#8220;sitting&#8221; &#40;sedentary&#41;&#44; assesses time spent sitting&#46; Continuous score IPAQ results are expressed as MET-min per week and calculated by multiplying the MET assigned to it &#40;vigorous &#8211; 8 MET&#44; moderate &#8211; 4 MET and walking &#8211; 3&#46;3 MET&#41; by the number of days it was performed during a week&#44; where MET corresponds to O<span class="elsevierStyleInf">2</span> consumption during the rest and equals 3&#46;5<span class="elsevierStyleHsp" style=""></span>mL O<span class="elsevierStyleInf">2</span>&#47;kg of the body mass per minute&#46; Finally&#44; intestinal permeability was assessed using the permeable-intestine-syndrome questionnaire&#44; consisting of 19 items&#44; using 4-point Likert scale ranging from 0 &#8220;never&#8221; to 3 &#8220;everyday&#8221;&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Clinical and functional assessment</span><p id="par0065" class="elsevierStylePara elsevierViewall">A psychopathological assessment was carried out with the Spanish version of the Positive and Negative Syndrome Scale &#40;PANSS&#41;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">25</span></a> and the Clinical Global Impression Scale &#40;CGI-S&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">26</span></a> Higher scores indicate greater severity&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">The functioning level was assessed by Global Assessment of Functioning &#40;GAF&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">27</span></a> It is a scale used to assess the severity of symptoms and the level of functioning&#44; on a numeric scale from 1 to 100&#46; Higher scores indicate better functioning&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Neuropsychological assessment</span><p id="par0075" class="elsevierStylePara elsevierViewall">To assess cognitive impairment the Spanish version of the Screen for Cognitive Impairment in Psychiatry &#40;SCIP-S&#41; has been administered&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">28</span></a> It has five subtests for evaluating immediate &#40;VLT-I&#41; and delayed verbal learning &#40;VLT-D&#41;&#44; working memory &#40;WMT&#41;&#44; verbal fluency &#40;VFT&#41;&#44; and processing speed &#40;PST&#41;&#46; The range score goes from 0 to 30 in VLT-I&#44; 0&#8211;24 in WMT&#44; &#8805;0 in VFT&#44; 0&#8211;10 in VLT-D and 0&#8211;30 in PST&#46; A total score is calculated from the sum of the subscale scores&#46; In all neurocognitive domains higher scores correspond to better performance&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Cognitive reserve assessment</span><p id="par0080" class="elsevierStylePara elsevierViewall">To assess CR&#44; the Cognitive Reserve Assessment Scale in Health &#40;CRASH&#41; was used&#46; It has showed optimal psychometric properties and it has been demonstrated to be a valid tool to assess CR&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">14</span></a> The scale&#39;s maximum total score is 90&#46; Higher score in this scale indicates greater CR&#46;</p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Statistical analysis</span><p id="par0085" class="elsevierStylePara elsevierViewall">Descriptive analyses were conducted using Student&#39;s <span class="elsevierStyleItalic">t</span>-test for continuous variables and chi-square for categorical variables&#46; To test the predictive capacity of CRASH for each diagnostic group&#44; a logistic regression analysis was conducted&#46; Pearson bivariate correlations were performed to identify continuous variables significantly correlated with cognitive reserve &#40;measured by CRASH&#41; and Student&#39;s <span class="elsevierStyleItalic">t</span>-test for categorical variables&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Hierarchical linear regression analyses were performed to explore the associations between CR and neurocognitive performance&#44; negative symptoms and functioning&#46; The five neurocognitive subtests&#44; PANSS negative and GAF scores were introduced as the dependent variables in each model&#46; We introduced independent variables based on data obtained in previous studies&#44; including current age&#44; cannabis use&#44; and sex&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">The mediation analyses were performed according to the principles of Baron and Kenny&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">29</span></a> In the first instance&#44; the independent variable &#40;lifestyle&#41; was significantly related to the dependent variable &#40;clinical&#44; functional and cognitive outcomes&#41; &#40;path c&#41;&#46; In the second equation&#44; the independent variable &#40;lifestyle&#41; was significantly related to the proposed mediator &#40;cognitive reserve&#41; &#40;path a&#41;&#46; Finally&#44; in the third equation&#44; the dependent &#40;clinical&#44; functional and cognitive outcomes&#41; was regressed onto the independent variable &#40;lifestyle&#41;&#44; adjusted for the mediator &#40;cognitive reserve&#41; &#40;see <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Hence&#44; if the independent variable is no longer significant when the mediator is controlled&#44; the finding supports full mediation&#46; If the independent variable is still significant&#44; the finding supports partial mediation&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">Statistical Package for the Social Sciences &#40;SPSS v26&#41; was used to analyze data&#46; All statistical tests were carried out two-tailed&#44; with an alpha level of significance set at <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#46;</p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Results</span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Differences in sociodemographic&#44; clinical&#44; functional and neurocognitive characteristics for schizophrenia and first-episode psychosis patients</span><p id="par0105" class="elsevierStylePara elsevierViewall">A total of 60 patients in the ESP and 225 patients with chronic SCZ were enrolled in the study&#46; A summary of the sociodemographic and clinical characteristics is shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; There were no differences between ESP and SCZ groups in terms of gender&#44; having a first-degree relative with SCZ&#44; treatment setting &#40;outpatient&#47;inpatient&#41;&#44; tobacco use and working memory performance&#46; Patients with SCZ were older &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; with lower cannabis and alcohol use &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001 and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;002&#44; respectively&#41;&#44; higher positive &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;007&#41; and negative &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; psychotic symptoms&#44; higher severity of illness &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;010&#41; and worse functioning &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; They also presented higher BMI &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; and body circumference &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; Regarding neurocognitive performance&#44; SCZ patients performed worse than patients in the ESP in verbal memory &#40;immediate and delayed&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001 and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;003&#41;&#44; verbal fluency &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; processing speed &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; and global cognitive performance &#40;total SCIP-S&#41; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; Patients with SCZ also showed lower CRASH scores than patients in the ESP &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; &#40;see <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; In fact&#44; lower CRASH was also associated with longer illness duration &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;335&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; Although higher age was associated with lower cognitive reserve &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;269&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; these differences remain significant after adjustment for age &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; After performing a logistic regression to assess the predictive power of CRASH for each group &#40;ESP&#47;SCZ&#41;&#44; the model explained between 11&#46;2&#37; &#40;Cox &#38; Snell R Square&#41; and 17&#46;5&#37; &#40;Nagelkerke R Square&#41; of the variance and correctly classified 79&#46;6&#37; of the cases &#40;<span class="elsevierStyleItalic">B</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;061&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#59; Exp&#40;<span class="elsevierStyleItalic">B</span>&#41;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;062&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0110" class="elsevierStylePara elsevierViewall">There were no differences between those patients who reported cannabis use and those who did not in terms of CR &#40;<span class="elsevierStyleItalic">t</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;1&#46;626&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;105&#41; or neurocognitive performance &#40;immediate verbal learning&#44; <span class="elsevierStyleItalic">t</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;213&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;832&#59; delayed verbal learning&#44; <span class="elsevierStyleItalic">t</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;543&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;588&#59; working memory&#44; <span class="elsevierStyleItalic">t</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;139&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;889&#59; verbal fluency&#44; <span class="elsevierStyleItalic">t</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;550&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;583&#59; processing speed&#44; <span class="elsevierStyleItalic">t</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;1&#46;188&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;236&#41;&#46; There were also no differences when patients in the ESP and SCZ were analyzed separately&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Predictive capacity of cognitive reserve on neurocognitive&#44; clinical and functional outcomes according to the stage of the disease &#40;ESP vs&#46; schizophrenia&#41;</span><p id="par0115" class="elsevierStylePara elsevierViewall">In patients in the ESP&#44; CR did not predict any neurocognitive domain&#46; Nevertheless&#44; a correlation was observed between higher CR and working memory &#40;<span class="elsevierStyleItalic">t</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;248&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;030&#41;&#46; CR &#40;<span class="elsevierStyleItalic">t</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#46;925&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; and cannabis use &#40;<span class="elsevierStyleItalic">t</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;023&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;048&#41; explained 26&#46;7&#37; of the variance on functioning &#40;<span class="elsevierStyleItalic">F</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>4&#46;650&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;003&#41;&#46; Although CR was related with negative psychotic symptoms &#40;<span class="elsevierStyleItalic">t</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;2&#46;300&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;027&#41;&#44; the model was not significant &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;115&#41;&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">In patients with SCZ&#44; CR explained 18&#46;2&#37; of the variance on immediate verbal learning &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; and 10&#46;1&#37; of working memory &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; Higher CR and lower age were significant predictors of delayed verbal learning performance &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;180&#44; <span class="elsevierStyleItalic">F</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>9&#46;026&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; verbal fluency &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;173&#44; <span class="elsevierStyleItalic">F</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#46;653&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; and processing speed &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;387&#44; <span class="elsevierStyleItalic">F</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>26&#46;010&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; Higher CR&#44; lower age and lower cannabis use predicted SCIP-S total score &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;324&#44; <span class="elsevierStyleItalic">F</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>19&#46;779&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; Finally&#44; higher CR predicted lower negative psychotic symptoms severity &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;091&#44; <span class="elsevierStyleItalic">F</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>4&#46;754&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; and better functioning &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;074&#44; <span class="elsevierStyleItalic">F</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#46;789&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;005&#41;&#46; A summary of the predictive capacity of cognitive reserve is shown in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0125" class="elsevierStylePara elsevierViewall">All results are maintained after controlling for clozapine use&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Cognitive reserve&#44; lifestyle habits and anthropometric measurements</span><p id="par0130" class="elsevierStylePara elsevierViewall">As already mentioned&#44; SCZ and patients in the ESP did not show differences in healthy lifestyle&#44; however SCZ patients had higher BMI &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; and body circumference &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; In patients in the ESP&#44; higher CR was associated with higher adherence to Mediterranean diet &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;386&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;003&#41;&#44; lower weight &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;289&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;029&#41;&#44; lower BMI &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;267&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;046&#41;&#44; and lower body circumference &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;407&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;003&#41; &#40;see <a class="elsevierStyleCrossRef" href="#sec0105">Supplementary Table 1</a>&#41;&#46; Regarding the mediation analysis&#44; intestinal permeability and physical activity were not related to CR&#44; and thus mediation analysis could not be carried out&#46; The effect of adherence to Mediterranean diet on functioning &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;037&#41; was mediated by CR level &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;003&#41; &#40;see <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; That is&#44; the independent variable &#40;diet&#41; was no longer significant &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;428&#41; when the mediator &#40;CR&#41; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;002&#41; was controlled&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0135" class="elsevierStylePara elsevierViewall">In patients with SCZ&#44; higher CR was associated with lower BMI &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;156&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;023&#41;&#44; and lower body circumference &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;141&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;048&#41;&#46; No relationship has been found between CR levels and substance use&#46; Intestinal permeability and physical activity were related to functioning but CR was not related to them&#44; and thus mediation analysis could not be carried out&#46;</p></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Discussion</span><p id="par0140" class="elsevierStylePara elsevierViewall">The most important finding of the study is that the patients in the ESP showed higher CR than patients with SCZ&#44; so that CR depends on the stage of the disease&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Patients in the ESP were younger&#44; with higher cannabis and alcohol use&#44; lower psychotic symptoms&#8217; severity and better functioning&#46; Previous literature&#44; but not our study&#44; has shown that patients in the ESP presented more positive symptoms but fewer negative symptoms&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">30</span></a> It is possible that the patients who entered in the study were more stable as most were recruited in outpatient setting&#46; Moreover&#44; not having found differences in negative symptoms may be due to the fact that primary negative symptoms are inherent to the disease process itself and they tend to be stable and persistent&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">31</span></a> Compared with patients in the ESP&#44; chronic SCZ patients performed worse in all cognitive domains except for working memory&#44; suggesting that these impairments might result from the burden of disease&#44; associated with the chronicity of the illness&#46; A recent review suggests that longitudinal studies with more than 10 years of follow-up support mild cognitive declines after psychosis onset until late adulthood&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">32</span></a> Our results are also in accordance with previous studies in which the working memory was not significantly different between patients in the ESP and chronic SCZ&#44; suggesting stability of the deficits over time&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">33</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Regarding CR&#44; it was higher in patients in the ESP&#46; We found that the CRASH scale correctly classified the sample into ESP or chronic SCZ &#40;79&#46;6&#37;&#41;&#46; The onset of psychosis supposes an interruption in life development at early stages that is closely related to the later functional outcomes&#46; Our results suggest that some determinants of CR such as intellectual and leisure activities &#40;physical&#44; intellectual&#44; artistic&#44; and cultural&#41; including sociability and withdrawal &#40;type and quantity of relationships&#41; may be more impaired in chronic patients&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">In accordance with previous literature&#44; we found that patients in the ESP who have a high CR presented fewer negative symptoms&#44; greater functioning and better working memory performance&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">2&#44;15</span></a> However&#44; other neurocognitive domains such as verbal memory have not been associated with CR&#46; This may be due to the fact that the neuropsychological assessment was performed using a screening scale&#44; whereas in the other articles a neuropsychological battery was used&#46; Other cognitive domains that have been found to be associated with CR&#44; such as attention and executive functioning&#44; were not collected in the present study&#46; In patients with SCZ&#44; CR predicted all cognitive domains&#44; negative symptoms and functioning&#46; Taking into account that patients in the ESP had lower structural and functional alterations than chronic SCZ patients&#44;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">34</span></a> and that CR refers to the brain&#39;s capacity to face a pathology using alternative&#44; or more efficient&#44; cerebral networks in order to minimize symptoms&#44;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">35</span></a> the effect is therefore expected to be greater in patients with SCZ&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Finally&#44; in terms of healthy lifestyle and anthropometric measurements&#44; patients with SCZ presented higher BMI and body circumference&#46; However&#44; they did not show differences in healthy lifestyle factors &#40;diet&#44; physical activity&#41; or reported intestinal permeability&#46; In both ESP and chronic SCZ groups&#44; higher CR was associated with lower BMI&#46; CR is associated with negative psychotic symptoms&#44;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">2&#44;3</span></a> and it has been demonstrated that lower negative symptoms were associated with higher BMI&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">36</span></a> Thus&#44; it seems that there is a complex relationship between CR&#44; negative symptoms and BMI&#46; In patients in the ESP&#44; higher CR was also associated with higher adherence to Mediterranean diet&#44; and the mediation analysis revealed that the effect of adherence to diet on functioning was mediated by the CR level&#46; Crichton et al&#46; found that in an Australian sample of middle-aged Mediterranean diet was not related to cognitive function&#44; but was positively associated with physical function and general health&#44; and negatively associated with trait anxiety&#44; depression and perceived stress&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">37</span></a> Our result suggests that CR should be taken into account to explore this relationship more accurately&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Notwithstanding&#44; some limitations should be considered&#46; Firstly&#44; to assess cognitive impairment&#44; the Screen for Cognitive Impairment in Psychiatry &#40;SCIP-S&#41; has been administered&#46; To evaluate patients in the ESP&#44; a comprehensive neuropsychological test could be more useful determining the severity of a person&#39;s cognitive difficulties and their functional limitations&#46; In addition&#44; the SCIP-S does not include key domains such as executive functions or attention&#46; Secondly&#44; although GAF is one of the of the most widely used scale in clinical and research practice&#44; it seems to reflect symptom severity whereas other scales such as the Functional Assessment Short Test &#40;FAST&#41;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">38</span></a> are designed to assess the main functioning problems experienced by psychiatric patients<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">39</span></a> and might better reflect the difficulties in daily functioning &#40;autonomy&#44; occupational functioning&#44; cognitive functioning&#44; financial issues&#44; interpersonal relationships&#44; and leisure time&#41;&#46; Thirdly&#44; in this study the diagnosis of the FEP group was not recorded&#46; Fourthly&#44; it is not a longitudinal study&#46; However&#44; this is a naturalistic and multicenter study which includes a large sample of patients with high heterogeneity corresponding to the usually treated population&#44; in which variables of high interest have been collected for the study of intestinal endothelial permeability as a cause of chronic low-grade inflammation in patients with SCZ&#44; and its relationship with diet&#44; metabolic syndrome&#44; disease severity and functionality&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">In conclusion&#44; the implications of CR depend on the stage of the disease&#44; with a greater effect on neurocognition and negative symptoms in patients with SCZ&#46; The results obtained suggest that CR can be used as a reliable indicator for the prognosis&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Authors&#8217; contributions</span><p id="par0175" class="elsevierStylePara elsevierViewall">BA and GS designed the project&#46; BA&#44; GS&#44; MB&#44; and MPGP coordinated the project development&#46; SA and GA drafted the manuscript&#46; SA&#44; GA&#44; GS&#44; MA&#44; CH&#44; MSA&#44; FPB&#44; LGB&#44; MPGP&#44; and BA participated in the recruitment&#46; SA performed the statistical analyses&#46; All authors reviewed and approved the final version of the manuscript&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Funding</span><p id="par0180" class="elsevierStylePara elsevierViewall">This study was supported by a grant from the <span class="elsevierStyleGrantSponsor" id="gs1">Instituto de Salud Carlos III-Fondos Europeos de Desarrollo Regional &#40;FEDER&#41;</span> &#40;grant number <span class="elsevierStyleGrantNumber" refid="gs1">PI17&#47;00246</span>&#41; and by the programme &#8220;<span class="elsevierStyleGrantSponsor" id="gs2">Ajuts per donar suport a l&#8217;activitat cient&#237;fica dels grups de recerca de Catalunya</span> &#40;<span class="elsevierStyleGrantNumber" refid="gs2">SGR-Cat 2021</span>&#41;&#8221;&#44; <span class="elsevierStyleGrantSponsor" id="gs3">Ag&#232;ncia de Gesti&#243; d&#8217;Ajuts Universitaris i de Recerca &#40;AGAUR&#41;</span> &#40;grant 2021 <span class="elsevierStyleGrantNumber" refid="gs3">SGR 01380</span>&#41;&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Conflicts of interest</span><p id="par0185" class="elsevierStylePara elsevierViewall">Gerard Anmella has received CME-related honoraria&#44; or consulting fees from Janssen-Cilag&#44; Lundbeck&#44; Lundbeck&#47;Otsuka&#44; and Angelini&#44; with no financial or other relationship relevant to the subject of this article&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">Silvia Amoretti has been a consultant to and&#47;or has received honoraria&#47;grants from Otsuka-Lundbeck&#44; with no financial or other relationship relevant to the subject of this article&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">Maria Paz Garcia-Portilla has been a consultant to and&#47;or has received honoraria&#47;grants from Adamed&#44; Angelini&#44; Casen Recordati&#44; Alianza Otsuka-Lundbeck&#44; Janssen-Cilag&#44; Lundbeck&#44; Otsuka&#44; and SAGE Therapeutics&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">Leticia Gonzalez-Blanco has received honoraria for lecturing&#44; research and&#47;or travel grants for attending conferences from the Spanish Foundation of Psychiatry and Mental Health&#44; Instituto de Salud Carlos III&#44; Otsuka-Lundbeck&#44; Janssen-Cilag&#44; Angelini&#44; Casen Recordati and Pfizer&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">Miquel Bernardo has been a consultant for&#44; received grant&#47;research support and honoraria from&#44; and been on the speakers&#47;advisory board of ABBiotics&#44; Adamed&#44; Angelini&#44; Casen Recordati&#44; Janssen-Cilag&#44; Menarini&#44; Rovi and Takeda&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">Belen Arranz has been a consultant&#47;has received honoraria or grants from Adamed&#44; Janssen-Cilag&#44; Lundbeck&#44; Otsuka and Takeda&#44; with no conflict of interest related to this manuscript&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">All other authors report no financial or other relationship relevant to the subject of this article&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Although there is evidence that higher cognitive reserve &#40;CR&#41; is a protective factor and it has been related to better prognosis&#44; there have been no studies to date that have explored the CR level and its impact in clinical&#44; neurocognitive and lifestyle outcomes according to the stage of the disease&#58; early stage of psychosis &#40;ESP&#41; or chronic schizophrenia &#40;SCZ&#41;&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Material and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A total of 60 patients in the ESP and 225 patients with SCZ were enrolled in the study&#46; To test the predictive capacity of CR for each diagnostic group&#44; a logistic regression analysis was conducted&#46; Hierarchical linear regression analyses were performed to explore the associations between CR and different outcomes&#46; The mediation analyses were performed according to the principles of Baron and Kenny&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Patients with SCZ showed lower CR than those in the ESP &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; CR correctly classified 79&#46;6&#37; of the cases &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#59; Exp&#40;<span class="elsevierStyleItalic">B</span>&#41;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;062&#41;&#46; In ESP group&#44; CR was related to working memory &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;030&#41; and negative symptoms &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;027&#41;&#46; CR &#40;<span class="elsevierStyleItalic">t</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#46;925&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; and cannabis use &#40;<span class="elsevierStyleItalic">t</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;023&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;048&#41; explained 26&#46;7&#37; of the variance on functioning &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;003&#41;&#46; In patients with SCZ&#44; CR predicted all cognitive domains&#44; negative symptoms &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;091&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; and functioning &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;074&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;005&#41;&#46; In both ESP and SCZ groups&#44; higher CR was associated with lower body mass index and circumference&#46; In ESP group&#44; the effect of adherence to Mediterranean diet on functioning &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;037&#41; was mediated by CR level &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;003&#41;&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The implications of CR depend on the stage of the disease &#40;ESP vs&#46; SCZ&#41;&#44; with a greater effect on neurocognition and negative symptoms in patients with chronic SCZ&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Introduction"
          ]
          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Material and methods"
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            "identificador" => "abst0015"
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            "identificador" => "abst0020"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">These authors should be considered joint first author&#46;</p>"
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          0 => array:4 [
            "apendice" => "<p id="par0250" class="elsevierStylePara elsevierViewall">The following are the supplementary data to this article&#58;<elsevierMultimedia ident="upi0005"></elsevierMultimedia></p>"
            "etiqueta" => "Appendix A"
            "titulo" => "Supplementary data"
            "identificador" => "sec0105"
          ]
        ]
      ]
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        "identificador" => "fig0005"
        "etiqueta" => "Fig&#46; 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Path analyses&#58; effect of subject on cognitive domains or clinical symptoms mediated by cognitive reserve&#46; <span class="elsevierStyleItalic">B</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>unstandardized values&#59; <span class="elsevierStyleItalic">&#946;</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>standardized values&#46; &#42;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#46; Mediation was identified if the following criteria were met&#58; &#40;1&#41; the independent variable was significantly related to the dependent variable &#40;path c&#41;&#59; &#40;2&#41; the independent variable was significantly related to the proposed mediator &#40;path a&#41;&#59; &#40;3&#41; the proposed mediator was significantly related to the dependent variable when controlling for the effects of the independent variable &#40;path b&#41;&#59; &#40;4&#41; the independent variable was not significantly related to the dependent variable when controlling for the effects of the proposed mediator &#40;path c&#8217;&#41;&#46;</p>"
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      1 => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Fig&#46; 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Box plot showing differences in CRASH score between patients in early stages of schizophrenia and chronic schizophrenia&#46;</p>"
        ]
      ]
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        "tipo" => "MULTIMEDIATABLA"
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          "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">CGI&#58; Clinical Global Impression Scale&#59; CRASH&#58; Cognitive Reserve Assessment Scale in Health&#59; GAF&#58; Global Assessment of Functioning&#59; IPAQ&#58; Short Scale of Physical Activity&#59; M&#58; mean&#59; MEDAS&#58; Mediterranean Diet Adherence Screener&#59; PANSS&#58; Positive and Negative Symptom Scale&#46; Significant differences &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; marked in bold&#46;</p>"
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                  \t\t\t\t">&#91;14&#46;66&#44; 20&#46;01&#93;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Sex&#58; Females <span class="elsevierStyleItalic">N</span> &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">89 &#40;40&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">24 &#40;40&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;004&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;532&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>First-degree relative with schizophrenia&#58; Yes <span class="elsevierStyleItalic">N</span> &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">16&#46;583&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleBold">&#60;0&#46;001</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#91;12&#46;65&#44; 16&#46;07&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Tobacco use&#58; Yes <span class="elsevierStyleItalic">N</span> &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">98 &#40;45&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">32 &#40;55&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;762&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;119&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;482 &#91;0&#46;827&#44; 2&#46;654&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Cannabis use&#58; Yes <span class="elsevierStyleItalic">N</span> &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14 &#40;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13 &#40;22&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11&#46;815&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">0&#46;001</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;921 &#91;1&#46;724&#44; 8&#46;918&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Alcohol use&#58; Yes <span class="elsevierStyleItalic">N</span> &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">38 &#40;19&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">22 &#40;38&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&#46;531&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">0&#46;002</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;670 &#91;1&#46;412&#44; 5&#46;047&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Anthropometric assessment &#40;M</span><span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">SD&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Weight &#40;kg&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">82&#46;35<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>19&#46;16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">72&#46;90<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>14&#46;93&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;986&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">&#60;0&#46;001</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#91;4&#46;76&#44; 14&#46;16&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Height &#40;m&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;69<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;70<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;09&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;0&#46;366&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;714&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#91;&#8722;0&#46;03&#44; 0&#46;02&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Body mass index &#40;kg&#47;m<span class="elsevierStyleSup">2</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">28&#46;82<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>6&#46;21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">25&#46;30<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5&#46;23&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;302&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">&#60;0&#46;001</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#91;1&#46;90&#44; 5&#46;15&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Body circumference &#40;cm&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">101&#46;28<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>16&#46;90&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">89&#46;61<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>11&#46;96&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;623&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">&#60;0&#46;001</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#91;7&#46;55&#44; 15&#46;78&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Intestinal permeability &#40;M</span><span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">SD&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>MEDAS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#46;79<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#46;59<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;604&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;546&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#91;&#8722;0&#46;44&#44; 0&#46;83&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Intestinal permeability&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;44<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;51&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;02<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;147&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;252&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#91;&#8722;0&#46;30&#44; 1&#46;14&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>IPAQ activity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1996&#46;07<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2320&#46;59&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2210&#46;15<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2950&#46;84&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Neurocognitive variables and cognitive reserve &#40;M</span><span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">SD&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Delayed verbal learning&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Working memory&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#8722;2&#46;071&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleBold">0&#46;045</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;253&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">2&#46;023&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleBold">0&#46;048</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="28" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Goodness of fit of the model</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="center" valign="middle">0&#46;035</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="center" valign="middle">0&#46;103</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="center" valign="middle">0&#46;176</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="center" valign="middle">0&#46;037</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="center" valign="middle">0&#46;153</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="center" valign="middle">0&#46;140</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="center" valign="middle">0&#46;034</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="center" valign="middle">0&#46;162</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">F</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="center" valign="middle">0&#46;367</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="center" valign="middle">1&#46;182</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="center" valign="middle">2&#46;184</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="center" valign="middle">0&#46;398</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="center" valign="middle">1&#46;846</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="center" valign="middle">1&#46;708</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="center" valign="middle">2&#46;286</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="center" valign="middle">1&#46;984</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="center" valign="middle">4&#46;650</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">p</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="center" valign="middle">0&#46;831</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="center" valign="middle">0&#46;333</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="center" valign="middle">0&#46;088</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="center" valign="middle">0&#46;809</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="center" valign="middle">0&#46;138</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="center" valign="middle">0&#46;166</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="center" valign="middle">0&#46;080</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="center" valign="middle">0&#46;115</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="center" valign="middle"><span class="elsevierStyleBold">0&#46;003</span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="28" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="28" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Chronic schizophrenia</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Goodness of fit of the model</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
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        "texto" => "<p id="par0220" class="elsevierStylePara elsevierViewall">We are extremely grateful to all participants&#46;</p><p id="par0225" class="elsevierStylePara elsevierViewall">We would also like to thank the Carlos III Healthcare Institute&#44; the Spanish Ministry of Science&#44; Innovation and Universities&#44; the European Regional Development Fund &#40;ERDF&#47;FEDER&#41; &#40;PI17&#47;00246&#41;&#44; CIBERSAM&#59; and the Government of the Principality of Asturias PCTI-2021-2023 IDI&#47;2021&#47;111&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">Silvia Amoretti has been supported by Sara Borrell doctoral programme &#40;CD20&#47;00177&#41; and M-AES mobility fellowship &#40;MV22&#47;00002&#41;&#44; from the Instituto de Salud Carlos III &#40;ISCIII&#41;&#44; and co-funded by European Social Fund &#8220;Investing in your future&#8221;&#46; This work was supported by La Marat&#243;-TV3 Foundation grants 202234-32 &#40;to SA&#41; and 202205-10 &#40;to MB&#41;&#46;</p><p id="par0235" class="elsevierStylePara elsevierViewall">Gerard Anmella is supported by a Rio Hortega 2021 grant &#40;CM21&#47;00017&#41; and M-AES mobility fellowship &#40;MV22&#47;00058&#41;&#44; from the Spanish Ministry of Health financed by the Instituto de Salud Carlos III &#40;ISCIII&#41; and co-financed by the Fondo Social Europeo Plus &#40;FSE&#43;&#41;&#46;</p><p id="par0240" class="elsevierStylePara elsevierViewall">Miquel Bernardo thanks the support of the Spanish Ministry of Science&#44; Innovation and Universities &#40;PI08&#47;0208&#59; PI11&#47;00325&#59; PI14&#47;00612&#41; integrated into the Plan Nacional de I&#43;D&#43;I y cofinanciado por el ISCIII-Subdirecci&#243;n General de Evaluaci&#243;n y el Fondo Eurpeo del Desarrollo Regional &#40;FEDER&#41;&#46; Uni&#243;n Europea&#46; Una manera de hacer Europa&#44; Centro de Investigaci&#243;n Biom&#233;dica en Red de salud Mental&#44; CIBERSAM&#44; by the CERCA Programme&#47;Generalitat de Catalunya AND Secretaria d&#8217;Universitats i Recerca del Departament d&#8217;Economia I Coneixement &#40;2017SGR1355&#41;&#46; Departament de Salut de la Generalitat de Catalunya&#44; en la convocatoria corresponent a l&#8217;any 2017 de concessi&#243; de subvencions del Pla Estrat&#232;gic de Recerca i Innovaci&#243; en Salut &#40;PERIS&#41; 2016-2020&#44; modalitat Projectes de recerca orientats a l&#8217;atenci&#243; prim&#224;ria&#44; amb el codi d&#8217;expedient SLT006&#47;17&#47;00345&#46; MB is also grateful for the support of the Institut de Neuroci&#232;ncies&#44; Universitat de Barcelona&#46;</p>"
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