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array:23 [ "pii" => "S0213616324000089" "issn" => "02136163" "doi" => "10.1016/j.ejpsy.2024.100258" "estado" => "S300" "fechaPublicacion" => "2024-10-01" "aid" => "100258" "copyright" => "Sociedad Española de Psiquiatría y Salud Mental" "copyrightAnyo" => "2024" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Eur J Psychiatry. 2024;38:" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "itemSiguiente" => array:18 [ "pii" => "S0213616324000120" "issn" => "02136163" "doi" => "10.1016/j.ejpsy.2024.100262" "estado" => "S300" "fechaPublicacion" => "2024-10-01" "aid" => "100262" "copyright" => "Sociedad Española de Psiquiatría y Salud Mental" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Eur J Psychiatry. 2024;38:" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:11 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>" "titulo" => "Psychopathological and cardiometabolic efficacy of a nutritional education intervention based on symbiotics in schizophrenia spectrum disorders. Two-arm Randomised Clinical Trial" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => "en" "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0002" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2811 "Ancho" => 2667 "Tamanyo" => 384623 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0002" "detalle" => "Fig " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spara002" class="elsevierStyleSimplePara elsevierViewall">CONSORT flow diagram.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Alfonso Sevillano-Jiménez, Guillermo Molina-Recio, Juan Antonio García-Mellado, Rafael Molina-Luque, Manuel Romero-Saldaña" "autores" => array:5 [ 0 => array:2 [ "nombre" => "Alfonso" "apellidos" => "Sevillano-Jiménez" ] 1 => array:2 [ "nombre" => "Guillermo" "apellidos" => "Molina-Recio" ] 2 => array:2 [ "nombre" => "Juan Antonio" "apellidos" => "García-Mellado" ] 3 => array:2 [ "nombre" => "Rafael" "apellidos" => "Molina-Luque" ] 4 => array:2 [ "nombre" => "Manuel" "apellidos" => "Romero-Saldaña" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0213616324000120?idApp=UINPBA00004N" "url" => "/02136163/0000003800000004/v1_202410020552/S0213616324000120/v1_202410020552/en/main.assets" ] "itemAnterior" => array:18 [ "pii" => "S0213616324000235" "issn" => "02136163" "doi" => "10.1016/j.ejpsy.2024.100273" "estado" => "S300" "fechaPublicacion" => "2024-10-01" "aid" => "100273" "copyright" => "The Author(s)" "documento" => "article" "crossmark" => 1 "subdocumento" => "sco" "cita" => "Eur J Psychiatry. 2024;38:" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:8 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Editorial</span>" "titulo" => "Is it possible to circumnavigate the APIcalypse? On challenges to study mental health in the age of digitalization and AI" "tienePdf" => "en" "tieneTextoCompleto" => "en" "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Christian Montag, Brian J. Hall, Yu-Hsuan Lin" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Christian" "apellidos" => "Montag" ] 1 => array:2 [ "nombre" => "Brian J." "apellidos" => "Hall" ] 2 => array:2 [ "nombre" => "Yu-Hsuan" "apellidos" => "Lin" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0213616324000235?idApp=UINPBA00004N" "url" => "/02136163/0000003800000004/v1_202410020552/S0213616324000235/v1_202410020552/en/main.assets" ] "en" => array:18 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>" "titulo" => "Serum GDNF levels as predictors of subjective cognitive complaints in male subjects with major depressive disorder" "tieneTextoCompleto" => true "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Pedro Borges de Souza, Taiane de Azevedo Cardoso, Thaise Campos Mondin, Luciano Dias de Mattos Souza, Ricardo Azevedo da Silva, Andressa Schneider Lobato, Miriam Haj Omar, Jean Pierre Oses, Carolina David Wiener, Karen Jansen, Fernanda Pedrotti Moreira" "autores" => array:11 [ 0 => array:3 [ "nombre" => "Pedro Borges de" "apellidos" => "Souza" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0001" ] ] ] 1 => array:3 [ "nombre" => "Taiane de Azevedo" "apellidos" => "Cardoso" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0002" ] ] ] 2 => array:3 [ "nombre" => "Thaise Campos" "apellidos" => "Mondin" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0003" ] ] ] 3 => array:3 [ "nombre" => "Luciano Dias de Mattos" "apellidos" => "Souza" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0001" ] ] ] 4 => array:3 [ "nombre" => "Ricardo Azevedo da" "apellidos" => "Silva" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0001" ] ] ] 5 => array:3 [ "nombre" => "Andressa Schneider" "apellidos" => "Lobato" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0001" ] ] ] 6 => array:3 [ "nombre" => "Miriam Haj" "apellidos" => "Omar" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0001" ] ] ] 7 => array:3 [ "nombre" => "Jean Pierre" "apellidos" => "Oses" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0004" ] ] ] 8 => array:3 [ "nombre" => "Carolina David" "apellidos" => "Wiener" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0001" ] ] ] 9 => array:3 [ "nombre" => "Karen" "apellidos" => "Jansen" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0001" ] ] ] 10 => array:4 [ "nombre" => "Fernanda" "apellidos" => "Pedrotti Moreira" "email" => array:1 [ 0 => "fepedrotti@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0001" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0001" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Postgraduate Program in Health and Behavior – Catholic University of Pelotas, Street Gonçalves Chaves 373, 96015560, Pelotas, Rio Grande do Sul, Brazil" "etiqueta" => "a" "identificador" => "aff0001" ] 1 => array:3 [ "entidad" => "Deakin University, IMPACT – the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Geelong, Australia" "etiqueta" => "b" "identificador" => "aff0002" ] 2 => array:3 [ "entidad" => "Pro-rectory of Student Affairs – Federal University of Pelotas, Street Almirante Barroso 1202, 96010280, Pelotas, Rio Grande do Sul, Brazil" "etiqueta" => "c" "identificador" => "aff0003" ] 3 => array:3 [ "entidad" => "Post Graduation Program in Biochemistry and Prospecting – Visiting Researcher – Federal University of Pelotas, 5HXM+QV, S/N, 96160-000, Capão do Leão, RS, Brazil" "etiqueta" => "d" "identificador" => "aff0004" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0001" "etiqueta" => "⁎" "correspondencia" => "Corresponding author at: Postgraduate Program in Health and Behavior – Catholic University of Pelotas, Street Gonçalves Chaves 373, room 324C, 96015560 Pelotas, Rio Grande do Sul, Brazil." ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0002" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 830 "Ancho" => 3583 "Tamanyo" => 138439 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0002" "detalle" => "Fig " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spara002" class="elsevierStyleSimplePara elsevierViewall">Correlation between serum GDNF levels in baseline and COBRA scores at follow-up. A) Correlation between serum GDNF levels and COBRA in total sample <span class="elsevierStyleItalic">r</span>= −0.052 (<span class="elsevierStyleItalic">p</span> = 0.485); B) Correlation between serum GDNF levels and COBRA in males <span class="elsevierStyleItalic">r</span>= −0.378 (<span class="elsevierStyleItalic">p</span> = 0.032); C) Correlation between serum GDNF levels and COBRA in females <span class="elsevierStyleItalic">r</span> = 0.003 (<span class="elsevierStyleItalic">p</span> = 0.977).</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0001" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0006">Introduction</span><p id="para0005" class="elsevierStylePara elsevierViewall">Major Depressive Disorder (MDD) is the psychiatric disorder with the highest worldwide prevalence, impacting approximately 5 % to 6 % of the population and representing a significant contributor to disability, morbidity, and mortality.<a class="elsevierStyleCrossRef" href="#bib0001"><span class="elsevierStyleSup">1</span></a> Through a lifespan, depression is twice as prevalent in women when compared to men, reaching its highest peak during the second and third decades of one's life.<a class="elsevierStyleCrossRef" href="#bib0002"><span class="elsevierStyleSup">2</span></a> Considering this, there is a research gap in understanding this sex disparity, prompting speculation if this difference might be linked to the pathophysiology of MDD. An emerging discussion in academia is surging where more studies are attempting to connect depression pathogenesis with the inflammatory and neurotrophic systems.</p><p id="para0006" class="elsevierStylePara elsevierViewall">A possible contributor is the pro-inflammatory cytokines, such as Interleukin 6 (IL-6) and Tumor Necrosis Factor Alpha (TNF-α). Responsible for triggering several signalling pathways that can induce alterations in monoamine levels, increasing neural excitotoxicity, impairing auto-regulatory endocrine pathways and reducing neurotrophins.<a class="elsevierStyleCrossRef" href="#bib0003"><span class="elsevierStyleSup">3</span></a> As a consequence of the inflammatory stimuli, oxygen and nitrogen species are released, which may contribute to depression by promoting brain excitotoxicity and suppressing neurogenesis, reducing protective factors such as neurotrophins.<a class="elsevierStyleCrossRef" href="#bib0004"><span class="elsevierStyleSup">4</span></a> Some studies highlight sex differences between the levels of pro-inflammatory cytokines in individuals with MDD. A current debate in research is that the levels of pro-inflammatory cytokines are responsible for the incidence of MDD being higher in females, due to some studies observing a higher immune response in males.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">5</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0006"><span class="elsevierStyleSup">6</span></a></p><p id="para0007" class="elsevierStylePara elsevierViewall">An additional potential contributor is neurotrophins, including Brain-Derived Neurotrophic Factor (BDNF), Nerve Growth Factor (NGF) and Glial Cell Line-Derived Neurotrophic Factor (GDNF). Neurotrophins play an important role in cell proliferation, maintaining migration during the development of the central nervous system (CNS), thus ensuring the structural integrity of neurons, and promoting neurogenesis.<a class="elsevierStyleCrossRef" href="#bib0007"><span class="elsevierStyleSup">7</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0008"><span class="elsevierStyleSup">8</span></a> 8 Some studies provided results where individuals with lower peripheral concentrations of neurotrophins are correlated with MDD diagnosis,<a class="elsevierStyleCrossRef" href="#bib0009"><span class="elsevierStyleSup">9</span></a> and in addition, they are also associated with lower performances in cognitive tests.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">10</span></a> As a conclusion to these results, the literature suggests that females with MDD may exhibit lower levels of NGF and BDNF compared to males.<a class="elsevierStyleCrossRef" href="#bib0011"><span class="elsevierStyleSup">11</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0012"><span class="elsevierStyleSup">12</span></a> Although, controversial findings were found where males diagnosed with MDD have also been found with decreased levels of GDNF,<a class="elsevierStyleCrossRef" href="#bib0013"><span class="elsevierStyleSup">13</span></a> and other studies found no differences in neurotrophin levels between sexes.<a class="elsevierStyleCrossRef" href="#bib0014"><span class="elsevierStyleSup">14</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">15</span></a></p><p id="para0008" class="elsevierStylePara elsevierViewall">Another important factor is the relationship between cognitive dysfunction and biomarkers. Cognitive dysfunction stands as a core consequence of MDD, where individuals often exhibit progressive cognitive impairment that may persist even after the disorder has been remitted.<a class="elsevierStyleCrossRef" href="#bib0016"><span class="elsevierStyleSup">16</span></a> It is observed in the literature that the relationship between cognitive impairments tends to positively correlate to pro-inflammatory cytokines, and negatively to neurotrophins in both healthy individuals and those diagnosed with MDD.<a class="elsevierStyleCrossRef" href="#bib0017"><span class="elsevierStyleSup">17</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0018"><span class="elsevierStyleSup">18</span></a> Therefore, research indicates that the relationship between cognitive function and immune systems differs between sexes, suggesting that IL6<a class="elsevierStyleCrossRef" href="#bib0019"><span class="elsevierStyleSup">19</span></a> and TNF-a<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">20</span></a> could be associated with cognitive impairment in females.</p><p id="para0009" class="elsevierStylePara elsevierViewall">However, this suggestion is controversial since a portion of the literature did not observe a difference between sexes and increased levels of cytokines and there is an absence of studies associating neurotrophins with cognition while stratifying the sample relating to sex.<a class="elsevierStyleCrossRef" href="#bib0021"><span class="elsevierStyleSup">21</span></a> Therefore, additional research is needed to address this gap.</p><p id="para0010" class="elsevierStylePara elsevierViewall">In light of this, there is a lack of consensus on the importance of the peripheral changes in sex-linked biomarkers within biological processes associated with MDD. The novel biomarkers for MDD hold significance for the development of diagnosis and the characterization of MDD-associated features, such as cognitive impairment. In this context, the search for prodromal biomarkers becomes crucial, given the substantial correlation between cognitive deficits in individuals with MDD. Potentially providing new tools to diagnose and prevent the progression of this disorder<a class="elsevierStyleCrossRef" href="#bib0007"><span class="elsevierStyleSup">7</span></a> Thus, the present study aims to identify prodromal serum biomarkers correlated with cognition in patients with MDD, as well as the possible sex-related differences.</p></span><span id="sec0002" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0007">Materials and methods</span><span id="sec0003" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0008">Participants</span><p id="para0011" class="elsevierStylePara elsevierViewall">This study was derived from a broader prospective study, previously published.<a class="elsevierStyleCrossRef" href="#bib0008"><span class="elsevierStyleSup">8</span></a> The initial phase of the study included 585 participants diagnosed with MDD, aged between 18 and 60 years. It was carried out at the Outpatient Clinic for Research and Extension in Mental Health of the Catholic University of Pelotas (UCPel), from 2012 to 2015. The subsequent stage of the study took place between 2017 and 2018, approximately 3 years following the first stage.</p><p id="para0012" class="elsevierStylePara elsevierViewall">All participants who agreed to participate in the study signed an informed consent form and, when deemed necessary, were referred to appropriate treatment options. Exclusion criteria included participants unable to comprehend the utilized instruments and those who declined blood collection during the initial stage. Additionally, individuals who failed to respond to the Cognitive Complaints in Bipolar Disorder Rating Assessment (COBRA) in the second stage were excluded. Thus, this article presented a final sample of 155 participants.</p></span><span id="sec0004" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0009">Instruments</span><p id="para0013" class="elsevierStylePara elsevierViewall">During the initial phase of the study, sociodemographic data were collected from the sample (sex, age, years of education, socioeconomic status) according to the Brazilian Association of Research Companies (ABEP).<a class="elsevierStyleCrossRef" href="#bib0022"><span class="elsevierStyleSup">22</span></a> The ABEP classification is grounded in the material possessions and educational background of the family head. This classification employs an economic class scale (A, B, C, D, and E), where "A" denotes a higher economic class and "E" denotes a lower economic class. For analytical purposes, this variable was categorized into high class (A/B) and low class (C/D/E).</p><p id="para0014" class="elsevierStylePara elsevierViewall">To assess the current use of psychiatric medications, self-report questionnaires were used. To assess alcohol and tobacco abuse or dependence, the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) was used. Scores above 4 points were considered as abuse/dependence in this study.<a class="elsevierStyleCrossRef" href="#bib0023"><span class="elsevierStyleSup">23</span></a></p><p id="para0015" class="elsevierStylePara elsevierViewall">The Mini International Neuropsychiatric Interview Plus (MINI-Plus)<a class="elsevierStyleCrossRef" href="#bib0024"><span class="elsevierStyleSup">24</span></a> was used for the diagnosis of MDD. In addition, the diagnosis was substantiated through a clinical interview conducted by qualified and trained psychologists, acknowledged as the gold standard in this assessment category. In instances where uncertainty regarding the diagnosis arose, patients went through reassessment with an experienced psychiatrist to either confirm or refute the initial diagnosis.</p><p id="para0016" class="elsevierStylePara elsevierViewall">To evaluate depressive symptoms, the Beck Depression Inventory (BDI) was applied. This is a 21-item multiple-choice self-report inventory designed to measure the severity of depression. The total score ranges from 0 to 63 points and enables the classification of symptom severity. A higher score indicates a greater manifestation of depressive symptoms.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">25</span></a> The scale also classifies the severity according to the score obtained. For the present article, subjects scoring between 0 and 13 were categorized as euthymic, while those with scores above 14 were considered to be experiencing a depressive episode.</p><p id="para0017" class="elsevierStylePara elsevierViewall">In the second stage of assessment, participants responded to the COBRA instrument, valid for use in Brazil.<a class="elsevierStyleCrossRef" href="#bib0026"><span class="elsevierStyleSup">26</span></a> The version utilized in this study included 16 items, evaluating subjective cognitive dysfunctions through self-report, and assessing domains such as executive function, processing speed, working memory, verbal learning and memory, attention/concentration and mental tracking.<a class="elsevierStyleCrossRef" href="#bib0027"><span class="elsevierStyleSup">27</span></a> Notably, none of the items are exclusively directed towards bipolar disorder. COBRA employs a 4-point scale for each item, with scores ranging from 0 to 48. A higher individual score indicates a greater expression of subjective cognitive complaints.<a class="elsevierStyleCrossRef" href="#bib0026"><span class="elsevierStyleSup">26</span></a></p><p id="para0018" class="elsevierStylePara elsevierViewall">Objective cognitive performance was evaluated through the Sequence of Numbers and Letters of the Wechsler Adult Intelligence Scale (WAIS-III), referred to as a number-letter sequence in the text. This subtest assesses memory and attention domains, including working memory, mental manipulation, attention, concentration, and short-term auditory memory. Comprising seven items, each with three attempts, the total score ranges from 0 to 21 points, with higher scores indicating superior cognitive performance.<a class="elsevierStyleCrossRef" href="#bib0028"><span class="elsevierStyleSup">28</span></a></p></span><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0010">Biochemical analysis</span><p id="para0019" class="elsevierStylePara elsevierViewall">Only in the first stage of the study, venous blood collection was performed. This procedure involved the venipuncture of 10 mL of blood, drawn into a vacuum tube devoid of anticoagulants, subsequent to the patient interview, and occurred between 8:00 am and 11:00 am. Post-collection, the blood was immediately centrifuged at 4000 g for 10 min. The resultant serum was segregated into microtubes and stored at −80 °C until analysis.</p><p id="para0020" class="elsevierStylePara elsevierViewall">For the measurement of serum levels of IL-6, TNF-α, BDNF, GDNF and NGF, a commercial immunoassay kit was used (DuoSet ELISA Development, R&D Systems, Inc., EUA). Serum levels of IL-6, TNF-α, GDNF and NGF were expressed in pg/mL, whereas BDNF levels were expressed in ng/mL.</p></span><span id="sec0006" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0011">Statistical analysis</span><p id="para0021" class="elsevierStylePara elsevierViewall">Statistical analyses were performed using SPSS 27.0 software (IBM Corporation, Armonk, NY, EUA) and GRAPHPAD PRISM 6.0 (GraphPad Software Inc., San Diego, EUA). To assess the differences between the groups concerning clinical and sociodemographic characteristics analyses were performed using the Mann-Whitney and Spearman correlation tests, as the serum levels of IL-6, TNF-a; BDNF; GDNF and NGF, as well as the COBRA scores did not show a parametric distribution. Data was presented by median and 25/75 interquartile range, and Spearman's correlation coefficient.</p><p id="para0022" class="elsevierStylePara elsevierViewall">Since the COBRA, number-letter sequence (objective cognition) and GDNF data did not have a normal distribution, to carry out the multiple linear regression, these findings were normalized using the square-root transformation (sqr).</p><p id="para0023" class="elsevierStylePara elsevierViewall">A multiple linear regression analysis (enter method) was carried out based on a conceptual model with three hierarchical levels: sociodemographic predictors (gender, age, socioeconomic status), clinical predictors (alcohol and tobacco abuse and dependence; use of psychiatric medication; depressive symptoms) and biomarkers (IL-6; TNF-a; BDNF; GDNF and NGF). The model was used to investigate to which extent the baseline results of the study had an impact on objective (sequence of numbers and letters) and subjective (COBRA) cognitive complaints at the follow-up. Multiple linear regression was performed for each dependent variable and to adjust for multiple testing, the p-values were corrected using a false discovery rate correction (FDR, the Benjamini-Hochberg method).</p></span></span><span id="sec0007" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0012">Results</span><p id="para0024" class="elsevierStylePara elsevierViewall">The total study sample consisted of 155 participants, initially diagnosed with MDD, who were stratified into two groups based on sex, 30 males and 125 females (<a class="elsevierStyleCrossRef" href="#fig0001">Fig. 1</a>). In the total sample, 79.40 % of individuals were on psychiatric medication, 21.30 % reported alcohol abuse/dependence, and 21.30 % tobacco abuse/dependence. The median and interquartile range of the severity of depressive symptoms, assessed by the BDI in the total sample, were 20.00 (8.00 - 34.00).</p><elsevierMultimedia ident="fig0001"></elsevierMultimedia><p id="para0025" class="elsevierStylePara elsevierViewall">In the sex-stratified sample, the use of psychiatric medication in the male subgroup was 73.30 %, alcohol abuse/dependence was 27.60 %, and tobacco abuse/dependence was 37.90 %. In the female subgroup, 80.80 % used psychiatric medication, 20.30 % reported alcohol abuse/dependence, and 17.90 % tobacco abuse/dependence. The median and interquartile range of the severity of depressive symptoms in the male subgroup was 14.00 (2.50 - 31.25), while in the female subgroup, it was 20.00 (9.00 - 35.50). <a class="elsevierStyleCrossRef" href="#tbl0001">Table 1</a> shows other sociodemographic and clinical characteristics of the total and stratified sample by sex. No statistically significant association was found when COBRA was related to sociodemographic variables (data not shown).</p><elsevierMultimedia ident="tbl0001"></elsevierMultimedia><p id="para0026" class="elsevierStylePara elsevierViewall">No significant results were observed between the correlation of serum biomarkers and number-letter sequence (<span class="elsevierStyleItalic">p</span> > 0.05) in any of the subgroups (<a class="elsevierStyleCrossRef" href="#tbl0002">Table 2</a>). However, a negative correlation was observed between COBRA and serum levels of GDNF (<span class="elsevierStyleItalic">r</span>= −0.339; <span class="elsevierStyleItalic">p</span> = 0.039) in the males (<a class="elsevierStyleCrossRef" href="#fig0002">Fig. 2</a>B), but not in the female group (<span class="elsevierStyleItalic">r</span> = 0.003; <span class="elsevierStyleItalic">p</span> = 0.977) (<a class="elsevierStyleCrossRef" href="#fig0002">Fig. 2</a>C).</p><elsevierMultimedia ident="tbl0002"></elsevierMultimedia><elsevierMultimedia ident="fig0002"></elsevierMultimedia><p id="para0027" class="elsevierStylePara elsevierViewall">In addition, a correlation was made between the severity of symptoms, assessed using the BDI, and cognitive performance measured by the number-letter sequence and COBRA. No correlation was observed between the BDI and the number-letter sequence (objective cognition), either in the total sample or when stratified by sex (data not shown). However, when BDI was correlated with COBRA, a significant correlation was observed in the total sample (<span class="elsevierStyleItalic">r</span> = 0.761; <span class="elsevierStyleItalic">p</span> < 0,001), as well as in the subgroups, males (<span class="elsevierStyleItalic">r</span> = 0.700; <span class="elsevierStyleItalic">p</span> < 0.001) and females (<span class="elsevierStyleItalic">r</span> = 0.769; <span class="elsevierStyleItalic">p</span> < 0.001).</p><p id="para0028" class="elsevierStylePara elsevierViewall">Furthermore, a correlation analysis was conducted between the two tools assessing subjective and objective cognitive function (COBRA and number-letter sequence) to evaluate potential discrepancies between scores. The results revealed no significant correlation between COBRA and number-letter sequence in the total sample (<span class="elsevierStyleItalic">r</span> = −0.057; <span class="elsevierStyleItalic">p</span> = 0.484), as well as in the male (<span class="elsevierStyleItalic">r</span> = 0.172; <span class="elsevierStyleItalic">p</span> = 0.362) and female (<span class="elsevierStyleItalic">r</span> = −0.110; <span class="elsevierStyleItalic">p</span> = 0.220) subgroups.</p><p id="para0029" class="elsevierStylePara elsevierViewall">Consecutively, <a class="elsevierStyleCrossRef" href="#tbl0002">Table 2</a> shows the correlation within the total sample and is further stratified by sex, depicting serum biomarker levels (BDNF, GDNF, NGF, IL-6 and TNF-α) at baseline with subjective and objective cognitive measurement scales (COBRA and number-letter sequence, respectively) in the follow-up. No significant correlation was observed in the total sample between biomarkers and COBRA variables. However, a correlation was found significant in the total sample between number-letter sequence and the biomarkers BDNF (<span class="elsevierStyleItalic">r</span> = −0.158; <span class="elsevierStyleItalic">p</span> = 0.049), IL-6 (<span class="elsevierStyleItalic">r</span> = 0.304; <span class="elsevierStyleItalic">p</span> < 0.01), and TNF-α (<span class="elsevierStyleItalic">r</span> = 0.606; <span class="elsevierStyleItalic">p</span> < 0.01).</p><p id="para0030" class="elsevierStylePara elsevierViewall">The multiple linear regression that used the number-letter sequence as the dependent variable showed that the overall model was not significant (Z (8, 49) = 0.849, <span class="elsevierStyleItalic">p</span> = 0.565; adjusted R<span class="elsevierStyleSup">2</span> = 0.122) (data not shown).</p><p id="para0031" class="elsevierStylePara elsevierViewall">When COBRA was used as the dependent variable, the results showed that the overall model was significant (Z (9, 50) = 2.611, <span class="elsevierStyleItalic">p</span> = 0.032; adjusted R<span class="elsevierStyleSup">2</span> = 0.620). <a class="elsevierStyleCrossRef" href="#tbl0003">Table 3</a> shows the impact of the coefficients for all the predictors analyzed. As can be seen, the variables that most strongly impact COBRA were sex (β = 0.442, <span class="elsevierStyleItalic">p</span> = 0.003, p<span class="elsevierStyleInf">adjFDR</span> = 0.019), symptom severity (β = 0.605, <span class="elsevierStyleItalic">p</span> < 0.001, p<span class="elsevierStyleInf">adjFDR</span> = 0.013) and GDNF levels (β = - 0.414, <span class="elsevierStyleItalic">p</span> = 0.005, p<span class="elsevierStyleInf">adjFDR</span> = 0.021).</p><elsevierMultimedia ident="tbl0003"></elsevierMultimedia></span><span id="sec0008" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0013">Discussion</span><p id="para0032" class="elsevierStylePara elsevierViewall">This study aimed to identify prodromal serum biomarkers correlated with cognition in patients with MDD. Our findings indicate that, among the evaluated biomarkers (IL-6, TNF-α, BDNF, GDNF, NGF), only GDNF may be suggested as a prodromal biomarker. However, only for subjective cognitive complaints, and specifically in males with MDD. This suggestion is based on the observed findings, where lower serum levels of GDNF at baseline were associated with higher COBRA scores in the male subgroup during follow-up assessments. In addition, we also observed an association between the severity of depressive symptoms and the subjective assessment of cognition, both in the total sample and stratified by sex.</p><p id="para0033" class="elsevierStylePara elsevierViewall">Our initial hypothesis was that a reduction in serum neurotrophin levels, and an increase in serum levels of pro-inflammatory cytokines at baseline, could serve as predictors of cognitive deficits in the follow-up assessments. Previous studies have indeed demonstrated the role of decreased neurotrophin levels (BDNF, GDNF and NGF)<a class="elsevierStyleCrossRef" href="#bib0009"><span class="elsevierStyleSup">9</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0011"><span class="elsevierStyleSup">11</span></a>, and increased levels of pro-inflammatory cytokines (IL-6 and TNF-α)<a class="elsevierStyleCrossRef" href="#bib0029"><span class="elsevierStyleSup">29</span></a> in subjects with MDD. Neurotrophins also seem to have a relationship with cognitive dysfunction in existing literature, where a recent meta-analysis showed that these molecules appear to reduce in subjects exhibiting cognitive deficits.<a class="elsevierStyleCrossRef" href="#bib0007"><span class="elsevierStyleSup">7</span></a> In addition, a potential association between decreased serum neurotrophin levels and complaints about cognitive performance, especially in memory and attention domains, which is plausible.<a class="elsevierStyleCrossRef" href="#bib0007"><span class="elsevierStyleSup">7</span></a> Identifying serum neurotrophin levels as potential prodromal biomarkers of cognitive deficits in individuals with MDD is promising for improving our understanding of the disorder and could contribute to the future development of specific interventions. <a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">30</span></a></p><p id="para0034" class="elsevierStylePara elsevierViewall">In our study, we found that GDNF, sex, and BDI were associated with COBRA (subjective cognition). After stratifying the sample by sex, we observed a negative correlation only between the GDNF biomarker and COBRA in the male group. The BDI showed a correlation both in the total sample and in stratified subgroups.</p><p id="para0035" class="elsevierStylePara elsevierViewall">Our study seems to be the first to longitudinally evaluate the correlation between neurotrophins, pro-inflammatory cytokines and cognitive impairment in a sample of subjects with MDD, considering the potential differences between the sexes. The evaluation of biomarkers through stratification by sex is of paramount importance, as it helps to determine whether any biomarker is associated with sex. Although the literature demonstrates that depression is more prevalent among females, the differences in the responses of males and females to biological processes linked to MDD, such as the hypothalamic-pituitary-adrenal axis, inflammatory response, and neurotrophic dysregulation have not yet been clarified. Furthermore, there is no consistent evidence to explain why MDD is more prevalent in females.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">5</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0006"><span class="elsevierStyleSup">6</span></a></p><p id="para0036" class="elsevierStylePara elsevierViewall">When looking at the influence of sex on biomarkers, some studies have suggested that inflammatory markers are more associated with males with MDD, as males may be more predisposed to an inflammatory state than females.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">5</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0006"><span class="elsevierStyleSup">6</span></a> This could be attributed to testosterone's ability to suppress the immune system in males, while estrogens strengthen the immune system in females.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">5</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0031"><span class="elsevierStyleSup">31</span></a> Additionally, genetic differences may also play a role, once immunological factors are linked to the X chromosome. Since females have double X chromosomes, they might have a more immunocompetent system.<a class="elsevierStyleCrossRef" href="#bib0031"><span class="elsevierStyleSup">31</span></a></p><p id="para0037" class="elsevierStylePara elsevierViewall">BDNF and NGF levels are reported to be lower in females with MDD compared to males with MDD.<a class="elsevierStyleCrossRef" href="#bib0011"><span class="elsevierStyleSup">11</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0012"><span class="elsevierStyleSup">12</span></a> However, GDNF tends to be decreased in the group of males with MDD, once compared to the females diagnosed with MDD subgroup.<a class="elsevierStyleCrossRef" href="#bib0013"><span class="elsevierStyleSup">13</span></a> Although, the mechanisms responsible for these sex differences remain unknown and existing results are contradictory in many cases. Despite this, studies evaluating these neurotrophins, cognition, and the difference between the sexes, are currently scarce.</p><p id="para0038" class="elsevierStylePara elsevierViewall">Furthermore, in our study, we observed that GDNF could serve as a prodromal biomarker for subjective cognitive complaints in the male group, rather than for objective cognitive measures. Although previous studies have identified differences between subjective and objective assessments<a class="elsevierStyleCrossRef" href="#bib0032"><span class="elsevierStyleSup">32</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0033"><span class="elsevierStyleSup">33</span></a>, none have compared the subjective COBRA scale and objective number-letter sequence subscale until our current study.</p><p id="para0039" class="elsevierStylePara elsevierViewall">The differences between subjective and objective measures observed in our study might be explained due to the challenge of correlating self-report cognitive symptoms with objectively assessed cognitive dysfunction. Typically, individuals tend to overreport cognition complaints when self-reporting.<a class="elsevierStyleCrossRef" href="#bib0034"><span class="elsevierStyleSup">34</span></a> Although, these subjective complaints may be viable as predictors of future cognitive impairments that might be evident in the objective evaluation. And therefore highlighting the importance of early intervention prior to apparent cognitive impairment. This could explain the lack of correlation between neurotrophins and number-letter sequence cognitive subscale scores. However, it is important to note that in our study, we exclusively utilized the number-letter sequence from the WAIS-III, which specifically assesses memory and attention domains. This is in contrast to the COBRA, which encompasses a broader range of cognitive functions. In this context, the absence of a correlation between COBRA and the number-letter sequence may be attributed to the possibility that patients might have deficits in other cognitive domains assessed solely by COBRA, not covered by the number-letter sequence.</p><p id="para0040" class="elsevierStylePara elsevierViewall">In our study, we observed an association between GDNF and subjective cognitive complaints exclusively in males. This discovery prompts further investigations into potential future cognitive deficits and the development of preventive measures against cognitive impairment in males diagnosed with MDD. However, our findings, which link reduced serum GDNF levels only in males and subjective cognitive measure, are different from other results in the literature. In published articles, this relationship is observed in the total sample and is found in objective measures of cognition. Zhang et al. (2014) observed a correlation between reduced GDNF levels and objectively assessed cognitive decline, using the Wisconsin Card Sorting Test (WCST), in the total sample with MDD.<a class="elsevierStyleCrossRef" href="#bib0018"><span class="elsevierStyleSup">18</span></a> Other studies showed a negative correlation between serum GDNF levels and executive function, using WCST, in the total sample of subjects with anorexia nervosa, when compared with healthy controls.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">35</span></a> In addition, a study found that repetitive transcranial magnetic stimulation improved depressive and cognitive symptoms in treatment-resistant depression subjects, as well as increased serum GDNF levels.<a class="elsevierStyleCrossRef" href="#bib0036"><span class="elsevierStyleSup">36</span></a></p><p id="para0041" class="elsevierStylePara elsevierViewall">The potential association between GDNF and cognition may stem from its ability to regulate neuronal and glial plasticity, as well as protect neural cells from oxidative stress.<a class="elsevierStyleCrossRef" href="#bib0037"><span class="elsevierStyleSup">37</span></a> A study conducted on mice with a deletion of the GDNF gene (GDNF<span class="elsevierStyleSup">+/−</span>) observed reduced GDNF mRNA and, consequently, spatial memory impairment.<a class="elsevierStyleCrossRef" href="#bib0038"><span class="elsevierStyleSup">38</span></a> Furthermore, overexpression of GDNF in hippocampal dorsal astrocytes CA1 has been linked to improved spatial learning and memory performance in elderly rats with cognitive impairment, as it enhances local cholinergic, dopaminergic, and serotonergic transmission.<a class="elsevierStyleCrossRef" href="#bib0039"><span class="elsevierStyleSup">39</span></a> These findings in the literature lead us to hypothesize that decreased levels of GDNF may diminish neuroprotection, rendering neurons susceptible to oxidative and immune damage, and disrupting neuronal and glial plasticity, thereby affecting cognition in individuals with MDD. To the present moment, our study is the first to find data that supports that cognitive impairment in MDD, linked to a decrease in serum GDNF levels, is exclusive to males.</p><p id="para0042" class="elsevierStylePara elsevierViewall">Finally, our study revealed an association between the severity of depressive symptoms, evaluated through the BDI, and COBRA, and a correlation in the total sample, in male and female subgroups independently. Other studies also corroborate our findings, noting a direct association between subjective cognitive complaints assessed through COBRA and depressive symptoms.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">40</span></a> Additionally, they indicate an indirect association between these complaints and the perception of overall health through depressive symptoms in Japanese adult volunteers.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">40</span></a> The same research group also observed a significant correlation between cognitive complaints, work limitations, and depressive symptoms in Japanese adult workers.<a class="elsevierStyleCrossRef" href="#bib0041"><span class="elsevierStyleSup">41</span></a> In addition, subsyndromal depression, brief depressive episodes, and depressive episodes were significantly associated with higher mean subjective cognitive complaints scores in all age groups, and both males and females.<a class="elsevierStyleCrossRef" href="#bib0042"><span class="elsevierStyleSup">42</span></a></p><p id="para0043" class="elsevierStylePara elsevierViewall">As with any research, we acknowledge the limitations of our study. First, we had a small sample size, particularly when stratified by sex, this may contribute to type II statistical error during analyses. Secondly, regarding the study design, although individuals with the highest depressive scores exhibited the highest subjective cognitive deficits in the follow-up, we cannot confirm a correlation since these symptoms were not assessed again during second phase of the study. Lastly, we only measured the levels of potential biomarkers at baseline. Correspondingly, cognition was evaluated at a single time point, restricting our ability to establish causality between variables. However, our study was the first to assess predictors of subjective cognitive complaints in subjects with MDD, while also stratifying the sample by sex. Thus facilitates future studies to further investigate and validate our findings, contributing to the understanding of predictive biomarkers that assist in clinical diagnosis.</p></span><span id="sec0009" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0014">Conclusion</span><p id="para0044" class="elsevierStylePara elsevierViewall">Our findings show a negative correlation between serum GDNF levels and subjective cognitive complaint scores (COBRA), only in males diagnosed with MDD. While this is not backed by current literature, it is an important finding that further supplements the content of this research matter. Future studies are needed to confirm the role of GDNF as a prodromal biomarker for subjective cognitive complaints in males.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:7 [ 0 => array:2 [ "identificador" => "xpalclavsec1886024" "titulo" => "Keywords" ] 1 => array:2 [ "identificador" => "sec0001" "titulo" => "Introduction" ] 2 => array:3 [ "identificador" => "sec0002" "titulo" => "Materials and methods" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0003" "titulo" => "Participants" ] 1 => array:2 [ "identificador" => "sec0004" "titulo" => "Instruments" ] 2 => array:2 [ "identificador" => "sec0005" "titulo" => "Biochemical analysis" ] 3 => array:2 [ "identificador" => "sec0006" "titulo" => "Statistical analysis" ] ] ] 3 => array:2 [ "identificador" => "sec0007" "titulo" => "Results" ] 4 => array:2 [ "identificador" => "sec0008" "titulo" => "Discussion" ] 5 => array:2 [ "identificador" => "sec0009" "titulo" => "Conclusion" ] 6 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2023-07-27" "fechaAceptado" => "2024-02-26" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1886024" "palabras" => array:6 [ 0 => "Biomarkers" 1 => "Cobra" 2 => "Cognitive complaints" 3 => "Depression" 4 => "Neurotrophins" 5 => "Sex" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:2 [ "resumen" => "<span id="abss0001" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0001">Background and Objectives</span><p id="spara007" class="elsevierStyleSimplePara elsevierViewall">Major Depressive Disorder (MDD) is characterized by cognitive dysfunction and neurotropic and inflammatory factors linked to its pathophysiology and cognitive impairment. This study aims to identify the prodromal serum biomarkers correlated to cognitive impairment in individuals diagnosed with MDD, including variation between sexes.</p></span> <span id="abss0002" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0002">Methods</span><p id="spara008" class="elsevierStyleSimplePara elsevierViewall">This study is part of a larger two-stage research. The initial stage involved the sample of participants aged between 18 and 60 years old, diagnosed with MDD. The second phase took place three years later. The baseline assessments included a biomarker blood test (BDNF, GDNF, NGF, IL-6 and TNF-α). Follow-up assessments used the Cognitive Complaints in Bipolar Disorder Rating Assessment (COBRA) for subjective cognition and the number-letter sequence of the Wechsler Adult Intelligence Scale (WAIS-III) for objective cognition.</p></span> <span id="abss0003" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0003">Results</span><p id="spara009" class="elsevierStyleSimplePara elsevierViewall">The sample consisted of 155 subjects, 30 males and 125 females. In the sex-stratified sample, a correlation was found between COBRA and GDNF biomarkers in males (<span class="elsevierStyleItalic">r</span>= -0.339; <span class="elsevierStyleItalic">p</span> = 0.039). When COBRA was applied as a dependent variable in the multiple linear regression, the overall model was significant (Z (9, 50) = 2.611, <span class="elsevierStyleItalic">p</span> = 0.032; adjusted R<span class="elsevierStyleSup">2</span> = 0.620), with the highest impact on sex (β = 0.442, <span class="elsevierStyleItalic">p</span> = 0.003, p<span class="elsevierStyleInf">adjFDR</span> = 0.019), symptom severity (β = 0.605, <span class="elsevierStyleItalic">p</span> < 0.001, p<span class="elsevierStyleInf">adjFDR</span> = 0.013) and GDNF levels (β = -0.414, <span class="elsevierStyleItalic">p</span> = 0.005, p<span class="elsevierStyleInf">adjFDR</span> = 0.021).</p></span> <span id="abss0004" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0004">Conclusions</span><p id="spara010" class="elsevierStyleSimplePara elsevierViewall">Our results suggest that GDNF might be a prodromal biomarker for the early detection of subjective cognitive complaints only when targeting males with MDD.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abss0001" "titulo" => "Background and Objectives" ] 1 => array:2 [ "identificador" => "abss0002" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abss0003" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abss0004" "titulo" => "Conclusions" ] ] ] ] "multimedia" => array:5 [ 0 => array:8 [ "identificador" => "fig0001" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 962 "Ancho" => 1917 "Tamanyo" => 92961 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0001" "detalle" => "Fig " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spara001" class="elsevierStyleSimplePara elsevierViewall">Flow diagram showing the inclusion of subjects in the study.</p>" ] ] 1 => array:8 [ "identificador" => "fig0002" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 830 "Ancho" => 3583 "Tamanyo" => 138439 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0002" "detalle" => "Fig " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spara002" class="elsevierStyleSimplePara elsevierViewall">Correlation between serum GDNF levels in baseline and COBRA scores at follow-up. A) Correlation between serum GDNF levels and COBRA in total sample <span class="elsevierStyleItalic">r</span>= −0.052 (<span class="elsevierStyleItalic">p</span> = 0.485); B) Correlation between serum GDNF levels and COBRA in males <span class="elsevierStyleItalic">r</span>= −0.378 (<span class="elsevierStyleItalic">p</span> = 0.032); C) Correlation between serum GDNF levels and COBRA in females <span class="elsevierStyleItalic">r</span> = 0.003 (<span class="elsevierStyleItalic">p</span> = 0.977).</p>" ] ] 2 => array:8 [ "identificador" => "tbl0001" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0003" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "<p id="spara006s" class="elsevierStyleSimplePara elsevierViewall">ABEP, Brazilian Association of Research Companies; BDI, Beck Depression Inventory; COBRA, Cognitive Complaints in Bipolar Disorder Rating Assessment; WAIS- III, Sequence of Numbers and Letters of the Wechsler Adult Intelligence Scale.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><a name="en0001"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Variables \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0002"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Full sample (<span class="elsevierStyleItalic">n</span> = 155) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0003"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Male (<span class="elsevierStyleItalic">n</span> = 30) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0004"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Female (<span class="elsevierStyleItalic">n</span> = 125) \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><a name="en0005"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">BASELINE</span> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0006"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0007"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0008"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0009"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">Age (mean)</span><a class="elsevierStyleCrossRef" href="#tb1fn3"><span class="elsevierStyleSup">b</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0010"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="top">98.93 ± 11.02 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0011"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">38.73 ± 10.34 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0012"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">38.98 ± 11.22 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0013"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">Years of education</span><a class="elsevierStyleCrossRef" href="#tb1fn3"><span class="elsevierStyleSup">b</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0014"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="top">11.21 ± 3.16 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0015"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">12.13 ± 2.89 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0016"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">10.99 ± 3.20 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0017"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">Socioeconomic status (ABEP)</span><a class="elsevierStyleCrossRef" href="#tb1fn2"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0018"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0019"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0020"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0021"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Upper (<span class="elsevierStyleItalic">A</span> + <span class="elsevierStyleItalic">B</span>) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0022"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="top">79 (49.00) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0023"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">19 (63.30) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0024"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">60 (48.00) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0025"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Lower (C + D + <span class="elsevierStyleItalic">E</span>) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0026"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="top">76 (51.00) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0027"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">11 (36.70) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0028"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">65 (52.00) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0029"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">Have a job</span><a class="elsevierStyleCrossRef" href="#tb1fn2"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0030"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0031"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0032"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0033"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Yes \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0034"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="top">90 (58,1) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0035"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">22 (73.30) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0036"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">68 (54.40) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0037"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0038"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="top">65 (41,9) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0039"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">8 (26.70) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0040"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">57 (45.60) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0041"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">Psychiatric medication</span><a class="elsevierStyleCrossRef" href="#tb1fn2"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0042"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0043"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0044"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0045"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Yes \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0046"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="top">123 (79.40) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0047"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">22 (73.30) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0048"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">101 (80.80) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0049"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0050"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="top">32 (20.60) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0051"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">8 (26.70) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0052"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">24 (19.20) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0053"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">Abuse/dependence alcohol</span><a class="elsevierStyleCrossRef" href="#tb1fn1">*</a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#tb1fn2"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0054"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0055"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0056"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0057"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Yes \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0058"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="top">33 (21.30) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0059"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">8 (27.60) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0060"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">25 (20.30) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0061"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0062"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="top">119 (76.80) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0063"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">21 (72.40) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0064"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">98 (79.70) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0065"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">Abuse/dependence tobacco</span><a class="elsevierStyleCrossRef" href="#tb1fn1"><span class="elsevierStyleSup">⁎</span></a><a class="elsevierStyleCrossRef" href="#tb1fn2"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0066"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0067"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0068"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0069"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Yes \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0070"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="top">33 (21.30) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0071"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">11 (37.90) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0072"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">22 (17.90) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0073"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0074"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="top">119 (76.80) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0075"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">18 (62.10) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0076"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">101 (82.10) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0077"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">BDI</span><a class="elsevierStyleCrossRef" href="#tb1fn4"><span class="elsevierStyleSup">c</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0078"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="top">20.00 (8.00 – 34.00) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0079"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">14.00 (2.50 – 31.25) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0080"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">20.00 (9.00 – 35.50) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0081"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">FOLLOW-UP</span> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0082"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0083"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0084"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0085"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">COBRA</span><a class="elsevierStyleCrossRef" href="#tb1fn4"><span class="elsevierStyleSup">c</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0086"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="top">11.00 (5.00 – 21.00) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0087"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">6.50 (5.00 – 20.50) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0088"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">12.00 (6.00 – 21.00) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0089"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">Number-letter sequence</span><a class="elsevierStyleCrossRef" href="#tb1fn4"><span class="elsevierStyleSup">c</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0090"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="top">8.00 (5.00 – 9.00) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0091"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">8.00 (5.00 – 9.00) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0092"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">8.00 (5.00 – 9.00) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3675695.png" ] ] ] "notaPie" => array:4 [ 0 => array:3 [ "identificador" => "tb1fn1" "etiqueta" => "⁎" "nota" => "<p class="elsevierStyleNotepara" id="notep0001">Variable contains missing data.</p>" ] 1 => array:3 [ "identificador" => "tb1fn2" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="notep0002">Represent by N (%).</p>" ] 2 => array:3 [ "identificador" => "tb1fn3" "etiqueta" => "b" "nota" => "<p class="elsevierStyleNotepara" id="notep0003">Mean ± SD.</p>" ] 3 => array:3 [ "identificador" => "tb1fn4" "etiqueta" => "c" "nota" => "<p class="elsevierStyleNotepara" id="notep0004">Represent by median and 25th/75th quartiles.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spara003" class="elsevierStyleSimplePara elsevierViewall">Clinical and socio-demographic characteristics of sample at baseline.</p>" ] ] 3 => array:8 [ "identificador" => "tbl0002" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0004" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><a name="en0093"></a><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_rowgroup " rowspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Variables</th><a name="en0094"></a><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_colgroup " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Total sample</th><a name="en0095"></a><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_colgroup " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Male</th><a name="en0096"></a><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_colgroup " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Female</th></tr><tr title="table-row"><a name="en0098"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">COBRA \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0099"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">WAIS-III \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0100"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">COBRA \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0101"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">WAIS-III \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0102"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">COBRA \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0103"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">WAIS-III \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><a name="en0104"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">BDNF<span class="elsevierStyleSup">c</span></span> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0105"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleItalic">r</span> = −0.123 (<span class="elsevierStyleItalic">p</span> = 0.127) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0106"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleItalic">r</span> = −0.158 (<span class="elsevierStyleItalic">p</span> = 0.049) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0107"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleItalic">r</span> = −0.068 (<span class="elsevierStyleItalic">p</span> = 0.721) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0108"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleItalic">r</span> = −0.225 (<span class="elsevierStyleItalic">p</span> = 0.233) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0109"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleItalic">r</span> = −0.145 (<span class="elsevierStyleItalic">p</span> = 0.107) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0110"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleItalic">r</span> = −0.128 (<span class="elsevierStyleItalic">p</span> = 0.128) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0111"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">GDNF<span class="elsevierStyleSup">c</span></span> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0112"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleItalic">r</span> = −0.066 (<span class="elsevierStyleItalic">p</span> = 0.412) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0113"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleItalic">r</span> = −0.032 (<span class="elsevierStyleItalic">p</span> = 0.695) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0114"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleItalic">r</span> = −0.378 (<span class="elsevierStyleItalic">p</span> = 0.039) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0115"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleItalic">r</span> = −0.190 (<span class="elsevierStyleItalic">p</span> = 0.315) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0116"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleItalic">r</span> = −0.003 (<span class="elsevierStyleItalic">p</span> = 0.977) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0117"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleItalic">r</span> = 0.003 (<span class="elsevierStyleItalic">p</span> = 0.978) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0118"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">NGF</span><a class="elsevierStyleCrossRef" href="#tb2fn1">*</a><span class="elsevierStyleBold"><span class="elsevierStyleSup">c</span></span> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0119"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleItalic">r</span> = −0.095 (<span class="elsevierStyleItalic">p</span> = 0.243) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0120"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleItalic">r</span> = 0.109 (<span class="elsevierStyleItalic">p</span> = 0.180) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0121"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleItalic">r</span>= −0.047 (<span class="elsevierStyleItalic">p</span> = 0.804) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0122"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleItalic">r</span> = 0.063 (<span class="elsevierStyleItalic">p</span> = 0.740) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0123"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleItalic">r</span> = −0.122 (<span class="elsevierStyleItalic">p</span> = 0.179) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0124"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleItalic">r</span> = 0.123 (<span class="elsevierStyleItalic">p</span> = 0.177) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0125"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">IL-6</span><a class="elsevierStyleCrossRef" href="#tb2fn1">*</a><span class="elsevierStyleBold"><span class="elsevierStyleSup">c</span></span> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0126"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleItalic">r</span> = 0.004 (<span class="elsevierStyleItalic">p</span> = 0.966) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0127"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleItalic">r</span> = 0.304 (<span class="elsevierStyleItalic">p</span> < 0.01) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0128"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleItalic">r</span> = 0.136 (<span class="elsevierStyleItalic">p</span> = 0.472) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0129"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleItalic">r</span> = 0.260 (<span class="elsevierStyleItalic">p</span> = 0.166) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0130"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleItalic">r</span> = −0.071 (<span class="elsevierStyleItalic">p</span> = 0.441) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0131"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleItalic">r</span> = −0.077 (<span class="elsevierStyleItalic">p</span> = 0.402) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0132"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">TNF-α</span><a class="elsevierStyleCrossRef" href="#tb2fn1">*</a><span class="elsevierStyleBold"><span class="elsevierStyleSup">c</span></span> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0133"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleItalic">r</span> = 0.002 (<span class="elsevierStyleItalic">p</span> = 0.977) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0134"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleItalic">r</span> = 0.606 (<span class="elsevierStyleItalic">p</span> < 0.01) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0135"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleItalic">r</span> = 0.188 (<span class="elsevierStyleItalic">p</span> = 0.339) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0136"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleItalic">r</span> = 0.174 (<span class="elsevierStyleItalic">p</span> = 0.376) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0137"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleItalic">r</span> = −0.050 (<span class="elsevierStyleItalic">p</span> = 0.588) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0138"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleItalic">r</span> = 0.027 (<span class="elsevierStyleItalic">p</span> = 0.769) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3675696.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tb2fn1" "etiqueta" => "⁎" "nota" => "<p class="elsevierStyleNotepara" id="notep0006">Variable contains missing data</p> <p class="elsevierStyleNotepara" id="notep0007">COBRA, Cognitive Complaints in Bipolar Disorder Rating Assessment; WAIS-III, number-letter sequence of the Wechsler Adult Intelligence Scale; BDNF, brain-derived neurotrophic factor; GDNF, glial cell line-derived neurotrophic factor; NGF, nerve growth factor; IL-6, interleukin 6, TNF-α, tumor necrosis factor alpha.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spara004" class="elsevierStyleSimplePara elsevierViewall">Correlation between serum levels of biomarkers at baseline with subjective cognitive function (COBRA) and objective cognitive function (WAIS-III) at the follow-up.</p>" ] ] 4 => array:8 [ "identificador" => "tbl0003" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0005" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "<p id="spara006" class="elsevierStyleSimplePara elsevierViewall">COBRA, Cognitive Complaints in Bipolar Disorder Rating Assessment; BDNF, brain-derived neurotrophic factor; GDNF, glial cell line-derived neurotrophic factor; NGF, nerve growth factor; IL-6, interleukin 6, TNF-α, tumor necrosis factor alpha.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><a name="en0139"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0140"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">β \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0141"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">t \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0142"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">p-valor \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0143"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black"><a class="elsevierStyleCrossRef" href="#tb3fn1">*</a>Adjusted p-valor \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><a name="en0144"></a><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="top"><span class="elsevierStyleBold">Predictors (Baseline)</span> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0145"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0146"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0147"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0148"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0149"></a><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Sex \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0150"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.442 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0151"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">3.180 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0152"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.003 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0153"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">0.019 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0154"></a><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Age \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0155"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">−0.034 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0156"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">−0.270 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0157"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.788 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0158"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">0.995 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0159"></a><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Socioeconomic status (ABEP) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0160"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.113 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0161"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.818 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0162"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.418 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0163"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">0.995 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0164"></a><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Have a job \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0165"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.009 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0166"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.064 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0167"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.949 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0168"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">0.995 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0169"></a><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Psychiatric medication \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0170"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.029 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0171"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.239 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0172"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.812 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0173"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">0.995 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0174"></a><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Abuse/dependence alcohol \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0175"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.127 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0176"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.938 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0177"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.355 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0178"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">0.995 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0179"></a><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Abuse/dependence tobacco \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0180"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">−0.080 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0181"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">−0.607 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0182"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.547 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0183"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">0.995 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0184"></a><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">BDI \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0185"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.605 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0186"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">4.244 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0187"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">< 0.001 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0188"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">0.013 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0189"></a><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">BDNF \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0190"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.060 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0191"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.464 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0192"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.645 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0193"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">0.995 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0194"></a><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">GDNF \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0195"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">−0.414 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0196"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">2.968 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0197"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.005 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0198"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">0.021 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0199"></a><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">NGF \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0200"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">−0.001 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0201"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">−0.007 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0202"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.995 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0203"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">0.995 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0204"></a><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">IL-6 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0205"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.015 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0206"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.085 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0207"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.932 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0208"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">0.995 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0209"></a><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">TNF-α \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0210"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">−0.041 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0211"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">−0.212 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0212"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.833 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0213"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">0.995 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3675694.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tb3fn1" "etiqueta" => "⁎" "nota" => "<p class="elsevierStyleNotepara" id="notep0009">adjusted p-value by the 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Papadopoulou-Daifoti" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1017/S1461145710000465" "Revista" => array:6 [ "tituloSerie" => "Int J Neuropsychopharmacol" "fecha" => "2010" "volumen" => "13" "paginaInicial" => "675" "paginaFinal" => "689" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20478108" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0006" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Sex Differences in Serum Markers of Major Depressive Disorder in the Netherlands Study of Depression and Anxiety (NESDA)" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.M. Ramsey" 1 => "J.D. Cooper" 2 => "M. Bot" 3 => "P.C. Guest" 4 => "F. Lamers" 5 => "C.S. Weickert" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1371/journal.pone.0156624" "Revista" => array:3 [ "tituloSerie" => "PLoS ONE" "fecha" => "2016" "volumen" => "11" ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0007" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Neurotrophins as a reliable biomarker for brain function, structure and cognition: a systematic review and meta-analysis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "G.M. McPhee" 1 => "L.A. Downey" 2 => "C. 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